Although all infectious agents in humans are parasites, by convention, parasitic diseases are defined as those caused by protozoa or helminths. [1, 2] The old classification, in which a single phylum of protozoa encompassed all unicellular eukaryotic microorganisms, is no longer valid because of new ultrastructural and molecular taxonomic information.
For instance, Giardia lamblia (see the image below) has been shown to lack mitochondria and shown to contain ribosomal RNA sequences that resemble bacteria. These protozoa have been proposed to represent an evolutionary transition between prokaryotic and eukaryotic microorganisms. Both Giardia and Microsporidia (which also shares similarities with bacteria) have been reclassified as Archezoa, a term that reflects their evolutionary transitional nature.
Clinicians can best classify unicellular eukaryotic microorganisms based on mode of transmission.
The classification of representative protozoa according to modes of transmission is as follows:
Enteric transmission - Balantidium, Giardia, Entamoeba, Cryptosporidium, Toxoplasma, Cyclospora, Microsporidia
Sexual transmission - Trichomonas
Arthropod transmission - Babesia, Plasmodium, Leishmania, Trypanosoma
Other modes of transmission - Naegleria, Acanthamoeba, Toxoplasma
Toxoplasma is the only pathogenic fecal-oral transmitted protozoa that has not been associated with gastroenteritis.
Among all intestinal protozoa, those listed in Table 1 have been confirmed to cause GI disease. Others, such as Trichomonas hominis (in infants) and Entamoeba polecki (associated with pigs), have rarely been associated with diarrheal disease and are not discussed in this article.
Table 1. Protozoa Associated with Intestinal Illness in Humans (Open Table in a new window)
|Name||Mode of Transmission||Symptoms|
|G lamblia||Contaminated water, fecal-oral||Nausea, bloating, gas, diarrhea, anorexia|
|Dientamoeba fragilis||Fecal-oral, associated with Enterobius||Previously thought commensal; may cause diarrhea, abdominal, pain, nausea|
|Entamoeba histolytica||Contaminated water, fecal-oral, contaminated food||Colitis, dysentery, diarrhea, liver abscess, other extraintestinal disease|
|Cryptosporidium parvum||Contaminated water, swimming pools, fecal-oral||Immunocompetent patients: Self-limited diarrhea Immunosuppressed patients: Severe and interminable diarrhea|
|Isospora belli||Fecal-oral||Same as in Cryptosporidium|
|Cyclospora cayetanensis||Fecal-oral, contaminated water and food||Same as in Cryptosporidium|
|Microsporidia (Septata intestinalis, Enterocytozoon bieneusi)||Fecal-oral, contaminated water||Same as in Cryptosporidium|
|Balantidium coli||Fecal-oral (frequently associated with pigs)||Colitis, diarrhea|
|Blastocystis hominis||Fecal-oral||May cause mild diarrhea|
See Common Intestinal Parasites, a Critical Images slideshow, to help make an accurate diagnosis.
Understanding the life cycle is essential to explain the pathophysiology of the diseases caused by these organisms. The life cycles of intestinal protozoa are very similar, with the exception of D fragilis, which lacks a cyst stage.
Mechanisms of diarrhea production by intestinal protozoa are related to direct cytotoxic effects, the ability to invade, and/or effects of the immune response on the intestinal epithelium. No evidence suggests that intestinal protozoa produce enterotoxins.
Mature cysts are ingested via contaminated water or food. After excystation in the small intestine, trophozoites inhabit the large intestine and can either invade the tissue (pathogenic amebas) or are eliminated in the stools. Trophozoites do not survive outside the body. This parasite was named for its remarkable ability to lyse human tissues. A prerequisite to amebic invasion is the parasite's ability to colonize and penetrate colonic mucins overlying the intestinal epithelium. At least 22 amebic strains or zymodemes have been identified based on pulsed-field gel electrophoresis patterns of the 4 isoenzymes isolated from ameba. Nine zymodemes have been associated inconsistently with invasiveness.
In 1982, Sargeaunt postulated that instead of pathogenic and nonpathogenic zymodemes, 2 different amebas were present.  The concept of E histolytica as a pathogenic ameba and E dispar as a nonpathogenic ameba is currently accepted. Furthermore, both immunologic assays and amplification tests have been developed to distinguish these two species among symptomatic and asymptomatic patients. Upon invasion of the host, amebas are capable of killing immune effector cells by contact-dependent cytolysis, possibly by a calcium-dependent mechanism. They then disseminate to the liver or other tissues.
After ingestion of mature cysts (infective dose varies from 10-100 cysts) via contaminated water or food, the trophozoite emerges in the small intestine, rapidly multiplies, and attaches to the small intestinal villi.  Mature infective cysts pass in feces and complete the cycle. The pathogenesis of diarrhea in giardiasis is thought to be related to the following factors: (1) the number of organisms ingested, (2) specific strain ingested, (3) nonantibody protective factors in the GI tract, and (4) the immune response of the host.
Giardia trophozoites attach to the cell surface of villi by means of a disk on their posterior or ventral surface. Lectin, a protein on the trophozoite lining, recognizes specific receptors on the intestinal cell and may be partly responsible for the tight attachment between the parasite and the villi, which is followed by mucosal damage, mechanical obstruction (only caused in the presence of numerous organisms), and deconjugation of bile salts. Recent data has indicated that inflammatory mast cells may interfere with duodenal growth of G lamblia trophozoites.  Other inflammatory cells, as well as CD8+ T cells, contribute to villus-shortening and crypt hyperplasia.
Strains that infect humans are biologically diverse, as shown by differences in antigens, restriction endonuclease patterns, DNA fingerprinting, isoenzyme patterns, and pulsed-field gel electrophoresis patterns.
In giardiasis, secretory immunoglobulin A (IgA) is presumed to be important in host protection because invasion of the mucosa is not part of the pathogenic mechanism.
Spore ingestion begins a life cycle that is similar in all 4 of the intestinal spore-forming protozoa (see Table 1). The ingested spores release sporozoites that invade enterocytes, primarily in the small intestine. The enterocyte infection progresses through 2 stages: merogenic and sporogonic.
The merogenic (or schizogonic) stage involves the maturation and development of meronts to reproduce and multiply in the infected cell or to infect other enterocytes. This asexual stage allows the infection to spread to many enterocytes, even if the host is not exposed repeatedly to the organism.
The sporogonic (ie, gametogonic, sexual) stage involves the maturation and development of sporozoites enclosed in cysts or spores. As the infected enterocytes die, cyst or spore shedding occurs. The spores are then excreted in the stool. The spore-forming protozoa are obligate intracellular pathogens. Infection by these protozoa has been associated with substantial alterations in intestinal structure and function, but the pathogenesis of the predominant symptom, diarrhea, is not completely understood.
Cryptosporidiosis is the best-studied spore-forming diarrhea, and its pathogenic mechanisms can also be related to other spore-forming protozoa. The hypothesized sequence of events is explained below.
After invasion of the enterocytes, the epithelial cells release cytokines. These cytokinins activate phagocytes and recruit new leukocytes, which, in turn, release soluble factors (resulting in intestinal secretion of chloride and water) and inhibit absorption. Enterocyte damage may be a direct consequence of parasite invasion, multiplication, and extrusion. Regardless of the specific mechanism, marked distortion of the villus architecture is accompanied by nutrient malabsorption and osmotic diarrhea. With the exception of the microsporidia S intestinalis, none of the spore-forming protozoa have the ability to invade beneath the mucosal layer of the intestine.
The exact mode of transmission of D fragilis has not been confirmed. This parasite is speculated to be transmitted when pinworm eggs containing D fragilis trophozoites are ingested and, by this mechanism, resist the acid pH in the stomach. It is not invasive and mostly inhabits the large intestine. The exact mechanisms of diarrhea are not known.
The cyst is the infectious stage and is acquired by ingestion of contaminated food or water. After excystation in the small intestine, the trophozoites colonize the terminal ileum and the large intestine. They can then invade tissues by mechanical action of ciliary movement and the secretion of hyaluronidase and probably other enzymes. Encystation occurs in the lumen of the colon or in freshly evacuated stools. As with E histolytica, invasiveness is the hallmark of the pathophysiology of balantidiasis.
Many experts believe that B hominis is pathogenic only when present in large numbers in the intestine (>5 organisms per 400X field) and when other infectious organisms are absent. Three distinct morphologic stages are recognized: vacuolar, granular, and ameboid. B hominis inhabits the large intestine and has no evident life cycle in humans. Cysticlike stages are rare and have been found in patients with acquired immunodeficiency syndrome (AIDS) and in vitro. The mechanisms of how this parasite causes illness have not been elucidated yet.
At least 325 water-associated outbreaks of parasitic protozoan disease have been reported.  North America and Europe accounted for 93% of all reports, and nearly two thirds occurred in the United States. G lamblia and C parvum account for most outbreaks (40.6% and 50.8%, respectively), followed by E histolytica and C cayetanensis (1-3% each), and, less frequently, (≤ 1%) by I belli, B hominis, and B coli.
Amebiasis: E histolytica is not endemic in the United States, but travelers to high-risk areas where amebiasis is endemic may acquire the infection during their travel. Prevalence of amebiasis has increased in the southwestern United States as a result of emigration from Mexico.
Giardiasis: Rate of prevalence varies from 3-13%. Giardiasis is one of several causes of traveler's diarrhea. Person-to-person transmission is associated with groups that exercise poor fecal-oral hygiene, such as children in childcare centers, male homosexuals, and institutionalized individuals. G lamblia is endemic in childcare centers and can be detected in approximately 20% of asymptomatic children. The attack rates of G lamblia during outbreaks in childcare centers range from 20-50%
- The epidemiology of the intestinal spore-forming protozoa is not fully understood. Work in this area has been hampered by a lack of complete surveillance and widespread serologic surveys.
- The generally quoted prevalence of cryptosporidia in stool specimens is 1-3%. C parvum is highly transmissible in the family setting, is one of many causes of traveler's diarrhea, and is associated with diarrhea outbreaks due to contaminated water supplies and in childcare centers, with attack rates that vary from 33-73%. New studies have provided more information regarding Cryptosporidium transmission.  C hominis is spread only between humans; however, the major reservoir for C parvum is domestic livestock (predominantly cattle), and direct contact with infected cattle is a major transmission pathway along with indirect transmission through drinking water.
- Isospora belli, which is less common than cryptosporidia, is endemic in many developing countries, with a lower prevalence in the United States. Even in the United States, sporadic outbreaks have occurred in mental institutions and childcare centers.
- The epidemiology of human microsporidia is less understood. Widespread distribution of E bieneusi in Europe, North America, and South America led to the suggestion that this organism may be common in immunocompetent individuals but causes disease only in those with immunocompromise.
- A report from Massachusetts showed that Cyclospora may cause community-acquired diarrhea in otherwise healthy persons.  Fecal-oral transmission through infected water caused an epidemic of cyclosporidiosis in Chicago. 
- All 4 spore-forming protozoa are frequent pathogens in individuals with human immunodeficiency virus (HIV) infection.  Cryptosporidia are found in the stools of 10-20% of patients with AIDS-associated diarrhea. Microsporidia are associated more commonly with chronic diarrhea in patients with AIDS than are cryptosporidia, and prevalence ranges from 6-50%. The frequency with which cryptosporidia and microsporidia are identified in the stools of patients with AIDS is related to the CD4 count (identification is more frequent when the CD4 count is < 100 cells/mL) and the presence of GI symptoms. Isospora are associated infrequently with AIDS-associated diarrhea in the United States and Europe (about 2%), and Cyclospora has been observed occasionally in patients with AIDS.
D fragilis: The exact frequency of dientamoebiasis is not known.
B coli: Sporadic infections have been reported in facilities for the handicapped, where poor conditions of personal hygiene prevail.
B hominis: Surveillance data from clinical microbiology laboratories report prevalence rates in the range of 10-18%, but frequency of the disease is extremely low.
Amebiasis: An estimated 10% of the world's population is infected with E histolytica, the highest prevalence is in developing countries with the lowest levels of sanitation. This results in 50-100 million cases of colitis or liver abscesses per year and up to 100,000 deaths annually.
Giardiasis: G lamblia is the most commonly isolated intestinal parasite throughout the world. Rates of 20-40% are reported in developing countries, especially in children.
Spore-forming protozoa: All of these organisms may be common worldwide, and their frequency may be related to the adequacy of sanitation. In general, the infections are more common in developing countries. Prevalence of cryptosporidia in Asia and Africa ranges from 5-10%, but antibodies to cryptosporidia have been found in 32-58% of adults. Isospora and Cyclospora are endemic in many parts of Africa, Asia, and South America. The prevalence rates among patients with AIDS are higher in developing countries than in the United States, possibly because of the common use of prophylactic trimethoprim-sulfamethoxazole and/or underlying low prevalence in the United States.
D fragilis: Data on the prevalence of this parasite are inadequate. Based on a few surveys, estimates among the general population in developed countries range from 2-4%. Much higher rates are observed among travelers and in institutions or crowded living groups in which hygiene is inadequate. Incidence of this parasite in a large series in Canada was 1-19% with a prevalence of 4%. A high frequency of concomitant infection with pinworms suggests that it is transmitted through the eggs of Enterobius vermicularis. D fragilis has infected 9% of children in childcare centers and 4% of childcare center providers. In a study performed in Belgium, D fragilis was associated with 6.3% of diarrhea cases among 448 patients. 
B coli: Infections are rare in humans, and approximately 25% of symptomatic patients have a history of contact with swine. B coli is uncommon in temperate climates, and it is found in association with pigs throughout the tropics, especially in the Philippines.
B hominis: This parasite is distributed throughout the world. Prevalence rates of 54% and 33% have been reported in Papua New Guinea and Nepal, respectively. In children, prevalence rates vary from 2% in Kuwait to 65% in Papua New Guinea. Studies performed in Africa have shown that B hominis could be a major cause of diarrhea in areas associated with deficient sanitation and low hygiene standards.  Furthermore, in a study done in Turkey, children with B hominis had a lower growth status compared with children with negative stool sample findings for any parasite. 
See the list below:
Amebiasis: Estimates suggest that almost 500 million people in the world are carrying E histolytica. Roughly 50 million people develop invasive disease each year, and 50,000-100,000 people die of amebiasis each year, resulting in a mortality rate of 1 in 500-1000 diagnosed cases. This makes amebiasis the third most common cause of death due to parasites worldwide, behind malaria and schistosomiasis; however, among patients with illness severe enough to require hospitalization, the case-fatality ratio is higher. One small study in children reported a 9% mortality rate and a 27% morbidity rate. Liver abscesses and resultant complications account for approximately 40% of deaths from amebiasis, followed in frequency by invasive colitis and associated complications.
- Giardiasis occurs worldwide and is the most common parasite identified in stool specimens in the United States.
- Longitudinal prospective studies, in which stool specimens were collected either weekly or monthly for one year, showed that 33-37% of children who were observed became infected. In these studies, most infections were asymptomatic. During outbreaks of diarrhea in which G lamblia was implicated as the etiologic agent, attack rates ranged from 17-54%.
- Although self-limited diarrheal disease is the most frequent symptomatic manifestation of Giardia infection, prolonged diarrhea with malnutrition and growth failure in infancy are occasional complications.
- A study performed by the Centers for Disease Control and Prevention (CDC) in the United States showed that the rate of hospital admissions for giardiasis (2 per 100,000 population) rivaled those for shigellosis (2.4 per 100,000 population). Typically, giardiasis is not associated with mortality, even in patients with immunocompromise.
Spore-forming protozoa: Based on studies done in the past, in which antibodies to cryptosporidia have been found in 32-58% of adults with much lower prevalences in stool specimens (1-10%), the presumption is that the morbidity rates associated with cryptosporidiosis in immunocompetent patients is low, although it is higher in outbreaks. Mortality is rare in this group of patients. The same can be said with other spore-forming protozoa, although their epidemiologies are less well known. All 4 intestinal spore-forming protozoa have much higher morbidity rates in patients with AIDS. In cases of cryptosporidiosis and microsporidiosis, presence of disease is intimately related to low CD4 counts and associated with higher mortality rates.
Dientamoebiasis: The exact morbidity rate is not known but is presumably very low. Practically no mortality is associated with this parasitosis.
Balantidiasis: Currently, precise information about exact morbidity and mortality rates of balantidiasis is lacking. A study performed in Amerindian populations of Amazonia found both a low prevalence of the disease and absence of symptoms or signs referable to this organism.  The nutritional state and the immune status of the host have been mentioned as important factors in determining parasitic invasion through the intestinal wall. Fatal cases have been reported in malnourished and immunocompromised hosts.
Blastocystosis: The exact morbidity rate is unknown, and whether this parasite is really a human pathogen is debatable. The isolation of this parasite with diarrhea in patients with renal transplants and other immunodeficiencies is correlated. Practically no mortality is associated with this parasitosis. Most individuals with AIDS and blastocystosis have spontaneous resolution of symptoms or successful identification of other infectious or noninfectious etiologies.
Prevalence of intestinal protozoal disease is not associated with racial background. One study performed in Mexico demonstrated an increased frequency of HLA-DR3 and complotype SCO1 in mestizo children with amebic liver abscess. 
A person's sex is neither a predisposing nor a protective factor for protozoal-associated diarrhea; however, amebic liver abscess is observed more frequently in men than in women (with male-to-female ratios of up to 10:1). The reason for this is unknown, although speculations regarding protective roles of estrogens versus invasiveness have been postulated.
See the list below:
Amebiasis: Elderly patients and pregnant women have more severe symptoms with amebiasis. Dysenteric amebiasis in young infants, although relatively uncommon, is associated with high morbidity rates. Liver abscess is more common in adolescents and adults. Invasive disease is much less common in young children than in adults, possibly because ingestion of contaminated food with E histolytica in this age group is less frequent.
Giardiasis: Infection is more common in children than in adults, except in epidemics, in which all age groups are equally affected. Infants younger than 12 months are less likely to be infected than older children.
Spore-forming protozoa: Studies performed with cryptosporidia have shown a higher rate of oocyst excretion in children younger than 3 years. In Peru, cryptosporidium and Cyclospora infections occurred at the same time of year and primarily affected children aged 1-2 years. Attack rates in patients with AIDS are very high in both pediatric and adult populations.
Dientamoebiasis: As mentioned before, this parasite has infected 9% of children in childcare centers and 4% of childcare center providers, which is probably related to fecal-oral transmission. Presumably, these protozoa infect children more frequently than adults, but this issue still needs to be examined. Exact estimates are difficult because of the high frequency of asymptomatic excretion.
Balantidiasis: Pigs are the main source of infection for humans; therefore, this infection is expected to be more frequent in older children, adolescents, or adults than in young infants.
Blastocystosis: No available data indicate that this disease has higher prevalence in any age group.
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