Cyclospora Infection (Cyclosporiasis)

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Background

Cyclospora cayetanensis (8-10 µm in diameter), a coccidian protozoan parasite, produces an intestinal infection (called cyclosporiasis) 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).

An increased incidence of cyclosporiasis has been reported in the United States (27 states reporting infections) from May to early August 2017 (206 cases vs 88 cases during the same period in 2016). This has prompted the CDC and the US Food and Drug Administration (FDA) to issue a health alert to clinicians to consider a diagnosis of cyclosporiasis in patients who experience prolonged or remitting-relapsing diarrhea.[1]

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.[2]

In 1993, in Lima, Peru, Ortega et al characterized and clarified remaining taxonomic issues for C cayetanensis.[3] 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.[4] Since then, numerous reports have documented its endemicity in 27 countries around the world (see Table).

Table 1. Epidemiology of C cayetanensis *



View Table

See Table

Transmission occurs primarily through ingesting contaminated food (eg, fruits, vegetables) and water. No documented human-to-human transmission exists.

Pathophysiology

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.[5]

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.[6] It has also been isolated from wastewater in Tunisia and in Arizona.[7, 8]

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.

Life cycle of Cyclospora

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.

Epidemiology

Frequency

United States

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).[9]

An increased incidence of cyclosporiasis has been reported in the United States (27 states reporting infections) from May to early August 2017 (206 cases vs 88 cases during the same period in 2016). This has prompted the CDC and the US Food and Drug Administration (FDA) to issue a health alert to clinicians to consider a diagnosis of cyclosporiasis in patients who experience prolonged or remitting-relapsing diarrhea.[1]

The disease rate after a presumed exposure has been reported to vary from 32.5-100%, with a median of 91.7%, suggesting that a small inoculum of organisms is sufficient to infect.

It is a cause of travelers' diarrhea in a small percentage of travelers returning to developing countries.

It has been reported as a cause of foodborne diarrhea in outbreaks secondary to imported food (eg, raspberries, mesclun, basil) in the United States (see Table).

International

C cayetanensis has been reported as endemic in at least 27 countries, mostly tropical (see Table).[10, 11, 12, 13, 14]

It has been reported as a cause of travelers' diarrhea after international travel by at least 11 countries.

It has been reported as a cause of foodborne diarrhea in outbreaks secondary to food imported to Canada (eg, raspberries, mesclun, basil) and Germany (lettuce) (see Table).

It has been reported as a cause of an outbreak in Mexico secondary to watercress (within the country).

Mortality/Morbidity

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.

Infants are at risk for critical dehydration due to protracted diarrhea. Worldwide diarrheal disease, in general, is responsible for more than 2 million deaths in children each year, mostly in developing countries. The percentage of these deaths that might be attributable to Cyclospora infection is not currently known.

A protracted course of several weeks to months with diarrhea, dehydration, and weight loss can produce significant morbidity. It is more severe in the immunologically naive, such as expatriates and travelers. In endemic countries, children often have asymptomatic infections (about 70%), and adults are infrequently infected.

If exposed to Cyclospora, patients with HIV who are not taking TMP-SMZ for prophylaxis have a significant risk for developing chronic and debilitating diarrhea.

Race

No racial predilection exists.

Sex

No sex predilection exists.

Age

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).

History

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.

Physical

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.

Causes

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.

Laboratory Studies

Stool examination

Stool examination for oocysts is the standard procedure for diagnosing C cayetanensis. Other specimens that may contain oocysts include intestinal aspirates and duodenal or jejunal biopsy samples. Unusual specimens include bile and pulmonary samples (eg, induced sputum, bronchial washings, biopsy) based on the growing reports of complicated cyclosporiasis.

Three specimens should be submitted for analysis, preferably on alternate days. The number of oocysts in the stool can vary considerably, but infected individuals with symptoms continuously excrete oocysts.

Standard laboratory procedures for ova and parasites do not identify Cyclospora; therefore, the laboratory must be notified that Cyclospora is a specific consideration.

Stool specimens are submitted to the laboratory as a fresh specimen or in some type of preservative. (Many laboratories require that specimens be submitted in a preservative.)

The stool specimen is recommended to be concentrated using the formalin–ethyl acetate technique, which leads to greater recovery of oocysts.

An important detail is that the specimen be centrifuged at 500 g for 10 minutes; if the speed is reduced, recovery of Cyclospora will be compromised.

Ethyl acetate has been substituted for ether because ethyl acetate is an excellent debris extractor and a much safer agent (ie, less explosive).

Microscopy

Cyclospora oocysts are difficult to identify with microscopic examination (high dry, 400X) without special techniques: acid-fast staining (fresh or preserved specimen), safranin staining (fresh or preserved specimen), direct wet smear (no preservative, no stain) using fluorescent microscope, direct wet smear with a differential interference contrast microscope (bright field), or lacto-phenol cotton blue staining (fresh specimen). Each of these techniques is discussed below.

If an unconcentrated wet mount is prepared, the entire cover-slipped area should be scanned. Concentration of the organism on the wet mount can be effected by adding a few drops of Sheather's sucrose solution to the wet mount; the oocysts float to the surface and, reportedly, appear faint pink.

If the stool specimen has been concentrated (not wet mount concentration), the recommendation is to scan 300 fields. A single negative specimen does not rule out the diagnosis.

When viewing coccidia microscopically, calibration of the microscope's ocular micrometer for measuring is important, because size matters when differentiating Cyclospora (8-10 µm) and cryptosporidium (4-5 µm).

In circumstances in which a confirmatory step is required to verify that the oocysts are indeed those of Cyclospora, a sporulation assay can be conducted using freshly passed oocysts. See the CDC for details.

Monoclonal antibodies

In 2005, monoclonal antibodies were not yet commercially available.

Acid-fast and safranin staining

C cayetanensis is an acid-fast organism, but the oocyst stains very unevenly with acid-fast stains (no staining, to mixed or variable staining, to full staining), complicating identification.

A modified acid-fast stain (less intense decolorizing) may be attempted using Kinyoun acid-fast stain (cold method) or Ziehl-Neelsen acid-fast stain (hot method). With the hot method, the stained material on the slide is heated to steaming (not boiling) and allowed to stand for 5 minutes before proceeding. With the cold method, heat is not applied.

The cold method is preferred because the hot method is not thought to have a significant advantage of improved staining.

Safranin staining has demonstrated superior results, producing reddish orange staining of more than 98% of oocysts on a slide, when heating the safranin application was performed using a microwave (650 W) at full power for 30 or 60 seconds. The CDC recommends heating the slide to boiling for 1 minute. The heating produces a more uniform staining.

Combining fluorescence and differential interference contrast (DIC) microscopy

The CDC states that, used together, these two techniques provide an efficient and reliable approach to the diagnosis.

Wet preparations of Cyclospora, independent of specimen age or type, exhibit an intense color when viewed with a fluorescence microscope. With a UV excitation filter set at 330-365 nanometers, the color is an intense blue. With a filter set at 450-490 nanometers, the color is a less intense green.

Wet preparations of Cyclospora viewed with a DIC microscope (bright field) appear as refractile spheres (8-10 µm in size) with a distinct oocyst wall.

Lactol-phenol cotton blue (LPCB) staining

In laboratories where acid-fast stains are not routinely used, such as in rural areas and in developing countries, the LPCB wet mount is a suitable and practicable substitute with many advantages. It is a single stain that can be used to detect both coccidian and noncoccidian parasites, and it is simpler and less expensive than the acid-fast stain.[15, 16]

Polymerase chain reaction

PCR of Cyclospora stages isolated from stool or other specimens has been used for diagnosis. The protocol originally developed by Relman in 1996 was unable to differentiate Cyclospora species and Eimeria species.

This protocol was modified using a restriction enzyme Mn/I to distinguish the two species, designated a nested-PCR restriction length fragment polymorphism (RLFP).

The PCR-RLFP protocol has been reliable for clinical purposes in detecting C cayetanensis in stool specimens but has been found to be unreliable when applied to environmental specimens because of the presence of genetically similar microorganisms. This has led to the development of PCR protocols that can reliably detect C cayetanensis in large numbers of environmental and clinical specimens (see below).

Environmental and outbreak sampling

C cayetanensis produces an environmentally resistant oocyst that is infective in humans (see Pathophysiology). The US Environmental Protection Agency's Interim Enhanced Surface Water Treatment Rule (EPA-IESWTR) sets zero as the maximum contaminant level goal for Cryptosporidium and other pathogens in water.

In the late 1990s, several outbreaks of cyclosporiasis were attributed to food imported into the United States. These outbreaks generated the need to have techniques for sampling large numbers of environmental specimens, as well as large numbers of clinical specimens in order to prevent outbreaks before they occur and to better and more rapidly manage them when they do occur.

Emerging techniques

Three techniques that meet these criteria and are evolving include the new PCR protocols, flow cytometry, and electrorotation.

PCR: Newer PCR assays have been reported that can be used to reliably screen large numbers of clinical and environmental specimens for C cayetanensis. New primers have been identified for C cayetanensis and used to modify existing protocols (an alternative nested-primer PCR-RFLP) or to develop new protocols. Such new protocols include single-nucleotide polymorphisms (SNP-PCR), which amplifies allelic sequences that differ by at least a single base pair; and real-time PCR, which uses the 5 prime-exonuclease activity of AmpliTaq Gold DNA polymerase to cleave C cayetanensis.

A modified Relman-PCR protocol was used to determine the sensitivity of PCR in detecting C cayetanensis in experimentally spiked raspberries, basil, and mesclun lettuce. The protocol detected 40 or fewer oocysts per 100 g of raspberries or basil and 1,000 per 100 g of mesclun lettuce. This experiment demonstrated the importance of testing different the various PCR protocols on food to determine the detection sensitivity.

Flow cytometry: Flow cytometry has been used to accurately detect and enumerate of various organisms in a prepared suspension (0.5 mL), including Cyclospora, by recording characteristic forward (size) and side (complexity) scattering of incident light emitted by an argon-ion laser operating at 488 nm. Scatter patterns are specific to the organism.

Electrorotation: This technique (which is not commercially available) takes advantage of the unique patterns of rotation around their axis of biological organisms, including Cyclospora, secondary to the application of uniform rotating alternating current fields. These real-time and noninvasive measurements are performed on a microscale (ie, one cell at a time). It allows the identification of the organism and the determination of its viability. It could potentially be used for rapid assessment of food and water.

Other procedures

Other procedures for the diagnosis of cyclosporiasis include demonstration of oocyst sporulation and polymerase chain reaction (PCR) of Cyclospora stages isolated from stool or duodenal or jejunal aspirates or biopsies. 

No reliable immunological techniques are available to detect Cyclospora.

Histologic Findings

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).

Total length of the villi is reduced. Villi are widened secondary to infiltration of both the surface epithelium and villous mucosa.

The surface epithelium is less organized with loss of normal polarity and infiltrated extensively with lymphocytes, which displace the nuclei.

Neutrophils are often present.

Vessel congestion and dilatation are increased.

Focal vacuolization is present.

Loss of the brush border and altered cell shape from columnar to cuboidal is observed (more at tips of villi).

The villous mucosa is diffusely edematous and infiltrated with a mixed inflammatory cell infiltrate of plasma cells, lymphocytes, and, in some cases, eosinophils.

Mitotic activity in the crypts is increased.

The lamina propria is mildly to intensely inflamed.

All stages of the known life cycle of C cayetanensis have been observed in the enterocytes.

Electron microscopy (EM) demonstrates pronounced enterocyte vacuolization and abundant intraepithelial reactive cells. Predominantly in the apical areas, numerous intraenterocytic coccidial organisms are within parasitophorous vacuoles. The concentration of cells with organisms decreased progressively to zero in the crypts.

Follow-up studies of a few patients indicate that mild inflammation may persist (duration not known), manifested on light microscopy as focal vacuolization and gapping of enterocytes and mild increase in intraepithelial lymphocytes or other reactive cells. On EM, myelinlike material was uncommon. Its significance is unknown. Scarce and moderate amounts have been noted in protozoal infections of the upper gastrointestinal tract. It may be a marker of cell injury, but that is not substantiated.

The above discussion of histology is adapted from Connor (1993[17] , 1999[18] ) and Ortega (1997[19] ).

Medical Care

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.

Medication Summary

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.[20] 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.

Trimethoprim-sulfamethoxazole (Bactrim, Bactrim DS, Septra, Septra DS)

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.

Ciprofloxacin (Cipro)

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.

Class Summary

Therapy must be comprehensive, covering all likely pathogens in the context of this clinical setting.

Further Outpatient Care

Administer a complete course of oral antibiotics.

Follow up 1 week after discharge to verify continuing clinical improvement.

Further Inpatient Care

Assess patients for response to rehydration and antibiotic therapy.

Discharge to outpatient management when patients demonstrate clinical improvement and can tolerate oral intake and oral medication.

Inpatient & Outpatient Medications

TMP-SMZ is the drug of choice. It is usually administered orally but can be administered intravenously if the patient cannot tolerate peroral medications because of nausea, vomiting, or underlying gastrointestinal problems.

Ciprofloxacin has been used as an alternative if the patient has an allergy to TMP-SMZ, but the response may not be as favorable.

Deterrence/Prevention

The risk of acquiring Cyclospora infection can be reduced significantly (but not eliminated), particularly in developing countries, by adhering to health guidelines, including the following:

Complications

Several complications have been reported as case reports and are detailed below.

Guillain-Barré syndrome (GBS): One week after the onset of Cyclospora infection secondary to Guatemalan raspberries, a 58-year-old man developed GBS (confirmed by nerve conduction study), initially manifested as generalized weakness and altered sensation in the hands and feet; within 18 hours he was quadriparetic, areflexic, and had to be mechanically ventilated. He responded to therapy for the GBS (plasmapheresis, intravenous immunoglobulin), but, at 2 months after hospital discharge, he still had significant bilateral hand weakness, although he could jog 50 yards.

Acalculous cholecystitis: Cyclospora trophozoites, merozoites, and oocysts demonstrated in gallbladder epithelium after resection. A 35 year-old man with history of HIV (CD4-11; noncompliant) developed Cyclospora infection and 5 days later developed acute right upper quadrant pain. He was admitted on day 10 of his illness. Because he was allergic to TMP-SMZ, he was treated with levofloxacin. On day 13 of his illness, he underwent a laparoscopic cholecystectomy. Pathology revealed acute and chronic cholecystitis and Cyclospora. Two weeks after surgery, his stool was negative for ova and parasites.

A 28 year-old man who had diarrhea for 6 months and a 46-year-old man who had diarrhea for 10 days, both with HIV, both treated with TMP-SMZ, developed right upper quadrant abdominal pain and elevated alkaline phosphatase levels. Gallbladder ultrasound demonstrated wall thickening in both patients. After TMP-SMZ treatment, symptoms resolved, alkaline phosphatase levels returned to normal, Cyclospora oocysts ceased to be excreted, and the ultrasound findings returned to normal. These findings suggest, but do not prove, Cyclospora -related reversible gallbladder pathology.

Reactive arthritis syndrome (RAS): RAS developed in a 31-year-old man with documented Cyclospora infection 5 months after the exposing event and approximately 2 months after the absence of Cyclospora on intestinal biopsies. He had not received TMP-SMZ because of sulfa allergy, and no other antibiotic was prescribed. At the time of the RAS diagnosis (dysuria, negative urinalysis, eye pain, documented iritis, arthralgias, right buccal painful ulcer), serology was negative for Lyme disease and chlamydia; HLA testing was negative for HLA-B27; and stools were negative for parasites. He responded dramatically to oral steroids and doxycycline.

Pulmonary conditions: Cyclospora has been isolated from the sputum of two patients: one with active tuberculosis and the other with weight loss, cough, and purulent sputum. Its role as a pulmonary pathogen is not clear.

Biliary disease: This condition has been reported in association with cyclosporiasis.

Prognosis

In immunocompetent patients, the prognosis is excellent.

In immunocompromised patients with HIV, diarrhea may last several months. After resolution, patients require prophylactic TMP-SMZ 3 times a week to prevent reinfection.

Patient Education

All travelers to developing countries should follow the food and water precautions outlined in Deterrence/Prevention.

Raspberries imported from developing countries may be contaminated with Cyclospora. Because of the nature of this berry, decontaminating with running water or the use of an iodine wash solution is considered very difficult, if not impossible. Anyone who is immunocompromised should be aware of the possibility of developing cyclosporiasis as a result of eating raspberries imported from developing countries.

Author

William H Shoff, MD, DTM&H, Former Director, PENN Travel Medicine; Former Associate Professor, Department of Emergency Medicine, Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

John W King, MD, Professor of Medicine, Chief, Section of Infectious Diseases, Director, Viral Therapeutics Clinics for Hepatitis, Louisiana State University Health Sciences Center; Consultant in Infectious Diseases, Overton Brooks Veterans Affairs Medical Center

Disclosure: Nothing to disclose.

Chief Editor

Pranatharthi Haran Chandrasekar, MBBS, MD, Professor, Chief of Infectious Disease, Department of Internal Medicine, Wayne State University School of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Jeffrey D Band, MD, FACP, FIDSA, Professor of Medicine, Oakland University William Beaumont School of Medicine; Health System Chair, Healthcare Epidemiology and International Medicine, Beaumont Health System; Former Chief of Infectious Diseases, Beaumont Hospital; Clinical Professor of Medicine, Wayne State University School of Medicine

Disclosure: Nothing to disclose.

Acknowledgements

Amy J Behrman, MD Associate Professor, Department of Emergency Medicine, Director, Division of Occupational Medicine, University of Pennsylvania School of Medicine

Amy J Behrman, MD is a member of the following medical societies: American College of Occupational and Environmental Medicine

Disclosure: Nothing to disclose.

Suzanne Moore Shepherd, MD, MS, DTM&H, FACEP, FAAEM Associate Professor, Education Officer, Department of Emergency Medicine, Hospital of the University of Pennsylvania; Director of Education and Research, PENN Travel Medicine

Suzanne Moore Shepherd, MD, MS, DTM&H, FACEP, FAAEM is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American Society of Tropical Medicine and Hygiene, International Society of Travel Medicine, Society for Academic Emergency Medicine, and Wilderness Medical Society

Disclosure: Nothing to disclose.

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Pattern of Spread Countries Comments
EndemicBangladesh, 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, ZimbabwePrevalence (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-relatedAustralia, Belgium, Czech Republic, Germany, Greece, Ireland, Italy, Japan, The Netherlands, Spain, Switzerland, United Kingdom, United States≤4% returning travelers with diarrhea
Foodborne outbreaksCanada, United States, Germany, MexicoCanada/United States: raspberries, blackberries, mesclun, basil‡; Germany: lettuce imported from Southern France/Southern Italy; Mexico: watercress
Waterborne outbreaksUnited States (Chicago), Nepal14 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