History and Geography

Infection with H. capsulatum was first described in April 1906 by Samuel Darling (1906). From an autopsy of a laborer who died while working on the Panama Canal, he described a disseminated infection of the reticuloendothelial system caused by an organism that he believed was protozoan. Macrophages were filled with small organisms. Within a few years he reported two other similar cases. In 1913, H. da Rocha-Lima discussed the published photomicrographs of Darling's cases and speculated that the organism might be a fungus rather than a protozoan (Rocha-Lima 1913).

Another autopsy case was reported in Minnesota in 1926 by W. A. Riley and C. J. Watson (1926), who credited Darling with being the first to describe the infection in 1906. Later, however, there was some confusion as to whether a case report of R. P. Strong (1906) from the Philippines in January 1906 had described histoplasmosis first. But in a personal letter many years later, Strong stated his belief that the case he had described was not histoplasmosis, but rather a rare human infection with Cryptococcus farciminosus, the cause of farcy in horses (Parsons and Zarafonetis 1945). Thus credit for the first case description remains with Darling, who recognized that the disease was previously undescribed and who named the organism and the illness.

After Riley and Watson's paper, scattered autopsy reports of similar cases followed, mostly from the central United States. Then in 1934, the first pre-mortem diagnosis of such a patient was made by finding the characteristic intracellular organisms on a peripheral blood smear (Dodd and Tompkins 1934). W. A. DeMonbreun (1934) isolated the infectious agent, proved that it was a fungus, and demonstrated its thermal dimorphism.

In January 1945, R. J. Parsons and C. J. Zarafonetis (1945) reported 7 cases, reviewed 71 previous cases, and concluded that histoplasmosis was a rare systemic infection that was nearly always fatal. However, in the same year, A. Christie and J. C. Peterson (1945) and also C. E. Palmer (1945), using antigen derived from the first isolate, demonstrated that great numbers of asymptomatic persons in the central United States had been infected with the fungus. Furthermore, they showed that almost all tuberculin-negative persons with calcifications on chest roentgenogram had positive histoplasmin skin tests. Quickly the endemic area was mapped and fungus was isolated from soil in areas with high skin-test positivity. The new conclusion was that histoplasmosis is very common and almost invariably benign and self-limited. The fatal cases were rare and exceptional.

Most of the skin-test reactors in the early surveys had had asymptomatic or minimally symptomatic nonspecific infections. The retrospective discovery of a highly symptomatic but also self-limited form of primary histoplasmosis soon followed. Small groups of patients exposed to high concentrations of organisms, often in closed spaces, had been verified as victims of epidemics of an unknown but relatively severe acute pulmonary illness. An epidemiological investigation of one such outbreak, which occurred in 1944 and was reported 3 years later (Cain et al. 1947), demonstrated convincingly that H. capsulatum had been the offending agent.

Upper-lobe cavitary histoplasmosis resembling tuberculosis was first described in Missouri in 1956 by M. L. Furculow and C. A. Brasher among sanitorium patients being treated for tuberculosis. The mechanism of infection was most likely progressive primary infection in an abnormal lung, and not reactivation (Goodwin et al. 1976).

In 1955, the isolation of amphotericin B was described by W. Gold and colleagues, and within a few years the drug was available for treatment of a wide variety of fungal infections. This drug, despite some toxicity, proved highly effective for histoplasmosis and remains the agent to which newer alternatives must be compared. Ketoconazole, a nontoxic oral imidazole, arrived in the 1980s. It is not as effective as amphotericin B but is reasonable therapy for mild to moderately ill patients with chronic cavitary disease and indolent forms of disseminated disease.

With the increase in the use of glucocorticoids and cytotoxic drugs for malignant and nonmalignant diseases, disseminated histoplasmosis assumed increasing importance (Davies, Khan, and Sarosi 1978; Kaufman et al. 1978). Endogenous reactivation was suspected as a mechanism in some cases because the illness presented as a nonspecific febrile illness. Treatment with amphotericin B was very effective if the diagnosis was made quickly and if the patient had some degree of cell-mediated immune response.

Finally, as previously noted, AIDS brought a new level of suppression of the cell-mediated immune system. The concept of endogenous reactivation received further support, for, unlike other immunosuppressed patients, even those AIDS patients who respond to treatment are not cured but require long-term suppressive therapy to prevent relapse of infection (Johnson et al. 1986).

Scott F. Davies

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