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Home , Cyclospora, Cyclospora cayetanensis, Cyclosporiasis, Isosporiasis, Sarcocystis

Cyclosporiasis: An Update

Cirle Alcantara Warren, MD

Corresponding author Cirle Alcantara Warren, MD has been reported in three epidemiologic Center for Global Health, Division of Infectious Diseases and settings: sporadic cases among local residents in an International Health, University of Virginia School of Medicine, MR4 Building, Room 3134, Lane Road, Charlottesville, VA 22908, USA. endemic area, travelers to or expatriates in an endemic E-mail: [email protected] area, and - or water-borne outbreaks in a nonendemic Current Infectious Disease Reports 2009, 11:108–112 area. In tropical and subtropical countries (especially Current Medicine Group LLC ISSN 1523-3847 Haiti, Guatemala, Peru, and Nepal) where C. cayetanen- Copyright © 2009 by Current Medicine Group LLC sis infection is endemic, attack rates appear higher in the nonimmune population (ie, travelers, expatriates, and immunocompromised individuals). Cyclosporiasis was a Cyclosporiasis is a food- and water-borne infection leading cause of persistent among travelers to that affects healthy and immunocompromised indi- Nepal in spring and summer and continues to be reported viduals. Awareness of the disease has increased, and among travelers in Latin America and outbreaks continue to be reported among vulnera- [8–10]. Almost half (14/29) the investigated Dutch attend- ble hosts and now among local residents in endemic ees of a scientifi c meeting of microbiologists held in 2001 areas. Advances in molecular techniques have in Indonesia had C. cayetanensis in stool, confi rmed by improved identifi cation of infection, but detecting and/or polymerase chain reaction (PCR), and food and water contamination remains diffi cult. most patients had gastrointestinal symptoms, particularly Further understanding of the biology, pathogenesis, fl atulence and loss of appetite [11]. and control of infection and transmission has been Endemic infection was noted to be highest among chil- hindered by the diffi culty of propagating the organ- dren and AIDS patients in Guatemala [12,13]. In a study of ism, lack of reliable oocyst viability and infectivity 253 children with persistent diarrhea in Nepal, severe mal- assays, and inability to experimentally infect ani- nutrition and HIV infection were associated with Cylcospora mals and human volunteers. This article provides a and infections [14]. Extreme poverty, liv- general review and presents recent insights into the ing in a hut or small house, lack of latrines, and contact with organism and disease. contaminated soil were reported to be associated with infec- tion in a community-based study in Venezuela [15•]. Cyclosporiasis in developed countries occurs in the Introduction setting of food- or water-borne outbreaks. In the United cayetanensis is a food- and water-borne coc- States and Canada, infections have been linked to impor- cidian parasite that causes acute and chronic diarrhea tation of fresh produce such as raspberries, blackberries, in immunocompetent and immunocompromised hosts. basil, and baby lettuce leaves [16]. Guatemalan raspberries Cyclospora is classifi ed in the phylum and have been associated with about 50 outbreaks from 1995 is phylogenetically related to other coccidian parasites, to 2000 [16,17]. More recently, fresh snow peas in a pasta including , Cryptosporidium, , Toxo- salad were associated with an outbreak of cyclosporiasis in plasma, and . Cyclospora spp are ubiquitous a residential facility in Pennsylvania [18]. The US Food and and infect a variety of animals, including , insecti- Drug Administration traced the snow peas to an exporter vores, and rodents. However, C. cayetanensis is the only from Guatemala. Thai basil imported from the United known to infect humans [1,2]. The protozoan par- States was linked to an outbreak among ethnic immigrants asite initially was referred to as (blue-green in Canada [19]. The use of untreated or poorly treated algae) or coccidian (“big” Cryptosporidium)-like bodies in water for irrigating crops, applying fertilizers, and wash- the stools of patients with prolonged diarrhea and fatigue ing and processing has been implicated as a source [3–6]. Although the organism has been recovered in stool of contamination for fruits and vegetables [20]. Cultivation from numerous regions, including North America, Cen- of produce near wastewater-fed bodies of water may also tral America, , Caribbean Islands, Eastern contribute to fecal and protozoal contamination of food , South , Southeast Asia, , Nepal, Peru, in developing countries [21]. Although reported previ- and Haiti, infection appears to be most common in tropi- ously, cyclosporiasis associated with recreational exposure cal and subtropical countries [7]. to water, especially swimming pools, has not been noted Cyclosporiasis: An Update I Warren I 109 recently [22,23]. Food-borne outbreaks have been reported asexual (merogony and schizogony) and sexual reproduc- in passenger ships, but Cyclospora spp have been linked tion (gametogony) within the gastrointestinal epithelium to only one of the 50 outbreaks reviewed by Rooney et al. [30]. specimens from the reveal that [24]. In this outbreak, 220 passengers and crew members C. cayetanensis infection is limited to the enterocytes and were affected. spares the lamina propia and submucosa [30,31]. Jejunal Recently, outbreaks among local residents in endemic villi are stunted, widened, and edematous, with mixed areas have been reported. The adult, local residents, espe- infl ammatory cell infi ltrate. Vascular congestion is also cially those of low socioeconomic status, initially were demonstrated. Parasitophorous vacuoles are formed at the thought to have acquired immunity to Cyclospora; thus, apical end of the enterocytes, exhibiting all the different the prevalence of the disease in this population was low. developmental stages of the parasite. Further understand- The fi rst of the three outbreaks involved attendees at a ing of how the excystation, attachment, pathologic wedding in Mexico [25]. The other two were in Peruvian changes, encystation, and clinical disease occur is ham- naval recruits in Lima [26,27•]. All the military recruits pered by the lack of animal models to study pathogenetic were male (mean age, 19 years) and of low socioeconomic mechanisms. Systematic attempts to infect numerous ani- status. The occurrence of infection in this group of healthy, mal species with C. cayetanensis have been unsuccessful young adults was suggested to be secondary to waning [32]. Similarly, a pilot study of seven healthy volunteers immunity or unequal geographic distribution of C. cay- fed 200 to 49,000 sporulated oocysts failed to induce etanensis even in endemic areas. With increased awareness clinical disease or demonstrate fecal evidence of infec- of the disease and improved diagnostic capabilities, more tion [33]. These observations highlight the need for better outbreaks among the local population in endemic settings viability and infectivity assays for C. cayetanensis. may be discovered. When freshly excreted, the oocysts of C. cayetanensis are unsporulated, thus noninfectious. Sporulation occurs in the laboratory with 2.5% potassium dichromate in Clinical Features about 1 to 2 weeks. Whether the rate of sporulation in the infects immunocompetent and environment is the same, and the environmental factors immunocompromised hosts. The incubation period is involved, are unknown. Duration of sporulation seems to estimated to be 1 to 14 days (average, 7 days) [16]. Infec- be affected variably by temperature in experiments per- tion with Cyclospora may be asymptomatic, may manifest formed in dairy and basil [34]. Extremes of temperature as mild to moderate self-limiting diarrhea (usually in the seem to be inhibitory in both food substrates, whereas no healthy host), or as protracted and severe diarrhea. In the effect was noted when incubation occurred at 4°C and immunocompetent host, the mean duration of diarrhea 23°C for up to 1 week. In another study, Cyclospora spor- ranges from 10 to 25 days in outbreak settings, which ulation was observed even with microwave exposure at may be followed by relapsing symptoms lasting several 100% power for 45 seconds [35]. Various fungicides and weeks to months [16,28]. In endemic infections and inter- insecticides also have been shown to not affect sporula- national travelers, mean duration of symptoms seems to tion [36]. Once sporulated, the Cyclospora oocysts remain be longer, about 6 to 7 weeks, but these differences may infectious and can persist in food, water, and the envi- be secondary to host factors and delayed diagnosis and ronment. Routine washing of fruits and vegetables may treatment [11,16]. In the immunocompromised host, the not be suffi cient to remove the oocysts [37]. High-hydro- diarrheal illness is usually prolonged with periods of static-pressure processing (HPP) and UV light treatment remission and relapse, and may last a few days to several have been shown to decrease the infectivity of Eimeria months. Diarrhea is characteristically watery, sometimes acervulina–contaminated raspberries and basil [38•]. explosive, and associated with , , abdomi- Although Eimeria may be a surrogate for C. cayetanen- nal cramps, and bloating. Profound fatigue and weight sis, the utility of HPP and UV treatment for decreasing loss are usually reported. is not common. Extraint- contamination with Cyclospora remains to be proven. estinal infection is very rare, although complications may include Reiter’s syndrome and Guillain-Barré syndrome. In the HIV-infected patient, Cyclospora causes symptoms Detection of the Parasite that are indistinguishable from those of cryptosporidi- The excreted oocysts are spherical, about 8 to 10 μm in osis and . The organism has been found in the size, and surrounded by a thick wall [20]. They are smaller gallbladder epithelium of an AIDS patient with acalculous than Isospora belli and twice the size of Cryptosporidium cholecystitis, and biliary disease has been reported in parvum. Cyclospora oocysts are visualized by light or similar patients with cyclosporiasis [29]. phase microscopy in wet mounts of stools as unsporu- lated, refractile spheres. The oocyst wall exhibits bright blue autofl uorescence when viewed by UV epifl uorescence Biology microscopy [39]. Concentration of stools by either forma- Infection is initiated by ingesting the sporulated oocysts. lin-ether sedimentation or sucrose fl otation has been used During excystation, sporozoites are released and undergo to maximize detection of oocysts, although examination 110 I Intra-abdominal Infections, Hepatitis, and of direct smear is still considered to be effective and rapid cyclosporiasis ranged from 71% to 87% in this study. [39,40]. Safranin staining enhances the outline of the Ciprofl oxacin, tetracycline, , , membrane, and the oocyst is variably acid-fast by modi- and spiramycin inhibit apicoplast (plastid-like organelle fi ed Ziehl-Nielsen stain [39]. Flow cytometry may be more of apicomplexan parasites)-located gyrase and transla- sensitive than microscopy and facilitates molecular analy- tion, respectively [51]. Although these antibiotics have sis of large numbers of specimens, but preparation takes been used to treat infections from other apicomplexan longer [41]. Recently, an enhanced method of concentrat- parasites, their utility against cyclosporiasis remains to be ing and purifying Cyclospora oocysts using a modifi ed proven, with the possible exception of ciprofl oxacin. detachment method and Renocal-sucrose gradient sedi- mentation was described as effective in processing fecal specimens for fl ow cytometry [42]. PCR amplifi cation of Conclusions DNA from C. cayetanensis is increasingly being used in Cyclosporiasis continues to be an important food- and research settings and outbreak investigations [43–45]. water-borne disease, causing signifi cant symptoms even Although detection of the parasite from clinical speci- in healthy individuals in endemic settings. Identifi cation mens has improved by molecular methods, recovery from of the parasites in feces is improving, although detec- contaminated food, water, or the environment remains tion of food and environmental contamination remains diffi cult because of the low levels of inocula. A validation challenging. A huge gap still exists in understanding study demonstrated specifi city, sensitivity, and reproduc- the biology, pathogenesis, and control of infection and ibility of a modifi ed DNA extraction and PCR technique transmission of C. cayetanensis largely because of the in detecting as few as one oocyst in water or basil wash inability to propagate the organism outside of natural sediment [46••]. In this study, a novel pair of oligonucle- infection, lack of reliable assays to detect viability and otide primers (CCITS2-F and CCITS2-R) was designed infectivity, and inability to establish infection in animals to amplify a 116-bp segment of the internal transcribed and human volunteers. spacer-2 region of C. cayetanensis rDNA. Enhanced methods of extracting and concentrating oocysts from specimens other than feces are urgently needed. Disclosure No potential confl ict of interest relevant to this article was reported. Treatment In the immunocompetent patient, the illness is usually self-limiting, but therapy with trimethoprim (TMP)- References and Recommended Reading sulfamethoxazole (SMX) results in symptom resolution Papers of particular interest, published recently, and decreases the shedding of oocysts. A 7-day course have been highlighted as: of oral TMP-SMX, 160 mg TMP plus 800 mg SMX • Of importance for adults, and 5 mg/kg TMP plus 25 mg/kg SMX for •• Of major importance children, twice daily, is usually suffi cient [47,48]. In the HIV-infected patient, recurrent episodes are prevented 1. Ortega YR, Gilman RH, Sterling CR: A new coccidian parasite (Apicomplexa: ) from humans. J Parasitol using prophylaxis with TMP-SMX (160 and 800 mg, 1994, 80:625–629. respectively) 3 days a week [49]. Agents effective against 2. Wurtz R: Cyclospora: a newly identifi ed intestinal pathogen other enteric pathogens (eg, , azithromycin, of humans. Clin Infect Dis 1994, 18:620–623. 3. 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