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Histoplasmosis Capsulati

Histoplasmosis capsulati is one of the many causes of a "flu-like" illness, with fever, painful muscles, and an irritating cough, which may not really be "just the flu."


Darling's disease. Classic histoplasmosis. Small-form histoplasmosis. Ohio or Mississippi Valley disease. Cave disease. Tingo Maria fever. Reticuloendothelial cytomycosis.


Histoplasmosis capsulate is a systemic granulomatous disease caused by the dimorphic pathogenic fungus, Histoplasma capsulatum var. capsulatum (teleomorph: Ajellomyces capsulatum). The African form of Histoplasma, Histoplasma capsulatum var. duboisii, is larger and described separately.

Geographic Distribution

Histoplasma capsulatum is found in tropical and nontropical countries around the world: most cases occur between latitudes 45 ° north and 30 ° south. It is most common in the central and eastern United States, in the Mississippi and Ohio Valleys and the Appalachian Mountains, eastern Canada, Mexico, Guatemala, Peru, and Venezuela. While highly endemic in some areas, prevalence can vary widely over short distances.

Epidemiology and Pathology

In the tropics, the fungi are found in both rural and urban areas, in soil around dead or hollow trees, in caves, and anywhere where there are bird or bat excreta. In more temperate climates they are found in the soil of hen houses and farmyards. There are animal reservoirs in dogs, cats, rats, mice, skunks and opossums, bats, and baboons. It is estimated that there are 500,000 new infections annually in the United States alone, but fortunately 90% are asymptomatic and heal without treatment.

The invasive fungi are saprophytic, small (3-4 mm in diameter), and round to oval in shape. After staining with hematoxylin and eosin there may be the false impression of a capsule. Histopathologically, the fungi are located centrally in the granulomas. In patients who are immunodeficient, there will be enormous numbers of organisms concentrated in the cytoplasm of phagocytic cells of the reticuloendothelial system, especially in circulating monocytes and in Kupffer cells, and in phagocytic cells of the spleen, bone marrow, and lymph nodes. In soil, however, the fungus is biphasic, the mycelia producing micro- and macroconidia, which are disturbed when soil is cultivated or excavated. The microconidia are smaller and may be the more infectious. Infection in man is by inhalation, the spores germinate in the alveoli and release yeast forms. Even though dissemination can occur from the lungs, in most patients it is usually well controlled after 2 or 3 weeks. The result is a granuloma containing very few fungi: some may caseate. The residual histoplasmoma is irregular, sometimes with central calcification surrounded by a thick fibrous capsule, within which there are the "ghost" remains of the fungi. The quantity of spores inhaled affects the risk and the severity of the infection, which may also be altered by previous exposure and partial immunity. When many conidia are inhaled, there may be many proliferating yeasts in the alveolae and interstitium of the lungs, resulting in necrosis. In patients who are immunodeficient, the yeast cells divide rapidly and produce large extracellular aggregates. Whatever the site of implantation, regional lymphadenopathy will follow if the infection progresses.

The yeast forms of H. capsulatum var. capsulatum may be mistaken for Leishmania or Toxoplasma. Depending on the method of staining, Torulopsis glabrata is another source of error. Penicillium marneffei can also resemble H. capsulatum in vivo.

Laboratory tests include an intradermal sensitivity reaction, which is often positive because of previously unknown infection, and is nonreactive in anergic patients. The skin test is not helpful clinically, but may be useful in epidemiological studies. The skin test can evoke antibody formation (a "false-positive") in individuals who have not been infected earlier. There are complement fixing, precipitin, and fluorescent antibody tests, but serological conversion takes 3-6 weeks, during which time these tests may be negative. In the chronic form of the disease, serological tests remain negative or only become weakly positive in about 50% of all patients.

The diagnosis is made by recognition of the fungus in the sputum or blood, by culture, and in disseminated histoplasmosis, by finding histoplasmal polysaccharide-containing antigen in the urine.

Clinical Characteristics

The clinical spectrum of histoplasmosis capsulati is very broad: fortunately only 5%-10% of all infections result in clinical disease. Pulmonary infections are the most significant, but disseminated infections may be the most serious for the patient. Pulmonary histoplasmosis resembles tuberculosis clinically and on imaging. The clinical syndromes are so varied that constant awareness of histoplasmosis is required to recognize the difference between histoplasmosis and tuberculosis early in the illness: geographical knowledge may be very important when considering the alternatives.

The clinical presentation of the pulmonary infection can be quite asymptomatic or progress through a wide spectrum, including severe acute illness. But pulmonary infection can also appear as a chronic progressive illness. Symptoms vary from mild fever, myalgia, and cough, with increased sputum, to lassitude, pain in the chest, and shortness of breath. These usually start 8-15 days after exposure, and may be accompanied by arthralgia and erythema nodosum. In the majority of patients the disease is self-healing and all that is left clinically after a few weeks is the positive histoplasmin skin test (developing after a few weeks). If there is a known active infection but a persistent negative skin reaction, the prognosis is poor. A rise in titer with complement fixation test is significant, because there can be cross-reactions with North American blastomycosis and some of the other mycoses.

The disseminated form of the infection can be acute or chronic, but is usually progressive. However, there is a silent form of disseminated histoplasmosis recognized where there is splenic calcification in patients who have died for some other reason. Dissemination is most common in children, particularly those who are already ill (e. g., with leukemia or lymphoma) and in the elderly and the immunosuppressed. In such patients it can be acute and fatal. The reticuloendothelial system and bone marrow are affected, resulting in anemia, purpura, and leukopenia. Hepatosplenomegaly and lymphadenopathy develop. Clinically the disseminated infection may closely resemble leishmaniasis or some of the leukemias.

When there is pulmonary progression, this can result in fibrosing mediastinitis, which is often worse than the original pulmonary disease. The mucous membrane of the alimentary tract can be ulcerated and the clinical presentation may be melena. With further systemic spread, cardiac valves, the meninges, brain, and adrenals can be involved. The clinical presentation may then be Addison's disease (H. capsulatum may be one of the commonest causes of a cystic mass in the adrenals worldwide). Occasionally oral or laryngeal infections, with laryngeal stricture, can develop. The mortality among patients with the acute dissemination infection is 80% or more unless treated.

However, the disseminated pattern of the disease can also progress slowly in adults, and appear clinically many years (even 30 years) after exposure. Residual nodules are less common in the liver, spleen, and elsewhere than in the lungs. Long-term, slowly progressing pulmonary infection may be more common in those who have been in the tropics or Southeast Asia, but is almost always associated with preexisting chronic obstructive pulmonary disease (emphysema).

The rare subcutaneous form of the disease results in chronic granulomatous ulceration, usually at the site of ulceration.


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Copyright: Palmer and Reeder