Cyclospora cayetanensis

Authors: Charles W. Hoge, M.D., David R. Shlim, M.D.

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PARASITOLOGY

Cyclospora spp. is a coccidia parasite that emerged in the last decade as an important enteric pathogen responsible for prolonged diarrhea among travelers (14, 18,28,31,35,37), indigenous persons living in developing countries (1,15,22,34), and immune compromised (particularly HIV infected) persons (18,27,37). Cyclospora has also been implicated in several outbreaks in developed countries, including large multi-state outbreaks in the U. S. and Canada linked to imported raspberries (12,13). The organism was first described in 1979 (2), but was not recognized as an important pathogen until additional reports were published in the late 1980s and early 1990s. The organism was initially referred to as a CLB (cyanobacterium or coccidia-like bodies), reflecting the fact that it morphologically resembled an alga in formalin preserved specimens, but had staining characteristics similar to Cryptosporidium parvum(14,18,28,31,35,37). In 1993 the organism was conclusively identified as a coccidia of the genus Cyclospora, an organism found in certain animals (22), and the name Cyclospora cayetanensis (23) was subsequently proposed. Sporulation of a Cyclospora oocyst is characterized by the development of two sporocysts with two sporozoites each.

EPIDEMIOLOGY

The organism appears to have a worldwide distribution based on numerous reports of the disease among travelers and indigenous persons in developing countries (1,14,15,18,22,27,28,31,34,35,37) and reports of outbreaks and sporadic non-travel related cases in developed countries (4,12,13,17,26). In passive surveillance studies of diarrhea among expatriate, tourist, and indigenous populations in Nepal, Cyclospora has been shown to be responsible for 5-10% of diarrheal episodes during the rainy season (14,31). The proportion of persons in two foreign diplomatic communities in Nepal and Indonesia who developed the disease during one season was 6-7% (9,14). However, in a prospective year-long study of foreign residents during their first year in Nepal, 32% became infected with Cyclospora(32). At Lahey Clinic, Massachusetts, Cyclospora was identified in 3 (0.3%) of 1042 consecutive stool samples; all three patients were immunocompetent and had no history of travel (26).

Immunocompetent individuals can be infected with Cyclospora more than one time, but immunity does appear to occur over time. The infection is rarely documented in expatriates who have lived in Nepal for more than five years.

There is substantial evidence that Cyclospora is transmitted in both food and water. The evidence that Cyclospora is a water-borne disease is based on case-control data from expatriates and tourist populations in Nepal (14), seasonal characteristics in some countries (14,22,31), data from environmental sampling (11,14,29), and data from two outbreaks, including an outbreak among house-staff physicians working at a hospital in Chicago (17) and an outbreak at a country club in New York (4). Of importance is that, like Cryptosporidium, Cyclospora may be resistant to chlorine (29) (and probably iodine), although it s larger size makes it more readily filterable.

Although water-borne transmission of Cyclospora is well documented, this route probably accounts for the minority of cases. In a case-control study in Nepal, only 28% of cases were linked epidemiologically to water, and it was hypothesized that the remaining cases were acquired either by the food-borne or person-to-person routes (14). There is increasing evidence that food-borne transmission is important (6, 8,12,13). In 1996, nearly 1500 cases of Cyclospora occurred in over 20 states in the U. S. and two provinces in Canada (12). Epidemiologic data implicated consumption of fresh raspberries from Guatemala, though the mode of contamination was not determined. Additional outbreaks linked to the same source occurred during the same time of year (late spring and early summer) in 1997 (13). There are data suggesting that lettuce, chicken, and unpasteurized milk are other potential sources of infection (6,10,11,14,25).

Attempts to infect human beings with inoculums of sporulated oocysts ranging from 200 to 49,000 oocysts per person were uniformly unsuccessful (1a). The environmental conditions that allow Cyclospora to become infective remain unknown.

CLINICAL MANIFESTATIONS

Cyclospora causes a syndrome of prolonged, intermittent diarrhea associated with profound fatigue and anorexia. In about 30% of cases, there are more severe initial symptoms that include the abrupt onset of watery diarrhea, fever, nausea, vomiting, and abdominal cramps. The severe symptoms resolve spontaneously within 2-3 days, and the chronic symptoms persist. In the majority of cases, symptoms begin gradually with bouts of watery diarrhea, fatigue, loss of appetite, and gradually increasing weight loss. Nausea often comes and goes, but vomiting is rare after the first few days of illness (14,17,31). The average duration of illness ranges from a few days to three months (average 6-7 weeks) (14,31) during which time malabsorption of d-xylose can be documented (31). In immunocompetent persons the disease eventually resolves without treatment (14,31). The incubation period observed in one outbreak was 7.5 (range 1-23) days (5).

LABORATORY DIAGNOSIS

The diagnosis is made by microscopic identification of oocysts in stool specimens.

PATHOGENESIS

As suggested by its symptoms, Cyclospora infects the upper intestine. Biopsies from the duodenum and jejunum of infected persons reveals flattening of the villi and inflammatory infiltrates of the basement membrane. Data suggest that the pathology of Cyclospora in the intestine is similar to that of Isospora and that the organism can complete its life cycle within a single human host (3,7,24,36).

SUSCEPTIBILITY IN VITRO AND IN VIVO

Cyclospora has not been able to be grown in vitro, either in media or in cell cultures, nor have any species of animals been able to be infected. Thus, there are no susceptibility studies available either in vitro or in animal models.

ANTIPARASITIC THERAPY

Immunocompetent Persons

The drug of choice for treatment of Cyclospora infection is trimethoprim-sulfamethoxazole (TMP-SMX) given at a standard dose (160 mg trimethoprim, 800 mg sulfamethoxazole twice daily) for seven days. Cyclospora and Isospora infections are similar with regard to their susceptibility to TMP-SMX in vivo. In a double blind, placebo controlled study among travelers in Nepal, Cyclospora was eradicated in 15 (94%) of 16 patients who received seven days of TMP-SMX, compared with 2 (12%) of 17 patients who received placebo (p<. 001) (16). Clinical improvement was highly correlated with eradication of the organism from stool, and there was no evidence of relapse of infection. The one person in the treatment group who failed to clear the organism after a week of therapy with TMP-SMX was successfully treated openly with an additional week of this antibiotic, suggesting that in some cases treatment may need to be extended beyond seven days. Patients who improve clinically post TMP-SMX therapy can assume to be cured; stool samples can be checked in patients in whom clinical improvement is not complete. For children, TMP-SMX given for only three days was shown to be significantly efficacious in a small double-blind placebo controlled trial from Peru (20). For patients who may be allergic to sulfamethoxazole or trimethoprim, ciprofloxacin may be effective. A report from Haiti showed that ciprofloxacin 500mg BID for 7 days eradicated Cyclosporain 70% of cases (39). However, attempts to replicate these results among immunocompetent expatriate patients in Nepal found that ciprofloxacin was not effective in several cases (unpublished observation). No other effective treatment has been identified, despite a number of informal trials. An open trial of trimethoprim alone failed to show efficacy (33). Other drugs that have been tried include tinidazole, quinacrine, diloxanide furoate, azithromycin, albendazole, and furazolidine (30,31).

Immunocompromised Hosts

TMP-SMX is also the drug of choice for immunocompromised persons, the best studied group being persons who have HIV infection. A clinical trial conducted in Haiti for the treatment of patients with HIV infection used twice the dose that was used among healthy travelers (160 mg TMP, 800 mg SMX four times a day) for 10 days based (27). In that trial, the response to therapy was as rapid as the response observed among immunocompetent persons. Standard doses may be equally effective but have not been systematically studied. Following treatment, all persons with immunocompromising conditions should be monitored closely for relapse (for example, by weekly stool examinations). In the same study in Haitian patients with HIV infection and chronic diarrhea due to Cyclospora, 43% of patients relapsed after initial treatment with TMP-SMX (27). Prophylaxis with 160 mg TMP and 800 mg SMX three times per week prevented further relapses.

ADJUNCTIVE THERAPY

There are no known adjunctive treatment measures.

ENDPOINTS FOR MONITORING THERAPY

Cyclospora infection is self-limited, with an average duration of illness of 6 weeks (range 1-12 weeks) (31). Clinical improvement is always associated with disappearance of the organism from the stool, which coincides with clinical improvement. Successful drug treatment is also always associated with clearing of Cyclospora from the stool exam. The organism is consistently shed during clinical illness (31), so its 1520 absence after therapy is highly predictive of cure. The diagnosis of Cyclospora depends on identification of unsporulated oocysts by light microscopy of either a fresh stool preparation or a stained preparation using a modified acid fast or other staining procedure (22,40) . A concentration procedure, such as formalin ethyl acetate, is an important step in the diagnosis, since up to 40% of infections will be missed on the direct unconcentrated preparations. The organism also exhibits auto fluorescence under UV microscopy (18,38).

VACCINES

There is no vaccine for Cyclospora cayetanensis.

PREVENTION

Antiparasitic Agent Prophylaxis

There have been no studies in immunocompetent persons testing prophylaxis for Cyclospora. The only available agent would be trimethoprim-sulfamethoxazole.

Indications

The risk of relapse following treatment for Cyclospora in patients with an immunocompromising condition is high. These patients should be monitored closely for relapse (for example, by weekly stool examinations). Early reinfection may be an indication for chemoprophylaxis with trimethoprim-sulfamethoxazole. In the same study in Haitian patients with HIV infection and chronic diarrhea due to Cyclospora, 43% of patients relapsed after initial treatment with TMP-SMX (27).

Doses, Schedules

Prophylaxis with 160 mg TMP and 800 mg SMX three times per week prevented further relapses in the Haitian study (27).

CONTROVERSIES, CAVEATS, OR COMMENTS

It will be necessary to perform further studies to determine if ciprofloxacin therapy is effective in a different population than the population that was studied in Haiti. Additional effective drugs are needed, as allergies to trimethoprim or sulfamethoxazole are common. Practitioners should be aware that in endemic regions, risk of Cyclospora infection tends to be highly seasonal. However, outbreaks in the U. S. A. and Canada have been associated with specific foodborne exposures, and thus were unpredictable. Stool examination must be done on a concentrated specimen in order to increase the chances of finding the organism by 40%.

REFERENCES

1. Albert MJ, Kabir I, Azim T, Hossain A, Ansaruzzaman M, Unicomb L. Diarrhea associated with Cyclospora species in Bangladesh. Diagn Microbiol Infect Dis 1994; 19: 47-9. [PubMed]

1a. Alfano-Sobsey EM, Eberhard ML, Seed JR, et al. Human challenge pilot study with Cyclospora cayetanensis. Emerging Infectious diseases 2004;10:726-728. [PubMed]
2. Ashford RW. Occurrence of an undescribed coccidian in man in Papua New Guinea. Ann Trop Med Parasitol 1979; 73: 497-500. [PubMed]
3. Bendall RP, Lucas S, Moody A, Tovey G, Chiodini PL. Diarrhoea associated with cyanobacterium-like bodies: a new coccidian enteritis in man. Lancet 1993; 341: 590-2.  [PubMed]
4. Carter RJ, Guido F, Jacquette G, Rapoport M. Outbreak of cyclosporiasis at a country club-New York, 1995 [ Abstract ] . In: 45th Annual Epidemic Intelligence Service (EIS) Conference. Atlanta, Georgia: U. S. Department of Health and Human Services, Public Health Service, April 1996: 58.
5. CDC. Outbreaks of Cyclospora cayetanensis infection: United States, 1996. MMWR 1996; 45: 549-51.  [PubMed]
6. CDC. Outbreaks of diarrheal illness associated with cyanobacteria (blue-green algae)-like bodies: Chicago and Nepal, 1989 and 1990. MMWR 1991; 40: 325-7. [PubMed]
7. Connor BA, Shlim DR, Scholes JV, Rayburn JL, Reidy J, Rajah R. Pathologic changes in the small bowel in 9 patients with diarrhea associated with a coccidian-like body. Ann Intern Med 1993; 119: 377-82. [PubMed]
8. Connor BA, Shlim DR. Foodborne transmission of Cyclospora [ Letter ]. Lancet 1995; 346: 1634.  [PubMed]

9. Fryauff DJ, Krippner R, Purnomo, Ewald C, Echeverria P. Short report: case report of Cyclospora infection acquired in Indonesia and treated with cotrimoxazole. Am J Trop Med Hyg 1996; 55: 584-5. [PubMed]
10. Garcia-Lopez HL, Rodriguez-Tovar LE, Medina-De la Garza CE. Identification of Cyclospora in poultry. Emerging Infectious Diseases 1996; 2: 356-7. [PubMed]
11. Hale D, Aldeen W, Carroll K. Diarrhea associated with Cyanobacteria-like bodies in an immunocompetent host: an unusual epidemiological source. JAMA 1994; 271: 144-5. [PubMed]
12. Herwaldt BL, Ackers ML and the Cyclospora Working Group. An outbreak in 1996 of cyclosporiasis associated with imported raspberries. N Engl J Med 1997; 336: 1548-56. [PubMed]
13. Herwaldt BL, Beach MJ and the Cyclospora Working Group. The return of Cyclospora in 1997: another outbreak of cyclosporiasis in North America associated with imported raspberries. Ann Interm Med 1999; 130: 210-20. [PubMed]

14. Hoge CW, Shlim DR, Rajah R, et. al. Epidemiology of diarrhoeal illness associated with coccidian-like organism among traveler's and foreign residents in Nepal. Lancet 1993; 341: 1175-79. [PubMed]
15. Hoge CW, Echeverria P, Rajah R, Jacobs J, Malthouse S, Chapman E, Jimenez LM, Shlim DR. Prevalence of Cyclospora species and other enteric pathogens among children less than 5 years of age in Nepal. J Clin Microbiol 1995; 33: 3058-60. [PubMed]
16. Hoge CW, Shlim DR, Ghimire M, Rabold JG, Pandey P, Walch A, Rajah R, Gaudio P, Echeverria P. Placebo-controlled trial of co-trimoxazole for Cyclospora infections among travelers and foreign residents in Nepal. Lancet 1995; 345: 691-693. [PubMed]
17. Huang P, Weber JT, Sosin DM, et. al. The first reported outbreak of diarrheal illness associated with Cyclospora in the United States. Ann Intern Med 1995; 123: 409-14. [PubMed]
18. Long EG, Ebrahimzadeh A, White EH, Swisher B, Callaway CS. Alga associated with diarrhea in patients with acquired immunodeficiency syndrome and in travelers. J Clin Microbiol 1990; 28: 1101-1104. [PubMed]
19. Long EG. White EH, Carmichael WW. , et al. Morphologic and staining characteristics of a cyanobacterium-like organism associated with diarrhea. J Infect Dis 1991; 164: 199-202. [PubMed]
20. Madico G, McDonald J, Gilman RH, Cabrera L, Sterling CR. Epidemiology and treatment of Cyclospora cayetanensis infection in Peruvian children. Clin Infect Dis 1997; 24: 977-81. [PubMed]
21. Medina-De La Garza CE, Garcia-Lopez HL, Salinas-Carmona MC, Gonzalez-Spencer DJ. Use of discontinuous Percoll gradients to isolate Cyclospora oocysts. Ann of Trop Med Parasitol 1997; 91: 319-321. [PubMed]

22. Ortega YR, Sterling CR, Gilman RH, Cama VA, Diaz F. Cyclospora species: a new protozoan pathogen of humans. N Engl J Med 1993; 328: 1308-12. [PubMed]
23. Ortega YR, Gilman RH, Sterling CR. A new coccidian parasite (Apicomplexa: Eimeriidae) from humans. J Parasitol 1994; 80: 625-9. [PubMed]
24. Ortega YR, Nagle R, Gilman RH, et al. Pathologic and clinical findings in patients with cyclosporiasis and a description of intracellular parasite life-cycle stages. J Infect Dis 1997; 176: 1584-9. [PubMed]
25. Ortega YR, Roxas CR, Gilman RH, et al. Isolation of Cryptosporidium parvum and Cyclospora cayetanensis from vegetables collected in markets of an endemic region in Peru. Am J Trop Med Hyg 1997; 57: 683-6. [PubMed]
26. Ooi WW, Zimmerman SK, Needham CA. Cyclospora species as a gastrointestinal pathogen in immunocompetent hosts. J Clin Microbiol 1995; 33: 1267-9. [PubMed]
27. Pape JW, Verdir RI, Boncy M, Boncy J, Johnson WD. Cyclospora infection in adults infected with HIV. Ann Intern Med 1994; 121: 654-7. [PubMed]
28. Pollok RC, Bendall RP, Moody A, Chiodini PL, Churchill DR. Traveler's diarrhoea associated with cyanobacterium-like bodies [letter]. Lancet 1992; 340: 556-557. [PubMed]
29. Rabold JG, Hoge CW, Shlim DR, Kefford C, Rajah R, Echeverria P. Cyclospora outbreak associated with chlorinated drinking water [ Letter ]. Lancet 1994; 344: 1360-61. [PubMed]
30. Shear M, Connor BA, Shlim DR, Taylor DN, Rabold JG. Azithromycin treatment for Cyclospora infections. Gastroenterology 1994; 106( suppl 4) : A772.
31. Shlim DR. Cohen MT, Eaton M, Rajah R, Long EG, Ungar BLP. An algae-like organism associated with an outbreak of prolonged diarrhea among foreigners in Nepal. Am J Trop Med Hyg 1991; 45: 383-389. [PubMed]
32. Shlim DR, Hoge CW, Rajah R, Scott RM, Pandy P, Echeverria P. Persistent high risk of diarrhea among foreigners in Nepal during the first two years of residence. Clin Infect Dis 1999; 29: 613-6. [PubMed]
33. Shlim DR, Pandey P, Rabold JG, Walch A, Rajah R. An open trial of trimethoprim alone against Cyclospora infections. J Travel Med 1997; 4: 44-5. [PubMed]
34. Sifuentes-Osornio J, Porras-Cortes G, Bendall RP, Morales-Villarreal F, Reyes-Teran G, Ruiz-Palacios GM. Cyclospora cayetanensis infection in patients with and without AIDS: biliary disease as another clinical manifestation. Clin Infect Dis 1995; 21: 1092-7. [PubMed]
35. Soave R, Dubey JP, Ramos LJ, Tummings M. A new intestinal pathogen? [ abstract ]. Clin Res 1986; 34: 533A.

36. Sun T, Ilardi CF, Asnis D, et. al. Light and electron microscopic identification of Cyclospora species in the small intestine. Am J Clin Pathol 1996; 105: 216-20. [PubMed]
37. Wurtz RM, Kocka FE, Peters CS, Weldon-Linne CM, Kuritza A, Yungbluth P. Clinical characteristics of seven cases of diarrhea associated with a novel acid fast organism in the stool. Clin nfect Dis 1993; 16: 136-8. [PubMed]
38. Varea M, Clavel A, Doiz O, Castillo FJ, Rubio MC, Gomez-Luiz R. Fuchsin fluorescence and auto fluorescence in Cryptosporidium, Isospora, and Cyclospora oocysts. Int J Parasitol 1998; 28: 1881-3. [PubMed]
39. Verdier RI, Fitzgerald DW, Johnson WD, Pape JW. 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: 885-8. [PubMed]
40. Visvesvara GS, Moura H, Kovacs-Nace E, Wallace S, Eberhard ML. Uniform staining of Cyclospora oocysts in fecal smears by a modified safranin technique with microwave heating. J Clin Microbiol 1997; 35: 730-3 (published erratum in J Clin Microbiol 1997; 35: 1648). [PubMed]