Infection with Histoplasma capsulatum occurs commonly in areas in the Midwestern United States and Central America, but symptomatic disease requiring medical care is manifest in very few patients. The extent of disease depends on the number of conidia inhaled and the function of the host's cellular immune system. Pulmonary infection is the primary manifestation of histoplasmosis, varying from mild pneumonitis to severe acute respiratory distress syndrome. In those with emphysema, a chronic progressive form of histoplasmosis can ensue. Dissemination of H. capsulatum within macrophages is common and becomes symptomatic primarily in patients with defects in cellular immunity. The spectrum of disseminated infection includes acute, severe, life-threatening sepsis and chronic, slowly progressive infection. Diagnostic accuracy has improved greatly with the use of an assay for Histoplasma antigen in the urine; serology remains useful for certain forms of histoplasmosis, and culture is the ultimate confirming diagnostic test. Classically, histoplasmosis has been treated with long courses of amphotericin B. Today, amphotericin B is rarely used except for severe infection and then only for a few weeks, followed by azole therapy. Itraconazole is the azole of choice following initial amphotericin B treatment and for primary treatment of mild to moderate histoplasmosis.
Histoplasmosis was first described a little over a century ago by an American physician, Samuel Darling, who was working in the Canal Zone in Panama. He described the disseminated form of the disease in a fatal case from Martinique (19 ). It took decades to prove that Histoplasma capsulatum is a dimorphic fungus, that histoplasmosis is primarily a pulmonary disease, and that the environmental reservoir is soil (25. 33 ).
There are two varieties of H. capsulatum that are pathogenic to humans, H. capsulatum var. capsulatum and H. capsulatum var. duboisii. and a third variety that is an equine pathogen, H. capsulatum var. farciminosum (63 ). H. capsulatum var. duboisii exists in Africa, and cases have been reported in both Africa and Europe, when patients from Africa seek care there. This review will focus solely on disease manifestations of H. capsulatum var. capsulatum. hereafter referred to as H. capsulatum.
H. capsulatum exists as a mold in the environment and forms a white to tan colony on Sabouraud dextrose agar at 25 to 30°C. Two types of conidia are formed. The macroconidia or tuberculate conidia are 8 to 15 μm in diameter and have a thick wall with distinctive projections on the surface; the microconidia are tiny, smooth structures that are 2 to 4 μm in diameter and are the infectious form. At 37°C in vitro and in tissues, the organism converts into the yeast phase that is composed of tiny 2- to 4-μm oval budding yeasts that are found both inside and outside macrophages. The organism is not encapsulated, although in tissues, it appears to be surrounded by a clear zone that was misinterpreted as being a capsule by Darling (19 ).
H. capsulatum occurs most commonly in North America and Central America, but the organism exists in many diverse areas around the world (63 ). In the United States, H. capsulatum is endemic in the Mississippi and Ohio River valleys and also exists in localized foci in many mideastern states. Soil containing large amounts of bird or bat guano, especially that found under blackbird roosts or next to chicken coops, supports luxuriant growth of the mold (11 ). Once contaminated, soil yields H. capsulatum for many years after birds no longer roost in the area. Caves can be highly contaminated by H. capsulatum that thrives on the bat guano (77 ).
Infection with H. capsulatum occurs during day-to-day activities in areas where H. capsulatum is highly endemic or in the course of occupational and recreational activities that disrupt the soil or accumulated dirt and guano in old buildings, on bridges, and in caves where bats have roosted (11. 59 ). Outbreaks that involve anywhere from a handful to tens of thousands of individuals have been described (8. 131. 136 ).
Every year, hundreds of thousands of individuals in the United States and Central America are infected with H. capsulatum. Most do not realize that they have had a fungal infection. The
true extent of infection with H. capsulatum in the Ohio and Mississippi River valleys was defined only after the development of a skin test antigen that could be used in epidemiological studies (12 ). The seminal studies by Christie and Peterson and Palmer established the relationship of histoplasmin skin test positivity to pulmonary calcifications in tuberculin-negative persons (12. 95 ). Subsequent large-scale population studies by the Public Health Service defined the area where H. capsulatum is endemic (32 ) and demonstrated that over 80% of young adults from the states bordering the Ohio and Mississippi Rivers had been previously infected with H. capsulatum.
This review will focus on the clinical, diagnostic, and therapeutic aspects of infection with this dimorphic fungus.
Exposure to H. capsulatum is exceedingly common for persons living within areas of endemicity, but symptomatic infection is uncommon (63 ). The vast majority of infected persons have either no symptoms or a very mild illness that is never recognized as being histoplasmosis. The clinical manifestations described below are those that occur in the small number (<1%) of persons who develop symptoms when infected with H. capsulatum.
Acute pulmonary histoplasmosis.
The usual case of acute pulmonary histoplasmosis is a self-limited illness occurring mostly in children exposed to the organism for the first time. Symptoms include fever, malaise, headache, and weakness; substernal chest discomfort and dry cough are helpful symptoms pointing toward acute pneumonia (49 ). Rales are heard in a minority of patients. Chest radiographs show a patchy pneumonia in one or more lobes; enlarged hilar and mediastinal lymph nodes are frequently noted (51. 156 ). Improvement is prompt in the majority of cases, but in some patients, fatigue may linger for several months. In some patients, chest radiographs are obtained only after the pulmonary infiltrate has cleared, and hilar lymphadenopathy is the primary finding.
Acute self-limited pulmonary histoplasmosis is accompanied by rheumatologic and/or dermatologic manifestations in approximately 5% of patients. Erythema nodosum and erythema multiforme are the most common skin manifestations; they occur most frequently in young women and are thought to be associated with a hypersensitivity response to the antigens of H. capsulatum (88. 94. 115 ). Myalgias and arthralgias are common symptoms during acute infection; however, a minority of patients may develop self-limited, polyarticular, symmetrical arthritis (108 ). Joint symptoms usually resolve over several weeks and respond to nonsteroidal anti-inflammatory agents. Patients who have hilar lymphadenopathy, arthralgias, and erythema nodosum can be mistakenly given the diagnosis of sarcoidosis (125. 144 ).
Included in the differential diagnosis of acute pulmonary histoplasmosis is acute pulmonary blastomycosis and atypical community-acquired pneumonias, such as those due to Mycoplasma. Legionella. and Chlamydia (see Table Table1). 1 ). Hilar or mediastinal lymphadenopathy is common with histoplasmosis and can be seen with blastomycosis but would be extremely uncommon with the above-listed agents that cause community-acquired pneumonia.
Differential diagnosis of pulmonary histoplasmosis
A careful history of possible exposure to H. capsulatum in the activities of daily living or during the course of travel is crucial to arriving at the correct diagnosis. Discovering that others with whom the patient has been associated have a similar illness is extremely useful information when a diagnosis of histoplasmosis is being sought (11 ).
Acute severe pulmonary infection also occurs when a person is exposed to a large inoculum of H. capsulatum (49. 154 ). The onset of illness is abrupt, and the patient presents with fever, chills, malaise, dyspnea, cough, and chest pain. Rales may be heard throughout the lungs. Chest radiographs show diffuse pulmonary infiltrates that usually are described as reticulonodular; coalescence of nodules sometimes occurs in discrete areas of the lung (Fig. (Fig.1). 1 ). Acute respiratory distress syndrome can occur within a few days (62. 164 ). Pleural involvement is rare. Mediastinal and hilar lymphadenopathy may or may not be present. Many patients will recover without treatment, but severe disease should always be treated, because respiratory compromise can occur and recovery without an antifungal agent is slow. As the pneumonia resolves, the remaining nodules often calcify, leaving the appearance of “buckshot” throughout the lung fields (49. 51 ).