Isospora belli

Authors:David S. Lindsay, Ph.D., Louis M. Weiss M.D., M.P.H 


Life Cycle

Isospora belli is a protozoan parasite in the Phylum Apicomplexa. This group of parasites are referred to as coccidia. This organism can be acquired by the ingestion of sporulated oocysts found in contaminated food or water. The oocyst stage is 23-36 by 12-17 µm and are much larger than the oocysts of related coccidial species such as Cryptosporidium parvum and Cyclospora cayetanensis. Sporulated oocysts of I. belli can survive for years in the environment. Endogenous stages of I. belli consist of schizonts (multinucleated asexual stages), merozoites (uninucleate asexual stages), macrogomonts (female sexual stages [ovum-like stage]), microgamonts (male sexual stages) with microgametes (sperm-like stages) and oocysts (formed by fertilization of macrogamont by a microgamete). The endogenous stages are usually located in a vacuole within enterocytes lining the villi of the small and large intestine (6, 37) or rarely bile duct epithelium (3). Some merozoites can also be observed in lamina propria (38) and probably give rise to extra-intestinal infections. Monozoic cysts have been observed in the lamina propria of patients with AIDS. Extra-intestinal infections with tissue cyst-like stages have been observed in the mesenteric, periaortic and mediastinal lymph nodes, liver and in the spleen of patients with AIDS (24,33) and probably also occur in immune competent patients. These extra-intestinal tissue cysts represent a dormant form of the infection and contain a single merozoite stage (24). It is believed that these extra-intestinal tissue cysts that are probably responsible for the recurrences seen in both immune compromised and immune competent patients (24).


Isospora belli infections are essentially cosmopolitan in distribution but are more common in tropical and subtropical regions, especially Haiti, Mexico, Brazil, El Salvador, tropical Africa, Middle East, and Southeast Asia (36). For example, Isospora belli has been reported as the most common protozoan parasite in HIV infected patients with acute or chronic diarrhea in India (14). In French HIV patients with I. belli a significant risk factor was being from sub-Saharan Africa (13). An outbreak of I. belli infections was reported in Antofagasta City Chile in 1977 (18). It was associated with ingestion of vegetables contaminated with irrigation water from a sewage treatment plant (18). Approximately 90 people were infected.

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Symptoms of I. belli infection include diarrhea, steatorrhea, headache, fever, malaise, abdominal pain, vomiting, dehydration, and weight loss (6, 22,37). Blood is not usually present in the feces. The disease is often chronic with parasites present in the feces or biopsies for several months to years. Recurrences are common. Isospora belli can cause a serious and sometimes fatal disease in immune competent patients. In patients with AIDS, or other immune compromised hosts, infection is often severe with a fluid, secretory-like, diarrhea that may lead to dehydration requiring hospitalization. This can be associated with fever and weight loss. In these immune compromised hosts recurrences are common and present the most challenging aspect of treating this infection. Isospora belli infection of the biliary tract can occur in patients with immune suppression or in immune competent patients (4). It has been suggested that intravenous administration of trimethoprim-sulfamethoxazole is more effective that orally administered drug in patients with hepatic infection and malabsorption due to I. belli (4). Rare infections have been reported outside the gastrointestinal tract. A case of suspected I. belli infection was observed in the glandular epithelium of a immunocompetent 63 year-old woman who presented with metrorrhagia and under went aspiration endometrial biopsy which demonstrated glandular endometritis (29).

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Isospora belli is diagnosed by detection of the oocysts in stool or rarely bile samples. Universal precautions should be followed when handling fresh stool samples. Oocysts can be observed in wet preparations, iodine stained preparations or acid-fast stained smears of concentrated stool specimens. Isospora belli oocysts are acid fast and will also stain positive using the auramine o protocol commonly used to detect mycobacteria (16). The sporont and sprobast fluoresce green when a fluorescent microscope is used to examine stool smears after auramine o staining. Autofluorescence of I. belli oocyst walls has been reported and can be used in diagnosis (5,43). Autofluoresence was superior to iodine staining in one study (5). A real-time PCR assay has been developed to detect I. belli in stool samples (17).


I. belli can cause marked villous atrophy, and crypt hyperplasia in the small intestine. Inflammatory infiltrates in the lamina propria include eosinophils, neutrophils, lymphocytes and plasma cells. The precise mechanism causing these changes is unknown, but they result in steatorrhea and malabsorption. Infection of the biliary tract by I. belli is also possible. The parasite can complete it’s life cycle in the biliary tract and oocysts can be observed in bile (4). Stages are located in the bile duct epithelium (3).

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There are no animal models of I. belli infection. Siripanth et al. (35) examined the development of I. belli in human iliocecal adenocarcinoma (HCT-8), human larynx carcinoma (Hep-2), human fibroblast, bovine endothelial kidney (BEK), and African green monkey (Vero) cell culture cells. Sporozoites inoculated onto HCT-8 cells underwent schizogony and produced sexual stages but no oocysts. Sporozoites inoculated onto Hept-2 cells underwent schizogony but did not produce sexual stages. They reported that unizoic cysts were observed after inoculation of sporozoites onto BEK and Vero cells. It is not clear from their report if these were sporozoites that entered cells and did not develop or if they were true unizoic cysts. They reported that sporozoites could not enter human fibroblast cells. Oliveira-Silva et al. (28) examined the development of I. belli sporozoites in HCT-8, epithelial carcinoma of the lung (A549), Maden-Darby bovine kidney (MDBK), and Vero cells. They found that sporozoites entered all cell types and underwent development by endodyogeny (a type of binary fission) by 24 hours. They did not observe sexual stages in any cell type (28). Most development occurred in Vero cells. No in vitro drug studies have been reported.

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Drug of Choice

Combination therapy with oral trimethoprim (160 mg)-sulfamethoxazole (800 mg)  4 times a day for 10 days results in a decrease in diarrhea and abdominal pain within 1 to 6 days (mean = 2.5 days) after treatment (30). Stool samples examined after 10 days usually do not contain oocysts. Combination therapy with oral trimethoprim (320mg)-sulfamethoxazole (1,600 mg) 2 times a day for 10 to 14 days is as effective and may be an easier course of therapy for some patients. It is important to note here that HIV patients have a very high rate of relapse and should receive secondary prophylaxis, until they are immune reconstituted by active antiretroviral therapy (ART).

Special Situations

Sulfonamide Allergies: Pyrimethamineused alone is effective in patients with sulfonamide allergies (41). Dosages between 50 and 75 mg per day are comparable to treatment with trimethoprim-sulfamethoxazole. Diclazuril (see below) has also been used effectively in patients with sulfonamide allergies.

Immunosuppressed Hosts Including HIV Patients, Transplant Recipients, etc: Isospora belli infections have been observed in a wide variety of immune compromised patients including patients with concurrent Hodgkin's disease (6), non-Hodgkin's lymphoproliferative disease (15,32), human T-cell leukemia virus type I-associated adult T-cell leukemia (12), and acute lymphoblastic leukemia (42). Isospora belli has been observed in both renal transplant (22,43) and liver transplant patients (1). A case of I. belli infection was also reported in a patient with sickle-cell anemia (25). Isospora belli was a cause of diarrhea in an 11 year-old child with fetal alcohol syndrome, immunodeficiency, malnutrition and renal tubular disease (8). It also was the cause of diarrhea in a 9 year-old malnourished girl (20). Such immune compromised hosts respond to specific anti-I. belli treatment with trimethoprim-sulfamethoxazole.

Isospora belli infections have been widely documented in patients with AIDS. Anti-I. belli treatment is usually effective in controlling symptoms, but recurrences are common after treatment is stopped. This is most likely because the agents used to treat the infection are not active against the extra-intestinal tissue cyst stage of the parasite. Prophylaxis is required to prevent reoccurrence in AIDS patients that do not receive ART. Additionally, severe diarrhea and wasting associated with I. belli infection and subtherapeutic levels of antiretroviral medications due to malabsorption from this gastrointestinal infection has been reported (7). Patients that do not respond adequately to ART are clearly at risk for I. belli infection (27).

Alternative Treatment

Pyrimethamine: Pyrimethamine is useful in sulfonamide allergic patients. It is related to trimethoprim and is an dihydrofolate synthetase inhibitor. Pyrimethamine has been used alone at dosages of 50 to 75 mg per day as an alternative to trimethoprim-sulfamethoxazole (41). In the two patients reported resolution of diarrhea occurred within 2 days of starting therapy (41), similar to what has been reported for treatment with treimethoprim-sulfamethoxazole. Pyrimethamine has been used for secondary prophylaxis following primary isosporiasis (see bellow). The major limiting toxicity of pyrimethamine is bone marrow suppression, which can be prevented by using folinic acid (5 to 10 mg/day) when pyrimethamine is administered.

Ciprofloxacin: Ciprofloxacin is a fluoroquinolone that inhibits DNA gyrase (topoisomerase). Many of these quinolones have demonstrated activity against protozoa including Apicomplexa such as malaria. There has been a study (40) comparing trimethoprim-sulfamethoxazole to ciprofloxacin (500 mg BID) for the treatment of isosporiasis in HIV infected patients. Of 22 patients with isosporiasis, 10 were randomized to receive trimethoprim-sulfamethoxazole and 12 ciprofloxacin. All of the patients treated with trimethoprim-sulfamethoxazole responded to treatment with clearance of the organism and resolution of diarrhea within a median of 2 days (40). Ciprofloxacin was effective in 10/12 (83%) of patients with a median time to cessation of diarrhea of 4.5 days. All three patients (2 with diarrhea and one without) who had persistent I. belli oocysts in their stools at the completion ciprofloxacin treatment responded to trimethoprim-sulfamethoxazole with elimination of organisms and resolution of diarrhea. In those patients responding to ciprofloxacin treatment continued prophylaxis with ciprofloxacin prevented recurrence of disease. Ciprofloxacin, therefore, while not as effective as trimethoprim-sulfamethoxazole can be used as an alternative agent. Ciprofloxacin is contraindicated in children and pregnant women as quinolones have been associated with cartilage problems in animal models.

Diclazuril: Diclazuril (Clinicox) is a triazin anticoccidial used in the poultry production industry. Diclazuril was used in a trial to treat 8 AIDS patients with I. belli diarrhea (19). Each patient received 200 mg of diclazuril orally for 7 days. Oocysts were eliminated from the stools by 2 to 3 days. Diarrhea completely stopped in 4 of 8 patients; however, severe diarrhea persisted in one patient. Oocysts were present in the stools of 1 of 3 patients examined a month following treatment. Diarrhea and oocyst excretion reoccurred 47 days after treatment had ended. Diclazuril has also been used successfully to treat an AIDS patient that was hypersensitive to both trimethoprim-sulfamethoxazole and pyrimethamine (23). Diclazuril given orally at 300 mg twice daily controlled the I. belli infection. When the dose was decreased to 300 mg once daily the patient had a relapse of disease.

Macrolide Antibiotics: Macrolide antibiotics have marginal efficacy in treating I. belli enteritis. Spiramycin given at   1.5g twice daily initially provided clinical improvement in a patient with AIDS who did not responded to trimethoprim-sulfamathoxazole, furazolidone or tetracycline treatments for I. belli enteritis (11). Response to treatment lasted about a month and then the patient suffered a relapse of infection. Roxithromycin (2.5 mg/kg every 12 hours) was used successfully to treat a patient with AIDS who was suffering from chronic I. belli induced diarrhea that did not respond to trimethoprim-sulfamathoxazole or pyrimethamine treatments (26). Roxithromycin was given orally for 15 days and the diarrhea became intermittent and less severe. Although diarrhea requiring hospitalization occurred twice during the 2 months after treatment, no I. belli was observed in stool samples.

Nitazoxanide: Nitazoxanide (Alinia), is a 5-nitrothiazole approved for the treatment of Giardia duodenalis and Cryptosporidium spp. infections in children in the United States. Nitazoxanide has been used to treat I. belli infections (10,34). Each of 2 patients that received 500 mg nitazoxanide twice daily for 3 days became oocyst negative (34). A single patient treated with 500 mg nitazoxanide twice daily for 7 days became oocyst negative by day 14 after treatment (10). Treatment failure using 2 g nitazoxanide twice daily orally was reported in a immune competent patient with biliary isosporiasis and malabsorption (4). Treatment failure was believed to be due to the lack of absorption of nitazoxanide and poor levels of the drug in the serum (4). Side effects of orally administered nitazoxanide include elevation in liver function tests and nausea.

Amprolium: Amprolium (Amprol, Corid) is an anticoccidial agent used in the poultry production industry. It is structurally related to the vitamin thiamine and it competitively inhibits the active transport of thiamine in coccidial parasites. Amprolium was used in an AIDS patient suffering from severe diarrhea caused by I. belli (39). Amprolium was given orally beginning at 10 mg/kg and increased to 90 mg/kg. The frequency of diarrhea lessened after 6 days of treatment. Amprolium treatment was stopped on day 7 because of polyneuropathy but re-initiated on day 20 at a reduced dose of 30 mg/kg. The stool became normal by day 28 of treatment and no oocysts were present after day 35.

Other Agents: Albendazolecombined with ornidazole has been used successfully in 2 patients with AIDS and I. belli infection (9). One patient received albendazole 400 mg TID for 20 days and ornidazole 2 gm single dose on days 1,10 and 20 and the other patient received albendazole 400 mg TID for 30 days and ornidazole 2 gm single dose on days 1,15 and 30. Both patients had clearance of symptoms and an absence of oocysts after 4 days of treatment. Treatment with other anti-protozoal agents such as metronidazole, tinidazole, quinacrine, furazolidone are probably of little value. The use of ART with its associated reconstitution of immune functions has brought about a decrease in the number of patients with opportunistic enteric parasitic infections (2); however, since infection occurs in immune competent hosts immune reconstitution alone is not sufficient to clear infection without specific anti-parasitic therapy. Patient undergoing ART are less likely to need prophylactic medications to prevent reoccurrence of symptoms.

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Severe dehydration can occur in AIDS patients with I. belli infections and intravenous or oral rehydration is appropriate in these patients. Folinic acid 5 to 10 mg per day can be used to prevent adverse effects of trimethoprim or pyrimethamine administration (41). Antimotility drugs can be used to control diarrhea. ART is indicated for patients with AIDS and I. belli infection. Immune reconstitution syndromes have not been reported with this infection.


Cessation of diarrhea and the disappearance of I. belli oocysts from stool samples are the endpoints for monitoring therapy. We suggest repeated fecal samples be examined, as is done for Giardia duodenalis and Entamoeba histolytica, and be negative before a patient is considered clear of the infection.

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There are no vaccines for I. belli infections.



Recurrence after apparently successful treatment occurred in about 1 in 2 AIDS patients prior to the advent of ART (30). This was probably because agents used to treat active infections have no effect on the dormant tissue cyst stage of the parasite.


Secondary prophylaxis is indicated in all patients with AIDS, and most likely other patients with immune suppression, because about 50% of patients will suffer a recurrence with in 2 months if no prophylaxis is given. Trimethoprim-sulfamethoxazole, ciprofloxacin, pyrimethamine-sulfadoxine, or pyrimethamine are effective in preventing recurrent diarrhea in most patients (40, 41). Trimethoprim-sulfamethoxazole is more effective than ciprofloxacin (40).

Dosing Schedules

Effective prophylaxis can be achieved with oral trimethoprim (160 mg)-sulfamethoxazole (800 mg) given 3 times a week, Ciprofloxacin (500 mg) daily, pyrimethamine (25 mg) combined with sulfadioxine (500 mg) once a week, or pyrimethamine 25 mg a day combined with 5 mg a day folinic acid (to decrease hematologic effects) (40, 41). Pyrimethamine is very useful in patients intolerant of sulfa drugs. In patients with AIDS on ART once the CD4 cell count is greater than 200 for a period of 3 to 6 months it is reasonable to discontinue secondary prophylaxis as the risk relapse of the infection is markedly decreased.

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We believe that atovaquone (Mepron) could be a useful drug for treating I. belli based on its effectiveness against Toxoplasma gondii (31); however, no case reports exist on this agent for I. belli. A reasonable dose to use would be 750 mg 2 to 4 times daily for 10 to 14 days. The effect of treatment with ART on the prevalence of I. belli infections in HIV patients has been examined by Bachur et al. (2). They found that 4.8% of 482 patients examined before the era of HAART treatment were positive and that 1.0% of 100 patients examined after the era of HAART were positive (2). It is likely that if the CD4 count rises above 200 when ART is given that secondary prophylaxis can be stopped. This has been the case for MAI and PCP prophylaxis (primary prevention) and is likely to be the case for PCP secondary prophylaxis (post infection). It is likely that once immune reconstitution induced by ART has been achieved that consideration should be given to stopping secondary prophylaxis for I. belli. As mentioned above patients that receive subtherapeutic levels or do not respond to ART are at risk of reoccurrence of I. belli infection.

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Isospora belli