Cystoisospora belli

MICROBIOLOGY

• Formerly known as Isospora belli, it was called Isosporiasis.
  
  • More recently, it has been termed Cystoisospora belli, with the disease = cytoisosporiasis.
• Intestinal unicellular protozoan parasite, classified under Coccidia.
• Isospora is the least commonly seen Coccidial infection compared to Toxoplasma or Cryptosporidia.
• Epidemiology: It is worldwide but especially prevalent in tropical/subtropical environments, especially in the Caribbean, Central and South America, India, Africa, and S.E. Asia.
  • In the U.S., usually associated with HIV infection and institutional living.
  • Also, travel-acquired, sporadic cases.
• Transmission occurs by the ingestion of fecally contaminated water and food.
• Life cycle [Figure 1].
  • Sporulated oocysts are ingested, sporozoites penetrate epithelial cells of the small intestine and develop into trophozoites.
  • A mature oocyst 23-36 x 12-15 microns contains two sporocysts, each containing 4 trophozoites [Figures 2 and 3 of immature oocysts].

CLINICAL

• Isospora causes a gastrointestinal infection that primarily afflicts patients with AIDS or profound immunosuppression; however, cases can occur in immunocompetent patients.
  • Incubation period ~7d.
    
    • Diarrhea may last for weeks without treatment.
  • The more severe disease is commonly seen in immunosuppressed patients (AIDS, solid organ transplants), infants and children.
    • Cases in the U.S. are relatively rare, perhaps due to routine use of TMP/SMX for PCP prophylaxis in all HIV+ patients w/ low CD4.
• Sx: typically profuse, watery, non-inflammatory diarrhea (although cases of hemorrhagic diarrhea were reported).
  • Malaise and crampy abdominal pain may accompany.
    
    • Fever uncommon
  • May result in malabsorption syndrome.
  • Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are both described as being associated with this infection.
• 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. Still, modified acid-fast stains may also be used to identify them (see CDC site for key points to differentiate among the human Coccidia).
    
    • Multiple samples improve sensitivity, as shedding is intermittent.
  • Epifluorescence microscopy is more sensitive than an iodine stain[21].
  • If stools are negative, duodenal aspirates (string test [Enterotest®]) or intestinal biopsy may yield a diagnosis.
  • Pathogen is not included in any currently commercially available molecular multiplex panel.
• Eosinophilia may be seen, which is different from other protozoal infections.

SITES OF INFECTION

• Small intestine: diarrhea, malabsorption
• Gallbladder and the biliary tree: acalculous cholecystitis, cholangitis
  • Note: reports suggest that gallbladder epithelial inclusions mimic the organism, which might be falsely concluded based on visual H&E stains.
  • Disregard papers suggesting this organism is found; see Gopinath 2021.[5]
• Liver: dissemination reported (rare).
• Spleen: dissemination reported (rare).
• Rheumatological: reactive arthritis may occur.
• Dissemination: generally only seen in AIDS or advanced immunosuppression.

TREATMENT

FOLLOW UP

• Shedding may persist even after adequate therapy; follow patients symptomatically.
• Continued prophylaxis is 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 is is considered less effective but a possible alternative regimen.

OTHER INFORMATION

• Other agents with case report level data reporting successes/failures include nitazoxanide, albendazole, spiramycin, doxycycline, roxithromycin, and diclazuril (veterinary compound).
• No cases of IRIS have been reported with the institution of ART in HIV-infected patients with cytoisosporiasis.

Basis for recommendation

1. Dubey JP, Almeria S. Cystoisospora belli infections in humans: the past 100 years. Parasitology. 2019;146(12):1490-1527.  [PMID:31303182]

   Comment: The first comprehensive review in ~ 20 years since earlier in the HIV/AIDS epidemic.
   

2. 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;65(12):e45-e80.  [PMID:29053792]

   Comment: Parasitic causes of diarrhea may be considered in diarrhea lasting > 14 days. TMP/SMX is the drug of choice for Cytoisospora belli.
   

3. CDC. Cystoisosporiasis. Resources for Health Professionals, Treatment.https://www.cdc.gov/cystoisospora/about/(page last updated 5/30/23; accessed 5/24/2024)

   Comment: The CDC resource page includes suggested treatments under the health professional resources tab. It lists ciprofloxacin as the second line, with pyrimethamine as the first alternative if one cannot use the preferred treatment with TMP/SMX.
   
   
   

4. 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 https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/adult-adolescent-oi/guidelines-adult-adolescent-oi.pdf. Accessed (5/24/202424, reviewed 1/10/24, last updated 6/14/2023).

   Comment: Guidance for treatment and prevention is stated in this module.
   

References

5. Gopinath A, Alkhasawneh A, Mubeen A, et al. Pitfalls in Morphologic Diagnosis of Pathogens: Lessons Learned From the Pseudo-Cystoisospora Epidemic. Int J Surg Pathol. 2021;29(2):169-173.  [PMID:33016162]

   Comment: Note that this report contradicts the findings of this organism, which is prevalent in gallbladders. NGS, EM and PCR techniques were used, and the thought is that these represent epithelial inclusions of degenerated cytoplasmic structures.
   Rating: Important
   

6. Noor M, Katzman PJ, Huber AR, et al. Unexpectedly High Prevalence of Cystoisospora belli Infection in Acalculous Gallbladders of Immunocompetent Patients. Am J Clin Pathol. 2019;151(1):100-107.  [PMID:30285068]

   Comment: A surprising report finding that nearly 10% of gallbladder removed for acalculous cholecystitis had C. belli organisms. Other reports have described such findings. Limitations included that this retrospective study had the organisms identified by H&E stain--unclear if identified at initial pathology read.
   

7. Swanson EA, March JK, Clayton F, et al. Epithelial Inclusions in Gallbladder Specimens Mimic Parasite Infection: Histologic and Molecular Examination of Reported Cystoisospora belli Infection in Gallbladders of Immunocompetent Patients. Am J Surg Pathol. 2018;42(10):1346-1352.  [PMID:30020094]

   Comment: One of several reports that counter the high incidence of C. belli seen in gallbladder usually diagnosed my H&E stain with microscopy.
   

8. Wang ZD, Liu Q, Liu HH, et al. Prevalence of Cryptosporidium, microsporidia and Isospora infection in HIV-infected people: a global systematic review and meta-analysis. Parasit Vectors. 2018;11(1):28.  [PMID:29316950]

   Comment: The review describes the pooled prevalence to be 14.0% (3283/43,218; 95% CI: 13.0-15.0%) for Cryptosporidium, 11.8% (1090/18,006; 95% CI: 10.1-13.4%) for microsporidia, and 2.5% (788/105,922; 95% CI: 2.1-2.9%) for Isospora. A low prevalence of microsporidia and Isospora infection was found in high-income countries, and a high prevalence of Cryptosporidium and Isospora infection was found in sub-Saharan Africa.
   

9. 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 disseminated infection in pt with AIDS where microscopy of blood detected parasites also identified through DNA analysis.
   

10. 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 subtle 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 liver transplantation. All cases were followed for 15 months without findings suggesting active biliary disease that suggests immunocompetent individuals don’t have ongoing problems with infection. NOTE: FINDINGS DISRPOVEN BY GOPINAATH PAPER.
    

11. Legua P, Seas C. Cystoisospora and cyclospora. Curr Opin Infect Dis. 2013;26(5):479-83.  [PMID:23982239]

    Comment: In the US, sporadic cases were seen, as well as travel-acquired.
    

12. 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. The authors postulate that host factors or TMP/SMX resistance may be at play.
    

13. 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: A study performed in Haiti included patients with I. belli diarrhea. Mortality was 10% in the group starting ART as opposed to 5% (p = 0.009) without diarrhea, suggesting that diarrhea is indeed linked to mortality risks when initiating antivirals.
    

14. 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 ribosomal RNA gene’s internal transcribed spacer 2 region was developed to detect Isospora belli DNA in fecal samples.
    

15. 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 an important reservoir for infectious pathogens, including Isospora; they suggest that control of roach populations might decrease disease transmission.
    

16. 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.
    

17. 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.
    

18. 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 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.
    Rating: Important
    

19. 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: An early study suggested activity against I. belli with nitazoxanide. Note failure with this drug is also cited in the literature.
    

20. 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: The 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 the presence of extraintestinal stages.
    

21. 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 a 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.
    

22. 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 and cryptosporidiosis were among the causes of HIV cholangiopathies, seen more frequently in the pre-ART era.
    

23. 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: The authors investigate 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.
    

24. 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.
    Rating: Important
    

25. 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 within 2 days of beginning oral TMP-SMX. Recurrent symptomatic isosporiasis developed in 47% but responded promptly to the re-initiation of therapy.
    Rating: Important
    

26. 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 and 2003, 19.7% were positive by modified Ziehl-Neelsen staining for coccidia (8.6% with Cryptosporidium sp, 10.3% with Cystoisospora belli and 0.8% with both coccidias). Only 8.5% of this group received ART. Of note, there was no seasonality to C. belli infection.
    

Media

Figure 2

Immature oocysts. Unstained wet mount. Source: CDC

Figure 3

Immature oocyst w/ stain. Oocysts, safranin stain. Source: CDC

Figure 1

Cystoisoporiasis Life Cycle. Source: CDC