Histoplasmosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Prince Tano Djan, BSc, MBChB [2], Aravind Kuchkuntla, M.B.B.S[3]

Histoplasma capsulatum was first described by Samuel Taylor Darling in 1906. Histoplasmosis is typically acquired via inhalation of airborne microconidia, often after disturbance of contaminated material in the soil. In majority of the patients the infection is asymtomatic and resolves with host’s immune response. In few patients inhalation of large amount of inoculum can result in an acute pulmonary infection with symptoms resembling pneumonia. Histoplasmosis can be classified with respect to the involved organ system. Patients with immunosupression, hematological malignancies, immunosuppresive therapy and infants are at a higher risk of developing disseminated histoplasmosis infection. The incidence of histoplasmosis is estimated by the Centers of Disease Control (CDC) to be around 500,000 every year in the United States. Majority of the patients are asymptomatic and few develop acute pulmonary histoplasmosis presenting with fever, cough and dyspnea. Few patients develop symptoms such as skin rash and symmetrical joint pain. Severe form of disseminated histoplasmosis presents with features of sepsis, acute respiratory distress syndrome and disseminated intravascular coagulation. Mild to moderate cases of acute pulmonary histoplasmosis will often resolve without treatment; however, treatment is indicated for moderate to severe acute pulmonary, chronic pulmonary, disseminated, and central nervous system (CNS) histoplasmosis. Typical treatment of severe disease first involves treatment with amphotericin B, followed by oral itraconazole. In many milder cases, itraconazole alone is sufficient.

Histoplasma capsulatum was first described by Samuel Taylor Darling in 1906, who coined the term to describe the “plasmodium-like” organisms in the histocytes. In 1912, Henrique da Rocha-Lima, a Brazilian tropical disease specialist, reported findings from a comparison between Leishmania and Histoplasma and concluded that Histoplasma more closely resembled a yeast than a protozoan. In the late 1940s, William A. DeMonbreun, the first person to culture the organism, suggested that the disease may be prevalent in the United States, not only the tropics, due to mild and carrier forms.

Histoplasmosis can be classified with respect to the involved organ system. This can include pulmonary, nervous system, cardiovascular system and mediastinum. Histoplasmosis can also be classified according to the severity in to mild, moderate and severe, according to disease duration into acute, sub-acute, chronic and recurrent and according to the progression of the disease into localized or disseminated histoplasmosis.

Histoplasmosis is typically acquired via inhalation of airborne microconidia, often after disturbance of contaminated material in the soil. In majority of the patients the infection is asymtomatic and resolves with host’s immune response. In few patients inhalation of large amount of inoculum can result in an acute pulmonary infection with symptoms resembling pneumonia. In patients with immunosuppression, they are unable to mount an adequate T-cell mediated immune response resulting in uncontrolled growth of the organism with spread to the surrounding tissue and increasing the morbidity and mortality of the infection.

Histoplasmosis is caused by Histoplasma capsulatum a fungus commonly found in bird and bat fecal material. It belongs to the recently recognized fungal family Ajellomycetaceae. It is dimorphic and switches from a mold-like (filamentous) growth form in the natural habitat to a small budding yeast form in the warm-blooded animal host. It is most prevalent in the Ohio and Mississippi River valleys.

Patients with acute and chronic pulmonary histoplasmosis present with features similar to pneumonia. Therefore it must be differentiated from conditions presenting with cough, fever and dyspnea such as tuberculosis, sarcoidosis and other fungal infections.

The incidence of histoplasmosis is estimated by the Centers of Disease Control(CDC) to be around 500,000 every year in the United States. In the United States, an estimated 60% to 90% of people who live in areas surrounding the Ohio and Mississippi River valleys (where Histoplasma is common in the environment) have been exposed to the fungus at some point during their lifetime.

There is no standard screening recommended for histoplasma infection.

Risk factors for histoplasmosis infection include living in or traveling to the Central or Eastern United States. Patients with immunosupression, hematological malignancies, immunosuppresive therapy and infants are at a higher risk of developing disseminated histoplasmosis infection.

Histoplasmosis is an endemic fungal infection and infection occurs by inhalation of the microconidia present in the soil. The average incubation period is around 2 to 3 weeks. Majority of the patients are asymptomatic and few develop acute pulmonary histoplasmosis presenting with fever, cough and dyspnea. In immunocompetent patients the infection is self limiting and symptoms resolve in 2 to 3 weeks. However patients in immunocompromised state can have complications due to the spread of infection to other organs and develop disseminated histoplasmosis. Prognosis of disseminated histoplasmosis is poor and is associated with increased mortality.

Majority of the patients are asymptomatic and few develop acute pulmonary histoplasmosis presenting with fever, cough and dyspnea. Few patients develop symptoms such as skin rash and symmetrical joint pain. Severe form of disseminated histoplasmosis presents with features of sepsis, acute respiratory distress syndrome and disseminated intravascular coagulation.

Physical examination findings in pulmonary histoplasmosis include erythema nodosum and rales on auscultation. In patients with disseminated histoplasmosis features similar to sepsis such as hypotension, altered mental status will be present.

There are no specific laboratory findings associated with acute histoplasma infection. Diagnosis is confirmed by the demonstration of the yeast cells from tissue samples or body fluids, culture and antigen detection.

Chest X-Ray in patients with pulmonary histoplasmosis will demonstrate hilar lymphadenopathy and pulmonary nodules.

Findings on CT are often related to complications of histoplasmosis and include: Calcified mediastinal and hilar lymph nodes and bronchial occlusion with intrabronchial broncholith.

Mild to moderate cases of acute pulmonary histoplasmosis will often resolve without treatment; however, treatment is indicated for moderate to severe acute pulmonary, chronic pulmonary, disseminated, and central nervous system (CNS) histoplasmosis. Typical treatment of severe disease first involves treatment with amphotericin B, followed by oral itraconazole. In many milder cases, itraconazole alone is sufficient. Asymptomatic disease is typically not treated.

Surgical intervention is not recommended for the management of histoplasmosis.

Prevention of histoplasma infection is to avoid activities that disturbing material (for example, digging in soil or chopping wood) where there are bird or bat droppings are present, cleaning chicken coops, exploring caves, leaning, remodeling, or tearing down old buildings. Minimizing the exposure to infective microconidia is the best preventive measure to reduce the risk of histoplasma infection.

Secondary preventive measures to be followed by patients are the same as primary preventive measures.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Serge Korjian M.D., Vidit Bhargava, M.B.B.S [2], Aravind Kuchkuntla, M.B.B.S[3]

Histoplasma capsulatum was first described by Samuel Taylor Darling in 1906, who coined the term to describe the “plasmodium-like” organisms in the histocytes. In 1912, Henrique da Rocha-Lima, a Brazilian tropical disease specialist, reported findings from a comparison between Leishmania and Histoplasma and concluded that Histoplasma more closely resembled a yeast than a protozoan. In the late 1940s, William A. DeMonbreun, the first person to culture the organism, suggested that the disease may be prevalent in the United States due to mild and carrier forms.^[1]

• Histoplasma capsulatum was first described by Samuel Taylor Darling, an American pathologist, during his work in the Panama Canal Zone.^[2]
• He observed an organism in a patient’s autopsy material that resembled Leishmania and at that time, he falsely identified it as a protozoa.
• The patient died of a generalized disease associated with hepatosplenomegaly and anemia, a syndrome similar to the findings of Leishman and Donovan.
• Despite his very crude equipment by modern standards, Darling was able to identify these “plasmodium-like” organisms in histiocytes, hence coining the name Histoplasma.
• The term “capsulatum” stemmed from Darling’s false assumption that the organism has a capsule.^[1]

• In 1912, Henrique da Rocha-Lima, a Brazilian tropical disease specialist, reported findings from a comparison between Leishmania and Histoplasma and concluded that Histoplasma more closely resembled a yeast than a protozoan.
• Up until the early 1940s, histoplasmosis was considered a fatal tropical disease not prevalent in the United States.
• Dr. Charles E. Smith was the first person to suggest that the rise in pulmonary calcifications in patients with a negative tuberculin test could be due to Histoplasma.^[1]

• In 1928, Dr. Edna H. Tompkins identified the first case of histoplasmosis by demonstrating the organism on the blood smear.
• In 1933, Dr. William A. DeMonbreun of Vanderbilt University became the first person to successfully culture Histoplasma capsulatum species from the same patient identified by Dr. Tompkins.
• Dr. DeMonbreun also fulfilled Koch’s postulates after he injected the culture material into animals.
• He also suggested that the disease may not be as low in prevalence as initially hypothesized due to mild and carrier forms.
• In 1948, Dr. Chester W. Emmons isolated and cultured Histoplasma capsulatum from a soil sample for the first time.^[1]

• Johnny Cash included a reference to the disease, and correctly noted its source in bird droppings, in the song “Beans for Breakfast”.
• Bob Dylan was hospitalized due to histoplasmosis in 1997, causing the cancellation of concerts in the United Kingdom and Switzerland.
• In the episode Family, episode 21 of season 3 of the television show ‘House, M.D.’ a patient was diagnosed with histoplasmosis.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aravind Kuchkuntla, M.B.B.S[2]

Histoplasmosis is typically acquired via inhalation of airborne microconidia, often after disturbance of contaminated material in the soil. In majority of the patients the infection is asymtomatic and resolves with host’s immune response. In few patients inhalation of large amount of inoculum can result in an acute pulmonary infection with symptoms resembling pneumonia. In patients with immunosuppression, they are unable to mount an adequate T-cell mediated immune response resulting in uncontrolled growth of the organism with spread to the surrounding tissue and increasing the morbidity and mortality of the infection.

• Soil is the reservior for histoplasma microconidia, particularly when heavily contaminated with bird or bat droppings.

• The areas contaminated with histoplasma microconidia are called microfoci and disturbance of these microfoci will result in exposure to them.
• The activities which expose the patient to histoplasma microconidia include farming, exposure to chicken coops or caves and sites where black birds have roosted.
• Histoplasmosis is typically acquired via inhalation of airborne microconidia, often after disturbance of contaminated material in the soil.

• In majority of the patients the infection is asymtomatic and resolves with host’s immune response. In few patients inhalation of large amount of inoculum can result in an acute pulmonary infection with symptoms resembling pneumonia.^[1]
• The cell mediated immune response is by the T-lymphocytes which recognize the organism and induce the release of cytokines such as tumor necrosis factor alpha and interferon gamma providing protection aganist re-infection.^[2]
• The release of cytokines activates macrophages, inhibiting the growth of the fungus and limit its spread to the surrounding tissue. This results in the formation of a granuloma where in the fungus is present in a nonviable state for life.
• In patients with immunosuppression, they are unable to mount an adequate T-cell mediated immune response resulting in uncontrolled growth of the organism with spread to the surrounding tissue and increasing the morbidity and mortality of the infection.^[3]
• Primary cutaneous histoplasmosis and solid organ donor-derived histoplasmosis have been observed although extremely uncommon.^[4][5]

• Histoplasma capsulatum is characterized by a budding yeast connected with a narrow base and is mostly identified within the macrophages and monocytes.
• In immunocompetent people, immune response by the macrophages results in the formation of a granuloma and the yeast forms are demonstrated within the histiocytes in the granuloma. However in patients with disseminated infection the yeast forms can be demonstrated in the histiocytes scattered throughout the organ and are not confined to the granulomas alone.
• Different stains such as the gram stain, Giemsa stain, Hematoxylin eosin stain, Mucicarmine stain, PAS stain and Wright Giemsa stain are useful for demonstration of the granulomas and the yeast forms in the tissue specimen or body fluid samples.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Serge Korjian M.D.

Histoplasma capsulatum is a fungus commonly found in bird and bat fecal material and is the causative agent of histoplasmosis.^[1] It belongs to the recently recognized fungal family Ajellomycetaceae. It is dimorphic and switches from a mold-like (filamentous) growth form in the natural habitat to a small budding yeast form in the warm-blooded animal host. It is most prevalent in the Ohio and Mississippi River valleys.

• Histoplasma capsulatum is an ascomycetous fungus.
• It is dimorphic and switches from a mold-like (filamentous) growth form in the natural habitat to a small budding yeast form in the host.
• It is potentially sexual, and its sexual state, Ajellomyces capsulatus, can readily be produced in culture, though it has not been directly observed in nature.
• H. capsulatum groups with B. dermatitidis and the South American pathogen Paracoccidioides brasiliensis in the recently recognized fungal family Ajellomycetaceae.^[2][3]
• Histoplasma capsulatum has two mating types “+” and “–”, as with B. dermatitidis.
• In its asexual form, the fungus grows as a colonial microfungus strongly similar in macromorphology to B. dermatitidis.
• A microscopic examination shows a marked distinction: H. capsulatum produces two types of conidia, globose macroconidia, 8–15 µm, with distinctive tuberculate or finger-like cell wall ornamentation, and ovoid microconidia, 2–4 µm, which appear smooth or finely roughened.
• It is not clear whether one or both of these conidial types is more important than the other as the principal main infectious particles.
• They form on individual short stalks and readily become airborne when the colony is disturbed.
• Ascomata of the sexual state are 80–250 µm, and are very similar in appearance and anatomy to those described above for B. dermatitidis. The ascospores are similarly minute, averaging 1.5 µm.
• The budding yeast cells formed in infected tissues are small (ca. 2–4 µm) and are characteristically seen forming in clusters within phagocytic cells, including histiocytes and other macrophages, as well as monocytes.

• The endemic zones of H. capsulatum can be roughly divided into core areas, where the fungus occurs widely in soil or on vegetation contaminated by bird droppings or equivalent organic inputs, and peripheral areas, where the fungus occurs relatively rarely in association with soil but is still found abundantly in heavy accumulations of bat or bird guano in enclosed spaces such as caves, buildings, and hollow trees.
• The principal core area for this species includes the valleys of the Mississippi, Ohio and Potomac rivers in the USA as well as a wide span of adjacent areas extending from Kansas, Illinois, Indiana and Ohio in the north to Mississippi, Louisiana and Texas in the south.^[4][5][6]
• In some areas, such as Kansas City, skin testing with the histoplasmin antigen preparation shows that 80–90 % of the resident population have an antibody reaction to H. capsulatum, probably indicating prior subclinical infection.^[4]
• Northern U.S. states such as Minnesota, Michigan, New York and Vermont are peripheral areas for histoplasmosis, but have scattered counties where 5–19 % of lifetime residents show exposure to H. capsulatum.

• Histoplasma capsulatum appears to be strongly associated with the droppings of certain bird species as well as bats.^[4]
• A mixture of these droppings and certain soil types is particularly conducive to proliferation.
• In highly endemic areas there is a strong association with soil under and around chicken houses, and with areas where soil or vegetation has become heavily contaminated with fecal material deposited by flocking birds such as starlings and blackbirds.
• Bird roosting areas that are Histoplasma-free appear to be lower in nitrogen, phosphorus, organic matter and moisture than contaminated roosting areas.^[4]
• The guano of gulls and other colonially nesting water-associated birds is rarely connected to histoplasmosis.^[7]
• Bat dwellings, including caves, attics and hollow trees, are classic H. capsulatum habitats.^[4][8]
• Histoplasmosis outbreaks are typically associated with cleaning guano accumulations or clearing guano-covered vegetation, or with exploration of bat caves.
• In addition, however, outbreaks may be associated with wind-blown dust liberated by construction projects in endemic areas: a classic outbreak is one associated with intense construction activity, including subway construction, in Montreal in 1963.^[9]
• As with blastomycosis, a good understanding of the precise ecological affinities of H. capsulatum is greatly complicated by the difficulty of isolating the fungus directly from nature.

• 
  Photomicrograph reveals some of the ultrastructural details exhibited by Histoplasma capsulatum fungal organisms that had been extracted from a Jamaican isolate, which included a number of tuberculate (knobby) spheroidal macroconidia, and diaphanous filamentous hyphae (800X). From Public Health Image Library (PHIL). ^[10]
• 
  This Giemsa-stained photomicrograph reveals numerous Histoplasma capsulatum fungal organisms in their yeast-stage of development, which were seen in this liver tissue specimen, in this case of disseminated histoplasmosis. From Public Health Image Library (PHIL). ^[10]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Prince Tano Djan, BSc, MBChB [2], Aravind Kuchkuntla, M.B.B.S[3]

Patients with acute and chronic pulmonary histoplasmosis present with features similar to pneumonia. Therefore it must be differentiated from conditions presenting with cough, fever and dyspnea such as tuberculosis, sarcoidosis and other fungal infections.

The following table is a list of diseases presenting with similar features of histoplasmosis such as cough and fever:

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Serge Korjian M.D., Aravind Kuchkuntla, M.B.B.S[2]

The incidence of histoplasmosis is estimated by the Centers of Disease Control to be around 500,000 every year in the United States. In the United States, an estimated 60% to 90% of people who live in areas surrounding the Ohio and Mississippi River valleys (where Histoplasma is common in the environment) have been exposed to the fungus at some point during their lifetime.

Histoplasmosis is the most common endemic fungal infection in the United States and parts of Mexico and South America.

• The incidence of histoplasmosis is estimated by the Centers of Disease Control to be around 500,000 every year in the United States.^[1]
• The incidence of histoplasmosis in adults aged 65 years and older in the U.S. is estimated to be 3.4 cases per 100,000 population.
• Rates are highest in the Midwest, with an estimated incidence of 6.1 cases per 100,000 population.

• In the United States, an estimated 60% to 90% of people who live in areas surrounding the Ohio and Mississippi River valleys (where Histoplasma is common in the environment) have been exposed to the fungus at some point during their lifetime.
• The true prevalence of chronic histoplasmosis infection is unknown.
• Histoplasmosis in Europe without travel to endemic areas is rare.

• Histoplasma capsulatum is distributed worldwide, except in Antarctica, but most often associated with river valleys.
• It is most commonly reported in the Ohio and Mississippi river valleys in the United States, but is observed throughout the Midwestern and Southern US.
• Histoplasmosis is reportable in the following states and U.S. territories:^[2]

• Alabama
• Arkansas
• Delaware
• Illinois
• Indiana
• Kentucky
• Michigan
• Minnesota
• Mississippi
• Nebraska
• Pennsylvania
• Puerto Rico
• Rhode Island
• Wisconsin

• Outbreaks have been reported associated with travel to many countries in Central and South America, most often associated with visiting caves.^[3]

• Infants and adults aged 55 years and older are at higher risk of developing the disease.^[2]

• Histoplasmosis does not have any gender or race predilection.

• Histoplasmosis also is endemic in parts of Asia, Southeast Asia, and India.
• In China, 75% of cases occur along the Yangtze River, and is usually seen in patients with AIDS.
• Histoplasmosis is especially a problem in areas of the world where antiretroviral therapy (ART) is not widely available, because ART helps keep HIV-infected people from reaching the stage where they are most vulnerable to histoplasmosis and other opportunistic infections.
• In Latin America, for example, histoplasmosis is one of the most common opportunistic infections among people living with HIV, and approximately 30% of HIV/AIDS patients diagnosed with histoplasmosis die from it.^[4]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aravind Kuchkuntla, M.B.B.S[2]

Risk factors for histoplasmosis infection include living in or traveling to the Central or Eastern United States. Patients with immunosupression, hematological malignancies, immunosuppressive therapy and infants are at a higher risk of developing disseminated histoplasmosis infection.

Risk factors for pulmonary histoplasmosis include:

• Living in or traveling to the Central or Eastern United States.
• Activities such as spelunking, mining, construction, excavation, demolition, roofing, chimney cleaning, farming, gardening, and installing heating and air-conditioning systems.
• Activities that expose people to areas where bats live and birds roost also increase risk. Exposure to soil or particles contaminated with droppings of chickens, bats, or blackbirds is the main mode of transmission.^[1]

Risk factors for severe acute disease or disseminated disease include:

• Infants
• Immunocompromised states
• AIDS Patients with CD4 counts of less than 150 cells/mm³ are at highest risk^[2]
• Hematologic malignancies
• Solid organ transplant^[3]
• Hematopoietic stem cell transplant
• Use of immunosuppressive agents such as corticosteroids and tumor necrosis factor antagonists
• Congenital T-cell deficiencies
• Gamma interferon receptor deficiency
• Hyperimmunoglobulin M syndrome is a risk factor for refractory and recurrent disseminated histoplasmosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aravind Kuchkuntla, M.B.B.S[2]

Histoplasmosis is an endemic fungal infection and infection occurs by inhalation of the microconidia present in the soil. The average incubation period is around 2 to 3 weeks. Majority of the patients are asymptomatic and few develop acute pulmonary histoplasmosis presenting with fever, cough and dyspnea. In immunocompetent patients the infection is self limiting and symptoms resolve in 2 to 3 weeks. However patients in immunocompromised state can have complications due to the spread of infection to other organs and develop disseminated histoplasmosis. Prognosis of disseminated histoplasmosis is poor and is associated with increased mortality.

The incubation period of histoplasmosis is typically 3–17 days for the acute disease. If left untreated immunocompromised patients can have complications such as pericarditis, broncholithiasis, pulmonary nodules, mediastinal granuloma, or mediastinal fibrosis. In persons who develop progressive, chronic, or disseminated disease, symptoms may persist for months or longer. Most people spontaneously recover 2–3 weeks after onset of symptoms, although fatigue may persist longer.^[1][2]

Some of the complications observed among patients with acute or chronic histoplasmosis include:^[3][4]

• Fibrosing mediastinitis
• Mediastinal granuloma
• Calcified lymph nodes
• Adrenal hyperplasia
• Macular degeneration (ocular histoplasmosis)
• Pericarditis
• Broncholithiasis
• Pulmonary nodules
• Disseminated histoplasmosis

Immunocompetent patients have excellent prognosis with symptoms resolving in 2 to 3 weeks. However, immunocompromised patients can have extensive spread of the infection and have poor prognosis. Mortality is high in HIV-infected persons who develop disseminated histoplasmosis and approximately 30% of HIV/AIDS patients diagnosed with histoplasmosis die from it.^[3][5]