- Formerly known as Isospora belli.
- More recently has been termed Cystoisospora belli.
- Intestinal unicellular protozoan parasite, classified under Coccidia.
- Isospora is the least commonly seen Coccidial infection compared to Toxoplasma or Cryptosporidia.
- Epidemiology: worldwide, but especially seen in tropical/subtropical environs, especially in Caribbean, Central and S. America, India, Africa, & S.E. Asia.
- In U.S., usually associated with HIV infection and institutional living.
- Also travel-acquired, sporadic cases.
- Transmission occurs by ingestion of fecally contaminated water and food. Life Cycle [ Figure 1].
- Isospora causes gastrointestinal infection that mostly afflicts patients with AIDS or profound immunosuppression; however, cases can occur in immunocompetent patients.
- Sx: typically profuse, watery, non-inflammatory diarrhea (although cases of hemorrhagic diarrhea reported).
- Malaise and crampy abdominal pain may accompany.
- Fever uncommon
- May result in malabsorption syndrome.
- Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) both described in association with this infection.
- Malaise and crampy abdominal pain may accompany.
- Extra-intestinal isosporiasis (hepatic, splenic, cholangitic/gallbladder involvement): rare and usually only occurs in immunocompromised patients.
- Dx: microscopic wet mount or iodine stains of fecal smears are adequate but also modified acid-fast stains may also identify (see CDC site for key points to differentiate among the human Coccidia).
- Multiple samples improve sensitivity, as shedding is intermittent.
- Epifluorescence microscopy more sensitive than iodine stain .
- If stools negative, duodenal aspirates (string test [Enterotest®]) or intestinal biopsy may yield diagnosis.
- Eosinophilia may be seen, which is different from other protozoal infections).
SITES OF INFECTION
- Small intestine: diarrhea, malabsorption
- Gallbladder and biliary tree: acalculous cholecystitis, cholangitis
- Liver: dissemination reported (rare).
- Spleen: dissemination reported (rare).
- Rheumatological: reactive arthritis may occur.
- Usually self-limiting infection in immunocompetent individuals, requiring only symptomatic support such hydration and nutrition.
- For immunocompromised or those with more severe infection:
- Adult: TMP/SMX (160/800) DS tab orally twice-daily x 10 d.
- Pediatric: TMP/SMX (TMP 10mg/kd/d/SMX 50mg/kg/d) PO in two doses daily x 10d.
- Sulfa allergic: pyrimethamine 50-75mg/d in divided doses x 14 days + folinic acid (leucovorin 10-25mg/kg/d).
- Other alternatives:
- Pregnancy (HIV): despite theoretical risk in first trimester, if significantly symptomatic, some recommend TMP/SMX.
- Consider holding therapy if possible to second trimester.
- Others have advocated that fluoroquinolones in the first trimester offer a better safety profile than TMP/SMX.
- Study of over 600 cases of quinolone use in pregnancy did not find an increased risk of birth defects or musculoskeletal abnormalities and a registry data base of over 1100 quinolone exposures during pregnancy found no increase in the rate of birth defects.
- TMP/SMX, use in the first trimester should be avoided, if possible, because of an association with an increased risk of birth defects, specifically neural tube defects, cardiovascular and urinary tract defects  .
- Consider in immunosuppressed populations as up to 50% relapse following primary therapy.
- Duration: indefinite unless immune recovery; no published recommendations on discontinuation of secondary prophylaxis with immune reconstitution, but presumably safe.
Selected Drug Comments
Use only if pt allergic to TMP/SMX; add folinic acid. May be used as well for secondary prophylaxis, e.g., AIDS patients with CD4
First-line agent. Highly effective. Preferred choice for secondary prophylaxis.
- Shedding may persist even after adequate therapy; follow patients symptomatically.
- Continued prophylaxis the norm for patients with AIDS unless ART provides immune reconstitution.
- No known cases of IRIS have been described in the treatment of C. belli.
- For AIDS, discontinue secondary prophylaxis when CD4 >200cell/ul x 6mos post ART initiation.
- Treatment failure is rare with TMP/SMX; ciprofloxacin considered less effective but a possible alternative regimen in this case.
Basis for recommendation
- Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents. T-34Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. Accessed (12/17/15)
Comment: Guidance for treatment, but also prevention as stated in this module.
- The Medical Letter. Drugs for Parasitic Infections; Medical Letter; 2013.
Comment: Usually self-limiting in non-immunosuppressed patients, higher doses may be needed in some immunosuppressed patients and longer duration. Pyrimethamine for sulfa intolerant patients.
- ten Hove RJ et al: Real-time polymerase chain reaction for detection of Isospora belli in stool samples. Diagn Microbiol Infect Dis 61:280, 2008 [PMID:18424043]
Comment: A real-time polymerase chain reaction assay targeting the internal transcribed spacer 2 region of the ribosomal RNA gene was developed for the detection of Isospora belli DNA in fecal samples.
- Tatfeng YM et al: Mechanical transmission of pathogenic organisms: the role of cockroaches. J Vector Borne Dis 42:129, 2005 [PMID:16457381]
Comment: Authors demonstrate that cockroaches represent important reservoir for infectious pathogens, including Isospora; they suggest that control of roach population might decrease disease transmission.
- Lindsay DS et al: Examination of extraintestinal tissue cysts of Isospora belli. J Parasitol 83:620, 1997 [PMID:9267401]
Comment: Authors focus on the extraintestinal stages of I. belli in a pt with HIV infection. These stages are important because relapse of diarrhea is common in humans infected with I. belli and is believed to be associated with presence of extraintestinal stages.
- Pape JW, Verdier RI, Johnson WD: Treatment and prophylaxis of Isospora belli infection in patients with the acquired immunodeficiency syndrome. N Engl J Med 320:1044, 1989 [PMID:2927483]
Comment: Authors investigation their experience in Haiti in a small cohort of 32 patients with AIDS and chronic diarrhea. In a subgroup, long-term prophylaxis for 16 months prevented relapse or reinfection.
- Bialek R et al: Case report: Nitazoxanide treatment failure in chronic isosporiasis. Am J Trop Med Hyg 65:94, 2001 [PMID:11508398]
Comment: Though a broad spectrum antiparasitic, there is little published experience using this drug for Isospora infection.
- Boyles TH et al: Failure to eradicate Isospora belli diarrhoea despite immune reconstitution in adults with HIV--a case series. PLoS One 7:, 2012 [PMID:22880120]
Comment: Case series of 8 patients from S. Africa reporting that despite ART and rise in CD4, there remained persistent parasitic infection despite therapy. Authors postulate that host factors or TMP/SMX resistance may be at play.
- de Oliveira-Silva MB et al: Seasonal profile and level of CD4+ lymphocytes in the occurrence of cryptosporidiosis and cystoisosporidiosis in HIV/AIDS patients in the Triângulo Mineiro region, Brazil. Rev Soc Bras Med Trop 40:512, 2007 Sep-Oct [PMID:17992404]
Comment: Brazilian cohort of patients with IDS who had coccidial diarrheal infections. Of the 389 patients seen between 1993-2003, 19.7% were positive by modified Ziehl-Neelsen staining for coccidian (8.6% with Cryptosporidium sp, 10.3% with Cystoisospora belli and 0.8% with both coccidian. Only 8.5% of this group received ART. Of note, there was no seasonality to C. belli infection.
- Cooper WO et al: Antibiotics potentially used in response to bioterrorism and the risk of major congenital malformations. Paediatr Perinat Epidemiol 23:18, 2009 [PMID:19228311]
Comment: Information on tetragenicity.
- Czeizel AE et al: The teratogenic risk of trimethoprim-sulfonamides: a population based case-control study. Reprod Toxicol 15:637, 2001 Nov-Dec [PMID:11738517]
Comment: Information that led to recommendations to generally avoid in early trimester.
- Doumbo O et al: Nitazoxanide in the treatment of cryptosporidial diarrhea and other intestinal parasitic infections associated with acquired immunodeficiency syndrome in tropical Africa. Am J Trop Med Hyg 56:637, 1997 [PMID:9230795]
Comment: Early study suggested activity against I. belli with nitazoxanide. Note failure with this drug also cited in the literature.
- Bialek R et al: Comparison of autofluorescence and iodine staining for detection of Isospora belli in feces. Am J Trop Med Hyg 67:304, 2002 [PMID:12408672]
Comment: Examination by autofluorescence of 192 stool samples (95.7%; 95% CI, 85.2-99.5) significantly more sensitive than iodine staining (48.4%; 95% CI, 37.7-59.1). Authors suggest that autofluorescence is simple, highly sensitive, inexpensive, and easily applicable method to detect Isospora oocysts in feces.
- French AL et al: Cholecystectomy in patients with AIDS: clinicopathologic correlations in 107 cases. Clin Infect Dis 21:852, 1995 [PMID:8645829]
Comment: I. belli microsporidiosis cryptosporidiosis
- Legua P, Seas C: Cystoisospora and cyclospora. Curr Opin Infect Dis 26:479, 2013 [PMID:23982239]
Comment: In US sporadic cases seen as well as travel-acquired.
- DeHovitz JA et al: Clinical manifestations and therapy of Isospora belli infection in patients with the acquired immunodeficiency syndrome. N Engl J Med 315:87, 1986 [PMID:3487730]
Comment: Study of 20 of 131 HIV+ pts in Haiti with diarrhea Dx'd with I. belli. Sx included chronic watery diarrhea & weight loss. In all pts with isosporiasis, diarrhea stopped within2 days of beginning oral TMP-SMX. Recurrent symptomatic isosporiasis developed in 47%, but responded promptly to re-initiation of therapy.
- Dillingham RA et al: High early mortality in patients with chronic acquired immunodeficiency syndrome diarrhea initiating antiretroviral therapy in Haiti: a case-control study. Am J Trop Med Hyg 80:1060, 2009 [PMID:19478276]
Comment: Study performed in Haiti included patients with I. belli diarrhea. Mortality was 10% in group starting ART as opposed to 5% (p = 0.009) without diarrhea, suggesting that diarrhea is indeed linked to mortality risks when initiating antivirals.
- Verdier RI et al: Trimethoprim-sulfamethoxazole compared with ciprofloxacin for treatment and prophylaxis of Isospora belli and Cyclospora cayetanensis infection in HIV-infected patients. A randomized, controlled trial. Ann Intern Med 132:885, 2000 [PMID:10836915]
Comment: This is the only randomized trial regarding this infection in HIV-infected individuals. This small study looked at 22 pts with with chronic diarrhea due to I. belli randomly assigned to receive PO TMP-SMX DS1 tab twice-daily or ciprofloxacin (500 mg) twice-daily x7d. Pts who responded received prophylaxis for 10 wks (1 tab 3x/wk). Diarrhea resolved more rapidly with TMP-SMX than with ciprofloxacin. All pts receiving secondary prophylaxis with TMP-SMX remained disease-free, and 15 of 16 receiving secondary prophylaxis with ciprofloxacin remained disease-free.
- Weiss LM et al: Isospora belli infection: treatment with pyrimethamine. Ann Intern Med 109:474, 1988 [PMID:3261956]
Comment: Two patients with AIDS, sulfonamide allergy, and I. belli infection are reported. They were treated successfully with pyrimethamine 75 mg/d alone; recurrence prevented with pyrimethamine 25 mg/d.
- Walther Z, Topazian MD: Isospora cholangiopathy: case study with histologic characterization and molecular confirmation. Hum Pathol 40:1342, 2009 [PMID:19447468]
Comment: Infection of the gallbladder described in AIDS patients, and such a case is presented here in a man from West Africa. The radiographic appearance resembled sclerosing cholangitis.
- Franzen C et al: Uvitex 2B stain for the diagnosis of Isospora belli infections in patients with the acquired immunodeficiency syndrome. Arch Pathol Lab Med 120:1023, 1996 [PMID:12049103]
Comment: Wet-mounts examined by phase-contrast and bright-field microscopy; smears stained with modified acid-fast stain compared to fluorescent stain with Uvitex 2B. Using fluorescent stain, the oocysts of I. belli stained bright white/blue fluorescent and showed a structure similar to that of oocysts in acid fast stains.
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