Amebiasis

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Chapter 273 Amebiasis

Entamoeba histolytica infects up to 10% of the world’s population; endemic foci are particularly common in the tropics, especially in areas with low socioeconomic and sanitary standards. In most infected individuals, E. histolytica parasitizes the lumen of the gastrointestinal tract and causes few symptoms or sequelae. The 2 most common forms of disease caused by E. histolytica are amebic colitis with parasitic invasion of the intestinal mucosa and amebic liver abscess with dissemination of the parasite to the liver.

Epidemiology

Prevalence of infection with E. histolytica varies greatly depending on region and socioeconomic status. Most prevalence studies have not distinguished between E. histolytica and E. dispar, and thus the true prevalence of E. histolytica infection is not known. It is estimated that infection with E. histolytica leads to 50 million cases of symptomatic disease and 40,000-110,000 deaths annually. Amebiasis is the 3rd leading parasitic cause of death worldwide. Prospective studies have shown that 4-10% of individuals infected with E. histolytica develop amebic colitis and that <1% of infected individuals develop disseminated disease, including amebic liver abscess. These numbers vary by region; for example, in South Africa and Vietnam, liver abscesses form a disproportionately large number of the cases of invasive disease due to E. histolytica. Amebic liver abscesses are rare in children and occur equally in male and female children; in adults, amebic liver abscesses occur predominantly in men.

Amebiasis is endemic to Africa, Latin America, India, and Southeast Asia. In the USA, amebiasis is seen most frequently in immigrants from and in travelers to developing countries. Residents of mental health institutions and men who have sex with men are also at increased risk for invasive amebiasis. Food or drink contaminated with Entamoeba cysts and direct fecal-oral contact are the most common means of infection. Untreated water and night soil (human feces used as fertilizer) are important sources of infection. Food handlers shedding amebic cysts play a role in spreading infection. Direct contact with infected feces also results in person-to-person transmission.

Pathogenesis

Trophozoites are responsible for tissue invasion and destruction. These attach to colonic epithelial cells by a galactose and N-acetyl-D-galactosamine (Gal/GalNac)-specific lectin. This lectin is also thought to be responsible for resistance to complement-mediated lysis. Once attached to the colonic mucosa, amebae release proteinases that allow for penetration through the epithelial layer. Host cells are destroyed by cytolysis and apoptosis. Cytolysis is mediated by trophozoite release of amoebapores (pore-forming proteins), phospholipases, and hemolysins. Amoebapores may also be partially responsible for the induction of apoptosis that occurs in mice with amebic liver disease and colitis. Early invasive amebiasis produces significant inflammation, due in part to parasite-mediated activation of nuclear factor-κB (NF-κB). Once E. histolytica trophozoites invade the intestinal mucosa, the organisms multiply and spread laterally underneath the intestinal epithelium to produce the characteristic flask-shaped ulcers. Amebae produce similar lytic lesions if they reach the liver. These lesions are commonly called abscesses, although they contain no granulocytes. Well-established ulcers and amebic liver abscesses demonstrate little local inflammatory response.

Immunity to infection is associated with a mucosal secretory IgA response against the Gal/GalNac lectin. Neutrophils appear to be important in initial host defense, but E. histolytica–induced epithelial cell damage releases neutrophil chemoattractants, and E. histolytica is able to kill neutrophils, which then release mediators that further damage epithelial cells. The disparity between the extent of tissue destruction by amebae and the absence of a local host inflammatory response in the presence of systemic humoral (antibody) and cell-mediated responses may reflect both parasite-mediated apoptosis and the ability of the trophozoite to kill not only epithelial cells but neutrophils, monocytes, and macrophages.

The sequencing of the E. histolytica genome has led to further insights into the pathogenesis of E. histolytica disease. The genome is functionally tetraploid, and there is evidence of lateral gene transfer from bacteria. It has been demonstrated that the amoebapore-A (Ap-A) gene along with other important genes can be epigenetically silenced using plasmids with specifically engineered sequences or short hairpin RNAs. Transcriptional profiling using proteomics and microarrays have likewise identified several candidate virulence factors. Several classes of proteases that may be associated pathogenesis have been identified, including a novel E. histolytica rhomboid protease 1 (EhROM1), which may be involved in immune evasion.

Clinical Manifestations

Clinical presentations range from asymptomatic cyst passage to amebic colitis, amebic dysentery, ameboma, and extraintestinal disease. E. histolytica infection is asymptomatic in about 90% of persons but has the potential to become invasive and should be treated. Severe disease is more common in young children, pregnant women, malnourished individuals, and persons taking corticosteroids. Extraintestinal disease usually involves the liver, but less common extraintestinal manifestations include amebic brain abscess, pleuropulmonary disease, ulcerative skin, and genitourinary lesions.

Diagnosis and Differential Diagnosis

A diagnosis of amebic colitis is made in the presence of compatible symptoms with detection of E. histolytica antigens in stool. This approach has a greater than 95% sensitivity and specificity and coupled with a positive serology test is the most accurate means of diagnosis in developed countries. The E. histolytica II stool antigen detection test (TechLab, Blacksburg, VA) is able to distinguish E. histolytica from E. dispar infection. Microscopic examination of stool samples has a sensitivity of 60%. Sensitivity can be increased to 85-95% by examining 3 stools, since excretion of cysts can be intermittent. However, microscopy cannot differentiate between E. histolytica and E. dispar unless phagocytosed erythrocytes (specific for E. histolytica) are seen. In highly endemic areas, trophozoites without phagocytosed erythrocytes may reflect co-infection with E. dispar in a patient with another cause of colitis, such as shigellosis. Endoscopy and biopsies of suspicious areas should be performed when stool sample results are negative and suspicion for amebiasis remains high.

Various serum antiamebic antibody tests are available. Serologic results are positive in 70-80% of patients with invasive disease (colitis or liver abscess) at presentation and in >90% of patients after 7 days of disease symptoms. The most sensitive serologic test, indirect hemagglutination, yields a positive result even years after invasive infection. Therefore, many uninfected adults and children in highly endemic areas demonstrate antibodies to E. histolytica. Polymerase chain reaction (PCR) detection in stool of E. histolytica is also able to distinguish E. histolytica from E. dispar but is less sensitive (72%) than the stool antigen test. Rapid antigen and antibody tests for bedside diagnosis in the developing world have been developed and are currently being tested. In addition, a loop-mediated isothermal amplification assay (LAMP) that can be optimized for field use is under development.

The differential diagnosis for amebic colitis includes colitis due to bacterial (Shigella, Salmonella, enteropathogenic Escherichia coli, Campylobacter, Yersinia, Clostridium difficile), mycobacterial (tuberculosis and atypical mycobacteria), and viral (cytomegalovirus) pathogens, as well as noninfectious causes such as inflammatory bowel disease (IBD). Pyogenic liver abscess due to bacterial infection, hepatoma, and echinococcal cysts are in the differential for amebic liver abscess. However, echinococcal cysts are rarely associated with systemic symptoms such as fever unless there is cyst rupture or leakage.

Treatment

Invasive amebiasis is treated with a nitroimidazole such as metronidazole or tinidazole and then a luminal amebicide (Table 273-1). Tinidazole has similar efficacy to metronidazole with shorter and simpler dosing and less frequent adverse effects. These adverse effects include nausea, abdominal discomfort, and a metallic taste that disappears after completion of therapy. Therapy with a nitroimidazole should be followed by treatment with a luminal agent, such as paromomycin (which is preferred) or iodoquinol. Diloxanide furoate can also be used in children >2 yr of age, but it is no longer available in the USA. Paromomycin should not be given concurrently with metronidazole or tinidazole, because diarrhea is a common side effect of paromomycin and may confuse the clinical picture. Asymptomatic intestinal infection with E. histolytica should be treated preferably with paromomycin or alternatively with either iodoquinol or diloxanide furoate. For fulminant cases of amebic colitis, some experts suggest adding dehydroemetine (1 mg/kg/day subcutaneously or IM, never IV), available only through the Centers for Disease Control and Prevention. Patients should be hospitalized for monitoring if dehydroemetine is administered. Dehydroemetine should be discontinued if tachycardia, T-wave depression, arrhythmia, or proteinuria develops.

Table 273-1 DRUG TREATMENT FOR AMEBIASIS

MEDICATION ADULT DOSAGE (ORAL) PEDIATRIC DOSAGE (ORAL)*
INVASIVE DISEASE
Metronidazole Colitis or liver abscess: 750 mg tid for 7-10 days Colitis or liver abscess: 35-50 mg/kg/day in 3 divided doses for 7-10 days
or
Tinidazole Colitis: 2 g once daily for 3 days Colitis: 50 mg/kg/day once daily for 3 days
Liver abscess: 2 g once daily for 3-5 days Liver abscess: 50 mg/kg/day once daily for 3-5 days
Followed by:
Paromomycin (preferred) 500 mg tid for 7 days 25-35 mg/kg/day in 3 divided doses for 7 days
or
Diloxanide furoate or 500 mg tid for 10 days 20 mg/kg/day in 3 divided doses for 7 days
Iodoquinol 650 mg tid for 20 days 30-40 mg/kg/day in 3 divided doses for 20 days
ASYMPTOMATIC INTESTINAL COLONIZATION
Paromomycin (preferred) As for invasive disease As for invasive disease
or
Diloxanide furoate
or
Iodoquinol

* All pediatric dosages are up to a maximum of the adult dose.

Not available in the USA.

Broad-spectrum antibiotic therapy may be indicated in fulminant colitis to cover possible spillage of intestinal bacteria into the peritoneum and translocation into the bloodstream. Intestinal perforation and toxic megacolon are indications for surgery. In amebic liver abscess, image-guided aspiration of large lesions or left lobe abscesses may be necessary if rupture is imminent or if the patient shows a poor clinical response 4-6 days after administration of amebicidal drugs. A Cochrane meta-analysis comparing metronidazole and metronidazole plus aspiration in uncomplicated amebic liver abscess showed that there is insufficient evidence to make any recommendation for or against this approach. Chloroquine, which concentrates in the liver, may also be a useful adjunct to nitroimidazoles in the treatment of amebic liver abscess. To confirm cure, stool examination should be repeated every 2 wk following completion of therapy until clear.