Cryptosporidiosis

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Background

Human cryptosporidiosis is caused by infection with apicomplexan protozoans of the genus Cryptosporidium. Human illness was formerly thought 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 are Cryptosporidium hominis, for which humans are the only natural host, and C parvum, which infects bovines as well as humans.[1, 2, 3] (See Etiology and Pathophysiology.)

Cryptosporidiosis mainly affects children. It causes a self-limited diarrheal illness in healthy individuals. Cryptosporidiosis is also recognized as a cause of prolonged and persistent diarrhea in children and of severe, prolonged diarrhea in persons with acquired immunodeficiency syndrome (AIDS). (See Prognosis and Presentation.)

Outbreaks of cryptosporidiosis should be detected by vigilant observation for increased case numbers at primary and public health care levels. (See Epidemiology, Workup, and Treatment.)

The genus Cryptosporidium consists of a group of protozoan parasites within the protist subphylum Apicomplexa. There are more than 26 known Cryptosporidium species, as recognized by host specificity, morphology, and molecular biology studies.[3] 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). (See Etiology.)



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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 are able to infect and reproduce in the epithelial cell lining of the GI and respiratory tracts without causing cytopathic effects.[1, 2, 3] C hominis and C parvum cause most human infections. In immunocompetent individuals, the organisms are primarily localized to the distal small intestines, whereas in immunocompromised hosts, the parasites have been identified throughout the gut, biliary tract, and respiratory tract. (See Etiology and Pathophysiology.)

Children with persistent cryptosporidiosis may have villous atrophy; in children with heavier infections, crypt hyperplasia and lymphocyte infiltration are also seen.[1]

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. Extensive waterborne outbreaks have resulted from contamination of municipal water and recreational waters (eg, swimming pools, ponds, lakes).[4, 5, 6]

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.

Life cycle

Cryptosporidium does not multiply outside of the host.[1, 2, 3] Cryptosporidium can complete its life cycle within a single host, including its asexual (merogony) and sexual (sporogony) reproductive cycles. 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.



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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 Cryptosporidium on the surface of the epithelial cells. Image c....

Once inside the epithelial cell, the parasite goes through a series of sexual and asexual multiplication steps 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 a patient experiences clinical improvement.

Etiology and Pathophysiology

Cryptosporidium oocysts are highly infectious, requiring only 101 -103 oocysts to cause human disease (50% infectious dose, 102). 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 caused by the host response to infection. In immunocompetent persons, the infection is usually limited to the small intestine. In persons with AIDS or certain congenital immunodeficiencies, the biliary tract may be involved.

Risk factors

Although healthy individuals can become ill from exposure to Cryptosporidium, immunodeficiency places an individual at increased risk for cryptosporidiosis, particularly for more severe and disseminated disease.

Immunodeficiency may be congenital or may be secondary to HIV infection, malnutrition, cancer chemotherapy, diabetes mellitus, or bone marrow or solid organ transplantation.

The following people have greater exposure to contaminated materials and are at more risk for infection.[1, 2, 3, 4, 5, 6]

Hospital-associated infection in patients and health-care providers has also been reported. Pregnancy is another predisposing factor for cryptosporidiosis.

In developing nations, 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.

Epidemiology

Occurrence in the United States

The frequency of cryptosporidiosis has not been well-defined in the United States. Most laboratories do not routinely test for Cryptosporidium. Laboratories that test for Cryptosporidium often use poorly sensitive 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 the highest rate recorded in 2007. There were a total of 8,008 cases of cryptosporidiosis reported in 2012, with the rate that year reaching 3 cases per 100,000 population.[5] However, estimates suggest that the frequency of infection is likely to be 100-fold higher than the number of reported cases.[7]

Studies in the United States have documented cryptosporidiosis in about 4% of stools sent for parasitologic examination. Seroprevalence studies using antibody assays 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.[8] Waterborne outbreaks continue to be common worldwide.[9]

Cryptosporidium parasites are ubiquitous, except in Antarctica, and infection is more common in warm, moist months. In the United States, incidence peaks from July through September. Wastewater sources, such as raw sewage and runoff from dairies and grazing fields, contaminate water sources. Outbreaks in daycare centers with incidence rates of 30-60% have been reported.

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 AIDS patients has dropped dramatically.

International statistics

Prevalence rates reported in large-scale surveys of fecal oocyst excretion generally range from 1-3% in developed countries in Europe and North America.[2] Children, especially those younger than 2 years, appear to have a higher prevalence of infection than do adults.[1, 2, 3, 4, 5, 6]

Cryptosporidiosis is a notifiable disease at the European Union level, and surveillance data are collected through the European Basic Surveillance Network.[10, 11] The crude incidence rate was similar to that in the United States, although considerable differences in the rates of cryptosporidiosis between countries were observed.[6, 10, 11] A pronounced seasonal peak was observed in the autumn season, with 59% of cases reported between August and November. However, Ireland and Spain experienced a peak in spring and summer, respectively. Routine cryptosporidiosis surveillance in northwest England over 17 years revealed that cases predominantly occurred in spring and autumn. There, most infections are caused by C hominis, while C parvum is associated with rural areas and animal contact.[6]

In August 2012, an unexpectedly large increase in Cryptosporidium infections occurred in the Netherlands, Germany, England, Wales, and Scotland. In the Netherlands, for instance, 8 medical microbiology laboratories reported the detection of 524 Cryptosporidium -positive fecal samples for weeks 31-42 of that year, compared with 115 in 2010. Reasons behind the increases in these countries were uncertain.[12]

In developing countries, cryptosporidiosis causes approximately 10-15% of cases of acute diarrheal illness.[2] Rates are often higher when molecular tests such as polymerase chain reaction (PCR) are used.[13, 14] In addition, investigations using PCR assays have found Cryptosporidium species in 6% of American travelers to Mexico.[15]

In developing countries, most people are infected as children. For example, studies in Brazil documented an infection rate of 90% for children younger than 5 years who were living in slums.

In persons with AIDS, cryptosporidiosis is more common in developing countries, ranging from 12-48% of persons with AIDS who have diarrhea.[1, 16, 17, 18]

Age-related demographics

The peak incidence of cryptosporidiosis is in children younger than 5 years. Infection is infrequently diagnosed in immunocompetent adults in developing countries.[1, 2, 3, 4, 5, 6] 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 -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 outcome.

Immunocompetent children infected with Cryptosporidium generally do 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.

Instruct immunocompromised patients to avoid newborn animals (eg, calves, lambs), including domestic animals, and people with diarrhea. They should also consider avoiding communal 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. 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, 16, 17, 18] In patients with CD4 cell counts of more than 200, most infections are self-limited, similar to those in normal 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, which can be complicated by malabsorption and volume depletion.[16] 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, 16, 22]

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 a manifestation 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 look 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. However, these numbers likely underrepresent the true number of infections, owing to the poor sensitivity of commonly used techniques.

Cryptosporidium can be difficult to diagnose and usually is missed unless specific tests are performed. Most often, stool specimens are examined microscopically using different techniques (eg, acid-fast staining, direct fluorescent antibody [DFA], enzyme immunoassays, or immunochromatographic tests for detection of Cryptosporidium species’ antigens). (See the image below.)[23]



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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, electrolyte, and liver function tests

Urea and electrolyte tests are used to assess electrolyte replacement requirements and the presence of prerenal uremia.

Elevated alkaline phosphatase and glutamyl transpeptidase without hyperbilirubinemia are typical signs of biliary infection.

Imaging studies

Imaging studies are not indicated as a first-line diagnostic approach in cryptosporidiosis. 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 by wet mount preparations. Concentration by the formalin ethyl acetate method is preferable. Optimal centrifugation time and speed, 10 minutes at 500 X, 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). Polyvinyl alcohol (PVA)-preserved specimens are not acceptable for modified acid-fast staining or antigen-detection assays for detection of Cryptosporidium.

Types of tests

Modified acid-fast staining procedure is useful for the identification of oocysts of the coccidian species, including those of Cryptosporidium (which may be difficult to detect with routine stains, such as trichrome). Cryptosporidium species stain a pinkish-red color. The background should stain uniformly green. Unlike the modified Ziehl-Neelsen acid-fast (MZN-AF) stain, this stain does not require the heating of reagents for staining. (See the images below.)



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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

Chalmers et al demonstrated that enzyme-linked immunosorbent assays and immunofluorescent tests have sensitivities above 90% and were significantly higher than that of modified Ziehl-Neelsen stains (75%).[23] Molecular tests such as PCR are even more sensitive and are increasingly being used for diagnosis. Immunochromatographic tests are less sensitive, especially for zoonotic species.

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, 24] This technique stains oocysts pink or red, whereas fecal debris or yeast assumes the color of blue or green counterstain. Oocysts are small (4-6 μm in diameter) and can be missed without a very careful examination of the slide.

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.[25]

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 (carinii) 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 significantly shortens the duration of diarrhea and can decrease the risk of mortality in malnourished children.[21] Trials have also demonstrated efficacy in adults.[26, 27]

Trials of antiparasitic drugs in patients with AIDS and cryptosporidiosis have been disappointing. Nitazoxanide, paromomycin, and azithromycin are partially active. Combination antiretroviral therapy that includes an HIV protease inhibitor is associated with dramatic improvement in many cases.[1, 2] Improvement is likely to result from immune reconstitution but may, in part, reflect the antiparasitic activity of protease inhibitors. Use of partially active antiparasitic drugs (eg, nitazoxanide or paromomycin combined with azithromycin) should be considered along with initiating antiretroviral therapy.[28, 29, 30, 31, 32]

However, in patients with AIDS, cryptosporidiosis usually cannot be eradicated prior to restoration of the CD4 cell count in response to combination antiretroviral therapy. During early immune reconstitution, patients should generally continue antiparasitic therapy (eg, nitazoxanide or paromomycin) and antimotility agents, as needed.[28, 31]

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.[31, 33] 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

As previously stated, 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.

A 3-day course of nitazoxanide oral suspension has been approved by the US Food and Drug Administration (FDA) for the treatment of cryptosporidiosis-related diarrhea in adults and in children older than 12 months.[21, 26, 27] In clinical trials, the agent significantly reduced the duration of diarrhea caused by Cryptosporidium infections.

Nitazoxanide also reduced the rate of death in malnourished children in Africa with Cryptosporidium infection.[21] 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.[21, 34]

In patients with AIDS, antiretroviral treatment has been associated with improvement, possibly because of general improvement of immune function.[1, 10, 31]

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. A 3-day course of nitazoxanide oral suspension has been approved by the FDA for the treatment cryptosporidiosis-related diarrhea in adults and in children older than 12 months.

Paromomycin

Clinical Context:  This 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 is recommended for the treatment of Diphyllobothrium latum, Taenia saginata, T solium, Dipylidium caninum, and Hymenolepis nana.

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

Azithromycin (Zithromax, Zmax)

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

Class Summary

Nitazoxanide,[28] paromomycin, and azithromycin have activity against Cryptosporidium. Paromomycin alone or with azithromycin is minimally effective (although paromomycin did reportedly cause symptomatic improvement but rarely parasite eradication).[28] In patients with HIV infection, improvement in the CD4 cell count with antiretroviral therapy can improve the course of disease.

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 and it is expensive.

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 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

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.

Coauthor(s)

A Clinton White, Jr, MD, The Paul R Stalnaker, MD, Distinguished Professor of Internal Medicine, Director, Infectious Disease Division, 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

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.

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 Cryptosporidium on 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 Cryptosporidium on 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