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Cryptosporidiosis
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Epidemiology

Cryptosporidiosis is caused by various species of the protozoan parasite Cryptosporidium, which infect the small bowel mucosa, and in immunosuppressed persons, the large bowel and extra-intestinal sites. Persons at greatest risk for disease have advanced immunosuppression, typically CD4+ counts of <100 cells/µL (232Flanigan T, Whalen C, Turner J, et al. Cryptosporidium infection and CD4 counts. Ann Intern Med 1992;116:840-2.). The three most common species infecting humans are C. hominis, C. parvum, and C. meleagridis. Infections are usually caused by one species but might be mixed (233Cama V, Gilman RH, Vivar A, et al. Mixed Cryptosporidium infections and HIV. Emerg Infect Dis 2006;12:1025-8.).

In developed countries with low rates of environmental contamination where potent ART is widely available, cryptosporidiosis occurs at an incidence of <1 per 100 person-years among persons with AIDS. Infection occurs through ingestion of Cryptosporidium oocysts. Viable oocysts in feces can be transmitted directly through contact with infected humans or animals, particularly those with diarrhea. Oocysts can contaminate recreational water sources (e.g., swimming pools, lakes) and public water supplies and might persist despite standard chlorination (see Appendix: Food and Water-Related Exposures). Person-to-person transmission is common, especially among sexually active men who have sex with men (MSM). Young children with cryptosporidial diarrhea might infect adults during diapering and cleaning after defecation.

Clinical Manifestations

Patients with cryptosporidiosis most commonly have acute or subacute onset of profuse, nonbloody, watery diarrhea, accompanied often by nausea, vomiting, and lower abdominal cramping (234Goodgame RW. Understanding intestinal spore-forming protozoa: cryptosporidia, microsporidia, isospora, and cyclospora. Ann Intern Med 1996;124:429-41.). Fever is present in approximately one third of patients and malabsorption is common. The epithelium of the biliary tract and the pancreatic duct can be infected with Cryptosporidium, leading to sclerosing cholangitis and to pancreatitis secondary to papillary stenosis, particularly among patients with prolonged disease and low CD4+ counts (235de Souza Ldo R, Rodrigues MA, Morceli J, Kemp R, Mendes RP. Cryptosporidiosis of the biliary tract mimicking pancreatic cancer in an AIDS patient. Rev Soc Bras Med Trop 2004;37:182-5., 236Chen XM, LaRusso NF. Cryptosporidiosis and the pathogenesis of AIDS-cholangiopathy. Semin Liver Dis 2002;22:277-89., 237Chen C, Gulati P, French SW. Pathologic quiz case: a patient with acquired immunodeficiency syndrome and an unusual biliary infection. Arch Pathol Lab Med 2003;127:243-4., 238Ducreux M, Buffet C, Lamy P, et al. Diagnosis and prognosis of AIDS-related cholangitis. AIDS 1995;9:875-80.). Pulmonary infections also have been reported (239Moore JA, Frenkel JK. Respiratory and enteric cryptosporidiosis in humans. Arch Pathol Lab Med 1991;115:1160-2., 240Mercado R, Buck GA, Manque PA, Ozaki LS. Cryptosporidium hominis infection of the human respiratory tract. Emerg Infect Dis 2007;13:462-4.).

Diagnosis

Cryptosporidium species can be cultivated in vitro, but not as a routine diagnostic procedure. Diagnosis of cryptosporidiosis can be made by microscopic identification of the oocysts in stool or tissue. Acid-fast staining methods, with or without stool concentration, are most frequently used in clinical laboratories. Oocysts stain varying intensities of red with a modified acid-fast technique, permitting their differentiation from yeasts, which are of similar size and shape but are not acid fast. Cryptosporidium oocysts also can be detected by direct immunofluorescence, which offers the greatest sensitivity and specificity, or by enzyme-linked immunosorbent assays (ELISAs) (241Weber R, Bryan RT, Bishop HS, et al. Threshold of detection of Cryptosporidium oocysts in human stool specimens: evidence for low sensitivity of current diagnostic methods. J Clin Microbiol 1991;29:1323-7.). Molecular methods such as PCR are predicted to enhance sensitivity further. Cryptosporidial enteritis also can be diagnosed from small intestinal biopsy sections. The organism, which appears basophilic with hematoxylin and eosin staining, occurs alone or in clusters in various developmental stages on the brush border of the mucosal epithelial surfaces.

Among persons with profuse diarrheal illness, a single stool specimen is usually adequate for diagnosis. Among persons with milder disease, repeat stool sampling is recommended, although no controlled studies have demonstrated the utility of three consecutive stool samples as is the case in Giardia duodenalis infection.

Preventing Exposure

HIV-infected persons should be educated and counseled concerning the different ways that Cryptosporidium can be transmitted (BIII). Modes of transmission include having direct contact with infected adults, diaper-aged children, and infected animals; coming into contact with contaminated water during recreational activities; drinking contaminated water; and eating contaminated food.

Scrupulous handwashing can reduce the risk for diarrhea in HIV-infected persons, including diarrhea caused by Cryptosporidium (242Huang DB, Zhou J. Effect of intensive handwashing in the prevention of diarrhoeal illness among patients with AIDS: a randomized controlled study. J Med Microbiol 2007;56:659-63.). HIV-infected persons should be advised to wash their hands after potential contact with human feces (including after diapering small children) and after the following activities: handling pets or other animals, gardening or other contact with soil, before preparing food, before eating, and before and after sex (BIII). HIV-infected persons should avoid unprotected sex practices, especially practices that could lead to direct (e.g., oral-anal) or indirect (e.g., penile-anal) contact with feces. Patients should be advised to use barriers during sex to reduce such exposures (e.g., condoms, dental dams) (BIII).

HIV-infected persons (particularly those with CD4+ counts < 200 cells/µL), should avoid direct contact with diarrhea or stool from pets, particularly any stray pets, or dogs and cats aged <6 months (BIII). Gloves should be worn when handling feces or cleaning areas that might have been contaminated by feces from pets (BIII). HIV-infected persons should limit or avoid direct exposure to calves and lambs (e.g., farms, petting zoos) (BII). Paying attention to hygiene and avoiding direct contact with stool are important when visiting premises where these animals are housed or exhibited.

HIV-infected persons should not drink water directly from lakes or rivers (AIII). Waterborne infection also can result from swallowing water during recreational activities. HIV-infected persons should be aware that lakes, rivers, and salt water beaches and some swimming pools, recreational water parks, and ornamental water fountains might be contaminated with human or animal waste that contains Cryptosporidium. They should avoid swimming in water that is likely contaminated and should avoid swallowing water while swimming or playing in recreational water (BIII).

Outbreaks of cryptosporidiosis have been linked to drinking water from municipal water supplies. During outbreaks or in other situations that impose a community advisory to boil water, boiling water for at least 3 minutes will eliminate the risk for cryptosporidiosis (AIII). Using submicron personal-use water filters (home/office types) or bottled water might also reduce the risk for infection from municipal and well water (CIII).

The magnitude of the risk for acquiring cryptosporidiosis from drinking water in a non-outbreak setting is uncertain, and available data are inadequate to recommend that all HIV-infected persons boil water or avoid drinking tap water in non-outbreak settings. However, HIV-infected persons who wish to take independent action to reduce the risk for waterborne cryptosporidiosis might take precautions similar to those recommended during outbreaks. Persons who opt to use a personal-use filter or bottled water should be aware of the complexities involved in selecting appropriate products, the lack of enforceable standards for the destruction or removal of oocysts, the costs of the products, and the logistic difficulty of using these products consistently.

Persons who take precautions to avoid acquiring cryptosporidiosis from drinking water should be advised that ice made from contaminated tap water also can be a source of infection. Such persons also should be aware that fountain beverages served in restaurants, bars, theaters, and other places also might pose a risk because these beverages, and the ice they contain, are usually made from tap water. Nationally distributed brands of bottled or canned carbonated soft drinks are safe to drink. Commercially packaged noncarbonated soft drinks and fruit juices that do not require refrigeration until after they are opened (i.e., can be stored unrefrigerated on grocery shelves) are also safe. Nationally distributed brands of frozen fruit juice concentrate are safe if the user reconstitutes them with water from a safe water source. Fruit juices that must be kept refrigerated from the time they are processed to the time of consumption might be either fresh (i.e., unpasteurized) or heat-treated (i.e., pasteurized); only those juices labeled as pasteurized should be considered free of risk from Cryptosporidium. Other pasteurized beverages and beers also are considered safe to drink.

HIV-infected persons should avoid eating raw oysters because cryptosporidial oocysts can survive in oysters for >2 months and have been found in oysters taken from certain commercial oyster beds (BIII). In a hospital, standard precautions (i.e., use of gloves and handwashing after removal of gloves) should be sufficient to prevent transmission of cryptosporidiosis from an infected patient to a susceptible HIV-infected person (BIII). However, because of the potential for fomite transmission, some specialists recommend that HIV-infected persons, specifically persons who are severely immunocompromised, should not share a room with a patient with cryptosporidiosis (CIII).

If HIV-infected persons travel in developing countries, they should be warned to avoid drinking tap water or using tap water to brush their teeth (BIII). Ice that is not made from bottled water also should be avoided. Raw fruits or vegetables that might have been washed in tap water also should be avoided (BIII). HIV-infected persons also should avoid other sources of Cryptosporidium oocytes as much as possible (BIII). These include working directly with people with diarrhea; with farm animals, cattle, and sheep; and with domestic pets that are very young or have diarrhea. If exposure is unavoidable, then the use of gloves and good hand hygiene is recommended.

Preventing Disease

Because chronic cryptosporidiosis occurs primarily in persons with advanced immunodeficiency, appropriate initiation of ART before the patient becomes severely immunosuppressed should prevent this disease (AIII). Rifabutin (RIF) or clarithromycin, when taken for MAC prophylaxis, have been found to protect against cryptosporidiosis (243Holmberg SD, Moorman AC, Von Bargen JC, et al. Possible effectiveness of clarithromycin and rifabutin for cryptosporidiosis chemoprophylaxis in HIV disease. JAMA 1998;279:384-6., 244Fichtenbaum CJ, Zackin R, Feinberg J, Benson C, Griffiths JK. Rifabutin but not clarithromycin prevents cryptosporidiosis in persons with advanced HIV infection. AIDS 2000;14:2889-93.). However, data are insufficient to warrant a recommendation for using rifabutin or clarithromycin as chemoprophylaxis for cryptosporidiosis.

Treatment of Disease

In the setting of severe immunosuppression, ART with immune restoration to a CD4+ count >100 cells/µL leads to resolution of clinical cryptosporidiosis (50Carr A, Marriott D, Field A, Vasak E, Cooper DA. Treatment of HIV-1-associated microsporidiosis and cryptosporidiosis with combination antiretroviral therapy. Lancet 1998;351:256-61., 245Miao YM, Awad-El-Kariem FM, Franzen C, et al. Eradication of cryptosporidia and microsporidia following successful antiretroviral therapy. J Acquir Immune Defic Syndr 2000;25:124-9.) and is the mainstay of treatment. Therefore, patients with cryptosporidiosis should be offered ART as part of the initial management of their infection (AII). Management should include symptomatic treatment of diarrhea (AIII). Rehydration and repletion of electrolyte losses by either the oral or IV route are important. Severe diarrhea can exceed >10 L/day among patients with AIDS, often requiring intensive support. Oral rehydration should be pursued aggressively with oral rehydration solutions (AIII).

Multiple agents have been investigated in small randomized controlled clinical trials of HIV-infected adults, including nitazoxanide, paromomycin, spiramycin, bovine hyperimmune colostrum, and bovine dialyzable leukocyte extract. No pharmacologic or immunologic therapy directed specifically against C. parvum has been shown to be consistently effective when used without ART (246Abubakar I, Aliyu SH, Arumugam C, Hunter PR, Usman NK. Prevention and treatment of cryptosporidiosis in immunocompromised patients. Cochrane Databse Syst Rev 2007;24:4932., 247Abubakar I, Aliyu SH, Arumugam C, Usman NK, Hunter PR. Treatment of cryptosporidiosis in immunocompromised individuals: systematic review and meta-analysis. Br J Clin Pharmacol 2007;63:387-93.).

Nitazoxanide is an orally administered nitrothiazole benzamide with in vivo activity against a broad range of helminths, bacteria, and protozoa (248Rossignol 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 2001;184:103-6., 249Rossignol JF, Hidalgo H, Feregrino M, et al. 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 1998;92:663-6., 250Simon DM, Cello JP, Valenzuela J, et al. Multicenter trial of octreotide in patients with refractory acquired immunodeficiency syndrome-associated diarrhea. Gastroenterology 1995;108:1753-60.). It has been approved by the Food and Drug Administration (FDA) for treatment of C. parvum in children and adults. When administered for 3 days at 500 mg twice daily to HIV-uninfected adults with cryptosporidiosis, nitazoxanide resulted in higher rates of diarrhea resolution and oocyst-free stools than placebo (248Rossignol 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 2001;184:103-6.). HIV-infected adults with cryptosporidiosis with CD4+ >50 cells/µL treated with 500-1,000 mg twice daily of nitazoxanide for 14 days experienced substantially higher rates of parasitological cure and resolution of diarrhea than persons receiving placebo treatment (249Rossignol JF, Hidalgo H, Feregrino M, et al. 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 1998;92:663-6.). Data from a compassionate use program before the advent of combination ART, which included primarily white male adults with a median CD4+ count ≤50 cells/µL, reported that a majority of patients experienced some degree of clinical response (reduction in frequency of total stool and of liquid stools), usually within the first week of treatment (251Rossignol JF. Nitazoxanide in the treatment of acquired immune deficiency syndrome-related cryptosporidiosis: results of the United States compassionate use program in 365 patients. Aliment Pharmacol Ther 2006;24:887-94.). Adverse events associated with nitazoxanide are limited and typically mild, and no important drug-drug interactions have been reported. Because of the clinical significance of cryptosporidiosis, a trial of nitazoxanide in conjunction with ART, but never instead of ART, may be considered (CIII).

Paromomycin is a nonabsorbable aminoglycoside indicated for the treatment of intestinal amebiasis but not specifically approved for cryptosporidiosis. It is effective in high doses for the treatment of cryptosporidiosis in animal models (252Tzipori S, Rand W, Griffiths J, Widmer G, Crabb J. Evaluation of an animal model system for cryptosporidiosis: therapeutic efficacy of paromomycin and hyperimmune bovine colostrum-immunoglobulin. Clin Diagn Lab Immunol 1994;1:450-63.). A meta-analysis of 11 published studies of paromomycin in humans reported a response rate of 67%; however, relapses were common, with long-term success rates of only 33%. A Cochrane review and a meta-analysis of the two randomized controlled trials comparing paromomycin with placebo among patients with AIDS found the drug was no more effective than placebo at reducing diarrheal frequency or parasite burden (246Abubakar I, Aliyu SH, Arumugam C, Hunter PR, Usman NK. Prevention and treatment of cryptosporidiosis in immunocompromised patients. Cochrane Databse Syst Rev 2007;24:4932., 247Abubakar I, Aliyu SH, Arumugam C, Usman NK, Hunter PR. Treatment of cryptosporidiosis in immunocompromised individuals: systematic review and meta-analysis. Br J Clin Pharmacol 2007;63:387-93., 253Hewitt RG, Yiannoutsos CT, Higgs ES, et al. Paromomycin: no more effective than placebo for treatment of cryptosporidiosis in patients with advanced human immunodeficiency virus infection. Clin Infect Dis 2000;31:1084-92., 254White AC, Chappell CL, Hayat CS, et al. Paromomycin for cryptosporidiosis in AIDS: a prospective, double-blind trial. J Infect Dis 1994;170:419-24.). In persons with CD4+ counts <100 cells/µL, a substantial clinical response to paromomycin is rare. Therefore, data do not support a recommendation for the use of paromomycin for cryptosporidiosis (DII).

Treatment with antimotility agents (e.g., loperamide, tincture of opium) can palliate symptoms by reducing diarrheal frequency and volume, but these agents are not consistently effective (BIII). Octreotide, a synthetic octapeptide analog of naturally occurring somatostatin that is approved for the treatment of secreting tumor-induced diarrhea, is no more effective than other oral antidiarrheal agents and is usually not recommended (DII) (250).

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

Patients should be monitored closely for signs and symptoms of volume depletion, electrolyte and weight loss, and malnutrition. Total parenteral nutrition might be indicated in certain patients (CIII).

IRIS has not been described in association with treatment of cryptosporidiosis.

Management of Treatment Failure

Supportive treatment and optimizing ART to achieve full virologic suppression are the only feasible approaches to the management of treatment failure (AIII).

Preventing Recurrence

No pharmacologic interventions are known to be effective in preventing the recurrence of cryptosporidiosis.

Special Considerations During Pregnancy

As with nonpregnant women, initial treatment should rely on rehydration and initiation of ART (AII). Pregnancy should not preclude the use of ART. Nitazoxanide is not teratogenic in animals but human data on use in pregnancy are not available. Nitazoxanide may be used in pregnancy after the first trimester in severely symptomatic pregnant women (CIII).

Drug therapy for treatment and chronic maintenance therapy of AIDS-associated opportunistic infections in adults and adolescents: Cryptosporidiosis
Preferred therapy, duration of therapy, chronic maintenanceAlternative therapyOther options/issues
Excerpted from Table 2
Preferred therapyAlternative therapy for cryptosporidiosisUse of antimotility agents such as loperamide or tincture of opium might palliate symptoms (BIII)
transparent gifgrey bulletInitiate or optimize ART for immune restoration (AII)
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transparent gifgrey bulletSymptomatic treatment of diarrhea (AIII)
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transparent gifgrey bulletAggressive oral or IV rehydration & replacement of electrolyte loss (AIII)
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transparent gifgrey bulletA trial of nitazoxanide 500-1,000 mg PO bid with food for 14 days (CIII) + optimized ART, symptomatic treatment and rehydration & electrolyte replacement
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References

50. Carr A, Marriott D, Field A, Vasak E, Cooper DA. Treatment of HIV-1-associated microsporidiosis and cryptosporidiosis with combination antiretroviral therapy. Lancet 1998;351:256-61.
232. Flanigan T, Whalen C, Turner J, et al. Cryptosporidium infection and CD4 counts. Ann Intern Med 1992;116:840-2.
233. Cama V, Gilman RH, Vivar A, et al. Mixed Cryptosporidium infections and HIV. Emerg Infect Dis 2006;12:1025-8.
234. Goodgame RW. Understanding intestinal spore-forming protozoa: cryptosporidia, microsporidia, isospora, and cyclospora. Ann Intern Med 1996;124:429-41.
235. de Souza Ldo R, Rodrigues MA, Morceli J, Kemp R, Mendes RP. Cryptosporidiosis of the biliary tract mimicking pancreatic cancer in an AIDS patient. Rev Soc Bras Med Trop 2004;37:182-5.
236. Chen XM, LaRusso NF. Cryptosporidiosis and the pathogenesis of AIDS-cholangiopathy. Semin Liver Dis 2002;22:277-89.
237. Chen C, Gulati P, French SW. Pathologic quiz case: a patient with acquired immunodeficiency syndrome and an unusual biliary infection. Arch Pathol Lab Med 2003;127:243-4.
238. Ducreux M, Buffet C, Lamy P, et al. Diagnosis and prognosis of AIDS-related cholangitis. AIDS 1995;9:875-80.
239. Moore JA, Frenkel JK. Respiratory and enteric cryptosporidiosis in humans. Arch Pathol Lab Med 1991;115:1160-2.
240. Mercado R, Buck GA, Manque PA, Ozaki LS. Cryptosporidium hominis infection of the human respiratory tract. Emerg Infect Dis 2007;13:462-4.
241. Weber R, Bryan RT, Bishop HS, et al. Threshold of detection of Cryptosporidium oocysts in human stool specimens: evidence for low sensitivity of current diagnostic methods. J Clin Microbiol 1991;29:1323-7.
242. Huang DB, Zhou J. Effect of intensive handwashing in the prevention of diarrhoeal illness among patients with AIDS: a randomized controlled study. J Med Microbiol 2007;56:659-63.
243. Holmberg SD, Moorman AC, Von Bargen JC, et al. Possible effectiveness of clarithromycin and rifabutin for cryptosporidiosis chemoprophylaxis in HIV disease. JAMA 1998;279:384-6.
244. Fichtenbaum CJ, Zackin R, Feinberg J, Benson C, Griffiths JK. Rifabutin but not clarithromycin prevents cryptosporidiosis in persons with advanced HIV infection. AIDS 2000;14:2889-93.
245. Miao YM, Awad-El-Kariem FM, Franzen C, et al. Eradication of cryptosporidia and microsporidia following successful antiretroviral therapy. J Acquir Immune Defic Syndr 2000;25:124-9.
246. Abubakar I, Aliyu SH, Arumugam C, Hunter PR, Usman NK. Prevention and treatment of cryptosporidiosis in immunocompromised patients. Cochrane Databse Syst Rev 2007;24:4932.
247. Abubakar I, Aliyu SH, Arumugam C, Usman NK, Hunter PR. Treatment of cryptosporidiosis in immunocompromised individuals: systematic review and meta-analysis. Br J Clin Pharmacol 2007;63:387-93.
248. 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 2001;184:103-6.
249. Rossignol JF, Hidalgo H, Feregrino M, et al. 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 1998;92:663-6.
250. Simon DM, Cello JP, Valenzuela J, et al. Multicenter trial of octreotide in patients with refractory acquired immunodeficiency syndrome-associated diarrhea. Gastroenterology 1995;108:1753-60.
251. Rossignol JF. Nitazoxanide in the treatment of acquired immune deficiency syndrome-related cryptosporidiosis: results of the United States compassionate use program in 365 patients. Aliment Pharmacol Ther 2006;24:887-94.
252. Tzipori S, Rand W, Griffiths J, Widmer G, Crabb J. Evaluation of an animal model system for cryptosporidiosis: therapeutic efficacy of paromomycin and hyperimmune bovine colostrum-immunoglobulin. Clin Diagn Lab Immunol 1994;1:450-63.
253. Hewitt RG, Yiannoutsos CT, Higgs ES, et al. Paromomycin: no more effective than placebo for treatment of cryptosporidiosis in patients with advanced human immunodeficiency virus infection. Clin Infect Dis 2000;31:1084-92.
254. White AC, Chappell CL, Hayat CS, et al. Paromomycin for cryptosporidiosis in AIDS: a prospective, double-blind trial. J Infect Dis 1994;170:419-24.
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