Background and Epidemiology
Cystoisospora belli, more commonly known as Isospora belli, is a coccidian protozoal parasite endemic to many regions of the world outside of the United States, including the Caribbean, Central and South America, Africa, and Southeast Asia.[,] Most cases of isosporiasis in the United States involve either persons who previously lived in an endemic region or recently traveled to an endemic region. Hispanic individuals living in the United States have approximately a 3.5-fold increased risk of developing this infection when compared with Caucasians. In a HIV-infected person, intestinal isosporiasis lasting longer than 1 month constitutes a diagnosis of AIDS. In the United States, isosporiasis is the initial AIDS-defining illness in less than 1% of persons diagnosed with AIDS. The number of cases of isosporiasis declined following the widespread use of trimethoprim-sulfamethoxazole (Bactrim, Septra) for Pneumocystis pneumonia prophylaxis. Although isosporiasis does not frequently occur among HIV-infected persons living in the United States, it frequently causes gastrointestinal illness among HIV-infected persons in the developing world, as shown by recent surveys in Latin America that reported isosporiasis as the cause of 7 to 14% of all cases of infectious diarrhea.[,,]
Life Cycle and Transmission
The transmission of I. belli occurs predominantly via ingestion of food or water contaminated with human feces laden with I. belli oocysts.[,] Most persons infected with I. belli excrete the oocysts in the stool in the non-infectious (unsporulated or partially sporulated) form; the organism requires a developmental phase (sporulation) outside the host before it transforms into an infectious form (mature oocyst with sporozoites) (Figure 1). Although one report from a case series suggested transmission of I. belli from oral-anal contact. others have concluded this mode of transmission probably occurs infrequently, given the substantial time required outside the host for the oocysts to transform to an infectious form. Moreover, one study found that sexual partners of infected individuals do not have an increased risk of developing isosporiasis. In rare circumstances, in place of (or in addition to) the normal development within the gastrointestinal tract, some sporozoites (or merozoites) leave the intestinal tract and invade extraintestinal sites, such as lymph nodes, spleen, and liver.[,,]
The three coccidian parasites that most commonly cause clinical disease in humans are I. belli, Cryptosporidium parvum, and Cyclospora species. Isospora belli primarily causes gastrointestinal disease; typical symptoms include fever, watery diarrhea, nausea, vomiting, abdominal pain, dehydration, weight loss, and headache.[,] These symptoms often resemble those caused by infection with C. parvum and Cyclospora species. Prior to the HIV epidemic, enteritis caused by C. belli was usually considered a self-limited disease. Among patients with AIDS, however, it typically causes chronic disease leading to weight loss and malabsorption. In these patients, relapse frequently occurs in the absence of maintenance therapy.[,] Several reports have documented cases of extraintestinal disease, but such cases are rare. Extraintestinal sites have included lymph nodes and spleen.[,,] In addition, one report described an AIDS patient with acalculous cystitis associated with C. belli infection.
Patients with isosporiasis often demonstrate peripheral eosinophilia, but this is a non-specific finding. The diagnosis of intestinal isosporiasis requires identification of the characteristic oocysts in a stool sample. The most common techniques used on stool samples include wet mount examination, modified acid-fast stain, or Safranin stain. The Sheather sugar flotation method or the sedimentation concentration method may also be used.[,] To enhance the yield the stool sample should be concentrated prior to microscopic examination. For evaluation of HIV-infected persons with diarrhea, the preferred test is usually either a modified acid-fast stain or Safranin stain, both of which stain the oocysts of I. belli, C. parvum, and Cyclospora spp. oocysts a deep red color. The unsporulated Isospora oocysts appear elliptical in shape, with one or both ends slightly tapered. Staining of the early phase oocyst often shows a internal granular mass (Figure 2), or as it matures, one or two internal sporoblasts may be seen (Figure 3). The I. belli oocysts are approximately 30 by 15 um in size and are distinctly larger and more oval than the C. parvum oocysts (4 to 6 um in diameter) and Cyclospora spp. oocysts (6 to 10 um in diameter) (Figure 4). The I. belli oocysts can also be visualized on wet mount samples using bright field microscopy, differential interference contrast, and UV fluorescence microscopy (Figure 5). Because fecal passage of I. belli oocysts may be intermittent, multiple stool samples are recommended to enhance the diagnostic yield. Antigen detection testing is not commercially available. The diagnosis of extraintestinal isosporiasis has historically been based on histologic findings that show tissue cysts that contain intracellular zoites. More recently, molecular diagnostic methods using PCR have shown promise as a diagnostic tool for I. belli in biopsy specimens.
The 2013 guidelines for the prevention and treatment of opportunistic infections recommends that initial management of patients with intestinal isosporiasis requires adequate rehydration and replacement of any deficient electrolytes. In addition, the guidelines recommend a 10-day course of trimethoprim-sulfamethoxazole as the initial antimicrobial treatment of choice. The alternative medications, pyrimethamine (Daraprim) or ciprofloxacin (Cipro), are reserved for those unable to take trimethoprim-sulfamethoxazole (Figure 6).[,,,] Inadequate data exist to support the use of other agents, such as albendazole (Albenza), nitazoxanide (Alinia), doxycycline, or spiramycin. Patients who have a CD4 count less than 200 cells/mm3 should take chronic maintenance therapy and trimethoprim-sulfamethoxazole is preferred (Figure 7); in this situation, trimethoprim-sulfamethoxazole should be utilized to provide Pneumocystis pneumonia prophylaxis. The first alternatives for chronic maintenance therapy is pyrimethamine plus leucovorin and the second alternative is ciprofloxacin.[,] Patients with a CD4 count greater than 200 cells/mm3 who experience a relapse after completing treatment should re-initiate full-dose therapy and should be considered for maintenance therapy following retreatment. Anecdotal information suggests that effective antiretroviral therapy with immune reconstitution would reduce the risk of relapse or the need for secondary prophylaxis, but data are lacking. The 2013 guidelines for the prevention and treatment of opportunistic infections recommends considering discontinuation of secondary prophylaxis in patients who sustain a CD4 count greater than 200 cells/mm3 for longer than 6 months in response to antiretroviral therapy and they have no evidence of active I. belli infection.