Cyclospora infection

INTRODUCTION — 

Cyclospora spp is a foodborne, waterborne, and soil-transmitted parasitic cause of diarrheal illness in children and adults; it is an intestinal coccidian recognized as a distinct protozoan genus [1].

Issues related to Cyclospora infection will be reviewed here. Issues related to other coccidial organisms that can cause gastrointestinal infections in humans (Cystoisospora belli, Cryptosporidium, Sarcocystis, and Toxoplasma) are discussed separately. (See related topics.)

EPIDEMIOLOGY — 

Humans are the only natural hosts of Cyclospora (figure 1). There are multiple species of Cyclospora that are found in a diversity of nonhuman hosts, but human infections are due to Cyclospora cayetanensis [2]. However, recent advances in molecular typing have shown that Cyclospora cayetanensis may be subdivided into two additional subspecies, Cyclospoea ashfordi and Cyclospora henanensis [3]; broad acceptance of a taxonomic change is yet to be forthcoming and likely to evolve as additional understanding of genetic variability emerges [4].

Cyclospora has a broad geographic distribution. The organism is most frequently reported in Latin America (especially Guatemala, Honduras, Haiti, Peru, Mexico, and Brazil), Egypt, sub-Saharan Africa, the Indian subcontinent, and Southeast Asia [2]. Risk factors for infection in endemic areas include contaminated water, food or soil, poor sanitation, and low socioeconomic status. Cyclospora are thought to be relatively chlorine insensitive; outbreaks from water sources with acceptable chlorination levels to remove coliforms have been described [5]. In a Vietnamese study, contamination with Cyclospora spp oocysts was observed in 11 percent of market herb and water samples and 8 percent of farm samples [6]. Contaminated wastewater sludge used to irrigate foods can contribute to infection risks.

Most cases in nonendemic regions are imported by international travelers [7-9] or by ingestion of contaminated foods [10]. Increasing globalization of the fresh food supply and global travel have contributed to spread of Cyclospora in nonendemic areas [11]. Food-borne outbreaks in the United States are often linked to produce (eg, raspberries, lettuce, cilantro, prepackaged salad mix, snow peas, mango, carrots, and other vegetables) from endemic countries [4,12-22].

Variable seasonal effects on cyclosporiasis have been observed [23]; infection is often associated with hot and/or rainy periods [24-27]. In a review of cyclosporiasis cases reported in the United States between 2015 and 2019, there were 1376 cases notified, for which one fifth were associated with travel (mainly Mexico and Guatemala) and two thirds were associated with outbreaks. Among the domestically acquired cases, most occurred in spring/summer months (May to August) [18,28].

MICROBIOLOGY AND PATHOLOGY — 

Cyclospora is an obligate intracellular parasite. Both asexual and sexual stages have been observed in hosts, suggesting that only a single human host is required to complete the life cycle (figure 1) [29]. Oocysts of Cyclospora passed in the stool are shed in a noninfective form and require several days before they become infectious, with sporulation occurring under environmental conditions of high temperature and humidity [30]. Thus, direct person-to-person transmission is not likely.

The infective dose is unknown; high attack rates after foodborne infection suggest that the infectious dose is very low (ingestion of 10 to 100 oocysts is probably sufficient for infection) [10].

Small bowel biopsies in symptomatic patients have demonstrated several developmental forms of the parasite within epithelial cells. There is also jejunal inflammation with heightened numbers of intraepithelial lymphocytes and degrees of villous atrophy and crypt hyperplasia [29].

CLINICAL MANIFESTATIONS — 

Cyclospora infection is often asymptomatic, but when symptoms occur, illness is characterized by anorexia, nausea, flatulence, fatigue, abdominal cramping, watery diarrhea, low-grade fever, and weight loss [1,7,11]. Abrupt onset of watery diarrhea containing mucus and/or blood can occur [30]. The median incubation period is about seven days following ingestion prior to onset of symptoms (range: 2 to >14 days) [12,31]. Infected patients may have a single self-limited episode or a prolonged waxing and waning course; sustained diarrhea, anorexia, and upper gastrointestinal symptoms lasting for weeks or months can also occur [32,33]. In one series, the average duration of symptoms was more than three weeks [33].

Severe clinical symptoms occur most often among young children and older adults [2]. As children get older, infection tends to be milder, and the duration of infection is shorter. Asymptomatic infection has been described both inside and outside of endemic areas. In one series including 60 Mexican children with cyclosporiasis detected in stool samples, diarrhea occurred in 46 percent of cases, abdominal pain occurred in 40 percent of cases, and vomiting occurred in 19 percent of cases [24].

Symptoms can be more severe in patients with HIV/AIDS or other forms of immunosuppression (eg, transplant recipients), although asymptomatic Cyclospora infection in the setting of HIV has also been described [34-39].

Biliary disease has been reported in association with Cyclospora infection. Acalculous cholecystitis has been described in patients with HIV and resolved after initiation of treatment [40].

DIAGNOSIS — 

The diagnosis of cyclosporiasis is established via stool microscopy; detection of oocysts in the stool of a symptomatic patient is considered presumptive evidence of infection.

Cyclospora cayetanensis oocysts (diameter 8 to 10 microns) can be detected by modified acid-fast staining of stool, in which oocysts can appear light pink to deep purple (picture 1) or remain unstained so they appear as pale, round bodies surrounded by the blue staining background. An alternative is to use the safranin stain, which stains oocysts red to reddish-orange (picture 2) [41,42]. Fluorescence microscopy can also be used for detection of oocysts, which are autofluorescent. A head-to-head comparison of UV fluorescence versus modified acid-fast stain showed similar performance, with a higher false positive rate for UV fluorescence and higher false negative rate for the modified acid-fast stain [43].

It is important to distinguish the Cyclospora oocysts from those of Cryptosporidium, which are also acid fast but smaller (diameter 5 microns). (See "Cryptosporidiosis: Epidemiology, clinical manifestations, and diagnosis", section on 'Diagnosis'.)

Polymerase chain reaction (PCR) assays have been developed for detection and identification of Cyclospora, and several commercial, FDA-approved panels are now available [44-50]. The BioFire FilmArray gastrointestinal panel includes Cyclospora. In a large Cyclospora outbreak, the BioFire Film array detected 95 percent of infections identified by autofluorescence microscopy and facilitated early recognition of the ongoing outbreak without reliance on stool microscopy [51]. This panel can detect samples with ≥20 Cyclospora oocysts in 100 percent of replicates, with varying detection among samples with 1, 5, or 10 Cyclospora oocysts [52]. There are no commercially available serologic assays available for diagnosis of Cyclospora infection.

Molecular tests have been developed to detect Cyclospora and other protozoa that may contaminate fresh produce [53-56].

DIFFERENTIAL DIAGNOSIS — 

The differential diagnosis of Cyclospora infection includes other protozoal parasites including giardiasis, cryptosporidiosis, and Cystoisospora belli. These may be distinguished from Cyclospora via stool microscopy or polymerase chain reaction (PCR). (See "Giardiasis: Epidemiology, clinical manifestations, and diagnosis" and "Cryptosporidiosis: Epidemiology, clinical manifestations, and diagnosis" and "Epidemiology, clinical manifestations, and diagnosis of Cystoisospora (Isospora) infections".)

TREATMENT — 

Treatment of cyclosporiasis in immunocompetent adults consists of trimethoprim-sulfamethoxazole (TMP-SMX; one double-strength 160 mg/800 mg tablet orally twice daily) for 7 to 10 days [57]. This was illustrated in a randomized trial including 40 adult foreigners living in Nepal with Cyclospora infection; after seven days of therapy, Cyclospora was detected in stool less frequently among those treated with TMP-SMX than those treated with placebo (6 versus 88 percent) [33]. Eradication of the organism correlated with clinical improvement, without relapse.

In the setting of immunosuppression due to HIV infection, higher doses and/or longer courses of antibiotic therapy may be needed for effective treatment; effective antiretroviral therapy for immune recovery is also important. In one series including 28 patients with HIV infection and Cyclospora infection, all responded to treatment with oral TMP-SMX therapy; recurrent symptomatic disease within one month was observed in 43 percent of cases [34]. The optimal dose and duration of TMP-SMX for patients with cyclosporiasis and HIV infection with CD4 count <200 cells/mm³ is uncertain; a reasonable approach consists of TMP-SMX (one double-strength 160 mg/800 mg tablet orally twice daily) for 14 days, followed by secondary prophylaxis with TMP-SMX (one double-strength 160 mg/800 mg tablet three times weekly) to prevent relapse [34].

Nitazoxanide (500 mg twice daily for seven days) may be an acceptable alternative regimen for patients with sulfa allergy; its efficacy has been described in case reports [30,58-60]. Ciprofloxacin may be another alternative therapy [61], although there is anecdotal evidence of treatment failure. Other antibiotics, such as azithromycin, norfloxacin, tinidazole, nalidixic acid, and quinacrine, have been evaluated without success [11].

Persistent or recurrent symptoms post treatment may be attributable to ongoing infection, reinfection, or post-infectious irritable bowel syndrome. Patients with recurrent or persistent symptoms should undergo repeat stool examination, and if negative for infection, should be considered for evaluation of noninfectious causes [62].

Prevention relies on adequate water supply infrastructure, proper disposal of wastewater, and protection of food from contamination. There is no vaccine available.  

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute diarrhea in adults".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology

•Cyclospora cayetanensis is a foodborne and waterborne parasitic cause of diarrheal illness in children and adults. Humans are the only natural hosts (figure 1). Cyclospora can occur as a locally acquired infection, among travelers, or in patients with HIV/AIDS. (See 'Introduction' above and 'Epidemiology' above.)

•Cyclospora is most frequently reported in Latin America, the Indian subcontinent, and Southeast Asia; many of the cases reported elsewhere have been imported by international travellers or contaminated food. Risk factors for infection in endemic areas include contaminated water, food or soil, poor sanitation, and low socioeconomic status. (See 'Epidemiology' above.)

●Microbiology and pathology – Oocysts of Cyclospora passed in the stool are shed in a noninfective form and require several days before they become infectious, so person-to-person transmission is not likely. A low infectious dose (10 to 100 organisms) is probably sufficient for infection. (See 'Microbiology and pathology' above.)

●Clinical manifestations – Cyclospora infection is characterized by anorexia, nausea, flatulence, fatigue, abdominal cramping, diarrhea, low-grade fever, and weight loss. In endemic areas, asymptomatic infections are more frequent, although more severe clinical symptoms occur in young children and older adults. The median incubation period is about seven days following ingestion prior to onset of symptoms. (See 'Clinical manifestations' above.)

●Diagnosis – The diagnosis of cyclosporiasis is established via molecular testing of stool or stool microscopy; oocysts can be detected by modified acid-fast staining of stool, in which oocysts appear light pink to deep purple (diameter 8 to 10 microns). It is important to distinguish the Cyclospora oocysts from those of Cryptosporidium, which are also acid fast but smaller (diameter 5 microns). (See 'Diagnosis' above.)

●Treatment – We suggest trimethoprim-sulfamethoxazole (TMP-SMX; one double-strength 160 mg/800 mg tablet orally twice daily for 7 to 10 days) for treatment of cyclosporiasis in immunocompetent hosts (Grade 2B). In the setting of immunosuppression, higher doses or longer courses of antibiotic therapy may be needed for effective treatment. (See 'Treatment' above.)