Cryptosporidium, Isospora, Cyclospora, and Microsporidia

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Chapter 275 Cryptosporidium, Isospora, Cyclospora, and Microsporidia

Patricia M. Flynn

The spore-forming intestinal protozoa Cryptosporidium, Isospora, and Cyclospora are important intestinal pathogens in both immunocompetent and immunocompromised hosts. Cryptosporidium, Isospora, and Cyclospora are coccidian parasites that predominantly infect the epithelial cells lining the digestive tract. Microsporidia were formerly considered spore-forming protozoa and have recently been reclassified as fungi. Microsporidia are ubiquitous, obligate intracellular parasites that infect many other organ systems in addition to the gastrointestinal tract and cause a broader spectrum of disease.

Cryptosporidium

Cryptosporidium is recognized as a leading protozoal cause of diarrhea in children worldwide and is a common cause of outbreaks in child-care centers; it is also a significant pathogen in immunocompromised patients.

Etiology

Cryptosporidium hominis and Cryptosporidium parvum cause most cases of cryptosporidiosis in humans. Disease is initiated by ingestion of infectious oocysts that release 4 sporozoites that invade enterocytes, primarily in the small intestine. The infection progresses through 2 stages: the asexual stage, which allows autoinfection at the luminal surface of the epithelium, and the sexual stage, which results in production of oocysts that are shed in the stools. The cysts are immediately infectious to other hosts or can reinfect the same host.

Epidemiology

Cryptosporidiosis is associated with diarrheal illness worldwide and is more prevalent in developing countries and among children <2 yr of age. It has been implicated as an etiologic agent of persistent diarrhea in the developing world and as a cause of significant morbidity and mortality from malnutrition, including permanent effects on growth.

Transmission of Cryptosporidium to humans can occur by close association with infected animals, via person-to-person transmission, or from environmentally contaminated water. Although zoonotic transmission, especially from cows, occurs in persons in close association with animals, person-to-person transmission is probably responsible for cryptosporidiosis outbreaks within hospitals and child-care centers where rates as high as 67% have been reported. Recommendations to prevent outbreaks in child-care centers include strict handwashing, use of protective clothes or diapers capable of retaining liquid diarrhea, and separation of diapering and food-handling areas and responsibilities.

Outbreaks of cryptosporidial infection have been associated with contaminated community water supplies and recreational waters in several states in the USA and the U.K. Wastewater in the form of raw sewage and runoff from dairies and grazing lands can contaminate both drinking and recreational water sources. It is estimated that Cryptosporidium oocysts are present in 65-97% of the surface water in the USA. The organism’s small size (4-6 µm in diameter), resistance to chlorination, and ability to survive for long periods outside a host create problems in public water supplies.

Clinical Manifestations

The incubation period is 2-14 days. Infection with Cryptosporidium is associated with profuse, watery, nonbloody diarrhea that can be accompanied by diffuse crampy abdominal pain, nausea, vomiting, and anorexia. Although less common in adults, vomiting occurs in >80% of children with cryptosporidiosis. Nonspecific symptoms such as myalgia, weakness, and headache also may occur. Fever occurs in 30-50% of cases. Malabsorption, lactose intolerance, dehydration, weight loss, and malnutrition often occur in severe cases. Recently, the clinical spectrum and disease severity has been linked with both the infecting species and host HLA class I and II alleles.

In immunocompetent persons, the disease is usually self-limiting, although diarrhea may persist for several weeks and oocyst shedding may persist many weeks after symptoms resolve. Chronic diarrhea is common in individuals with immunodeficiency, such as congenital hypogammaglobulinemia or HIV infection. Symptoms and oocyst shedding can continue indefinitely and may lead to severe malnutrition, wasting, anorexia, and even death.

Cryptosporidiosis in immunocompromised hosts is often associated with biliary tract disease, characterized by fever, right upper quadrant pain, nausea, vomiting, and diarrhea. It also has been associated with pancreatitis. Respiratory tract disease, with symptoms of cough, shortness of breath, wheezing, croup, and hoarseness, is very rare.

Diagnosis

Infection can be diagnosed by microscopy using modified acid-fast stain or polymerase chain reaction (PCR), but enzyme-linked immunoassays are the diagnostic method of choice. In stool, oocysts appear as small, spherical bodies (2-6 µm) and stain red with modified acid-fast staining. Because Cryptosporidium does not invade below the epithelial layer of the mucosa, fecal leukocytes are not found in stool specimens. Oocyst shedding in feces can be intermittent, and several fecal specimens (at least 3 for an immunocompetent host) should be collected for microscopic examination. Serologic diagnosis is not helpful in acute cryptosporidiosis.

In tissue sections, Cryptosporidium organisms can be found along the microvillus region of the epithelia that line the gastrointestinal tract. The highest concentration usually is detected in the jejunum. Histologic section results reveal villus atrophy and blunting, epithelial flattening, and inflammation of the lamina propria.

Treatment

Often the diarrheal illness due to cryptosporidiosis is self-limited in immunocompetent patients and requires no specific antimicrobial therapy. Treatment should focus on supportive care, including rehydration orally or, if fluid losses are severe, intravenously. Nitazoxanide (100 mg bid PO for 3 days for children 1-3 yr of age, 200 mg bid PO for children 4-11 yr of age; 500 mg bid PO for children ≥12 yr of age) has been approved for treatment of diarrhea caused by Cryptosporidium. Clinical studies have not demonstrated that nitazoxanide is superior to placebo in trials of HIV-infected or immunocompromised patients. In adult patients with AIDS, combination therapy with paromomycin (1 g bid PO) and azithromycin (600 mg/day PO) for 4 wk followed by paromomycin monotherapy for 8 wk has been used with limited success. Treatment with orally administered human serum immunoglobulin or bovine colostrum has been successful in several anecdotal reports.

Isospora

Like Cryptosporidium, Isospora belli has been implicated as a cause of diarrhea in institutional outbreaks and in travelers and has also been linked with contaminated water and food. Isospora appears to be more common in tropical and subtropical climates and in developing areas, including South America, Africa, and Southeast Asia. Isospora has not been associated with animal contact. It is also an infrequent cause of diarrhea in patients with AIDS in the USA but may infect up to 15% of AIDS patients in Haiti.

The life cycle and pathogenesis of infection with Isospora species are similar to those of Cryptosporidium organisms except that oocysts excreted in the stool are not immediately infectious and must undergo further maturation below 37°C. Histologic appearance of gastrointestinal epithelium reveals blunting and atrophy of the villi, acute and chronic inflammation, and crypt hyperplasia.

The clinical manifestations are indistinguishable from those of cryptosporidiosis, although fever may be a more common finding. Eosinophilia may be present, contrasting with other enteric protozoan infections. The diagnosis is established by detecting the oval, 22-33 µm long by 10-19 µm wide, oocysts by using modified acid-fast staining of the stool. Each oocyst contains 2 sporocysts with 4 sporozoites in each. Fecal leukocytes are not detected.

Isosporiasis responds promptly to treatment with oral trimethoprim-sulfamethoxazole (TMP-SMZ) (5 mg TMP and 25 mg SMZ/kg/dose; maximum 160 mg TMP and 800 mg SMZ/dose qid for 10 days, and then bid for 3 wk). In patients with AIDS, relapses are common and often necessitate maintenance therapy. Ciprofloxacin, nitazoxanide, or a regimen of pyrimethamine alone or with folinic acid is effective in patients intolerant of sulfonamide drugs.

Cyclospora

Cyclospora cayetanensis is a coccidian parasite similar to but larger than Cryptosporidium. The organism infects both immunocompromised and immunocompetent individuals and is more common in children <18 mo of age. The pathogenesis and pathologic findings of cyclosporiasis are similar to those of isosporiasis. Asymptomatic carriage of the organism has been found, but travelers who harbor the organism almost always have diarrhea. Outbreaks of cyclosporiasis have been linked with contaminated food and water. Implicated foods include raspberries, lettuce, snow peas, basil, and other fresh food items. After fecal excretion, the oocysts must sporulate to become infectious. This finding explains the lack of person-to-person transmission.

The clinical manifestations of cyclosporiasis are similar to those of cryptosporidiosis and isosporiasis and follow an incubation period of approximately 7 days. Moderate Cyclospora illness is characterized by a median of 6 stools/day with a median duration of 10 days (range 3-25 days). The duration of diarrhea in immunocompetent persons is characteristically longer in cyclosporiasis than in the other intestinal protozoan illnesses. Associated symptoms frequently include fatigue; abdominal bloating or gas; abdominal cramps or pain; nausea; muscle, joint, or body aches; fever; chills; headache; and weight loss. Vomiting may occur. Bloody stools are uncommon. Biliary disease has been reported. Intestinal pathology includes inflammation with villus blunting.

The diagnosis is established by identification of oocysts in the stool. Oocysts are wrinkled spheres, measure 8-10 µm in diameter, and resemble large Cryptosporidium organisms. Each oocyst contains 2 sporocysts, each with 2 sporozoites. The organisms can be seen by using modified acid-fast, auramine-phenol, or modified trichrome staining but stain less consistently than Cryptosporidium. They can also be detected with phenosafranin stain and by autofluorescence using strong green or intense blue under ultraviolet epifluorescence. New molecular diagnostic testing, including real-time PCR, is currently under investigation. Fecal leukocytes are not present.

The treatment of choice for cyclosporiasis is TMP-SMZ (5 mg TMP and 25 mg SMZ/kg/dose bid PO for 7 days, maximum 160 mg TMP and 800 mg SMZ/dose). Ciprofloxacin or nitazoxanide is effective in patients intolerant of sulfonamide drugs.

Microsporidia

Microsporidia are ubiquitous and infect most animal groups, including humans. At least 14 species of the phylum Microsporidia have been linked with human disease in both immunocompetent and immunocompromised hosts. The species most commonly associated with gastrointestinal disease are Enterocytozoon bieneusi and Encephalitozoon intestinalis.

Although still not definitive, the source of human infections is likely zoonotic. Like Cryptosporidium, there is concern for water-borne transmission through occupational and recreational contact with contaminated water sources. There is also the potential for food-borne outbreaks; the organisms have been identified on vegetables as a consequence of contaminated irrigation water. Vector-borne transmission is hypothesized because one species, Brachiola algerae, typically infects mosquitoes. Finally, transplacental transmission has been reported in animals but not in humans. Once infected, intracellular division produces new spores that can spread to nearby cells, disseminate to other host tissues, or be passed into the environment via feces. Spores also have been detected in urine and respiratory epithelium, suggesting that some body fluids may also be infectious. Once in the environment, microsporidial spores remain infectious for up to 4 mo.

Initially, microsporidial intestinal infection had been almost exclusively reported in patients with AIDS, but there is increasing evidence that immunocompetent individuals are also commonly infected. Microsporidia-associated diarrhea is intermittent, copious, watery, and nonbloody. Abdominal cramping and weight loss may be present; fever is unusual. Disseminated disease involving most organs, involving liver, heart, kidney, bladder, biliary tract, lung, bone, skeletal muscle, and sinuses, has been reported.

Microsporidia stain with hematoxylin-eosin, Giemsa, Gram, periodic acid–Schiff, and acid-fast stains but are often overlooked because of their small size (1-2 µm) and the absence of associated inflammation in surrounding tissues. Electron microscopy remains the reference method of detection. Multiple research laboratories report success with PCR technology in detecting microsporidia, both in human and environmental samples.

There is no proven therapy for microsporidial intestinal infections. E. intestinalis infection usually responds to albendazole (adult dose 400 mg bid PO for 3 wk). Fumagillin (adult dose 20 mg tid PO for 2 wk) was effective in a small controlled study. Atovaquone and nitazoxanide have also been reported to decrease symptoms, but controlled clinical trials have not been performed. Improvement in underlying HIV infection with aggressive antiviral therapy also improves microsporidiosis symptoms.

Bibliography

Abubakar I, Aliyu SH, Arumugam C, et al: Prevention and treatment of cryptosporidiosis in immunocompromised patients, Cochrane Database Syst Rev CD004932, 2007.

Cama VA, Ross JM, Crawford S, et al. Differences in clinical manifestations among Cryptosporidium species and subtypes in HIV-infected persons. J Infect Dis. 2007;196:684-691.

Chen X-M, Keithly JS, Paya CV, et al. Cryptosporidiosis. N Engl J Med. 2002;346:1723-1731.

Didier ES, Weiss LM. Microsporidiosis: current status. Curr Opin Infect Dis. 2006;19:485-492.

Huang DB, Chappell C, Okhuysen PC. Cryptosporidiosis in children. Semin Pediatr Infect Dis. 2004;15:253-259.

Kirkpatrick BD, Haque R, Duggal P, et al. Association between Cryptosporidium infection and human leukocyte antigen class I and class II alleles. J Infect Dis. 2008;197:474-478.

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Tremoulet AH, Avila-Aguero ML, Paris MM, et al. Albendazole therapy for Microsporidium diarrhea in immunocompetent Costa Rican children. Pediatr Infect Dis J. 2004;23:915-918.

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