Cryptosporidiosis

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Background

Human cryptosporidiosis is caused by infection with apicomplexan protozoans of the genus Cryptosporidium.[1, 2] Human illness was once believed to be caused by a single species, but molecular studies have demonstrated that it is caused by at least 15 different species. Among the more common species is Cryptosporidium hominis, for which humans are the only natural host, and Cryptosporidium parvum, which infects a range of mammals, including humans.[1, 2, 3] (See Etiology and Pathophysiology.)

Cryptosporidiosis mainly affects children. It causes a self-limited diarrheal illness in otherwise healthy adults. However, it is also recognized as a cause of prolonged and persistent diarrhea in children, which can result in malnutrition.[4, 5] Cryptosporidiosis can manifest as chronic severe diarrhea in persons with acquired immunodeficiency syndrome (AIDS). (See Prognosis and Presentation.)

Cryptosporidium can also cause waterborne and, less frequently, foodborne outbreaks. (See Epidemiology, Workup, and Treatment.)

The genus Cryptosporidium consists of a group of protozoan parasites within the phylum Apicomplexa. As of 2019, there were at least 35 named Cryptosporidium species, as recognized by host specificity, morphology, and molecular biology studies.[6, 7, 8] Besides humans, the parasite can infect many other species of animals, such as mammals, birds, and reptiles, and is pathogenic to immunocompetent and immunocompromised hosts (see the image below).



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Modified acid-fast stain of stool shows red oocysts of Cryptosporidium parvum against the blue background of coliforms and debris.

See Common Intestinal Parasites, a Critical Images slideshow, to help make an accurate diagnosis.

Cryptosporidium species that infect humans replicate in the epithelial cell lining of the GI tract. They can complete their entire live cycle within a single host, but some species can also spread between host species.[1, 2] C hominis and C parvum cause most human infections. Both can spread person to person. C parvum can also be zoonotic.

Transmission

The disease is transmitted via the fecal-oral route from infected hosts. Most sporadic infections occur through person-to-person contact. Nonetheless, transmission can also occur following animal contact, ingestion of water (mainly during swimming), or through food.[9, 10, 11] Waterborne outbreaks have resulted from contamination of municipal water and recreational waters (eg, swimming pools, ponds, lakes).

Animal contact can also be associated with transmission of zoonotic species. (See Etiology and Treatment.)

Cryptosporidium has emerged as the most frequently recognized cause of recreational water–associated outbreaks of gastroenteritis, particularly in treated (disinfected) venues. This is because, in the oocyst stage of its life cycle, Cryptosporidium can resist disinfection, including chlorination, and can survive for a prolonged period in the environment. Foodborne outbreaks also occur but with frequency.

Life cycle

Cryptosporidium species do not multiply outside the host.[1, 2, 3] Infection is initiated by ingestion of oocysts, which are activated in the stomach and upper intestines to release 4 infective sporozoites (see the first image below). These motile sporozoites bind to the receptors on the surface of the intestinal epithelial cells (see the second image below) and are ingested into a parasitophorous vacuole near the surface of the epithelial cell, separated from the cytoplasm by a dense layer. Cryptosporidium oocysts are round and measure 4.2-5.4 µm in diameter.



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Cryptosporidium species oocysts are rounded and measure 4.2-5.4 µm in diameter. Sporozoites are sometimes visible inside the oocysts, indicating that ....



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Hematoxylin and eosin stain of intestinal epithelium. The blue dots (arrows) represent intracellular Cryptosporidium organisms along the surface of th....

Once inside the epithelial cell, the parasites enlarge, divide, and reinvade other cells in a series of sexual and asexual multiplication steps, eventually leading to the production of oocysts. Two morphologic forms of the oocysts have been described: thin-walled oocysts (asexual stage) excyst within the same host (causing self-infection), whereas the thick-walled oocysts (sexual stage) are shed into the environment. Oocyst shedding can continue for weeks after the host experiences clinical improvement.

Etiology and Pathophysiology

Cryptosporidium oocysts are highly infectious, requiring fewer than 10 oocysts to cause human disease for some isolates.[12, 13] The oocysts are infectious immediately after excretion, and the life cycle of the parasite produces forms that reinvade the intestine. The location of the parasite in the intestine is intracellular but extracytoplasmic, which may contribute to the marked resistance of Cryptosporidium species to treatment. Large numbers of oocysts are excreted and are resistant to harsh conditions, including chlorine at levels usually applied in water treatment.

Cryptosporidiosis typically presents with watery diarrhea. The mechanism by which Cryptosporidium causes diarrhea includes a combination of increased intestinal permeability, chloride secretion, and malabsorption, which are all thought to be mediated by the host response to infection.[2, 14, 15] Severe disease is characterized by villous atrophy and crypto-hyperplasia.[15] In immunocompetent persons, the infection is usually limited to the small intestine. In persons with AIDS or certain congenital immunodeficiencies, the biliary and respiratory tracts may be involved.[16]

Risk factors

Among healthy individuals, cryptosporidiosis is primarily a childhood disease. Daycare center–related outbreaks have a high infection rate (30%-60%). Risk groups include childcare workers; parents of infected children; international travelers, including backpackers and hikers who drink unfiltered untreated water; swimmers who swallow contaminated recreational water; people who handle infected animals; and people exposed to human feces through sexual contact.[1, 2, 9, 10, 11, 17, 18]

Individuals with compromised cellular immunity are at an increased risk of symptomatic cryptosporidiosis, particularly severe disease. Immunodeficiency may be congenital (especially in individuals with hyper–immunoglobulin M [IgM] syndrome) or may result from HIV infection, malnutrition, or organ transplantation. Pregnancy is another predisposing factor for cryptosporidiosis. In resource-limited countries, the prevalence of Cryptosporidium infection is significantly higher than in industrialized countries because of a lack of clean water and sanitary facilities, crowding, and animal reservoirs in close proximity to residences. In a systematic review, overcrowding, diarrhea in household, and animal contact were the major risk factors for infection in low- and middle-income countries.[5, 19] No increased risk with water source was observed.

Epidemiology

Occurrence in the United States

The frequency of cryptosporidiosis has not been well-defined in the United States. Many laboratories do not routinely test for Cryptosporidium. Laboratories that test for Cryptosporidium often use insensitive tests.[1, 2] The number of reported cases has increased with increased awareness and improved diagnostic testing. From 2006-2010, the rate was between 2.3 and 3.9 cases per 100,000 population, with 13,453 cases reported in 2016.[20, 21] However, estimates suggest that the frequency of infection is likely to be 100-fold higher than the number of reported cases.[22]

Studies in the United States have documented cryptosporidiosis in about 4% of stools sent for parasitologic examination. Seroprevalence studies suggest that 25%-35% of the population in industrialized countries (including the United States) have had cryptosporidiosis at some time in their life. Cryptosporidium species also cause waterborne outbreaks of diarrhea. In 1993, more than 400,000 cases of diarrheal illness due to Cryptosporidium infection were reported in Milwaukee, Wisconsin.[23] Waterborne outbreaks continue to be common worldwide.[9, 10, 24]

Cryptosporidium parasites are ubiquitous, except in Antarctica, and infection is more common in warm, moist months.[1, 20] In the United States, the incidence peaks from July through September. In England, there are separate peaks, in the spring (associated with C parvum and farm animals) and the fall (associated with C hominis and recreational water).[10, 11] Outbreaks in daycare centers with incidence rates of 30%-60% have been reported.[25]

Prior to the availability of combination antiretroviral therapy, approximately 10%-15% of patients with AIDS developed cryptosporidiosis over their lifetime. As with other opportunistic infections, the prevalence of cryptosporidiosis in patients with AIDS has dropped dramatically.[26]

International statistics

Cryptosporidiosis is a notifiable disease at the European Union level, and surveillance data are collected through the European Basic Surveillance Network.[27] The crude incidence rate was similar to that in the United States, although considerable differences in the rates of cryptosporidiosis were observed between countries and over time. In resource-limited countries, most infections occur in children.

In a large multicenter study of moderate to severe diarrhea in sub-Saharan Africa and South Asia, Cryptosporidium was second only to rotavirus as a cause of diarrhea in children younger than 2 years and was associated with 200,000 deaths.[28] A multicenter birth cohort study from Asia, Africa, and Latin America (the malnutrition and enteric disease study) also found Cryptosporidium to be among the top causes of diarrheal disease, and nondiarrheal infection was associated with malnutrition.[5, 29] Studies suggest that the burden of disease related to malnutrition may be greater than that due to diarrhea.[4, 30]

Reported rates are often higher when molecular tests such as polymerase chain reaction (PCR) are used.[31] For example, investigations using PCR assays have found Cryptosporidium species in 6% of American travelers to Mexico.[32]

In persons with AIDS, cryptosporidiosis is more common in developing countries, affecting 12%-48% of persons with AIDS who have diarrhea.[1, 30, 33, 34]

Age-related demographics

The peak incidence of cryptosporidiosis is in children younger than 5 years. Infection is infrequently diagnosed in immunocompetent adults in resource-limited countries. A second peak includes women of childbearing age (likely due to contact with infected children). Cryptosporidiosis can occur in persons with AIDS of any age.

Children younger than 2 years may be more susceptible to infection, possibly because of increased fecal-oral transmission in this age group and because of a lack of protective immunity. Waterborne epidemics in industrialized countries affect all ages.

Prognosis

In most healthy individuals, Cryptosporidium infection–induced diarrhea is usually self-limited. However, diarrhea is often prolonged (>1 week) or persistent (>2 weeks). In patients who are severely immunocompromised, cryptosporidiosis may be chronic, severe, sometimes fatal, and with extraintestinal manifestations.

Individuals with AIDS and cryptosporidiosis tend to develop chronic symptoms more often, and about 10% have a fulminant course.[1, 15] Antiretroviral treatment improves outcomes.

Immunocompetent children with Cryptosporidium infection generally fare well. However, persistent abdominal pain, loose stools, and extraintestinal sequelae (eg, joint pain, eye pain, headache, dizzy spells, fatigue) have been reported, especially with C hominis infection.[10]

Morbidity and Mortality

Complications of cryptosporidiosis include the following:

Patient Education

Thorough hand washing should be practiced by patients with diarrhea to avoid the spread of the disease. The effectiveness of alcohol-based hand sanitizers has not been well studied, and their use should not be recommended.

Subjects with diarrhea should avoid using public swimming pools during their illness and at least 2 weeks after diarrhea has subsided.

Encourage immunocompromised patients to consider using 1-μm water filters when drinking tap water. Also consider boiled or bottled drinking water for patients who are immunocompromised, particularly those with HIV who have fewer than 200 CD4 cells/µL. Persons living in countries with a high risk of transmission should also be encouraged to use bottled or filtered water.

Immunocompromised patients (eg, patients with AIDS or solid organ transplant recipients) should avoid newborn animals (eg, calves, lambs), including domestic animals, and people with diarrhea. They should also consider avoiding communal recreational water such as public swimming pools. New pets for patients with AIDS should be older than 6 months and should not have diarrhea.

Instruct patients with AIDS, daycare workers, food handlers, and healthcare workers to avoid fecal-oral spread by wearing gloves and washing their hands after contact with human feces. Spread can occur after activities such as changing diapers.

History

After an incubation period of 5-10 days (range 2-28 days), an infected individual develops watery diarrhea, which may be associated with abdominal cramps.[1, 23, 41, 42] In sporadic cases, fever may be low grade or nonexistent; however, during outbreaks, fever may occur in 30%-60% of patients.

Diarrhea, with or without crampy abdominal pain, may be intermittent and scant or continuous, watery, and copious; sometimes, the diarrhea is mucoid. It rarely contains blood or leukocytes. In individuals who are immunocompetent, the median duration of diarrhea ranges from 5-10 days (mean of 10 days). Relapses may follow a diarrhea-free period of several days to weeks. Diarrhea can persist longer in individuals who are immunosuppressed.

The clinical manifestations of cryptosporidiosis in patients with HIV vary.[1, 30, 43] In patients with CD4 cell counts of more than 200/µL, most infections are self-limited, similar to those in healthy hosts. Other patients develop chronic diarrheal illness with frequent, foul-smelling, bulky stools associated with significant weight loss. A minority of patients develop a profuse, choleralike diarrhea that can be complicated by malabsorption and volume depletion. The volume of fluid losses through diarrhea may be extremely high, particularly in individuals with AIDS and CD4 cell counts below 50 cells/μL.

Biliary tract involvement is seen in persons with AIDS who have very low CD4 cell counts and is common in children with X-linked immunodeficiency with hyper–immunoglobulin M (IgM). Biliary involvement may include acalculous cholecystitis, sclerosing cholangitis, papillary stenosis, or pancreatitis. All are associated with right upper quadrant pain, nausea, and vomiting.[1, 37, 38]

Although the main symptoms of cryptosporidiosis are related to the gastrointestinal (GI) tract, in immunocompromised patients, respiratory symptoms may also develop. Respiratory tract involvement is often asymptomatic, but it may manifest as bilateral pulmonary infiltrates with dyspnea. Nonspecific respiratory symptoms, including shortness of breath, wheezing, cough, hoarseness, and croup, may be manifestations of respiratory infection. Rarely, conjunctival irritation is also present.

In waterborne outbreaks, immunocompetent patients present with subclinical or milder illness that lasts for less than 5 days.

Physical Examination

Physical findings are nonspecific. Temperature higher than 39°C is not characteristic of cryptosporidiosis and warrants investigation for other infections. The patient may have signs of volume depletion or wasting from malabsorption.

Other signs related to GI illness include right upper-quadrant or epigastric tenderness, icterus, and, rarely, ascites related to pancreatic involvement. Reactive arthritis that affects the hands, knees, ankles, and feet has been described.

Approach Considerations

Many laboratories do not routinely test for Cryptosporidium, and, in many instances, the tests used to evaluate for this organism are insensitive.[1] Studies in the United States have documented cryptosporidiosis in about 4% of stools sent for parasitologic examination, while, overall, about 13% of stool studies submitted for parasitologic studies in developing countries reveal Cryptosporidium oocysts.

Cryptosporidium infection can be difficult to diagnose via standard methods and is often missed unless specific tests are performed. Traditionally, it was diagnosed via microscopic examination with special staining techniques (eg, acid-fast staining, direct fluorescent antibody [DFA], enzyme immunoassays, or immunochromatographic tests for detection of Cryptosporidium antigens) (See the image below.)[44] Currently, PCR multiplex molecular tests have widely increased sensitivity and specificity.



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Modified acid-fast stain of stool shows red oocysts of Cryptosporidium parvum against the blue background of coliforms and debris.

Urea, electrolytes, and liver function tests

Diarrhea causes volume depletion, so urea and electrolyte tests are used to assess electrolyte and volume replacement requirements. Elevated alkaline phosphatase and glutamyl transpeptidase without hyperbilirubinemia are typical signs of biliary involvement.

Imaging studies

Imaging studies are not indicated as a first-line diagnostic approach in cryptosporidiosis but can aid in the diagnosis. Abdominal radiography and computed tomography (CT) scanning are nonspecific but may reveal distended loops of bowel, air-fluid levels, and disrupted bowel motility.

When indicated, as guided by symptoms, ultrasonography or CT scanning may reveal an enlarged gallbladder with a thickened wall, dilated or irregular intrahepatic and extrahepatic biliary ducts, and a normal or stenotic distal common bile duct. Cholangiography may reveal beading of the common bile duct or papillary stenosis.

In cases of respiratory involvement, chest radiography is unremarkable, with modest infiltrates or increased bronchial markings.

Stool Tests

Processing

Unconcentrated fresh specimens can be examined with wet mount preparations but are not recommended owing to high infectivity and unreliability. Despite different methods available, the formalin ethyl acetate concentration method is the most sensitive and widely used.[45] Optimal centrifugation time and speed are critical for concentrating Cryptosporidium oocysts. Commercial fecal concentration tubes are available that decrease processing time and supplies needed for concentrating specimens (eg, Fecal Parasite Concentrator, Evergreen Scientific). Immunomagnetic separation commercial kits are also available. Polyvinyl alcohol (PVA)–preserved specimens are not acceptable for modified acid-fast staining or antigen-detection assays for detection of Cryptosporidium.

Types of tests

Since the oocyst is small (4-6 µm), it requires staining to be identified via light microscopy.[44] Modified acid-fast staining procedure is useful for the identification of oocysts (which may be difficult to detect with routine stains, such as trichrome). Cryptosporidium species stain a pinkish-red color on a uniformly green background. Unlike the modified Ziehl-Neelsen acid-fast stain, this stain does not require the heating of reagents for staining (See the images below.). Other studies have found the fluorogenic stain auramine-phenol to be a more sensitive and faster option, which has been adopted by many laboratories as the standard staining method.[44, 46]



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Cryptosporidium parvum oocysts revealed with modified acid-fast stain. Against a blue-green background, the oocysts stand out with a bright red stain.....



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Cryptosporidium oocysts revealed with modified acid-fast stain

The criterion standard for stool examination is the immunofluorescence assay, which is based on oocyst cell wall antigens targeted by specific fluorescent monoclonal antibodies. The main disadvantages for this method are the inability to process large amounts of samples and the need for a specialized microscope and technician. Antigen detection via enzyme-linked immunosorbent assays (ELISA) or enzyme immunoassay (EIA) has also been developed with variable sensitivities and specificities depending on the commercial kit used, limiting its use in epidemiological studies. Chalmers et al demonstrated that enzyme-linked immunosorbent assays (ELISA) and immunofluorescent tests (IFA) have sensitivities above 90%, significantly higher than that of modified Ziehl-Neelsen stains (75%).[46, 47]

In the past few years, various PCR-based commercial multiplex molecular assays to detect Cryptosporidium species have been approved by the FDA. These tests can detect various pathogens (eg, parasites, bacteria, viruses) that cause diarrhea. They are costly and highly sensitive and require careful clinical correlation so are not readily available in all laboratories.[44, 45, 48]

Specimen examination

Concentrated sediment of fresh (within 30 min after passage of stools) or formalin-preserved stool may be used. Other types of clinical specimens, such as duodenal fluid, bile, and pulmonary samples (induced sputum, bronchial wash, biopsies) may also be stained.

The formalin ethyl acetate method is used to concentrate stool before staining with a modified acid-fast stain, because routine laboratory examination of stool for ova and parasites does not detect Cryptosporidium.[1] This technique allows for differentiation from fecal debris or yeast, which stains blue or green, versus oocysts, which counterstain pink or red. Careful examination of slides is imperative, as oocysts can easily be missed.

Because shedding may be intermittent, examine at least 3 stool specimens collected on separate days before considering the test results negative. Fecal leukocytes are not found in stool specimens, because invasion does not occur below the epithelial layer of the mucosa.

Other testing strategies include the following:

Evaluation of Immune Function

Lymphocyte subset analysis

CD4+ lymphocyte counts predict the duration of disease in patients infected with HIV. When the counts are greater than 150 cells/μL, the diarrhea is likely to resolve spontaneously. With lower counts, however, the diarrhea may be chronic. Counts are typically less than 50 cells/μL in patients with either biliary involvement or choleralike syndromes.

HIV testing

Prolonged diarrhea caused by cryptosporidiosis may warrant HIV testing.

Primary immunodeficiencies

Children with chronic diarrhea from cryptosporidiosis should be screened for primary immunodeficiencies associated with depressed cellular immune function. The most commonly identified immunodeficiency is hyper-IgM syndrome, which can be identified by antibody screening. T-cell deficiencies can be identified by examining lymphocyte numbers and subsets.[49]

Secondary immunodeficiencies

In organ transplant recipients who are receiving immunosuppressive medications, immunosuppression should be minimized and levels of tacrolimus and cyclosporine monitored to avoid toxicity.[38]

Abdominal Ultrasonography and ERCP

Dilated or irregular intrahepatic and extrahepatic bile ducts, along with a thickened gallbladder, as detected with abdominal ultrasonography, indicate biliary involvement.

Endoscopic retrograde cholangiopancreatography (ERCP) is often needed to diagnose sclerosing cholangitis or papillary stenosis.

ERCP identification of Cryptosporidium oocysts in bile or intracellular forms on biopsy confirms the diagnosis of biliary cryptosporidiosis. Papillary stenosis may be present and responds symptomatically to endoscopic sphincterotomy, often with stent placement.

Biopsy and Lavage

GI or liver biopsy

GI or liver biopsy may be indicated in cases of diagnostic uncertainty. Different parts of the intestinal tract may be affected. Liver biopsy findings may reveal the organism attached to bile duct epithelial cells. Concurrent infection with cytomegalovirus (CMV), Enterobacter cloacae, and microsporidia is common.

Bronchoalveolar lavage and lung biopsy

In patients with related symptoms, bronchoscopy may reveal the parasite in lavage fluid, in brushing specimens, and in biopsy specimens attached to the surface of bronchial mucosal cells or in macrophages. In most instances, another pulmonary pathogen, such as CMV or Pneumocystis jiroveci, is concurrently detected; however, in a series of 4 patients infected with HIV, Cryptosporidium was the only pathogen identified in the respiratory tract. Clear association with intestinal cryptosporidiosis or diarrhea has not been shown in these cases.

Histologic Findings

Histologic examination of the small intestine is not required to confirm the diagnosis of cryptosporidiosis, although the small intestine does show the parasite projecting from the brush border of the mucosal surface. Parasites may also be identified in bile or biliary tract biopsies.

Villous atrophy with blunting, epithelial flattening, and an increase in lamina propria lymphocytes are seen in patients with persistent cryptosporidiosis. In patients with heavier infection, crypt hyperplasia and marked infiltration with lymphocytes, plasma cells, and neutrophils are also noted.

Approach Considerations

Optimal therapy for cryptosporidiosis includes attention to fluids and electrolytes, antimotility agents, antiparasitic drugs, nutritional support, and/or reversal of immunosuppression.[1, 2]

Diet

Attention to the nutritional aspects of patient care to avoid potentially fatal malnutrition is crucial. Mature epithelial cells at the tips of the villi are preferentially lost; hence, enzymes expressed on these cells (including lactase) are also lost. This leads to secondary lactose intolerance. Therefore, supportive care should include a lactose-free diet. Enteral nutrition is usually sufficient; studies have not supported the use of parenteral nutrition. Infection may improve with nutritional supplementation, particularly with regimens including zinc or glutamine.

Surgery

Patients with acalculous cholecystitis should generally be treated with cholecystectomy.

Consultations

The following specialists should be consulted:

Antiparasitic Therapy

Nitazoxanide inhibits the growth of Cryptosporidium parvum and Giardia lamblia trophozoites.[50] It significantly shortens the duration of diarrhea and can decrease the mortality risk in malnourished children.[40] Trials have also demonstrated efficacy in adults.[51, 52] Trials of antiparasitic drugs in patients with AIDS and cryptosporidiosis have been disappointing. Nitazoxanide, paromomycin, and azithromycin are partially active.[53] It is administered in a 3-day, twice-daily course of tablets or oral suspension.[52, 54] In clinical trials, nitazoxanide significantly reduced the duration of diarrhea, increased the rate of parasitological eradication, and improved the mortality rate in malnourished children with Cryptosporidium infection who were HIV seronegative.[40] The most common adverse effects reported were abdominal pain, diarrhea, vomiting, and headache; adverse effects were not significantly different from those reported with a placebo. However, the use of nitazoxanide alone has not been successful in controlled trials in patients with AIDS.[40, 55] In patients with HIV/AIDS and renal transplant recipients, studies have proposed off–label prolonged courses.

No antiparasitic drug has been proven to reliably cure cryptosporidiosis in immunocompromised patients. In patients with AIDS, cryptosporidiosis usually cannot be eradicated prior to restoration of the CD4 cell count in response to combination antiretroviral therapy.[1, 56] During early immune reconstitution, patients should generally continue antiparasitic therapy (eg, nitazoxanide or paromomycin) and antimotility agents, as needed. In transplant recipients, reduction of immunosuppression, change from tacrolimus-based treatment to cyclosporine treatments, and combination antiparasitic therapy have proven satisfactory results.[1, 38]

Symptomatic Therapy

Symptomatic therapy includes replacement of fluids, provision of appropriate nutrition, and treatment with antimotility agents. Loperamide or diphenoxylate-atropine may help in some cases. More potent opiates, including anhydrous morphine (Paregoric), may work in some cases that fail to respond to milder agents.

Octreotide, a somatostatin analogue and substance P antagonist, suppresses diarrhea in chronic cryptosporidiosis.

Fluid and electrolyte loss

Replacement of fluids and electrolytes is the critically important first step in the management of cryptosporidiosis, particularly in patients with large diarrheal losses. Fluids should include sodium, potassium, bicarbonate, and glucose. Oral rehydration is the preferred mode, but severely ill patients may require parenteral fluids.

Biliary involvement

Biliary involvement in cryptosporidiosis requires specific interventions. Acalculous cholecystitis should be treated with cholecystectomy.

Patients with sclerosing cholangitis can usually be treated with endoscopic retrograde cholangiopancreatography (ERCP), although sphincterotomy may result in temporary relief. In selected cases, recurrence may be prevented by placing a stent.

Prevention of Cryptosporidiosis

Water purification is the most important public health measure in the prevention of cryptosporidiosis.[56, 57] Because chlorination has little effect on the oocysts, water purification should involve flocculation and filtration (using filters with a pore size of 1-4 μm). Ultraviolet radiation and ozonization are other means of disinfecting contaminated water. Decontamination can also be achieved by bringing water to a boil.

Prompt, aggressive measures, including temporary closure of pools, must be carried out in cases of suspected fecal contamination of recreational water. People with diarrhea should not use recreational water, and those with cryptosporidiosis should not use recreational waters for 2 weeks after symptoms resolve.

Wearing gloves and handwashing after handling diapers can prevent person-to-person spread in daycare centers and hospitals. Endoscopes and similar instruments should be disinfected between uses. Prompt antiparasitic treatment of infected children decreases oocyst shedding.

Individuals with AIDS or another immunosuppressive condition should avoid swimming in communal pools or recreational water.

In hospitalized patients, contact precautions are strictly recommended in addition to standard precautions for patients who are incontinent or who use diapers.

Medication Summary

Supportive therapy is the key component in the management of cryptosporidiosis. Replacement of fluids and electrolytes is the critically important first step in the management of this diarrheal illness. Oral rehydration is the preferred mode, but severely ill patients may require parenteral fluids.

Nitazoxanide, paromomycin, and azithromycin have activity against Cryptosporidium.[1] A 3-day course of nitazoxanide oral suspension has been approved by the FDA for the treatment of cryptosporidiosis-related diarrhea in adults and in children older than 12 months who do not have HIV infection. In patients with AIDS, antiretroviral treatment has been associated with improvement, possibly because of general improvement of immune function.[56] Paromomycin alone or with azithromycin is minimally effective (although paromomycin has been found to improve symptoms but rarely eradicates parasites) but may facilitate improvement in response to antiretroviral therapy. In solid organ transplant recipients, studies have shown that the heterogeneity of its prevalence varies by type of immunosuppression. In renal transplant recipients, for example, cyclosporine-based regimens were associated with a lower incidence of Cryptosporidium infections than tacrolimus-based regimens.[58] Treatment may require prolonged courses of nitazoxanide or combination therapy plus reduction of immunosuppression.[38] Mofetil mycophenolate may affect Cryptosporidium by inhibiting folate metabolism, although this theory has not been confirmed.

Several novel compounds are being developed with efficacy in animal models.[59] For example, clofazimine is currently being studied in a randomized clinical trial in patients with AIDS.[60] Clofazimine accumulates within the epithelial cells of the intestine, acting as a potential target for Cryptosporidium.[61] With proven in vitro activity, clofazimine has yet to show results in randomized control trials, which is currently being studied in Africa.[60]

Nitazoxanide (Alinia)

Clinical Context:  Nitazoxanide inhibits the growth of Cryptosporidium parvum and Giardia lamblia trophozoites. It elicits antiprotozoal activity by interfering with pyruvate-ferredoxin oxidoreductase (PFOR) enzyme–dependent electron transfer reaction, which is essential to anaerobic energy metabolism. Nitazoxanide is the only medication approved by the FDA for the treatment for cryptosporidiosis in adults and children older than 12 months. It is administered in a 3-day, twice-daily course of tablets or oral suspension.

Paromomycin

Clinical Context:  Paromomycin is an oral, nonabsorbed aminoglycoside that is partially active in cryptosporidiosis. An amebicidal and antibacterial agent, it is obtained from a strain of Streptomyces rimosus that is active in intestinal amebiasis.

Paromomycin has been used in patients who have AIDS and cryptosporidiosis; it was reported to cause symptomatic improvement but rarely parasite eradication. It has also been used for intestinal tapeworms.

Azithromycin (Zithromax, Zmax)

Clinical Context:  Azithromycin is a macrolide antibiotic. In a clinical study, it provided good symptom control in combination with paromomycin.

Clofazimine (Lamprene)

Clinical Context:  This is an orally administered medication. It is the only FDA-approved drug for the treatment of leprosy and is used off-label to treat non-tuberculous Mycobacteria. Clofazimine accumulates within the epithelial cells of the intestine, acting as a potential target for Cryptosporidium.

Class Summary

Nitazoxanide is the only FDA-approved treatment for cryptosporidiosis in HIV-negative children and adults. Antiparasitic drugs may be used as an adjunct to therapy in patients with AIDS or organ transplant recipients undergoing immunosuppression. However, the mainstay of therapy is reversal of immunosuppression by antiretroviral drugs in AIDS or reduction of immunosuppressants in transplant recipients.

Loperamide hydrochloride (Imodium, Diamode)

Clinical Context:  This agent has an antimotility effect on the GI tract via cholinergic and opiate receptors. It is the first choice as an antidiarrheal agent. Loperamide hydrochloride has a more potent effect than diphenoxylate hydrochloride or codeine. It acts on intestinal muscles to inhibit peristalsis and slow intestinal motility. The drug prolongs the movement of electrolytes and fluid through bowel, increases viscosity, and decreases the loss of fluids and electrolytes.

Diphenoxylate and atropine (Lomotil)

Clinical Context:  The drug combination consists of diphenoxylate, which is an opiate constipating meperidine congener, and atropine, which an anticholinergic drug that inhibits excessive GI propulsion and motility.

Paregoric

Clinical Context:  The opiate anhydrous morphine, which is contained in paregoric, can decrease motility more than loperamide or the combination of diphenoxylate and atropine can.

Bismuth subsalicylate (Pepto-Bismol, Bismatrol, Kaopectate)

Clinical Context:  This agent exerts antisecretory and antibacterial effects to control diarrhea.

Attapulgite

Clinical Context:  Attapulgite is an adsorbent and protectant that controls diarrhea.

Class Summary

These agents are used to decrease the frequency of diarrheal stools and possibly the duration of episodes.

Octreotide (Sandostatin)

Clinical Context:  Octreotide primarily acts on somatostatin receptor subtypes II and V. It inhibits growth hormone secretion and has a multitude of other endocrine and nonendocrine effects, including inhibition of glucagon, vasoactive intestinal peptide (VIP), and GI peptides.

Class Summary

These agents inhibit the secretion of hormones involved in vasodilation. Octreotide (Sandostatin) may help, but no solid data show superiority over other antimotility agents. Cost and need for intravenous administration are the main factors that limit its use to only severe diarrheal cases.

What is cryptosporidiosis?How is cryptosporidiosis transmitted?What is the life cycle of cryptosporidium that cause cryptosporidiosis?What is the pathophysiology of cryptosporidiosis?What are risk factors in the development of cryptosporidiosis?What is the prevalence of cryptosporidiosis in the US?What is the global prevalence of cryptosporidiosis?Which age groups have the highest prevalence of cryptosporidiosis?What is the prognosis of cryptosporidiosis?What are the complications of cryptosporidiosis?What should be included in patient education about cryptosporidiosis?Which clinical history findings are characteristic of cryptosporidiosis?Which physical findings are characteristic of cryptosporidiosis?Which other infections should be considered in the differential diagnoses of cryptosporidiosis?What are the differential diagnoses for Cryptosporidiosis?What is the role of cryptosporidium tests in the workup of cryptosporidiosis?What is the role of lab tests in the workup of cryptosporidiosis?What is the role of imaging studies in the workup of cryptosporidiosis?How are stool specimens tested for cryptosporidiosis?Which stool tests are performed in the workup of cryptosporidiosis?What are procedures for stool specimen exam in the evaluation of cryptosporidiosis?What is the role of lymphocyte subset analysis in the workup of cryptosporidiosis?What is the role of HIV testing in the workup of cryptosporidiosis?What is the role of primary and secondary immunodeficiency screening in the workup of cryptosporidiosis?What is the role of abdominal ultrasonography in the workup of cryptosporidiosis?What is the role of endoscopic retrograde cholangiopancreatography (ERCP) in the workup of cryptosporidiosis?What is the role of biopsy in the workup of cryptosporidiosis?What is the role of bronchoalveolar lavage in the workup of cryptosporidiosis?What are histologic features of cryptosporidiosis?What is included in the treatment of cryptosporidiosis?Which dietary modifications are used in the treatment of cryptosporidiosis?What are indications for surgery in cryptosporidiosis?Which specialists should be consulted in the treatment of cryptosporidiosis?What is included in antiparasitic therapy for cryptosporidiosis?What is included in symptomatic therapy for cryptosporidiosis?What is the role of fluids and electrolytes for the management of cryptosporidiosis?How is biliary involvement treated in patients with cryptosporidiosis?How is cryptosporidiosis prevented?What are the key component in the treatment of cryptosporidiosis?Which medications in the drug class Somatostatin Analogues are used in the treatment of Cryptosporidiosis?Which medications in the drug class Antidiarrheal Agents are used in the treatment of Cryptosporidiosis?Which medications in the drug class Antiparasitics are used in the treatment of Cryptosporidiosis?

Author

Melinda B Tanabe, MD, Fellow, Division of Infectious Disease, Department of Internal Medicine, University of Texas Medical Branch School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

A Clinton White, Jr, MD, FACP, FIDSA, FASTMH, The Paul R Stalnaker, MD, Distinguished Professor of Internal Medicine, Director, Division of Infectious Disease, Department of Internal Medicine, University of Texas Medical Branch School of Medicine

Disclosure: Nothing to disclose.

Maria A Caravedo, MD, Fellow, Division of Infectious Disease, Department of Internal Medicine, University of Texas Medical Branch School of Medicine

Disclosure: Nothing to disclose.

Chief Editor

Michael Stuart Bronze, MD, David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of Physicians, London

Disclosure: Nothing to disclose.

Additional Contributors

Jaya Sureshbabu, MBBS, MRCPCH(UK), MRCPI(Paeds), MRCPS(Glasg), DCH(Glasg), Consultant Pediatrician and Neonatologist, PRS Hospital, India

Disclosure: Nothing to disclose.

Miguel M Cabada, MD, MSc, Assistant Professor, Division of Infectious Diseases, University of Texas Medical Branch School of Medicine; Director, Universidad Peruana Cayetano Heredia and University of Texas Medical Branch Collaborative Research Center in Cusco, Peru

Disclosure: Nothing to disclose.

Poothirikovil Venugopalan, MBBS, MD, FRCPCH, Consultant Pediatrician with Cardiology Expertise, Department of Child Health, Brighton and Sussex University Hospitals, NHS Trust; Honorary Senior Clinical Lecturer, Brighton and Sussex Medical School, UK

Disclosure: Nothing to disclose.

Acknowledgements

Jeffrey D Band, MD Professor of Medicine, Oakland University William Beaumont School of Medicine; Director, Division of Infectious Diseases and International Medicine, Corporate Epidemiologist, William Beaumont Hospital; Clinical Professor of Medicine, Wayne State University School of Medicine

Disclosure: Nothing to disclose.

Damon Eisen, MD Clinical Senior Lecturer, Department of Medicine, University of Queensland

Disclosure: Nothing to disclose.

Joseph F John Jr, MD, FACP, FIDSA, FSHEA Clinical Professor of Medicine, Molecular Genetics and Microbiology, Medical University of South Carolina College of Medicine; Associate Chief of Staff for Education, Ralph H Johnson Veterans Affairs Medical Center

Disclosure: Nothing to disclose.

Athena P Kourtis, MD, PhD Associate Professor, Department of Pediatrics, Divisions of Infectious Diseases and Epidemiology, Emory University School of Medicine; Senior Fellow, Centers for Disease Control and Prevention

Athena P Kourtis, MD, PhD is a member of the following medical societies: American Academy of Pediatrics and Pediatric Infectious Diseases Society

Disclosure: Nothing to disclose.

Russell W Steele, MD Head, Division of Pediatric Infectious Diseases, Ochsner Children's Health Center; Clinical Professor, Department of Pediatrics, Tulane University School of Medicine

Russell W Steele, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Microbiology, Infectious Diseases Society of America, Louisiana State Medical Society, Pediatric Infectious Diseases Society, Society for Pediatric Research, and Southern Medical Association

Disclosure: Nothing to disclose.

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

Disclosure: Medscape Salary Employment

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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Modified acid-fast stain of stool shows red oocysts of Cryptosporidium parvum against the blue background of coliforms and debris.

Cryptosporidium species oocysts are rounded and measure 4.2-5.4 µm in diameter. Sporozoites are sometimes visible inside the oocysts, indicating that sporulation has occurred on wet mount.

Hematoxylin and eosin stain of intestinal epithelium. The blue dots (arrows) represent intracellular Cryptosporidium organisms along the surface of the epithelial cells. Image courtesy of Carlos Abramowsky, MD, Professor of Pediatrics and Pathology, Emory University School of Medicine.

Modified acid-fast stain of stool shows red oocysts of Cryptosporidium parvum against the blue background of coliforms and debris.

Cryptosporidium parvum oocysts revealed with modified acid-fast stain. Against a blue-green background, the oocysts stand out with a bright red stain. Image courtesy of CDC DPDx parasite image library

Cryptosporidium oocysts revealed with modified acid-fast stain

Modified acid-fast stain of stool shows red oocysts of Cryptosporidium parvum against the blue background of coliforms and debris.

Hematoxylin and eosin stain of intestinal epithelium. The blue dots (arrows) represent intracellular Cryptosporidium organisms along the surface of the epithelial cells. Image courtesy of Carlos Abramowsky, MD, Professor of Pediatrics and Pathology, Emory University School of Medicine.

Cryptosporidium species oocysts are rounded and measure 4.2-5.4 µm in diameter. Sporozoites are sometimes visible inside the oocysts, indicating that sporulation has occurred on wet mount.

Cryptosporidium parvum oocysts revealed with modified acid-fast stain. Against a blue-green background, the oocysts stand out with a bright red stain. Image courtesy of CDC DPDx parasite image library

Cryptosporidium oocysts revealed with modified acid-fast stain