General Characteristics

Cryptosporidium spp. are intracellular parasites that primarily infect epithelial cells of the stomach, intestine, and biliary ducts. The organism previously called Cryptosporidium parvum, thought to be the primary Cryptosporidium species infecting humans, now is classified as two species, C. parvum (mammals, including humans) and C. hominis (primarily humans) (see Table 1, Figures 1 to 3). Differentiation of these two species based on oocyst morphology is not possible. Currently, more than 20 established Cryptosporidium species have been identified in vertebrates, and more than 10 Cryptosporidium spp. have been reported in humans.

Table1. Morphologic Criteria Used to Identify Intestinal Protozoa (Coccidia, Blastocystis hominis)

Fig1. Life cycle of Cryptosporidium. (a) Sporulated oocyst in  feces. (b) Excystation in intestine. (c) Free sporozoite in intestine. (d)  Type I meront (six or eight merozoites). (e) Recycling of type I merozoite. (f) Type II meront (four merozoites). (g) Microgametocyte with  approximately 16 microgametes. (h) Microgamete fertilizes macrogamete (i) to form zygote (j). Approximately 80% of the zygotes form  thick-walled oocysts (k), which sporulate within the host cell. About  20% of the zygotes do not form an oocyst wall; their sporozoites are  surrounded only by a unit membrane (l). Sporozoites in “autoinfective,” thin-walled oocysts (l) are released into the intestinal lumen (m)  and reinitiate the endogenous cycle (at c). (Courtesy William L.  Current, Lilly Research Laboratories, Greenfield, Ind.)

Fig2. Cryptosporidium. A, Oocysts recovered from a Sheather’s sugar flotation; organisms measure 4 to 6 µm. B, Scanning electron  microscopy view of organisms at brush border of epithelial cells. (From Garcia LS, Bruckner DA: Diagnostic medical parasitology, Washington,  DC, 1993, ASM Press.)

Fig3. Cryptosporidium oocysts and Giardia cysts stained  with monoclonal antibody–conjugated fluorescent reagent. (Cour tesy Merifluor, Meridian Diagnostics, Cincinnati, Ohio.)

Cryptosporidium infections begin with ingestion of viable oocysts. Upon contact with gastric and duodenal fluid, each oocyst releases four sporozoites, which invade the epithelial cells and develop into trophozoites sur rounded by a parasitophorous vacuole (layers of endo plasmic reticulum around an intracellular parasite). In the epithelial cells, trophozoites undergo two or three generations of asexual amplification, called merogony, leading to the formation of different types of meronts containing four to eight merozoites. The merozoites differentiate into sexually distinct stages in a process called gametogony. New oocysts are then formed in the epithelial cells in a process called sporogony. About 20% of the oocysts are thin walled and may excyst in the digestive tract of the host, leading to the infection of new cells (autoinfection). The remaining 80% of the oocysts are excreted into the environment; are resistant to low temperature, high salinity, and most disinfectants; and can initiate infection in a new host. Cryptosporidium oocysts in humans measure 4 to 6 µm in diameter.

Epidemiology

Humans can acquire cryptosporidiosis through several transmission routes, such as direct contact with infected people or animals or consumption of contaminated water (drinking or recreational) or food. The interval between ingestion of infective oocysts to completion of the life cycle and excretion of new oocysts usually is 4 to 10 days. The only extracellular stage in the Cryptosporidium life cycle is the oocysts; these are the environmental stage of the parasite and are immediately infectious when passed in the stool.

Cryptosporidium spp. have a worldwide distribution, and the oocysts are ubiquitous in the environment. In developing countries, human Cryptosporidium infection occurs mostly in children younger than 5 years, with peak occurrence of infections and diarrhea in children under 2 years of age. In developed countries, pediatric cryptosporidiosis occurs in older children, probably because, as a result of better hygiene, exposure to contaminated environments occurs later. Cryptosporidiosis is also common in the elderly in nursing homes, where person-to-person transmission occurs. In the general population, sporadic infections occur in all age groups in the United States and the United Kingdom, and traveling to developing countries and consumption of contaminated food and water can lead to infection. Cryptosporidiosis is common in immunocompromised individuals, such as those with AIDS or primary immunodeficiency and cancer and transplant patients undergoing immunosuppressive therapy.

Calves and perhaps other animals serve as potential sources of human infection. Contact with these animals may be an unrecognized cause of gastroenteritis in humans in both rural and urban settings. Direct person to-person transmission is also likely and may occur through direct or indirect contact with stool material. Direct transmission may occur during sexual practices involving oral-anal contact. Indirect transmission may occur through exposure to positive specimens in a laboratory setting or from contaminated surfaces or food or water.

Pathogenesis and Spectrum of Disease

Immunocompetent Individuals. In immunocompetent people with sporadic cryptosporidiosis in industrialized nations, the most common symptom is diarrhea. Clinical symptoms include nausea, low-grade fever, abdominal cramps, anorexia, and five to 10 watery, frothy bowel movements per day, which may be followed by constipation. Some patients may have diarrhea, and others may have few symptoms, particularly later in the course of the infection. In patients with the typical watery diarrhea, the stool contains mainly water and mucus. Often the organ isms are entrapped in the mucus, and diagnostic procedures are performed accordingly. Generally a patient with a normal immune system has a self-limited infection; however, patients who are immunocompromised may have a chronic infection with a wide range of symptoms. The illness usually lasts 9 to 21 days and may require hospitalization in up to 20% of those infected. Patients infected with C. hominis are more likely to have joint pain, eye pain, recurrent headache, dizziness, and fatigue than those infected with C. parvum.

Immunocompromised Individuals. Hemodialysis patients with chronic renal failure and renal transplant patients with cryptosporidiosis can have chronic, life-threatening diarrhea. In individuals infected with the human immunodeficiency virus (HIV), cryptosporidiosis increases as the CD4+ lymphocyte count falls, especially below 200 cells/µL. Sclerosing cholangitis and other biliary involvement are also seen in AIDS patients with cryptosporidiosis. The combination of AIDS and cryptosporidiosis often leads to increased mortality and diminished survival. In these patients, Cryptosporidium infections are not always confined to the gastrointestinal tract; additional symptoms (respiratory problems, cholecystitis, hepatitis, and pancreatitis) have been associated with extraintestinal infections. Although the clinical features of sclerosing cholangitis secondary to opportunistic infections of the biliary tree in patients with AIDS are well known, the mechanisms by which pathogens such as Cryptosporidium spp. actually cause disease are unclear.

Laboratory Diagnosis

Routine Methods. Oocysts in clinical specimens are difficult to see without special staining techniques, such as the modified acid-fast, Kinyoun’s, or Giemsa method, or the newer immunoassay methods. The four sporozoites may be seen in the oocyst wall in some of the organisms, although they are not always visible in freshly passed specimens.

Antigen Detection. Immunoassays are very helpful, because they are a more sensitive method of detecting organisms in stool specimens. A direct fluorescent antigen (FA) procedure with excellent specificity and sensitivity has been developed and results in a significantly increased detection rate over conventional staining and microscopy methods. Some of these reagents, particularly the combination direct FA product used to identify both Giardia spp. cysts and Cryptosporidium spp. oocysts, are being widely used in water testing and outbreak situations. Most antibodies in commercial direct fluorescent antibody (DFA) kits react with oocysts of almost all Cryptosporidium species, making identification to the species level impossible. Enzyme immunoassay (EIA) tests also provide excellent specificity and sensitivity for laboratories using this approach, as do the immunochromatographic cartridge rapid test formats. It is important to remember that if a patient is in the carrier state or undergoing self-cure, the number of oocysts may drop below the sensitivity levels of these kits, producing a false-negative result.

Nucleic Acid-Based Methods. Molecular techniques, especially polymerase chain reaction (PCR) and PCR related methods, have been used to detect and differentiate Cryptosporidium spp., and a few of the PCR assays are commercially available. Several genus-specific PCR restriction fragment length polymorphism–based genotyping tools have been developed for detecting and differentiating Cryptosporidium organisms at the species level. Other genotyping techniques are designed mostly for differentiation of C. parvum and C. hominis and cannot detect and differentiate other Cryptosporidium spp. or genotypes.

Antibody Detection. In the United States, drinking untreated surface water has been identified as a risk factor for cryptosporidiosis; residents living in cities with surface-derived drinking water generally have higher antibody levels against Cryptosporidium spp. in their blood than those living in cities with ground water as drinking water. However, antibody detection is not available on a routine basis and currently is not used in the diagnosis of cryptosporidiosis.

Histology. In the examination of histologic preparations, developmental stages (sporozoites, trophozoites, merozoites, and oocysts) in the life cycle of Cryptosporidium spp. can be found at all levels of the intestinal tract, with the jejunum being the most heavily infected site. Routine hematoxylin and eosin staining is sufficient to demonstrate these parasites. Under regular light micros copy, the organisms are visible as small, round structures (about 1 to 3 µm in diameter) aligned along the brush border. They are intracellular but extracytoplasmic and are found in parasitophorous vacuoles. Developmental stages are more difficult to identify without a transmission electron microscope. It also is important to remember that in severely compromised patients, Cryptosporidium spp. have been found in other body sites, primarily the lungs, as a disseminated infection.

Therapy

Oral or intravenous rehydration and antimotility drugs are used whenever severe diarrhea is associated with cryptosporidiosis. Nitazoxanide is the only drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of cryptosporidiosis in immunocompetent individuals. This drug can shorten the clinical disease and reduce the number of parasites present. However, nitazoxanide is not effective in treating cryptosporidiosis in immunodeficient patients; paromomycin and spiramycin have been used in these individuals.

In industrialized nations, the most effective prophylaxis and treatment for cryptosporidiosis in patients with AIDS is highly active antiretroviral therapy (HAART). Eradication and prevention of the infection are related to replenishment of CD4+ cells in treated individuals and the antiparasitic activities of the protease inhibitors used in HAART. Relapse of cryptosporidiosis is common in patients with AIDS who have stopped HAART.

Prevention

 Effective concentrations of most substances used for disinfection are not practical outside the laboratory, and high concentrations that significantly reduce oocyst infectivity are either very expensive or quite toxic. Cryptosporidium oocysts are highly resistant to most commercial disinfectants, including iodine water purification tablets. Although chlorine and related compounds can dramatically reduce the ability of oocysts to excyst or infect, high concentrations and long exposure times are required, making this approach impractical.

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