- Formerly known as Isospora belli and was called Isosporiasis.
- 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.
- Incubation period ~7d.
- May last for weeks without treatment.
- More severe disease commonly seen in immunosuppressed patients (AIDS), infants and children.
- Cases in the U.S. are relatively rare due to routine use of TMP/SMX for PCP prophylaxis in all HIV+ patients w/ low CD4.
- Incubation period ~7d.
- 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.
- Not included in any currently available molecular multiplex panel.
- 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.
- Dissemination: generally only seen in AIDS or advanced immunosuppression.
- Usually self-limiting infection in immunocompetent individuals, requiring only symptomatic support such hydration and nutrition.
- For immunocompromised or those with more severe or prolonged 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
- Alternatives: if sulfa allergic or intolerant.
- First line: pyrimethamine 50-75mg/d in divided doses x 14 days + folinic acid (leucovorin 10-25mg/kg/d)
- 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.
- TMP/SMX DS 1 tab PO 3x/wk for secondary prophylaxis.
- Duration: indefinite unless immune recovery; no published recommendations on discontinuation of secondary prophylaxis with immune reconstitution, but presumably safe once CD4 > 200 cells/mm3.
- Prevention is achieved by avoiding eating infected foot or drinking contaminated water.
- Insufficient evidence for any general recommendation for primary prophylaxis.
- One RCT and indirect evidence from use of antimicrobials for other indications in HIV/AIDS population suggests that prophylaxis reduces incidence of C. belli infection.
Selected Drug Comments
Less effective than TMP/SMX; appropriate when sulfa drug or pyrimethamine cannot be used.
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
- Shane AL, Mody RK, Crump JA, et al. 2017 Infectious Diseases Society of America Clinical Practice Guidelines for the Diagnosis and Management of Infectious Diarrhea. Clin Infect Dis. 2017. [PMID:29053792]
Comment: Parasitic causes of diarrhea may be considered in diarrhea lasting > 14 days. TMP/SMX is the drug of choice fo rCytoisospora belli.
- 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 (12/1/17)
Comment: Guidance for treatment, but also prevention as stated in this module.
- Velásquez JN, di Risio CA, Etchart CB, et al. First report of Cystoisospora belli parasitemia in a patient with acquired immunodeficiency syndrome. Acta Parasitol. 2016;61(1):172-7. [PMID:26751889]
Comment: Reported dissminated infection in pt with AIDS where microscopy of blood detected parasites also identified through DNA analysis.
- Lai KK, Goyne HE, Hernandez-Gonzalo D, et al. Cystoisospora belli Infection of the Gallbladder in Immunocompetent Patients: A Clinicopathologic Review of 18 Cases. Am J Surg Pathol. 2016;40(8):1070-4. [PMID:27158759]
Comment: Authors suggest that Cystoisospora infection of the gallbladder may be more common than suspected due to suple findings. Infection was not suspected in any of 11 cases done for biliary dyskinesia (n=7), abdominal pain (n=7), suspected cholelithiasis (n=5), and cholecystitis (n=3). In 2 cases, Cystoisospora was found in donor gallbladders resected at the time of liver transplantation. All cases were followed for 15 months, without findings suggestive of active biliary disease that suggests immunocompetant individuals don’t have ongoing problems with infection.
- Legua P, Seas C. Cystoisospora and cyclospora. Curr Opin Infect Dis. 2013;26(5):479-83. [PMID:23982239]
Comment: In US sporadic cases seen as well as travel-acquired.
- Boyles TH, Black J, Meintjes G, et al. Failure to eradicate Isospora belli diarrhoea despite immune reconstitution in adults with HIV--a case series. PLoS One. 2012;7(8):e42844. [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.
- Walther Z, Topazian MD. Isospora cholangiopathy: case study with histologic characterization and molecular confirmation. Hum Pathol. 2009;40(9):1342-6. [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.
- Dillingham RA, Pinkerton R, Leger P, 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. 2009;80(6):1060-4. [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.
- ten Hove RJ, van Lieshout L, Brienen EA, et al. Real-time polymerase chain reaction for detection of Isospora belli in stool samples. Diagn Microbiol Infect Dis. 2008;61(3):280-3. [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, Usuanlele MU, Orukpe A, et al. Mechanical transmission of pathogenic organisms: the role of cockroaches. J Vector Borne Dis. 2005;42(4):129-34. [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.
- Bialek R, Binder N, Dietz K, et al. Comparison of autofluorescence and iodine staining for detection of Isospora belli in feces. Am J Trop Med Hyg. 2002;67(3):304-5. [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.
- Bialek R, Overkamp D, Rettig I, et al. Case report: Nitazoxanide treatment failure in chronic isosporiasis. Am J Trop Med Hyg. 2001;65(2):94-5. [PMID:11508398]
Comment: Though a broad spectrum antiparasitic, there is little published experience using this drug for Isospora infection.
- Verdier RI, Fitzgerald DW, Johnson WD, 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. 2000;132(11):885-8. [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.
- Doumbo O, Rossignol JF, Pichard E, 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. 1997;56(6):637-9. [PMID:9230795]
Comment: Early study suggested activity against I. belli with nitazoxanide. Note failure with this drug also cited in the literature.
- Lindsay DS, Dubey JP, Toivio-Kinnucan MA, et al. Examination of extraintestinal tissue cysts of Isospora belli. J Parasitol. 1997;83(4):620-5. [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.
- Franzen C, Müller A, Salzberger B, et al. Uvitex 2B stain for the diagnosis of Isospora belli infections in patients with the acquired immunodeficiency syndrome. Arch Pathol Lab Med. 1996;120(11):1023-5. [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.
- French AL, Beaudet LM, Benator DA, et al. Cholecystectomy in patients with AIDS: clinicopathologic correlations in 107 cases. Clin Infect Dis. 1995;21(4):852-8. [PMID:8645829]
Comment: I. belli microsporidiosis cryptosporidiosis
- Pape JW, Verdier RI, Johnson WD. Treatment and prophylaxis of Isospora belli infection in patients with the acquired immunodeficiency syndrome. N Engl J Med. 1989;320(16):1044-7. [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.
- Weiss LM, Perlman DC, Sherman J, et al. Isospora belli infection: treatment with pyrimethamine. Ann Intern Med. 1988;109(6):474-5. [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.
- DeHovitz JA, Pape JW, Boncy M, et al. Clinical manifestations and therapy of Isospora belli infection in patients with the acquired immunodeficiency syndrome. N Engl J Med. 1986;315(2):87-90. [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.
- de Oliveira-Silva MB, de Oliveira LR, Resende JC, 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. 2007;40(5):512-5. [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.
Immature oocysts. Unstained wet mount. Source: CDC
Immature oocyst w/ stain. Oocysts, safranin stain. Source: CDC
Cystoisoporiasis Life Cycle. Source: CDC
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