Cryptosporidiosis is the infection in humans and animals with Cryptosporidium species, which are protozoan, obligate intracellular parasites. These were first discovered in mice in 1912 and first linked with disease in man in 1976. A single species was first thought to cause disease in man but now several species have been identified. Cryptosporidium hominis is found only in humans and this, together with Cryptosporidium parvum (which also infects cattle), are amongst the most common species found in man.¹

It has emerged as an important cause of diarrhoeal illness worldwide, particularly in young children and immunocompromised patients.² The clinical problems associated with Cryptosporidium spp. are being recognised more widely and the parasite was included in the World Health Organization's 2004 list of diseases that "exhibit a considerable and increasing global burden, and impair the ability of those infected to achieve their full potential, both developmentally and socio-economically".²

Pathophysiology

Cryptosporidial oocysts when ingested are immediately infectious at quite low doses (10 to 1,000 oocysts required to produce human disease). Oocysts attach to cells of the small bowel and invade the cells of the intestine. They become intracellular but extracytoplasmic and are resistant to treatment. The life cycle is completed in the host and large numbers of oocytes are then excreted with the potential to spread the infection. The oocytes are resistant to quite harsh environmental conditions and can resist chlorine levels used in water treatment.
Cryptosporidia cause diarrhoea in a number of different ways, including malabsorption. Essentially, all are part of the host response to infection. In normal subjects the infection is confined to small intestine but, in the immunocompromised (for example AIDS and congenital immunodeficiency), it may spread to the biliary tree.

Epidemiology

• About 30% of the adult population in the USA will be seropositive.
• In the UK about 5-6,000 cases are reported annually.
• Before the advent of highly active retroviral treatment, 10-15% of AIDS patients developed cryptosporidiosis but the incidence has fallen, as have other opportunistic infections with better treatments.
• Asymptomatic carriage of the organism is possible and a recent study of young children in day care nurseries found 3 out of 230 (1.3%) were carrying the parasite without any symptoms.²
• In developing countries, high percentages of children are infected. In some countries studies show that as many as 90% of children under the age of five are infected. Oocysts are present in stools in about 4% of stools in the USA and three to four times more frequently in developing countries.
• The high prevalence of AIDS in developing countries is associated with a high prevalence of cryptosporidiosis (found in as many as 50% of patients with diarrhoea).
• Children with acute leukaemia seem also to be at risk from cryptosporidiosis.³
• Interestingly, epidemic peaks in incidence have been identified in spring and autumn coinciding with high precipitation.⁴ This can occur where the water supply is from underground sources of drinking water.⁵

Risk factors

The risk factors for acquisition of cryptosporidiosis are determined by the modes of transmission. Transmission is:

• Direct from livestock (common).⁶ Beware of risk from:
  • Farms or petting zoos (especially in young ruminants).
  • Contact with animal dung (for example during outdoor recreation).
• From personal contact with infected individuals (who may or may not have symptoms). Beware particularly of the risk within playgroups, nurseries and day centres.
• Waterborne. Note that new standards relating to monitoring of water supply were introduced in 2000 in the UK.⁷ Beware of risk from:
  • Contaminated water supply.^8,9
  • Contamination of swimming pools and other water-based recreation sites.
  • Through travel to less developed countries.
• Foodborne (salads, meat products, unpasteurised dairy products and milk).¹⁰
• From infected patients in hospital.

Presentation

• The incubation period is dose-dependent and typically 5-10 days. However, it can be less and also up to 28 days.
• Can be asymptomatic in developing countries; rarely so in developed countries.
• The fever is characteristically low-grade and a fever over 39°C should alert to other infections.
• In healthy subjects it presents with:²
  • Mild fever (59% of consulting patients).
  • General malaise progressing rapidly to further symptoms.
  • Sudden onset of watery diarrhoea (often green and offensive, sometimes with blood) accompanied by abdominal cramps, nausea and anorexia (96% of consulting patients).
  • Symptoms are prolonged and last on average for two weeks but can persist for up to one month.
  • Relapse of symptoms, indicating persistent infection, occurs in over a third of cases.
  • Other more protracted symptoms following infection have been reported (headaches, dizzy spells, fatigue, joint pains), more commonly with C. hominis.¹¹
  • Illness can be severe enough to necessitate admission to hospital (14% of patients in one study).²

Immunocompromised patients

Those patients most at risk are those with:²

• T-cell immune deficiency (including those with haematological malignancies - especially children).
• Patients with HIV infection and CD4 counts lower than 200 cells/mm³ (and in particular those with counts below 50 cells/mm³).
• Patients with primary T-cell deficiencies (for example, severe combined immunodeficiency)

Immunocompromised patients:

• Commonly experience more chronic symptoms.
• Have more widespread infection within the gastrointestinal tract which may involve the pancreatic duct and gallbladder.
• Can experience more profuse diarrhoea with almost cholera-like intensity, accompanied by dehydration, malabsorption and collapse.³
• Experience more complications. With biliary complications, right upper quadrant pain and vomiting may be prominent.³

Differential diagnosis

This includes the range of other forms of gastroenteritis including:

• Campylobacter enteritis
• E. coli enteritis
• Salmonellosis
• Shigellosis
• Giardiasis
• Viral gastroenteritis
• Amoebiasis

Investigations

• Request stool microscopy for oocysts. However, routine requests may not include microscopy for Cryptosporidium. It is important to specify this request where infection is suspected. Special tests and staining can be used, including immunofluorescent assays, enzyme-linked immunosorbent assay (ELISA) and the most sensitive polymerase chain reaction (PCR) assays.¹²
• Stool culture.
• Urea and electrolytes; liver function tests may be necessary in more protracted infection.
• Other tests of immune function may be required in the immunocompromised (e.g. CD4 counts, etc).

Management

Immunocompetent patients

In healthy individuals, the disease is self-limiting and requires no treatment other than routine rehydration measures.

Immunocompromised patients

In malnourished or immunocompromised patients, drug management can be more complicated and should be referred for specialist advice. The aim of treatment is symptomatic improvement and clearance of the infection. Complete clearance of the parasite is unlikely without correction of the immunodeficiency.

• Treatment of the immunodeficiency:
  • In patients with HIV, highly active antiretroviral therapy (HAART) is the treatment of choice. These are given in combination after the antiparasitic drugs, to assist absorption of subsequent antiretroviral drugs.^13,14
  • Protease inhibitors can produce dramatic improvements in clinical response. As well as improving the CD4 cell level and restoring a degree of immunity, protease inhibitors have reduced cryptosporidial host cell invasion and parasite development in vitro.²
  • In other patients, improving immunity can also lead to improvement. For example, reduction of immunosuppression in transplant patients has been associated with parasite clearance and resolution of complications.
• Specific treatment:
  • Nitazoxanide is not licensed in the UK but is available on a named patient basis. It shortens duration and reduces mortality in malnourished children.
  • Nitazoxanide is well tolerated with a good safety profile.
  • Nitazoxanide, paromomycin and azithromycin are only partially effective and results with cryptosporidiois in AIDS patients remain disappointing.
  • All the drugs currently available in the UK are of unproven benefit and unlicensed for treatment of cryptosporidiosis. Trials are small and evidence is conflicting. Drugs include the aminoglycoside paromomycin, and macrolides such as spiramycin, azithromycin, and clarithromycin.

Complications

These are more common in immunocompromised patients. For example:

• Pancreato-biliary infection leading to pancreatitis, cholecystitis (acalculous), sclerosing cholangitis and, rarely, subsequent biliary cirrhosis. Papillary stenosis has also been reported.³
• Tracheo-bronchial and sinus involvement (rare).
• Pneumatosis cystoides intestinalis (cysts containing gas occur in the gut wall) occurs rarely in cryptosporidiosis with advanced HIV infection. Cysts can rupture causing pneumoretroperitoneum and pneumomediastinum.

Acalculous cholecystitis may need treating with cholecystectomy. Lactose intolerance may develop and need dietary advice. Complications are unusual in the immune-competent person.

Prognosis

In healthy patients the condition is self-limiting and a full recovery is normal. With complications or in immunocompromised patients the prognosis will be determined by the nature of the complication and by the underlying condition.
Prolonged diarrhoea of more than a month and biliary disease carry a poor prognosis in AIDS.³

Prevention

• Boiling water to kill oocysts:
  • When contamination of water supply is notified.³
  • When T-cell function is compromised.² Special filtration or boiling of water in high-risk patients is recommended.¹⁵The Department of Health in England advises that those with compromised T-cell function should boil all drinking water (including bottled water) to reduce the risk of infection.²
• Boiling or filtration¹⁶ of water is also recommended in countries with high rates of contamination and/or transmission.
• In particular, avoid newborn animals, including pets, especially in the immunocompromised.
• Healthcare workers and childcare workers should prevent faecal-oral spread with wearing of gloves and with hand washing.

Document references

1. Hunter PR, Thompson RC; The zoonotic transmission of Giardia and Cryptosporidium.; Int J Parasitol. 2005 Oct;35(11-12):1181-90. [abstract]
2. Davies AP, Chalmers RM; Cryptosporidiosis. BMJ. 2009 Oct 19;339:b4168. doi: 10.1136/bmj.b4168.
3. Hunter PR, Nichols G; Epidemiology and clinical features of Cryptosporidium infection in immunocompromised patients.; Clin Microbiol Rev. 2002 Jan;15(1):145-54. [abstract]
4. Naumova EN, Christodouleas J, Hunter PR, et al; Effect of precipitation on seasonal variability in cryptosporidiosis recorded by the North West England surveillance system in 1990-1999.; J Water Health. 2005 Jun;3(2):185-96. [abstract]
5. Hunter PR; Climate change and waterborne and vector-borne disease.; J Appl Microbiol. 2003;94 Suppl:37S-46S. [abstract]
6. Hunter PR, Hughes S, Woodhouse S, et al; Sporadic cryptosporidiosis case-control study with genotyping.; Emerg Infect Dis. 2004 Jul;10(7):1241-9. [abstract]
7. Barrell RA, Hunter PR, Nichols G; Microbiological standards for water and their relationship to health risk.; Commun Dis Public Health. 2000 Mar;3(1):8-13. [abstract]
8. Howe AD, Forster S, Morton S, et al; Cryptosporidium oocysts in a water supply associated with a cryptosporidiosis outbreak.; Emerg Infect Dis. 2002 Jun;8(6):619-24. [abstract]
9. Hunter PR, Colford JM, LeChevallier MW, et al; Waterborne diseases.; Emerg Infect Dis. 2001;7(3 Suppl):544.
10. Dawson D; Foodborne protozoan parasites.; Int J Food Microbiol. 2005 Aug 25;103(2):207-27. [abstract]
11. Hunter PR, Hughes S, Woodhouse S, et al; Health sequelae of human cryptosporidiosis in immunocompetent patients.; Clin Infect Dis. 2004 Aug 15;39(4):504-10. Epub 2004 Aug 2. [abstract]
12. Carey CM, Lee H, Trevors JT; Biology, persistence and detection of Cryptosporidium parvum and Cryptosporidium hominis oocyst.; Water Res. 2004 Feb;38(4):818-62. [abstract]
13. Smith HV, Corcoran GD; New drugs and treatment for cryptosporidiosis.; Curr Opin Infect Dis. 2004 Dec;17(6):557-64. [abstract]
14. Mofenson LM, Oleske J, Serchuck L, et al; Treating opportunistic infections among HIV-exposed and infected children: recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America.; MMWR Recomm Rep. 2004 Dec 3;53(RR-14):1-92. [abstract]
15. Colford JM Jr, Saha SR, Wade TJ, et al; A pilot randomized, controlled trial of an in-home drinking water intervention among HIV + persons.; J Water Health. 2005 Jun;3(2):173-84. [abstract]
16. Goh S, Reacher M, Casemore DP, et al; Sporadic cryptosporidiosis decline after membrane filtration of public water supplies, England, 1996-2002.; Emerg Infect Dis. 2005 Feb;11(2):251-9. [abstract]

Acknowledgements