Cyclospora cayetanensis (8-10 µm in diameter), a coccidian protozoan parasite, produces an intestinal infection in nonimmune persons that is ultimately self-limited (lasting up to 7-9 wk) and characterized by cyclical diarrhea (explosive at times; up to numerous times per day), accompanied by fatigue, malaise, anorexia, nausea, weight loss, and abdominal cramping and interspersed with periods of remission. It may be preceded by a flulike prodrome. Low-grade fever and malabsorption (as demonstrated by a D-xylose test) may occur. The diarrhea may continue for weeks to months if left untreated. Cyclospora infection affects both immunocompetent and immunocompromised individuals, the latter potentially more severely (ie, chronic, relapsing, protracted symptoms). The only consistently effective treatment is with trimethoprim-sulfamethoxazole (TMP-SMZ).
Cyclospora was first reported in Papua New Guinea in 1979 as an oocystlike body found in 3 patients with intestinal infections. From 1986-1991, several reports described diarrhea associated with a large " Cryptosporidium " or cyanobacteriumlike bodies in both immunocompetent and immunosuppressed patients from North, Central, and South America; the Caribbean; Nepal; India; and Southeast Asia. Shlim et al reported on the largest series of cases (55) from the CIWEC Clinic Travel Medicine Center in Katmandu, Nepal.
In 1993, in Lima, Peru, Ortega et al characterized and clarified remaining taxonomic issues for C cayetanensis. Also in 1993, a prospective study of 1042 stool specimens in patients with diarrhea at the Lahey Clinic in Massachusetts yielded 3 patients with Cyclospora infection. In the late spring and early summer of 1996, an outbreak affecting approximately 1450 individuals (70% laboratory confirmed) was described in Canada and the United States. Since then, numerous reports have documented its endemicity in 27 countries around the world (see Table).
Table 1. Epidemiology of C cayetanensis *
Transmission occurs primarily through ingesting contaminated food (eg, fruits, vegetables) and water. No documented human-to-human transmission exists.
Characteristic of coccidia (phylum Apicomplexa), sporozoites of Cyclospora within the sporocyst have a membrane-bound nucleus and micronemes.
Cyclospora undergo both sexual and asexual reproduction. They appear microscopically as nonrefractile, double-walled spheres 8-10 µm in diameter. On a modified acid-fast stain, the organism stains variably acid-fast because some organisms resist staining ("ghosts"). Cyclospora fluoresces blue under ultraviolet light.
Cyclospora is a small bowel pathogen. After ingestion, Cyclospora oocysts excyst in the GI tract and invade small bowel epithelia, where they undergo asexual division followed by sexual division and produce mature oocysts that are shed in the stool.
Grossly, moderate to severe erythema of the distal duodenum is observed in patients with Cyclospora infection. Distal duodenal histopathological findings include acute and chronic inflammation, reactive hyperemia with vascular dilatation and villous capillary congestion, parasitophorous vacuoles that contain both asexual and sexual forms, crypt hyperplasia, epithelial disarray, and partial villous atrophy. Electron micrographs have demonstrated intracellular particles similar to sporozoites.
Abnormal findings on lactulose or mannitol studies or studies of both have demonstrated intestinal barrier disruption. Abnormal findings on D-xylose studies have demonstrated malabsorption. The nature of the immune response to Cyclospora is not clear, and only a few observations can currently be made. Patient sera have demonstrated Cyclospora -specific antibodies. Long-term expatriates tend to have fewer recurrences than short-term expatriates. In Haiti, patients with AIDS have recurrent disease.
C cayetanensis infection occurs only in humans (ie, not in other animals). Of the 16 known Cyclospora species that infect animals (primates, other mammals, reptiles), none infects humans. Therefore, no animal reservoir for C cayetanensis is known or suspected. Cyclospora does not survive in biosolids (soil-like residue removed from sewage during the treatment process) secondary to heat of the process. Cyclospora has been demonstrated in source waters in several countries. It has also been isolated from wastewater in Tunisia and in Arizona.[6, 7]
In endemic countries, soil contact is an important risk factor for children younger than 2 years. Oocysts can survive in water for 2 months at 39.2°F (4°C) and for 7 days at 98.6°F (37°C). Heating them at 140°F (60°C) for 60 minutes prevents sporulation. Freezing them at -0.4°F (-18°C) prevents sporulation. Desiccation for 15 minutes ruptures the oocyst wall. They are resistant to chlorine disinfection at standard water treatment levels. Pesticides at recommended levels (fungicides: Captan 50% WP, benomyl 50% WP, zineb 75% WP; insecticides: malathion 25% WP, diazinon 4E 47.5%) do not affect sporulation. Washing contaminated vegetables does not completely remove all of the sporocysts.
In endemic countries, the prevalence (1-15%) varies with the season (usually highest in spring and early summer) and from year to year in the same locale. Children (< 10-20 y, depending on the study) account for about 70% of infections, and 72-94% of these children are asymptomatic. Some adults in endemic countries have asymptomatic infections as well but do not excrete many oocysts. These observations suggest the possibility of a carrier state, but the certainty of this is far from demonstrated. Although more is becoming known about the biology of C cayetanensis, it remains unclear how the organism persists in the environment.
Humans ingest sporulated oocysts (the infectious stage) of C cayetanensis, which only infects humans. The oocyst excysts in the small intestine, usually in the jejunum, and invades the intestinal epithelial cells. The next process is schizogony, which begins with the formation of a trophozoite that grows into a mature schizont that contains 8-12 merozoites, which are then released, presumably by cell rupture, to invade other epithelial cells and repeat the process. These merozoites are called type I meronts, which are asexual forms.
After several cycles of type I schizogony, type II meronts (sexual forms) develop, with each cell containing 4 merozoites. After invading epithelial cells, some of these form single macrogametes and others divide multiple times to form microgametes. When released, a microgamete fertilizes a macrogamete, which develops into a zygote. The zygote, in turn, develops into an oocyst with an environmentally resistant wall. The oocyst passes into the environment in the feces, as a nonsporulated noninfectious oocyst.
Consequently, human-to-human transmission does not occur. During infection, best evidence suggests that oocysts are continuously excreted. In the environment, the oocyst sporulates, becoming infectious for humans. During sporulation, the sporont divides into 2 sporocysts, each containing 2 sporozoites. Time course in the environment is days to weeks. In culture, 10-20% of sporonts have completed the process in 5 days. In other experimental studies, sporulation at ambient temperature occurs in 7-12 days. The preferred temperature is 78.8-86°F (26-30°C). Contamination of food or drinking water leads to human ingestion and infection. The infectious inoculum is small but has not been precisely quantitated.
Cyclosporiasis has been demonstrated to be seasonal in Guatemala (May through August), Haiti (January through March or April), Nepal (May through August), and Peru (December through May), often disappearing for months at a time.
C cayetanensis causes an estimated 16,264 cases of foodborne illness in the United States each year out of the estimated 76 million cases of foodborne illness overall (325,000 hospitalizations; 5,000 deaths). No deaths have been reported secondary to Cyclospora infection (CDC data).
C cayetanensis has been reported as endemic in at least 27 countries, mostly tropical (see Table).[9, 10, 11, 12, 13]
Cyclospora infection is not considered a fatal disease. No reported deaths have been directly attributed to it in the United States. The greatest risk comes from dehydration in susceptible hosts.
No racial predilection exists.
No sex predilection exists.
In endemic countries, infections are much more common in children younger than 10-15 years (about 80% of infections). In this group, infections tend to be less frequent in infants younger than 12-18 months (see Table).
After exposure in nonimmune individuals, the incubation period is usually 1-11 days (mean, 7 d). The onset of illness may be abrupt in as many as 30% of cases. It may be preceded by a flulike illness. After a few days, acute symptoms subside and then may recur (61% of cases) in a waxing-waning pattern. Alternatively, a patient may experience persistent symptoms. The illness usually lasts 6-7 weeks but has been reported to persist for several months. The duration can be several months to a year in patients with HIV.
Vital signs are normal in most cases. Fever is unusual but, when present, is low grade. In the presence of moderate to severe dehydration, compensatory tachycardia, systolic blood pressure (SBP) less than 90 mm Hg, and decreased skin turgor may occur, and the patient may appear ill.
Risk of infection is secondary to the consumption of contaminated fruits, vegetables, water, or other foodstuffs (see Deterrence/Prevention for strategies that decrease the risk of acquiring this infection). The infectious inoculum is not known but is thought to be small.
Duodenal and jejunal overall microscopic architecture is altered with mild to moderately severe villous atrophy (villous-to-crypt ratio reported 0.6-1.5:1 versus normal 3-4:1).
The above discussion of histology is adapted from Connor (1993 , 1999 ) and Ortega (1997 ).
Medical care includes oral or intravenous rehydration (appropriate to the degree of dehydration) and antibiotics. The antibiotic of choice for treating Cyclospora infection is TMP-SMZ.
TMP-SMZ is the drug of choice. Immunocompetent patients become symptom-free within a median of 3 days. In a study of Haitian patients with AIDS, individuals cleared the organism on average 2.5 days into treatment during a 10-day regimen.
One small study of 20 patients with HIV compared TMP-SMZ (n = 9) with ciprofloxacin (n = 11) in the treatment of C cayetanensis infection. With TMP-SMZ by day 7, diarrhea had ceased in 9 of 9 patients, and stools were negative for oocysts in all 9 patients. With ciprofloxacin by day 7, diarrhea ceased in 10 of 11 patients, and stools were negative for oocysts in 7 of 11 patients (64%). The conclusion was that, although ciprofloxacin is not as effective as TMP-SMZ, it is an acceptable alternative for patients unable to tolerate TMP-SMZ. However, this study has not been replicated, and other studies have commented that ciprofloxacin treatment did not produce a good response. The consensus among many practitioners is that ciprofloxacin is not a satisfactory treatment for cyclosporiasis, and they do not use it if the patient is allergic to sulfa.
Results from small studies have not demonstrated norfloxacin, metronidazole, tinidazole, quinacrine, and azithromycin to be effective.
Nitazoxanide, a 5-nitrothiazole derivative with broad-spectrum activity against helminths and protozoans, has been shown to be effective against C cayetanensis, with an efficacy 87% by the third dose (first, 71%; second 75%). Three percent of patients had minor side effects.
Clinical Context: Combination antibiotic inhibits 2 sequential steps in bacterial folate synthesis. It has a wide spectrum of activity and reduced resistance because of the combined action of 2 drugs. Most gram-positive and gram-negative organisms are sensitive. Typically resistant organisms include Pseudomonas aeruginosa, Bacteroides fragilis, and enterococci. After oral administration, TMP peaks by 2 h and SMZ by 4 h. Respective half-lives are 11 h and 10 h.
Clinical Context: Fluorinated 4-quinolone. Broad-spectrum antimicrobial inhibits gyrase-mediated DNA supercoiling in bacteria, leading to disruption of bacterial DNA replication. Effective against many gram-positive and gram-negative organisms. Inhibits several intracellular bacteria (ie, Chlamydia, Mycoplasma, Legionella, Brucella, Mycobacterium). In one study, 1 of 7 patients administered 500 mg 3 times qwk had a recurrence after 4 wk of therapy (no recurrences with TMP-SMZ). Well-absorbed after PO administration, peaks within 1-3 h, and serum elimination half-life is 5-6 h.
Therapy must be comprehensive, covering all likely pathogens in the context of this clinical setting.
Pattern of Spread Countries Comments Endemic Bangladesh, Brazil, Chile, China, Cuba, Dominican Republic, Egypt, Guatemala, Haiti, India, Indonesia, Jordan, Mexico, Morocco, Nepal, Nigeria, Pakistan, Peru, Puerto Rico, Romania, Saudi Arabia, Tanzania, Thailand, Turkey, Venezuela, Viet Nam, Zimbabwe Prevalence (1-15%†) varies significantly with the season and from year to year; children (≤ 9 y, most studies) account for 70-80% cases, which are typically asymptomatic (72-94%); asymptomatic disease is higher in older children (10-18 y) and adults (>18 y); infection rate in those with HIV is significantly higher than overall prevalence International travel-related Australia, Belgium, Czech Republic, Germany, Greece, Ireland, Italy, Japan, The Netherlands, Spain, Switzerland, United Kingdom, United States ≤4% returning travelers with diarrhea Foodborne outbreaks Canada, United States, Germany, Mexico Canada/United States: raspberries, blackberries, mesclun, basil‡; Germany: lettuce imported from Southern France/Southern Italy; Mexico: watercress Waterborne outbreaks United States (Chicago), Nepal 14 cases of cyclosporiasis; tap water in medical dormitory, suspected source was contaminated water storage tank; 12 of 14 developed cyclosporiasis * Community-based studies
† Highest in spring and early summer
‡ Fresh produce. Raspberries from Guatemala; blackberries from Guatemala or undetermined source; mesclun (young salad greens, eg, spring mix, field greens, baby greens, gourmet salad mix) from Peru or United States; basin from Mexico or United States