Answer: Histoplasma capsulatum
This small oval-shaped fungus has a very similar appearance to the amastigotes of Leishmania species (and Trypanosoma cruzi), as well as the tachyzoites of Toxoplasma gondii. It is therefore always in my differential of small intracellular objects when I am looking at blood smears, bone marrow aspirates and tissue sections. All of these objects measure 2 to 5 micrometers in greatest dimension and can be found within phagocytic cells. However, there are several key differentiating features that allow for a correct identification to be made:
1. Leishmania spp. amastigotes - have a single nucleus and rod-shaped kinetoplast. They are found within macrophages/monocytes.
2. T. cruzi amastigotes - are indistinguishable from Leishmania amastigotes but have a different tissue tropism (e.g. cardiac and smooth muscle cells) and associated clinical presentation.
3. Toxoplasma gondii tachyzoites - are arc-shaped (but can appear oval in tissue) and have a single nucleus with no kinetoplast. They can infect any nucleated cell.
4. Histoplasma capsulatum yeasts - are found within macrophages/monocytes and divide by narrow-based budding. As Sugar Magnolia mentioned, their cell wall does not take up many stains well (e.g. Giemsa, H&E), and therefore they appear to have a surrounding capsule (sometimes termed a pseudocapsule). This is where the species name, capsulatum, comes from. A silver fungal stain (e.g. Gomori methenamine silver) will stain all of the yeast including its cell wall. In contrast, amastigotes and tachyzoites do NOT stain with GMS.
It's important to note that other yeasts such as Penicillium marneffei and Cryptococcus neoformans will also stain with silver fungal stains and may have a similar appearance to H. capsulatum in peripheral blood films. They can be differentiated through a careful examination of several morphologic features; Cryptococcus neoformans has a true capsule, unlike H. capsulatum, and exhibits more size variability, whereas Penicillium marneffei divides by formation of transverse septations rather than budding.
Whew! That was a long explanation. Kudos to my excellent parasitology technologists who correctly detected and identified the H. capsulatum on the malaria smears. I later found out that the patient was severely immunocompromised with AIDS - a common scenario for histoplasmosis detected on peripheral blood films.