Cryptosporidiosis

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Practice Essentials

Cryptosporidiosis is an infection caused by the protozoan Cryptosporidium, transmitted via the fecal-oral route.[64] The primary symptom is watery diarrhea, often accompanied by other gastrointestinal distress. In immunocompetent individuals, the illness usually is self-limiting, but it can be severe and persistent in patients with human immunodeficiency virus (HIV), particularly those with advanced disease. Diagnosis is made by identifying the organism or its antigen in stool samples. Treatment for immunocompetent patients, when needed, involves oral nitazoxanide. For patients with HIV, highly active antiretroviral therapy (ART) and supportive care are essential; although oral nitazoxanide may alleviate symptoms, it does not guarantee a cure, especially in those with end-stage HIV.

Background

Human cryptosporidiosis is caused by infection with apicomplexan protozoa of the genus Cryptosporidium.[1, 2, 3]  Human illness formerly was 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 Cryptosporidium parvum, which infects a range of mammals as well as humans.[1, 2]  (See Etiology and Pathophysiology.) 

Cryptosporidiosis mainly affects children. It causes a self-limited diarrheal illness in healthy adults. However, it also is recognized as a cause of prolonged and persistent diarrhea in children, which can result in malnutrition.[4, 5]  Cryptosporidiosis can present as a chronic, severe diarrhea in persons with AIDS, solid and bone marrow transplants or immunosuppression due to chemotherapy/immunotherapy.[6]  (See Prognosis and Presentation.) Cryptosporidium also can 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. To date there are at least 44 validated species of Cryptosporidium,  recognized by host specificity, morphology, and molecular biology studies.[3, 7, 9, 10]  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 life cycle within a single host, but some species also can spread between host species.[1, 2, 11]  C hominis and C parvum cause most human infections. Both can be spread from person to person. C parvum also can be zoonotic. Other species can infect humans but are less common such as C cuniculus, C meleagridis, C tyzzeri, and C viatorum.[11]

Transmission

The disease is transmitted via the fecal-oral route from infected hosts.[1]  Most sporadic infections occur through person-to-person contact. Nonetheless, transmission can occur following animal contact, ingestion of water (mainly during swimming), or through food. Waterborne outbreaks have resulted from contamination of municipal water and recreational waters (eg, swimming pools, ponds, lakes).[3, 9, 10]  Animal contact can also be associated with transmission of zoonotic species.[9, 11]  (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.[13] 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 species do not multiply outside the host.[1, 2]  Infection is initiated by ingestion of oocysts, which are activated in the stomach and upper intestines to release four 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 a patient experiences clinical improvement.

Etiology and Pathophysiology

Cryptosporidium oocysts are highly infectious, requiring < 10 oocysts to cause human disease for some isolates.[13, 14, 15]  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 extra cytoplasmic, 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 all are thought to be mediated by the host response to infection.[2]  Severe disease is characterized by villous atrophy and crypto hyperplasia.[14] 14 In immunocompetent persons, the infection is usually limited to the small intestine, however in immunocompromised individuals infection can be pan-enteric to ileo-colonic.15 In persons with AIDS or certain congenital immunodeficiencies, the biliary tract and respiratory tract may be involved.16 

 

 

 

 

 

Cryptosporidium oocysts are highly infectious, requiring < 10 oocysts to cause human disease for some isolates.[15, 16]  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 extra cytoplasmic, 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, 17]  In addition, it is thought to cause a change on microbiome diversity.[18]  Severe disease is characterized by villous atrophy and crypto hyperplasia.[19]  In immunocompetent persons, the infection is usually limited to the small intestine, however in immunocompromised individuals infection can be pan-enteric to ileo-colonic.[20]  In persons with AIDS or certain congenital immunodeficiencies, the biliary tract and respiratory tract may be involved.[21]

Risk factors

Among healthy individuals, cryptosporidiosis is primarily a disease of children. 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, 8, 10, 22, 23, 24]  Individuals with compromised cellular immunity are at increased risk for symptomatic cryptosporidiosis, particularly for more severe disease.[6]  Immunodeficiency may be congenital (especially Hyper IgM syndrom) or may be secondary to HIV infection, malnutrition, or organ trasnplantation.[26, 27]  

Pregnancy is another predisposing factor for cryptosporidiosis. In resource-limited 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 near residences. In a systematic review in low- and middle-income countries overcrowding, diarrhea in household and animal contact were the major risk factors for infection,[5]  whereas a survey-based study in Africa demonstrated water sources as a significant risk factor for the infection.[28]

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. In 2022, there were 10,169 cases of confirmed cryptosporidiosis according to CDC.[29]  Studies in the United States have documented cryptosporidiosis in about 4% of stools sent for parasitologic examination. Seroprevalence studies in the United States suggest that 21.2% of the population older than 6 years had cryptosporidiosis at some time in their life with higher odds in low-income households.[30]  Cryptosporidium species is associated to waterborne outbreaks of diarrhea. The most significant outbreak was in 1993, when more than 400,000 cases of diarrheal illness due to Cryptosporidium infection were reported in Milwaukee, Wisconsin.[31]  For the period 2015–2019, a total of 208 outbreaks associated with treated recreational water were reported to the CDC. Cryptosporidium caused 76 outbreaks, resulting in 2492 cases.[34]  Waterborne outbreaks continue to be reported worldwide in industrialized countries.[32, 33, 34]

Cryptosporidium parasites are ubiquitous, except in Antarctica, and infection is more common in warm, moist months.[1, 29]  In the United States, 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).[9, 35]  Outbreaks in daycare centers with incidence rates of 30-60% have been reported.[24]  Prior to the availability of combination antiretroviral therapy, approximately 10-15% of patients with AIDS developed cryptosporidiosis over their lifetime. Although the prevalence of cryptosporidiosis in AIDS patients has dropped dramatically, it continues to be prevalent in the HIV/AIDS population.[36, 37]  

International statistics

Cryptosporidiosis is a notifiable disease at the European Union level, and surveillance data are collected through the European Basic Surveillance Network.[35]  The crude incidence rate was similar to that in the United States, with six countries accounting for 94% of confirmed cases, although considerable differences in the rates of cryptosporidiosis were observed between countries and over time.[35]  In resource-limited countries, most infections are in children. In a large multicenter study of moderate to severe diarrhea in sub-Saharan Africa and South Asia, Cryptosporidium was second to rotavirus as a cause of diarrhea in children younger than 2 and associated with 200,000 deaths.[38]  A multicenter birth cohort study from Asia, Africa, and Latin America (the malnutrition and enteric disease study) also found Cryptosporidium was among the top causes of diarrheal disease and non-diarrheal infection was associated with malnutrition.[5, 38]  Studies suggest that the burden of disease related to malnutrition may be greater than that due to diarrhea.[4, 39]  Rates are often higher when molecular tests such as polymerase chain reaction (PCR) are used.[38, 40]  In persons with AIDS, cryptosporidiosis si more common in developing countries, ranging from 12-26% of persons with AIDS who have diarrhea.[41, 42, 43, 44]  Data about incidence and prevalence of infection in solid and bone marrow organ transplant are limited. A few retrospective case reports in renal transplant recipients report a prevalence between 4.5% and 53%.[21]

Age-related demographics

The peak incidence of cryptosporidiosis is in children younger than 5 years.[1, 2, 3, 4]  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).[1, 45]  Cryptosporidiosis can occur in persons with AIDS of any age.[42, 44]  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.[39]  Waterborne epidemics in industrialized countries affect all ages.[32, 33, 34]

Prognosis

In most healthy individuals, Cryptosporidium-induced diarrhea usually is self-limited. However, diarrhea is often prolonged (>1 week) or persistent (>2 weeks). In patients who are severely immunocompromised and young children, cryptosporidiosis may be chronic, severe, and sometimes, fatal.[41, 46]  Individuals with AIDS and cryptosporidiosis tend to develop chronic symptoms more often and about 10% have a fulminant course.[1, 31]  Antiretroviral treatment improves outcome.

Immunocompetent individuals infected with Cryptosporidium generally do well. However, persistent abdominal pain, loose stools, and extraintestinal sequelae (eg, joint pain, eye pain, headache, dizzy spells, fatigue), especially with C hominis infection. Symptoms have been reported at 12 months post infection in children and adults, associated with a threefold risk for reporting any symptoms 10 years post-infection.[47, 48]

 

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, 32, 33, 34]  In sporadic cases, fever may be low grade or nonexistent; however, during outbreaks, a low-grade fever may occur in 30-60% of patients.[54]  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. In rare cases, abdominal symptoms, joint pain, nausea and fatigue can persists 5 or more years after infection.[47, 55]  Diarrhea can persist longer in individuals who are immunosuppressed.[44]

The clinical manifestations of cryptosporidiosis in patients with HIV vary.[1, 41]  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, cholera-like diarrhea, which 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 [MT1] .[56]

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).[21]  Biliary involvement may include acalculous cholecystitis, sclerosing cholangitis, papillary stenosis, or pancreatitis. All are associated with right upper quadrant pain, nausea, and vomiting.[41, 52, 57]

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.[51]  It has been described in HIV patients, where it can associated with another pulmonary pathogen, such as CMV or Pneumocystis jiroveci.[58]  Some studies have suggested an association between respiratory cryptosporidiosis and tuberculosis independently of HIV status.[59]  A recent cross-sectional study in children from Uganda with intestinal cryptosporidiosis, demonstrated that those with positive sputum were more likely hypoxic, and around 37.7% had no other potential cause of the symptoms.[51]  Most of the children were HIV negative.

Rarely, conjunctival irritation is also present.[13]  In waterborne outbreaks, immunocompetent patients present with subclinical or milder illness that lasts for less than 5 days.[54]

Physical Examination

Physical findings are nonspecific. Temperature higher than 39°C is not characteristic of cryptosporidiosis and warrants investigation for other infections.[1]  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.[52, 57]  Reactive arthritis that affects the hands, knees, ankles, and feet has been described.[47, 55]

Approach Considerations

Studies in North America have documented cryptosporidiosis in approximately 7% of stool specimens sent for parasitologic examination, whereas, averall, about 2-27% of stool specimens submitted for parasitologic studies in developing countries reveal Cryptosporidium oocysts varying on the basis of the method of diagnosis.[5, 60, 61]

Cryptosporidium can be difficult to diagnose by standard methods; usually it was missed unless specific tests ere performed. Traditionally it was diagnosed by microscopic examination with special staining techniques (eg, acid-fast staining, direct fluorescent antifody [DFA], enzyme immunoassays, or immunochromatographic tests for detection of Cryptosporidium species' antigens) (See the image below.)[62]  PCR multiplex molecular tests have widely increased the sensitivity and specificity of their diagnoses.[57, 63]



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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, therefore 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.[1, 64]

Imaging studies

Imaging studies are not indicated as a first-line diagnostic approach in cryptosporidiosis but can aid in the diagnosis. Ultrasound can show dilation of intrahepatic or extrahepatic ducts followed by dilated common bile ducts.[57]  Studies have shown that if abnormal US, there is a good correlation with abnormal ERCP.[65]  Abdominal radiography and computed tomography (CT) scanning are nonspecific but may reveal distended loops of bowel, air-fluid levels, and disrupted bowel motility.[57]  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.[65]

In cases of respiratory involvement, chest radiography is unremarkable, with modest infiltrates or increased bronchial markings.[50, 51]

Stool Tests

Processing

Unconcentrated fresh specimens can be examined by wet mount preparations, but this is not recommended due to high infectivity and its unreliability. Despite different methods available, formalin ethyl acetate concentration method is the most sensitive and widely used.[66]  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). Polyvinyl alcohol (PVA)-preserved specimens are not acceptable for modified acid-fast staining or antigen-detection assays for detection of Cryptosporidium. Immunomagnetic separation commercial kits are also available mainly for waste water screening.[67]

Types of tests

Since the oocyst is small (4-6 um), it requires staining to be identified by light microscopy.[68]  Modified acid-fast staining procedure is useful for the identification of oocysts from Cryptosporidium (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 fluorogenic stain auramine-phenol a more sensitive and faster option which have been adopted by many labs as their standard staining method.[62, 68]



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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 gold standard for stool examination is the immunofluorescence assay, which is based on oocyst cell wall antigens targeted by specific fluorescent monoclonal antibodies.[69]  The main disadvantage of this method is the inability to process a large amount of samples and the need for a specialized microscope and technician. Antigen detections via enzyme-linked immunosorbent assays (ELISA) or enzyme immunoassay (EIA) also were developed with variable sensitivities and great specificities depending on the commercial kit used, which limits its use in epidemiologic studies.[70]

Various PCR-based commercial multiplex molecular assays to detect Cryptosporidium spp have been approved by the FDA. These tests are able to detect a variety of pathogens that cause diarrhea such as parasites, bacteria, and viruses. They are costly, highly sensitive, and require careful clinical correlation; therefore, they are not readily available in all laboratories.[38, 63]

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) also may 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 will stain blue or green, versus oocysts that will 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, diarrhea is likely to resolve spontaneously. With lower counts, however, the diarrhea may be chronic. Counts typically are less than 50 cells/μL in patients with either biliary involvement or cholera-like 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.[51]

Secondary immunodeficiencies

Patients who are on immunosupressive medications in the setting of organ transplantation behave similarly to HIV patients. Immunosupression should be minimized and levels of tacrolimus and cyclosporine should be checked to avoid toxicity.[21]

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.[57]  Magnetic resonance cholangiopancreatography (MRCP) can detect ductal abnormalities including intrahepatic strictures, papillary stenosis, and long segmental extrahepatic strictures.[71]

Endoscopic retrograde cholangiopancreatography (ERCP) often is 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. In the setting of concomitant inflammatory bowel disease with persistent symptoms, gastrointestinal biopsies have incidentally diagnosed cryptosporidium.  

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.

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 also may 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 also are noted.

Approach Considerations

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

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) also are lost. This leads to secondary lactose intolerance mainly in chronic cases.[72] Therefore, supportive care should include a lactose-free diet. Enteral nutrition usually is sufficient; studies do not support 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 for mortality in malnourished children.[73]  Trials also have demonstrated efficacy in adults.[74]  Trials of antiparasitic drugs in patients with AIDS and cryptosporidiosis have been disappointing. Nitazoxanide, paromomycin, and azithromycin are partially active.[76]  No antiparastic drug has been proven to reliably cure cryptosporidiosis in immunocompromised patients. In patients with AIDS, cryptosporidiosis usually cannot be eradicated without restoration of the CD4 cell count in response to combination antiretroviral therapy.[1, 77, 78]  

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, combination antiparasitic therapy have proven satisfactory results.[1, 21]  Most recently, a case report of cryptosporidium on a renal transplanted patient-reported resolution of infection with a combination therapy of nitazoxanide, azithromycin, and rifaximin.[6]  New therapeutic strategies are being developed via screening drug libraries, through drug repurposing, or new target based therapies.[79, 80]    

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 usually can 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.[33, 34, 54, 81]  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.[82, 83]  Decontamination also can 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.

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.

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

Patient education

Thorough hand washing should be practiced by patients with diarrhea to avoid the spread of the disease. 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. The effectiveness of alcohol-based hand sanitizers has not been well studied and their use should not be recommended.[81]  New studies suggested inactivation of the cysts in vitro at concentrations of 70% or higher of ethanol and methanol, but more research is needed.[84]

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.[81]  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.[85]

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.[86]  They should also consider avoiding communal recreational water such as public swimming pools. For patients with AIDS, new pets should be older than 6 monthers, should not have diarrhea, and should be tested for infection.[87]

Lastly, sexual intercourse is a newly recognized route of transmission for infection. The recommendations are to wait at least 2 weeks to have sexual intercourse after diarrhea, wash genitals and sexual devices (ie, sex toys) with soap and water, and use barriers of protection during sexual activity (condoms, globes, dental dams) to prevent direct contact with cysts.[37, 81]

There is currently no vaccine against cryptosporidiosis for humans, however vaccine for cattle has recently been approved.[88]

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.

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 cryptosporidiosis-related diarrhea in adults and in children older than 12 months who do not have HIV infection.[89]  In patients with AIDS, antiretroviral treatment has been associated with improvement, possibly because of general improvement of immune function.[78, 90]  Nitazoxanide is not effective but may serve as an adjunct to antiretroviral therapy. Paromomycin alone or with azithromycin is minimally effective (although paromomycin caused symptomatic improvement but rarely parasite eradication and frequent relapses),but may facilitate improvement in response to antiretroviral therapy. 

In the solid organ transplant population, studies have shown that the heterogeneity of its prevalence is based on the type of immunosuppression.[21]  In renal transplant patients, for example, cyclosporine-based regimens had less incidence of cryptosporidium infections as compared to tacrolimus based regimens. Treatment, as in HIV patients, may require prolonged courses of nitaxozanide or combination therapy plus reduction of the immunosuppression.[91]  Studies have been considering a combination therapy with nitazoxanide to aid in clearance of infection and intestinal cellular regeneration but those studies are still ongoing.[92]  

Cryptosporidiosis is recognized as a neglected tropical disease.[93]  Several novel compounds are being developed with efficacy in animal models.[79, 80]  New drug development strategies are being applied. However, none have documented efficacy in clinical trials.

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.

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

Ewa Tomczak, MD, Assistant Professor, Department of Internal Medicine, Division of Infectious Disease, The University of Texas Medical Branch at Galveston

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.

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.

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 Neonatologist and Pediatrian, Sree Gokulam Medical College and Research Foundation, India

Disclosure: Nothing to disclose.

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

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.