Cryptosporidium

OVERVIEW: What every clinician needs to know

Parasite name and classification

Cryptosporidium spp. – intracellular protozoan parasite.

Two species are responsible for most human infections: Cryptosporidium hominis, which primarily infects humans; and Cryptosporidium parvum, which infects humans and animals, such as cattle. Species distinction between C. hominis and C. parvum is quite recent, and for several years, both parasites were referred to as C. parvum (genotypes 1 and 2). Other species have also been reported to cause disease in humans, including C. felis, C. meleagridis, C. canis, and C. muris.

What is the best treatment?

Treatment of cryptosporidiosis in immunocompetent patients

In most immunocompetent patients, cryptosporidiosis is self-limited, and, in many cases, no pharmacological treatment is required.
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When a decision is made to treat, nitazoxanide, a nitrothiazolyl-salicylamide derivative, is the treatment of choice for cryptosporidiosis in immunocompetent adults and children.
Adverse events associated with nitazoxanide are limited and typically mild, and no important drug-drug interactions have been reported.
In two randomized control trials (RCTs), a 3-day course of nitazoxanide administered to HIV-seronegative adults and children with cryptosporidiosis was shown to result in higher rates of diarrhea resolution and oocyst-free stools when compared to placebo.
In another RCT, a 3-day course of nitaxozanide was shown to reduce the duration of both diarrhea and C. parvum oocyst shedding among HIV-seronegative children.
Current US treatment guidelines recommend as first-line treatment in non-HIV infected adults and children for more than 12 years: nitazoxanide 500mg PO bid x 3d; in children 1-3 years of age, 100mg PO bid x 3d; and in children 4-11 years of age, 200mg PO bid x 3d.
Nitazoxanide is the only FDA approved agent for the treatment of cryptosporidiosis.

Treatment of cryptosporidiosis in immunocompromised patients

The treatment of cryptosporidiosis in immunocompromised patients remains controversial because of the limited evidence for effective treatment options.
In the setting of severe immunosuppression in HIV-infected individuals, the use of combination anti-retroviral therapy (cART) with immune restoration to a CD4+ count greater than 100cells/µL leads to resolution of clinical cryptosporidiosis and is the mainstay of treatment.
Where possible, cART should include a boosted protease inhibitor, as these drugs may have anti-cryptosporidial activity and can be synergistic in combination with nitazoxanide.

Alternative agents

The main alternative agent is paromomycin, an oral aminoglycoside that is poorly absorbed by the gut epithelium and has been suggested to have a modest activity against cryptosporidium in several small and mostly uncontrolled clinical studies.
A combination of paromomycin and azithromycin, in combination with effective cART, may also be tried to decrease diarrhea in chronic cryptosporidiosis.

What are the clinical manifestations of infection with this organism?

Key symptoms of the disease

Infection with Cryptosporidium spp. can result in a wide range of manifestations, from asymptomatic infections to severe, life-threatening illness. Manifestations can be significantly different in immunocompromised and immunocompetent people.

Asymptomatic infection

Asymptomatic infection can occur in immunocompetent and immunodeficient patients.
As many as 30% of childhood infections have been reported asymptomatic.
Rates of asymptomatic infection in HIV-positive patients are reported to be 1-5% but may be higher in patients with C. hominis as compared to patients with C. parvum infection (14 versus 2% in a small study).

Symptomatic gastrointestinal cryptosporidiosis

The duration and severity of clinical symptoms depends largely on the immune status of the infected individual.
The incubation period is dose dependent but is generally 3-12 days.
In immunocompetent individuals, symptoms are typically self-limited and last approximately 5-14 days.
Immunocompromised patients commonly experience chronic or intractable disease. In these individuals, especially in HIV/AIDS patients with CD4 counts less than 100/ mm³, cryptosporidiosis may present as chronic diarrhea or severe, life-threatening illness, leading to wasting, malabsorption of anti-retroviral drugs, and reduced life expectancy.
Severe disease has also been reported in bone marrow and solid-organ transplant patients.
The most common clinical feature is watery diarrhea accompanied by abdominal cramps (seen in 96% of patients who present for consultation).
Other features include: vomiting, mild fever, dehydration, loss of appetite, abdominal pain.
Occasionally, patients may also complain of myalgia, weakness, malaise, headache, and anorexia.

Extra-intestinal disease

Biliary tract involvement is commonly seen in patients with AIDS and can result in acalculous cholecystitis, sclerosing cholangitis, hepatitis, and pancreatitis. These patients may present with right upper quadrant pain, nausea, vomiting, and fever, and may have simultaneous diarrhea.
Respiratory tract involvement has been described, but it is unclear whether the organism is a true pathogen or merely colonizes the respiratory tract. Symptoms reported include cough, shortness of breath, wheeze, and hoarseness.

Key physical findings of the disease

Watery diarrhea (stool volumes may range from 1-25 liters/day)
Dehydration
Mid-epigastric or RUQ pain/tenderness (biliary tract involvement)
Jaundice (in biliary tract involvement)

Do other diseases mimic its manifestations?

Major diseases that can mimic this parasitic disease include:

Giardiasis (Giardia lamblia infection)
Isosporiasis (Isospora belli infection)
Cyclosporiasis (Cyclospora cayetanensis infection)
Amoebiasis (Entamoeba histolytica infection)
Dientamoeba fragilis infection Irritable bowel syndrome inflammatory bowel disease
Blastocystis hominis (pathogenic role is still somewhat controversial)
Coeliac disease

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

The metabolic panel is usually normal, except in severe cases in which there may be elevated blood urea nitrogen (BUN) and reductions in serum bicarbonate.
There may be mild liver enzyme abnormalities, especially if there is biliary involvement (mainly obstructive picture).

Results that confirm the diagnosis

Diagnosis can be made by microscopic identification of the oocysts in stool or tissue. Cryptosporidium oocysts are smaller (4-5µm in diameter) than the fecal stages of most other parasites. Stool sample:

Oocysts can be identified by stool microscopy (with or without stool concentration). Modified acid-fast stains are usually used, although the organisms can also be seen using hematoxylin and eosin (H&E) staining, Giemsa, or malachite green staining.
Among those with profuse diarrhea, a single stool specimen is usually sufficient for diagnosis; however, the sensitivity of a single specimen may be insufficient, so several samples should be tested before a negative diagnostic interpretation is reported.
Stool specimens may be submitted fresh, preserved in formalin, or suspended in storage medium. Oocysts in stool specimens remain infective for extended periods; therefore, stool specimens should be preserved in formalin to render oocyts nonviable.
Fecal specimens usually lack leukocytes and erythrocytes.
On H&E staining, developmental stages of cryptosporidium appear as small, spherical, basophilic bodies, 2-5µm in size, either alone or in clusters on the brush border of the intestinal mucosa.
Because infection can be patchy, biopsy specimens may be less sensitive than stool examination.
Cryptosporidium oocysts can also be identified in paraffin-embedded tissue sections using indirect immunofluorescent-antibody (IFA) techniques.
Polymerase chain reaction (PCR) testing has the advantage of being able to differentiate between Cryptosporidium genotypes but is only available in specialized research laboratories.
A commercially available PCR- enzyme-linked immunosorbent assay (ELISA)-based method also allows for detection and genotyping of cryptosporidium in biological samples and, compared to microscopy, has been demonstrated to have a sensitivity and specificity of 97 and 100%, respectively.
Although serologic assays using IFA or ELISA for the detection of Cryptosporidium-specific antibodies are available, they are generally used only as an epidemiologic tool, because antibody persistence limits their usefulness in the diagnosis of acute infection.
Small intestinal biopsy can demonstrate cryptosporidial enteritis. The organism appears basophilic with H&E staining, and occurs alone or in clusters in various developmental stages on the brush border of the mucosal epithelial surfaces.
Transmission electron microscopy reveals distinct life cycle forms, each within a parasitophorous vacuole confined to the microvillous region of the host cell.

What imaging studies will be helpful in making or excluding the diagnosis of cryptosporidium?

Imaging studies are not useful in cryptosporidiosis but may be useful in ruling other diagnoses in or out.

What complications can be associated with this parasitic infection, and are there additional treatments that can help to alleviate these complications?

Although the small intestine is the most commonly affected site, in immune compromised patients the entire gastrointestinal tract can be affected, including the pancreatic duct and gall bladder. This can lead to pancreatitis, sclerosing cholangitis, and, rarely, subsequent biliary cirrhosis.
Patients with HIV/AIDS with CD4 counts less than 200/mm³ and patients with primary T-cell deficiencies, such as severe combined immunodeficiency and CD40- ligand deficiency (hyper IgM syndrome), are at more risk of pancreato-biliary infection.
Pulmonary tract infections have also been reported, generally as a rare, late-stage complication of chronic intestinal infection in persons with HIV/AIDS.
Rarely, in advanced HIV, cryptosporidiosis is associated with pneumatosis cystoides intestinalis in which cysts containing gas occur in the gut wall and can rupture, leading to pneumoretroperitoneum and pneumomediastinum.
In malnourished children in developing countries, cryptosporidiosis can have negative long-term effects on growth, weight gain, and physical and cognitive development. Malnutrition is both a contributing factor to, and a result of, Cryptosporidium spp. infection.

What is the life cycle of the parasite, and how does the life cycle explain infection in humans?

Parasite life cycle

Sporulated oocysts (containing four sporozoites) are the infective stage of Cryptosporidium spp and may be excreted by humans or animals into the environment.
Oocysts are infective on excretion, thus, permitting direct and immediate fecal-oral transmission. Oocysts can survive for prolonged periods in damp soil.
The infectious dose depends on the infecting strain, with as few as ten oocysts sufficient to cause infection.
Sporulated oocysts are ingested by the host and undergo excystation in the gastrointestinal tract.
The sporozoites are released into the intestinal lumen and invade epithelial cells, particularly in the terminal ileum.
The parasites then undergo replication via asexual (schizogony or merogony) and then sexual cycles (gametogony) within a parasitophorus vacuate located in the intestinal (and possibly respiratory) epithelial cells, eventually producing microgamonts (male) and macrogamonts (female).
On fertilization of the macrogamonts by the microgametes, oocysts develop that sporulate in the infected host.
Two different types of oocysts are produced. The thick-walled oocyst is commonly excreted from the host in feces, and is the form seen on microscopy. The thin-walled oocyst is primarily involved in autoinfection and is able to undergo excystation in the gastrointestinal tract (Figure 1).
Cryptosporidiosis is transmitted via the fecal-oral route either by ingestion of contaminated water or food or by direct person-to-person (anthroponotic) or animal-to-person (zoonotic) contact.
Animal vectors include cows, sheep, cats, dogs, and rodents.
Waterborne outbreaks of cryptosporidiosis have been reported all over the world and may be related to contamination of drinking water or contamination of recreational water sources, such as swimming pools and water parks.
Food-borne infection occurs less frequently, but it has been tied to contaminated apple cider, unpasteurized milk and raw produce.
A recent meta-analysis revealed that, in tropical locations, precipitation is a strong seasonal driver for cryptosporidiosis, whereas temperature is the main driver for cryptosporidiosis in mid-latitude and temperature climates.
In the United States, cases of cryptosporidiosis peak in July-September, coinciding with peak times for swimming.
In the United Kingdom, C. parvum infections peak in spring and C. hominis peaks in late summer and autumn.
Cryptosporidium oocysts are resistant to chlorination and can survive in water for prolonged periods of time.
Temperature is a critical parameter in the survival and infectivity of oocysts shed into the environment (higher temperatures increase metabolic activity and decrease autonomous survival and infectivity).
Oocysts can be killed by freezing or removed by filtration.
Exposure to sunlight reduces oocyst viability, with studies suggesting 12 hours of strong sunlight leading to a reduction in oocyst viability from 98 to 0.3%. Isolated UV light is rapidly germicidal for Cryptosporidium spp.
Cryptosporidiosis is prevalent worldwide, and Cryptosporidium spp. have been identified on every continent, except Antarctica. The prevalence varies widely among different geographic regions and populations at risk.
Seroprevalence studies suggest much higher rates of infection than reports based on detection of the parasite in the stool and range from 30 to 89%, depending on age, geographic location and drinking water source.
In patients with HIV/AIDS, reported prevalence rates of cryptosporidiosis vary widely, ranging from 0 to 100%, with a median of 32%. Rates of infection among HIV-positive patients in Europe have been reported as 6.6%, and those in Los Angeles in the United States as 3.8%.
Children and AIDS patients in resource-poor settings are disproportionately affected.
Cryptosporidiosis is also associated with sporadic, often water-related outbreaks of self-limited diarrhea in immunocompetent hosts. A large outbreak in Milwaukee, WI, in 1993 was reported to affect more than 400,000 people.
In the United States, Cryptosporidium spp. infections have recently been reported as increasing, most likely because of increased detection of recreational water outbreaks.
Cryptosporidiosis is significantly more common among HIV-infected patients than seronegative individuals.
The risk of severe and/or prolonged disease is increased in patients with immunosuppression from a range of different causes, including patients with HIV, patients undergoing chemotherapy, organ transplantation patients, those with IgA deficiency, and those with hypogammaglobulinemia.
Children younger than 5 years of age are at more risk of infection, as are children within a child care program. Children in resource-poor settings are particularly at risk, not only with an increased incidence of Cryptosporidium spp. infection, but also with increased acute and long-lasting morbidity.
Travelers are also at risk, with studies suggesting that Cryptosporidium spp. is the causative organism in approximately 10% of cases of traveler’s diarrhea.
Other risk factors include ingestion of contaminated recreational or drinking water, drinking well water, swimming in fresh water or public pools, contact with children in child care or children who wear diapers, contact with infected persons, and contact with farm or domestic animals. Outbreaks related to public swimming pools occur commonly.

Infection control issues

No chemoprophylaxis is recommended.
No vaccine is available.
Ordinary water disinfection processes do not kill Cryptosporidium, and filtering is required to remove the parasite.
Patients with diarrheal illness should be advised not to go swimming; patients with confirmed diagnosis of cryptosporidiosis should be discouraged from using swimming pools for 2 weeks after diarrhea has stopped, because oocysts can still be shed during this time.
Fruit and vegetables should be washed in filtered water.
Because filtering can remove Cryptosporidium, it may be advisable for HIV-positive patients with low CD4 counts to filter their water before drinking if the quality of their water source is questionable.

How does this organism cause disease?

Cryptosporidium sporozoites, released from oocysts, are engulfed by the apical surface of the intestinal epithelium after recognition and attachment to surface receptors. Epithelial cell infection is associated with activation of nuclear factor κB, which activates anti-apoptotic mechanisms and also leads to up-regulation of a proinflammatory cascade with increased expression of cytokines and markers of inflammation, including TNFα, IL-1, IL-8, and lactoferrin.
Infection of the gut epithelium may result in villus flattening, resulting in malabsorption and diarrhea. The secretory component to the diarrhea may be due to increased substance P or prostaglandin production and disruption of the intestinal epithelium, which can inhibit NaCl absorption. The parasite may promote apoptosis in adjacent epithelial cells, while inhibiting apoptosis in the infected cells, thereby facilitating prolonged survival of the parasite.
Heavy infection in patients who have AIDS is associated with villous atrophy, crypt hyperplasia, and marked infiltration with lymphocytes, plasma cells and even neutrophils.
Cell-mediated immune responses play a crucial role in protection from, and resolution of, cryptosporidiosis. AIDS patients with CD4+ cell counts less than 50cells/mm³ are more likely to have a fulminant form of the disease.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

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Amadi, B, Mwiya, M, Musuku, J, Watuka, A, Sianongo, S, Ayoub, A, Kelly, P. “Effect of nitazoxanide on morbidity and mortality in Zambian children with cryptosporidiosis: a randomised controlled trial”. Lancet. vol. 360. 2002. pp. 1375-80.

Borad, A, Ward, H. “Human immune responses in cryptosporidiosis”. Future Microbiol. vol. 5. 2010. pp. 507-19.

Chen, XM, LaRusso, NF. “Cryptosporidiosis and the pathogenesis of AIDS-cholangiopathy”. Semin Liver Dis. vol. 22. 2002. pp. 277-89.

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Davies, AP, Chalmers, RM. “Cryptosporidiosis”. Brit Med J. vol. 339. 2009. pp. 963-7. (This source is an excellent review of the literature to date)

Duombo, O, Rossignol, JF, Pichard, E. “Nitazoxanide in the treatment of cryptosporidial diarrhea and other intestinal parasitic infections associated with acquired immunodeficiency syndrome in tropical Africa”. Am J Trop Med Hyg. vol. 56. 1997. pp. 637-9.

Garcia, L, Shimizu, R. “Evaluation of nine immunoassay kits (enzyme immunoassay and direct fluorescence) for detection of Giardia lamblia and Cryptosporidium parvum in human fecal specimens”. J Clin Microbiol. vol. 35. 1997. pp. 1526-9.

Guerrant, DI, Moore, SR, Lima, AA, Patrick, PD, Schorling, JB, Guerrant, RL. “Association of early childhood diarrhea and cryptosporidiosis with impaired physical fitness and cognitive function four-seven years later in a poor urban community in northeast Brazil”. Am J Trop Med Hyg. vol. 61. 1999. pp. 707-13.

Houpt, E, Bushen, O, Sam, N. “Asymptomatic Cryptosporidium hominis infection among human immunodeficiency virus-infected patients in Tanzania”. Am J Trop Med Hyg. vol. 73. 2005. pp. 520-2.

Huang, D, White, A. “An updated review on Cryptosporidium and Giardia”. Gastroenterol Clin North Am. vol. 35. 2006. pp. 291-314.

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Miao, YM, Awad-El-Kariem, FM, Franzen, C. “Eradication of cryptosporidia and microsporidia following successful antiretroviral therapy”. J Acquir Immune Defic Syndr. vol. 25. 2000. pp. 124-9.

Moore, JA, Frenkel, JK. “Respiratory and enteric cryptosporidiosis in humans”. Arch Pathol Lab Med. vol. 115. 1991. pp. 1160-2.

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Rossignol, JF. “Cryptosporidium and Giardia: treatment options and prospects for new drugs”. Exp Parasitol. vol. 124. 2010. pp. 45-53.

Rossignol, JF, Ayoub, A, Ayers, MS. “Treatment of diarrhea caused by Cryptosporidium parvum: a prospective randomized, double-blind, placebo-controlled study of Nitazoxanide”. J Infect Dis. vol. 104. 2001. pp. 103-6.

Rossignol, JF, Hidalgo, H, Feregrino, M. “A double-blind placebo-controlled study of nitazoxanide in the treatment of cryptosporidial diarrhoea in AIDS patients in Mexico”. Trans R Soc Trop Med Hyg. vol. 92. 1998. pp. 663-6.

Rossignol, JF, Kabil, SM, Younis, AM, El-Gohary, Y. “Double-blind placebo-controlled study of nitazoxanide in the treatment of cryptosporidial diarrhea in 90 immunocompetent adults and adolescents from the Nile delta of Egypt”. Clin Gastroenterol Hepatol. vol. 4. 2006. pp. 320-4.

Savin, C, Sarfati, C, Menotti, J. “Assessment of cryptodiag for diagnosis of cryptosporidiosis and genotyping Cryptosporidium species”. J Clin Microbiol. vol. 46. 2008. pp. 2590

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