Classical histoplasmosis, also known as Darling's disease, small-form histoplasmosis, American histoplasmosis, cave disease, Ohio Valley disease, or reticuloendotheliosis, is a systemic infection caused by the thermally dimorphic fungus Histoplasma capsulatum var. capsulatum. 

Classical histoplasmosis is endemic to the Ohio / Mississippi River Valley, South and Central America, northern South America, Brazil, Argentina, Uruguay, and Paraguay.

Bird and bat excrement enhance the growth of the organism in the soil; however, patients frequently do not recollect a definitive exposure.  Initially, microconidia are inhaled into the lungs where they transform into yeast forms and are ingested by macrophages.

Most patients with histoplasmosis are asymptomatic. When symptomatic, there are 3 forms of the disease: pulmonary (acute and chronic), disseminated (acute and chronic), and primary cutaneous histoplasmosis.

Pulmonary:
In acute pulmonary histoplasmosis, the patient presents with cough, chest pain, fever, polyarticular arthritis, and occasionally a rash caused by an immunologic reaction to the fungus (erythema multiforme, or erythema nodosum) 3-17 days after a prodrome of an influenza-like illness. In immunocompetent patients, acute pulmonary histoplasmosis is most likely asymptomatic or paucisymptomatic.

Chronic pulmonary histoplasmosis resembles pulmonary tuberculosis clinically and radiographically. It is not usually associated with skin findings. Patients may have persistent mild pulmonary symptoms and are found to have cavitation and fibrosis on chest imaging. It is most commonly seen in patients with preexisting pulmonary disease. Pericarditis may develop (in 5% of cases).

Disseminated:
In patients with acute disseminated histoplasmosis, hematogenous spread of the fungus allows for extrapulmonary infection in the lymph nodes, liver, spleen, skin, gastrointestinal tract, and bone marrow. This form is most commonly seen in immunocompromised patients and can be fatal if untreated. Skin involvement is more common in the disseminated form, where there may be widespread umbilicated papules, pustules, nodules, ulcers, or subcutaneous nodules representing erythema nodosum. Gastrointestinal involvement is common, and patients may report abdominal pain, diarrhea, nausea, anorexia, gastrointestinal bleeding, and melena. Severe weight loss, fever, anemia, and hepatosplenomegaly can result. Rarely, perforation can occur; the most common sites are the terminal ileum and proximal colon.

Chronic disseminated histoplasmosis commonly appears months to years after a patient has left an endemic area. Patients may present with hepatosplenomegaly, pancytopenia, oral or pharyngeal ulcerations, or adrenal insufficiency after adrenal infiltration.

Disseminated histoplasmosis may be complicated by central nervous system infection in 5%-10% of cases and can manifest as meningitis.

Immunocompromised patients have a high risk of dissemination, particularly those with HIV or lymphoma. The severity of disease is often influenced by other predisposing factors such as corticosteroid use, diabetes, malignancy, and connective tissue disease. Infants and adults older than 55 years are also at risk for disseminated disease.

Cutaneous:
Primary cutaneous histoplasmosis is rare and occurs after trauma to the skin with an infected instrument. Cutaneous histoplasmosis may present as an umbilicated papule, nodule, or indurated ulcer with associated lymphadenopathy.

In general, people at higher risk of exposure to infected soils include spelunkers, construction workers, and agricultural workers. Risk factors for systemic histoplasmosis include many immunosuppressed states. Disseminated histoplasmosis is considered an AIDS-defining illness. Patients who have AIDS along with histoplasmosis usually present with weight loss and fever.