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In the lungs, histoplasma converts to a yeast phase, a vacuolated intracellular parasite similar to Leishmania donovani and L. mexicana, that then disseminates into the liver and spleen. It has a predilection for mononuclear phagocytes and grows readily in phagolysosomes. The survival strategy is unclear, but it appears that the organism can alkalinize the phagolysosome to a pH of 6.0 or 6.5, low enough that it can still scavenge iron but high enough to mitigate the effects of acid proteases that are present in the phagolysosome. If the inoculum is sufficiently high with the pulmonary infection, the individual can become moderately to severely ill. In most individuals the infection is self-resolving, often either asymptomatic or with flu-like symptoms. When the immune system is suppressed, however, the organism will disseminate and reactivate to cause progressive disseminated histoplasmosis that, if untreated, can be life-threatening.

When coccidioides enters the lungs it is transformed into spherules that can become quite large, containing up to 1,000 endospores. As with histoplasma, the infection is often self-resolving and asymptomatic, but in an immunocompromised host the organism can disseminate and reactivate, causing Valley fever—progressive disseminated coccidioidomycosis. It shows a predilection for the skin and the meninges, as well as the lungs, and like histoplasma it likes viscera that are rich in mononuclear phagocytes.

Both organisms pose the biggest threat to immunocompromised hosts, in the form of a reactivation disease. Primary infection is followed by a dormant phase that is held in check until a perturbation in the immune system allows the organism to flourish. Except where known, immunosuppressive agents are involved, researchers do not know why otherwise healthy immune systems should break down and allow the organism to replicate.

Incidence and Burden. Incidence can be very high in areas where the pathogen is endemic. During the 1950s, approximately 90 percent of Navy recruits from the Cincinnati area were skin-test positive for histoplasma. The figure may be lower today, yet clinical observations indicate that about 75 percent of the people in Cincinnati who undergo routine chest x-rays have calcifications in their lungs or spleens, and an autopsy series demonstrated that—at least in Cincinnati—most of those calcifications were correlated with the presence of organisms consistent with Histoplasma capsulatum. When the National Institute of Occupational Safety and Health (NIOSH), which is located in Cincinnati, tested for the presence of histoplasma in a building being renovated, they found the organism not only in accumulated bat guano inside the building, but also in soil samples from outside the building. After the bat guano was treated with hypochlorite solution, it still tested positive for histoplasma (the usual treatment is formaldehyde).

Immunology. With both histoplasma and coccidioides, cell-mediated immunity is of primary importance. CD4 cells appear to be the primary mediator, although CD8 cells play a smaller role. Humoral immunity has little or no role. In both cases, the transfer of hyperimmune serum results in very little enhancement of phagocytosis by mononuclear phagocytes. One reason is the



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