Pediatric Amebiasis 

Amebiasis is a parasitic infection caused by the protozoon Entamoeba histolytica.^[1] Amebiasis is the third leading parasitic cause of death worldwide, surpassed only by malaria and schistosomiasis. On a global basis, amebiasis affects approximately 50 million persons each year, resulting in nearly 100,000 deaths.

Fedor Aleksandrovich Lošch, in St. Petersburg, Russia, first described amebiasis in 1875. He originally named the organism Amoeba coli and documented its pathogenicity in a dog fed with dysenteric stools from a patient. In 1886 in Egypt, Kartulis proved amebae to be the cause of intestinal and hepatic lesions in patients with diarrhea. In 1891, Councilman and Lafleur, at Johns Hopkins University Hospital, distinguished between bacillary and amebic dysentery. In 1913 in the Philippines, Walker and Sellards described the pathogenic role of amebae in extensive studies.

The parasite has 2 forms: a motile form, called the trophozoite, and a cyst form, responsible for the person-to-person transmission of infection. The trophozoite of E histolytica inhabits the large intestine to produce lesions of amebic colitis. Invasion of the colonic mucosa leads to dissemination of the organism to extracolonic sites, predominantly the liver. Faced with an adverse colonic environment, the trophozoite changes to the cystic form, better adapted to survival.

The trophozoite of E histolytica averages 25 mm, ranging from 10-60 mm (see following image). It has a clear ectoplasm and a somewhat granular endoplasm that contains several vacuoles. The trophozoite has a single 3-mm to 5-mm nucleus with fine peripheral chromatin and a central nucleolus. Ingested RBCs may be present within the trophozoite.

The cyst of E histolytica averages 12 mm, ranging from 5-20 mm (see following image). It has 1-4 nuclei that are morphologically similar to the nuclei of the trophozoite. The cyst may have iodine-stainable glycogen clumps and chromatoid bodies with smooth rounded edges.

The life cycle of E histolytica is depicted in the following image. Humans are the only reservoir of E histolytica. Cysts passed in the feces can survive in moist environmental conditions for weeks to months. Upon ingestion of fecally contaminated food or water, the cysts travel to the small intestine, where the trophozoites are released. In 90% of patients, the trophozoites re-encyst and produce asymptomatic infection, which usually spontaneously resolves within 12 months. In the remaining 10% of patients who are infected, the parasite causes symptomatic amebiasis. Under unfavorable conditions, the trophozoite reverts to the cyst form, and the life cycle is repeated.

Entamoeba dispar and Entamoeba moshkovskii are nonpathogenic parasites that are identical morphologically to E histolytica. The previously reported asymptomatic infections due to the so-called nonpathogenic strains of E histolytica are now recognized to be due to E dispar and E moshkovskii. Specific and sensitive means to detect E histolytica in stool are now available and include antigen detection and polymerase chain reaction (PCR). Other morphologically distinct organisms, such as Entamoeba coli and Entamoeba hartmanni, are also nonpathogenic. Infections due to E histolytica cause a spectrum of illnesses, as follows:

• Intestinal disease

  • Asymptomatic infection
  • Symptomatic noninvasive infection
  • Acute proctocolitis (dysentery)
  • Fulminant colitis with perforation
  • Toxic megacolon
  • Chronic nondysenteric colitis
  • Ameboma
  • Perianal ulceration
• Extraintestinal disease

  • Liver abscess
  • Pleuropulmonary disease
  • Peritonitis
  • Pericarditis
  • Brain abscess
  • Genitourinary disease

Amebiasis is acquired by the fecal-oral route through consumption of fecally contaminated food or water. Direct oral-anal contact (anilingus) can also lead to fecal exposure to E histolytica. The ingestion of E histolytica cysts is followed by excystation in the small bowel and invasion of the colon by the trophozoites. The incubation period varies from 2 days to 4 months. Invasive disease begins with the adherence of E histolytica to colonic mucins, epithelial cells, and leukocytes. Adherence of the trophozoite is mediated by a galactose-inhibitable adherence lectin. This lectin is a 260-kd surface protein that contains a 170-kd subunit and a 35-kd subunit. The heavier subunit has galactose-binding activity and at least 6 distinct epitopes. These epitopes are different in E dispar.

After adherence, trophozoites invade the colonic epithelium to produce the ulcerative lesions typical of intestinal amebiasis.

The trophozoites of E histolytica lyse the target cells by using lectin to bind to the target cells' membranes and using the parasite's ionophorelike protein to induce a leak of ions (ie, Na⁺, K⁺, Ca⁺) from the target cell cytoplasm. Numerous hemolysins, encoded by plasmid (ribosomal DNA [rDNA]) and cytotoxic to the intestinal mucosal cells, have been described in E histolytica. An extracellular cysteine kinase causes proteolytic destruction of the tissue, producing flask-shaped ulcers (see following image). Phorbol esters and protein kinase C activators augment the cytolytic activity of the parasite.

Spread of amebiasis to the liver occurs via the portal blood. The pathogenic strains evade the complement-mediated lysis in the bloodstream. Trophozoites ascend the portal veins to produce liver abscesses filled with acellular proteinaceous debris. This material has the appearance of anchovy paste. The trophozoites of E histolytica lyse the hepatocytes and the neutrophils. This explains the paucity of inflammatory cells within the liver abscesses. The neutrophil toxins may contribute to hepatocyte necrosis. Triangular areas of hepatic necrosis may also occur due to ischemia caused by portal venous obstruction. The trophozoites of E histolytica may be present along the periphery of these hepatic lesions.

Serum antibodies in patients with amebic liver abscess develop in 7 days and persist for as long as 10 years. E dispar infections do not elicit antibody response, unlike asymptomatic E histolytica infections. Mucosal immunoglobulin A (IgA) response to E histolytica occurs during invasive amebiasis. However, no evidence suggests that invasive amebiasis is increased in incidence or severity in patients with IgA deficiency.

Cell-mediated immunity is important in limiting the disease and preventing recurrences. Antigen-specific blastogenic responses occur, leading to production of lymphokines, including interferon-d (IFN-d), which activates the killing of E histolytica trophozoites by the macrophages. This killing depends on contact, oxidative pathways, nonoxidative pathways, and nitric oxide (NO). Lymphokines, such as tumor necrosis factor-alpha (TNF-a), are capable of activating the amebicidal activity of neutrophils. Incubation of CD8⁺ lymphocytes with E histolytica antigens in vitro elicits cytotoxic T-cell activity against the trophozoites. During acute invasive amebiasis, T-lymphocyte response to E histolytica antigens is depressed by a parasite-induced serum factor.

Frequency

United States

In the United States, amebiasis is most commonly seen in immigrants from developing countries and travelers to those areas. In one study, the rate of acute amebic diarrhea ranged from 1.5% in travelers returning from Southeast Asia to 3.6% in those returning from Central America, with an overall rate of 2.7%.^[2] Additionally, increased prevalence of amebiasis in the United States is noted in institutionalized persons (especially with mental retardation), male homosexuals, and those who live in communal settings.

The prevalence rate of amebiasis in the United States is approximately 4%. E dispar infection, which is always asymptomatic, is 10 times more common than E histolytica infection. Moreover, only 10% of E histolytica infections cause invasive disease. Therefore, only 1% of persons with stool microscopy findings that reveal Entamoeba develop symptomatic amebiasis.

International

Worldwide, approximately 50 million cases of invasive E histolytica disease occur each year, with as many as 100,000 deaths. This represents the tip of the iceberg because only 10%-20% of infected individuals become symptomatic.

Earlier estimates of E histolytica infection based on examination of stool for ova and parasites, are inaccurate because this test can not differentiate E histolytica from E dispar and Entamoeba moshkovskii, which are morphologically identical but nonpathogenic organisms. Prevalence rates of E histolytica, as determined by enzyme-linked immunosorbent assay (ELISA) or PCR tests on stool from asymptomatic persons in developing countries range from 1-21%.

Incidence of amebiasis is higher in developing countries. Areas of high prevalence include the Indian subcontinent, southern and western Africa, the Far East, South America, and Central America. In endemic areas, as many as 25% of patients may be carrying antibodies to E histolytica due to prior infections, which may be largely asymptomatic. A study in Bangladesh indicated that preschool children experienced 0.09 episodes of E histolytica -associated diarrhea and 0.03 episodes of amebic dysentery each year. The annual incidence of amebic liver abscess was reported to be 21 cases per 100,000 inhabitants in Hue City, Vietnam.^[3] An epidemiologic study in Mexico City reported that 9% of the population was infected with E histolytica in the 5-year to 10-year period preceding the study. Various factors, such as poor education, poverty, overcrowding, contaminated water supply, and unsanitary conditions, contribute to the fecal-oral transmission.

Travel to endemic areas can predispose individuals to amebiasis. However, amebiasis is an uncommon cause of traveler's diarrhea. The disease usually occurs after a longer stay in endemic areas (eg, >1 mo).

The impact of the acquired immunodeficiency syndrome (AIDS) pandemic on the prevalence of invasive amebiasis remains controversial. Earlier reports suggested that invasive amebiasis was not increased among patients with human immunodeficiency virus (HIV) infection. However, reports suggest that amebic liver abscess is an emerging parasite infection in individuals with HIV infection in disease-endemic areas as well as nondisease-endemic areas.^[4] Of 31 patients with amebic liver abscess at Seoul National University Hospital from 1990-2005, 10 (32%) were HIV positive.^[5]

Mortality/Morbidity

Amebic infections lead to significant morbidity while causing variable mortality as described below.

• Mortality rate in patients with uncomplicated amebic liver abscess is less than 1%.
• Fulminant amebic colitis has a mortality rate of more than 50%.
• Pleuropulmonary amebiasis has a mortality rate of 15-20%.
• Amebic pericarditis has a case fatality rate of 40%.
• Cerebral amebiasis is highly fatal, with a 90% death rate.
• Increased severity of amebiasis is noted in children (especially neonates), women who are pregnant or postpartum, individuals who use corticosteroids, individuals with malignancy, and malnourished individuals.

Sex

Invasive amebiasis, including amebic liver abscess, is much more common in adult males than in females. However, amebic liver abscess is equally common in both sexes among prepubertal children. Acuna-Soto and colleagues have noted that asymptomatic E histolytica infection is distributed equally between sexes.^[6] Therefore, the higher proportion of men with invasive amebiasis may be due to a male susceptibility to invasive disease.

Age

Symptomatic intestinal amebiasis occurs in all age groups. Liver abscesses due to amebiasis are 10 times more frequent in adults than in children.