Clinical Manifestations and Pathology

Primary Pulmonary Histoplasmosis

This disease is asymptomatic at least half of the time. Symptomatic patients become ill about 2 weeks after exposure. They have an influenza-like illness with fever, chills, myalgias, headache, and a nonproductive cough. Rare manifestations include arthralgias, arthritis, and erythema nodosum. With or without symptoms, the chest roentgenogram may show patchy areas of pneumonitis and prominent hilar adenopathy.

A primary fungemia probably occurs in most cases. The calcified granulomas commonly found in spleens and livers of patients from endemic areas result from this primary, self-limited fungemia, not from progressive dissemination.

Following exposure to an unusually heavy inoculum, a more diffuse pulmonary involvement may occur, with an extensive nodular infiltrate on the chest roentgenogram. Dyspnea may be added to the other symptoms, and symptoms are more severe and last longer. Most patients recover without treatment, but extreme cases may progress to respiratory failure.

The chest roentgenogram often returns to normal after a primary pulmonary infection, but a variety of residual abnormalities may be seen. Initial soft infiltrates may harden and contract, leaving one or several nodules. Central necrosis may result in a dense core of calcium (a "target" lesion), but this is not universal. Infrequently, alternate periods of activity followed by healing may result in concentric rings of calcium as the lesion slowly enlarges. Lymph node calcification, either in association with a parenchymal nodule or as a solitary finding, is common. Finally, small "buckshot" calcifications may be scattered over both lung fields, a pattern characteristic of uneventful recovery after exposure to a heavy inoculum of organisms.

Primary histoplasmosis has several uncommon local complications within the chest. Involvement of the pericardium can cause a nonspecific acute pericarditis (Wheat et al. 1983). The inflammation probably represents a response to adjacent infection in the lung, as the cultures of pericardial fluid are usually sterile. Many cases are probably misdiagnosed as benign viral pericarditis. Rarely, the process progresses to chronic constrictive pericarditis. More delayed and more serious, an extensive fibrosing process in the mediastinum can cause vascular compression and result in the superior vena caval syndrome with edema of the head and upper extremities and development of superficial venous collaterals across the chest wall. Inflammation adjacent to the esophagus may cause a traction diverticulum. A lymph node impinging on a bronchus may cause a chronic cough. If a calcified lymph node erodes through a bronchus, it becomes a broncholith. Hemoptysis is a common clinical manifestation.

Chronic Cavitary Histoplasmosis

Although it may occur anywhere in the lung, chronic cavitary histoplasmosis usually involves both upper lobes and closely resembles reinfection tuberculosis in its roentgenographic appearance. The mechanism of infection, however, is not endogenous reactivation. Rather the infection is the result of a primary infection in abnormal lungs, typically the lungs of middle-aged or older male smokers who have centrilobular emphysema (Goodwin et al. 1976). Acute pulmonary histoplasmosis in this setting usually resolves uneventfully although very slowly. In about a third of cases, infected air spaces persist. A progressive fibrosing and cavitary process gradually destroys adjacent areas of the lung. Chronic cough is the most common symptom. Constitutional symptoms, including low-grade fever, night sweats, and weight loss, increase as the illness progresses.

Disseminated Histoplasmosis

This condition refers to any progressive extrapulmonary infection. There is a range of infection with different tissue responses. At one extreme there are massive numbers of organisms in all reticuloendothelial organs with little tendency to granuloma formation. Clinical features include high fever, hepato-splenomegaly, lymphadenopathy, and pancytopenia due to bone marrow involvement. This type of disseminated histoplasmosis has been called the "infantile" form and may lead to death within days or weeks. Other patients, often older adults, have a more indolent illness, many months in duration, characterized by low or moderate fever, weight loss, and skin and mucous membrane lesions. Biopsies of involved tissues show well-formed granulomas similar to sarcoidosis. Organisms are scanty and often are demonstrated only with special stains.

Disseminated histoplasmosis also occurs as an opportunistic infection. The degree of granulomatous tissue response may vary from none to a considerable amount and has prognostic value. If the bone marrow biopsy shows epitheloid granulomas or even recognizable aggregates of macrophages, the response to treatment is quite good. If the biopsy shows no granulomas, tissue necrosis, and a large number of organisms, the prognosis is very poor (Davies, McKenna, and Sarosi 1979).

Disseminated histoplasmosis often presents as a nonspecific systemic febrile illness rather than as a pulmonary infection. There is usually no cough. The chest roentgenogram may be normal. If abnormal, it often shows a diffuse infiltrate, suggesting hematogenous spread to the lung, rather than a focal infiltrate.

Immunosuppressed patients probably get disseminated histoplasmosis in two ways. If they inhale the organisms while immunosuppressed, the primary infection will progress, as documented in the Indianapolis outbreak (Wheat et al. 1982). On the other hand, if they become profoundly immunosuppressed long after their primary infection, the disease may reactivate (Davies, Kahn, and Sarosi 1978). This is suggested by the systemic, nonpulmonary nature of the illness and is supported by the recent experience with the acquired immune deficiency syndrome (AIDS). Patients with past exposure to endemic areas are developing disseminated histoplasmosis while living in nonendemic areas such as New York City (Huang et al. 1988), San Francisco, and Los Angeles.

Disseminated histoplasmosis may also present as a more localized infection. Examples include central nervous system histoplasmosis, meningeal histoplasmosis, and isolated gastrointestinal histoplasmosis, which often involves the terminal ileum. All are extremely rare.

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