Entamoeba histolytica (Amebiasis)

Authors: Eric Houpt, M.D., Chien-Ching Hung, M.D., M.Sc., William Petri, M.D.,Ph.D.

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PARASITOLOGY

Entamoeba histolytica is a protozoan parasite that accounts for an estimated 100,000 annual deaths (71). Infection ranges from asymptomatic colonization of the large bowel to severe invasive intestinal and extra-intestinal disease. The parasite life cycle is relatively simple: humans orally ingest the cyst form from contaminated sources, excystation to the trophozoite form occurs in the small bowel, then the trophozoite either colonizes or invades the large bowel. When the trophozoite encysts the life cycle is complete and the organism can be transmitted (20).

EPIDEMIOLOGY

The epidemiology of Entamoeba histolytica has been complicated by the mid-1990's redescription of E. histolytica into two species: E. histolytica, which is pathogenic, and E. dispar, which is not (71). Further molecular studies have identified a third species, E. moshkovskii, that also tends to be non-pathogenic (2). The bulk of previous studies on the prevalence of E. histolytica were based on stool microscopy, which is of low sensitivity and specificity and cannot distinguish E. histolytica cysts or trophozoites from E. dispar or E. moshkovskii. Thus the conclusions that 10% of the world's population is infected with E. histolytica is probably an overestimate (59). Serologic studies are more reliable, since only E. histolytica infection generates a serum antibody response (54) and these suggest that up to 8.4% of persons in endemic countries have been exposed (8).

In developed countries, populations at risk for E. histolytica infection include returned travelers or expatriates and immigrants from endemic countries and most cases of invasive disease are imported. Although previous studies suggest that men who have sex with men (MSM) are at a higher risk of intestinal infection with E. dispar (3, 47, 51) due to increased oral-anal sexual contact (29), invasive disease is rare. In a retrospective review of medical records of more than 34,000 HIV-infected patients in the U.S. (34) 111 (0.3%) patients were diagnosed as having E. histoytica or E. dispar infection, and only 2 had extra-intestinal amebiasis. Over the past several years, many investigators in Japan, Taiwan, Korea, and Australia have found that amebiasis is increasingly diagnosed among HIV-infected MSM (23, 24, 43, 45, 61,62, 65). Of the estimated 500 to 600 reported cases of amebiasis annually in Japan, 80% of them occurred in MSM (42).

While an estimated 90% of E. histolytica infections are asymptomatic, prospective studies of asymptomatic carriers indicate a risk of invasive disease of 5/56 (9%) over the course of 6-12 months (26). Invasive disease has a high mortality, estimated at >10% for either dysentery severe enough to require hospitalization or liver abscess. Accordingly, the risk of developing invasive disease, as well as decreased transmission, are rationales for treating asymptomatic carriers of E. histolytica, however WHO recommends against treatment of asymptomatic patients when only a morphologic diagnosis by stool examination is available (i.e., E histolytica/E dispar/E moshkovskii).

CLINICAL MANIFESTATIONS

Intestinal Amebiasis

Infection with E. histolytica may be asymptomatic or cause intestinal or extraintestinal disease. Asymptomatic infection with E. histolytica but not E. dispar is associated with a positive serum anti-amebic antibody and, frequently, a positive stool antigen test. Clinical syndromes associated with intestinal E. histolytica disease include diarrhea, acute rectocolitis (dysentery), fulminant colitis (acute necrotizing colitis) with perforation, toxic megacolon, chronic nondysenteric colitis, ameboma, and perianal ulceration. The onset of acute rectocolitis is usually gradual over 1 to 3 weeks. Most patients have abdominal pain, tenderness, watery or bloody diarrhea while only one third are febrile. Most patients have heme-positive stools, but fecal leukocytes may not be present.

Fulminant colitis is rare (<0.5% of cases) but associated with a mortality of more than 40%; malnourished persons, pregnant women, corticosteroid users, and very young children may be at increased risk. Patients typically appear very ill and have fever, profuse bloody mucoid diarrhea, diffuse abdominal pain, and hypotensive with signs of peritoneal irritation. Intestinal perforation usually manifests as a slow leakage rather than an acute event. Surgical intervention is indicated for bowel perforation or patients with no response to antiamebic therapy although attempts to suture such necrotic bowels are usually unsuccessful. Toxic megacolon is also rare (0.5% of cases).

Some report a syndrome of intermittent diarrhea, abdominal pain, flatulence, and weight loss for months in patients with amebas in the stool and positive for antiamebic serologic tests. Not all patients respond to antiamebic therapy so the role of E. histolytica in all instances is unclear. However a trial of therapy is certainly reasonable, as is ruling out inflammatory bowel disease, since amebiasis may worsen if corticosteroids begun. Ameboma is the formation of annular colonic granulation tissue at a single or multiple sites. It usually involves the cecum or ascending colon, and may mimic carcinoma of the colon. Perianal amebiasis may result from extension of severe bowel disease to the skin. Lesions can be ulcerative or condylomatous, enlarge slowly over weeks to months, and result in pain and bleeding.

Extraintestinal Amebiasis

Amebic liver abscess is the most common extraintestinal manifestation of amebiasis and is 10 times more common in adult men despite an approximately equal sex distribution of colonic amebic disease. Approximately 80% of patients manifest relatively quickly, typically within 2 to 4 weeks (20). However, 95% of travelers develop liver abscess within 2 to 5 months (median 3 months) after leaving the endemic area. The acute symptoms include fever and a constant, dull, aching pain in the right upper quadrant or epigastrium while a subacute course may present with prominent weight loss with less fever or abdominal pain. Hepatomegaly with point tenderness over the liver below the ribs or in the intercostals spaces is a typical finding. Right-sided pleural pain or referred shoulder pain occurs when the diaphragmatic surface of the liver is involved. Associated gastrointestinal symptoms occur in 10%-35% of patients. Leukocytosis without eosinophilia is noted in 80% of cases and mild anemia in more than half. Patients with acute amebic liver abscess tend to have a normal alkaline phosphatase level and an elevated alanine aminotransferase level; the opposite is true for those with chronic disease. Ultrasonography, abdominal computed tomography, and magnetic resonance imaging are all excellent for detecting liver lesions but are not specific for amebic liver abscess.

Pleuropulmonary amebiasis is the most common complication of amebic liver abscess. It occurs as a result of the rupture of a superior right lobe abscess with erosion through the diaphragm to involve the pleural space or lung parenchyma. Serous pleural effusion and atelectasis are common findings and do not indicate extension of disease. In addition, formation of a hepatobronchial fistula is not uncommon. Intraperitoneal rupture occurs in 2%-7% of cases, and sudden perforation is associated with a high mortality. Left lobe abscess are more likely to progress to rupture due to late clinical presentation. Pericardial amebiasis, an unusual but serious complication, usually presents with fever and abdominal pain with progression to substantial chest pain and signs of congestive heart failure although acute perforation with cardiac tamponade and shock can occur. Cerebral amebiasis has abrupt onset, and progresses rapidly to death over 12-72 hours without adequate therapy. Thus, when patients with known amebiasis have alteration of mental states or focal signs, amebic brain abscess should be considered. Genitourinary amebiasis is rare and includes rectovaginal fistulas and vulvar lesions in women and penile amebiasis in men.

LABORATORY DIAGNOSIS

When the diagnosis of asymptomatic intestinal infection with E. histolytica is sought (e.g., for epidemiologic studies, in a traveler returning from a highly endemic area, or when E. histolytica/E. dispar trophozoites or cysts are seen incidentally on stool microscopy), one should ideally use fecal antigen detection assays (66). There are presently several commercially available antigen kits for detecting Entamoeba (TechLab E. histolytica II, Blacksburg, VA; Ridascreen Entamoeba, R-Biopharm, Germany; Triage Micro Parasite Panel, Biosite Diagnostics, Inc., San Diego CA; ProSpecT E. histolytica, Remel Inc., Lenexa, KS; CELISA Path, Cellabs, Brookvale, Australia). Unfortunately, these tests require fresh (not formalin-preserved) stool for analysis, and only the TechLab and Cellabs kits report being specific for E. histolytica not E. dispar. Stool PCR is a promising new technique. Performing isoenzyme analysis on trophozoites cultured from stool is another possible but laborious and impractical method. Serum antibodies should be present in >70% of patients with amebic colitis or liver abscess and thus are useful in a person from a non-endemic country.

The diagnosis of amebic colitis can be difficult to make. Laboratory values should reveal a leukocytosis and in most a high-titer E. histolytica serum antibody level. Demonstration of E. histolytica trophozoites in tissue from a biopsy of a colonic ulcer (see Figure 2) is the gold standard for diagnosis. When biopsy material is unavailable, another compatible finding is the presence of hematophagous trophozoites on stool microscopy (see Figure 1). Amebic liver abscesses (see Figure 3) are usually visible on ultrasound, CT scan, or hepatic scintiscan. Liver enzymes can be normal or elevated. Serology is again almost always positive (>90%). Serum antigen is becoming validated as a sensitive test as well, and has the distinct advantage of allowing one to follow therapy (19). The gold standard for diagnosis is direct visualization or culture of trophozoites from the abscess; this is most successful when the tissue can be carefully obtained from the junction of the abscess and viable liver as during an open drainage procedure (41). Material from percutaneously-obtained aspirates is usually of lower yield for microscopy or culture (70).

PATHOGENESIS

The parasite is appropriately named “histolytica” for its cellular destructive nature. The trophozoite initiates infection with adherence to colonic mucin and epithelial cells via a Gal/GalNAc lectin (46). The serine-richE. histolytica protein may also play a role in adherence, as antibodies to SREHP partially inhibit adherence in vitro (60). Upon Entamoeba-cell co-culture experiments, cells undergo morphologic and DNA degradative changes consistent with apoptosis as well as necrosis (52). The mechanism of apoptosis appears to involve direct activation of downstream caspases including caspase 3 (25). Entamoeba then engulf apoptotic corpses, and this feature correlates with virulence in vitro (7). Other pathogenic events are mediated through the secretion of amebic proteinases (28, 53). Recent work on the host response to E. histolytica infection has brought insight into mechanisms of protection. In mice neutrophils and Natural Killer T cells afford some protection against intestinal and liver infection, respectively (4, 33). In a childhood cohort in Bangladesh, mucosal IgA to the parasite Gal/GalNAc lectin Carbohydrate Recognition Domain and parasite-specific interferon gamma production and were also associated with protection (21). When paired with the observation that IL-4 promotes infection persistence in mice (18), a Th1-type immune response appears desirable.

SUSCEPTIBILITY IN VITRO AND IN VIVO

The cyst form of the parasite cannot be cultured in vitro, so there are no in vitro cysticidal data available. Axenic growth of E. histolytica trophozoites was developed in 1968 (12) and has allowed for limited in vitroefficacy studies for relevant drugs (see Table 1). Acquired drug resistance to E. histolytica has historically been extremely difficult to develop in vitro, presumably because the metronidazole-activating enzyme pyruvate ferredoxin oxidoreductase is required for Entamoeba metabolism.

ANTIPARASITIC THERAPY

Asymptomatic Intestinal Colonization

There are at least three classes of drugs that have shown efficacy in clinical trials for asymptomatic intestinal colonization: dichloracetanilide derivatives, oral aminoglycosides, and 5-hydroxyquinolines. The specific agents include diloxanide furoate (Furamide), paromomycin (Humatin), and iodoquinol (Yodoxin, also known as diiodohydroxyquin) (see Table 2). All have a large worldwide experience. All have poor gastrointestinal absorption, which allows high luminal concentrations but renders them less effective in invasive disease. Because of rare optic toxicity and long duration of therapy with iodoquinol, and because in one recent study from Vietnam paromomycin was superior to diloxanide, paromomycin is our preferred agent (6). Paromomycin has also been effective in a number of trials over the last 40 years. Many of these have shown cure rates for mild invasive disease as well (E. histolytica/E. dispar-associated diarrhea) (56, 63). Side effects with oral therapy are generally mild, but include diarrhea and other gastrointestinal disturbances and less commonly, headache and dizziness. Therapy should be given with meals and for a full 7 or 10 days as failures have occurred with shorter courses.

Amebic Colitis

The mainstay of therapy for amebic colitis since the 1960s has been the nitroimidazoles, in particular metronidazole (Flagyl) and tinidazole (Fazigyn) (see Table 2). Powell and coworkers performed the first clinical trial of metronidazole in patients with acute amebic dysentery (diagnosis made by the presence of hematophagous E. histolytica in stools and rectal biopsies) which demonstrated the superiority of 800 mg tid given for 10 days (48). Lower doses were less effective but subsequent studies have demonstrated that the 800 mg po tid regimen can be shortened to 5 days (49, 50). Newer studies have successfully used nitroimidazoles with longer half-lives (namely tinidazole) (17), secnidazole (57), and ornidazole) for even shorter durations. Tinidazole has had the most experience, is better tolerated than metronidazole, and can be administered for only 3-5 days (5). The common side effects of metronidazole include nausea, headache, anorexia, and a metallic taste; less common ones include a disulfuram-like reaction to alcohol, vomiting, and peripheral neuropathy. The nitroimidazoles are rapidly absorbed after oral administration and are not effective against luminal trophozoites. Indeed there is a 40-60% rate of parasite persistence in the intestine after therapy with these agents (26, 58). Therefore a course of treatment should be followed with a course of diloxanide or paromomycin. The metronidazole trials to date have been in "not severely ill patients". Regarding severe or "fulminant" amebic colitis there is no specific therapy recommendation. It is logical to assume that intravenous metronidazole would be effective in these patients, but data is limited to a case series from Japan that showed promise (30). Based on old data the addition of parenteral emetine could be considered in refractory cases but data is lacking. Dehydroemetine is available in the United States from the CDC Drug Service (1600 Clifton Road, MS/D09, Atlanta, GA 30333; Tel (404) 639-3670, Fax (404) 639-3717). When patients fail medical treatment and undergo open surgery for acute abdomen, gastrointestinal bleeding, or toxic megacolon (64), mortality is extremely high and broad-spectrum antibiotics should probably be added for bacterial spillage into the peritoneum. A promising new agent for intestinal amebiasis is nitazoxanide. This drug administered at 500mg po bid for 3 days was associated with resolution of E. histolytica/dispar associated diarrhea in 80-90% of patients (vs. 40-50% in placebo) along with microscopic improvement (55).

Liver Abscess

The initial amebic colitis trials also included groups of "not severely ill patients" with amebic liver abscess. Liver abscess was found to be in general more responsive than colitis, with cure in all 210 patients regardless of the regimen. However because recovery was perceptibly slower in the lower dose (200 mg po tid) groups and single dose therapy has been associated with a 6% failure rate (32) we recommend the standard high dose of metronidazole for 10 days or tinidazole for 5 days (22). As with amebic colitis, after a course of therapy patients should receive a course of paromomycin. Additionally, the use of dehydroemetine or chloroquine could be considered in severe or refractory cases. Nitazoxanide has not been studied in amebic liver abscess.

Special Situations

Extrahepatic Abscess

Abscess formation by E. histolytica has been reported in other sites such as the skin, lung, and brain, presumably after hematogenous spread. Therapy is anecdotal, but would generally follow that of liver abscess, i.e use of metronidazole and consideration of local drainage.

Immunosuppressed Hosts

It remains unclear whether HIV-positive persons are more likely to develop invasive amebiasis than HIV-negative persons after infection with E. histolytica occurs. Clinical manifestations of invasive amebiasis among HIV-positive persons appear similar to those of HIV-negative persons and amebic liver abscess and colitis are the two most common presentations of invasive amebiasis. In a study of 64 HIV-positive patients with 67 case of invasive amebiasis (52 amebic colitis, 40 amebic liver abscess, and 25 both), most of the patients become afebrile within 3 to 4 days after receipt of metronidazole despite moderate to severe immunosuppression; none of the patients died of invasive amebiasis (24). Therefore, we would advise the conventional recommendations.

Pregnancy

Of the drugs mentioned for asymptomatic infection, paromomycin has been used safely in pregnancy (31) and would be the drug of choice. For invasive intestinal disease, there is continued controversy over the use of metronidazole in pregnancy. There have been reports of facial defects and CNS tumors in children born from mothers taking metronidazole in the first trimester (67) but large analyses have simultaneously found no increased risk above controls (9). A caveat is that the dose used for E. histolytica infection is higher than that used in most analyses. Some would recommend a trial of paromomycin for mild invasive intestinal disease (37). For severe colitis or liver abscess we feel that the risk of metronidazole to the fetus is less than that of the disease to the mother. One could consider trying chloroquine for liver abscess since this drug has been used safely (at lower doses) in pregnant women for malaria prophylaxis, but we would again recommend metronidazole.

Alternative Therapy

Diloxanide furoate is a relative of chloramphenicol used since the 1950s. The U.S. CDC experience with the drug from 1977 to 1990 documented a parasitologic cure rate in 86% of patients with asymptomatic E. histolytica/E. dispar infection (36). The drug is well tolerated, with only fourteen percent of patients reporting mild side effects, mainly flatulence or other gastrointestinal symptoms. In the U.S. the drug is only available through compounding pharmacies such as Panorama Compounding Pharmacy (6744 Balboa Blvd, Van Nuys, CA 91406, Tel: 800-247-9767) or Medical Center Pharmacy, New Haven, CT (Tel: 203-688-6816). Other compounding pharmacies may be found through the National Association of Compounding Pharmacies (Tel: 800-687-7850).

Iodoquinol has been widely used for asymptomatic intestinal colonization because it is effective and inexpensive. A large study in India found it to be 85% effective in non-dysenteric E. histolytica/E. dispar patients (27). However, there have been case reports of loss of vision (14) and several reports of myelo-optic neuropathy in patients taking the related drug iodochlorohydroxyquin (39). We would thus consider it a second-line agent, though some may disagree. Common side effects include constipation and enlargement of the thyroid gland (the drug contains 64% iodine).

As far as alternative agents for amebic colitis, the tetracyclines can be used but they are not as effective as metronidazole (35). Paromomycin and etophamide (a dichloracetanilide) have also been used successfully either alone or in combination (44).

For liver abscess, chloroquine was used for years with good success (despite poor in vitro activity) prior to the advent of metronidazole. Indeed a comparative trial of the two drugs found similar cure rates (>94%) (11). It has often been used effectively inpatients failing metronidazole, and should be remembered in this situation. It is reported to have no effect on amebic colitis. Extended courses have been recommended because relapses have historically been common, but these probably reflect the drug's ineffectiveness against intestinal parasites, and 20 days should be adequate if followed by a course of a luminal agent.

Another potential alternative or addition to metronidazole for either colitis or liver abscess is emetine. It is derived from ipecac, has been used since the 1920s, and is as potent as the nitroimidazoles in vitro. The problem is the drug is relatively unsafe owing to drug accumulation with cardiotoxicity and deaths have been reported. Bedrest and electrocardiogram monitoring is recommended. The drug must be given by subcutaneous or intramuscular injection. The synthetic derivative 2-dehydroemetine may be less cardiotoxic and would be recommended over emetine if available. In the U.S. it is available from the CDC Drug Service (1600 Clifton Road, MS/D09, Atlanta, GA 30333; Tel (404) 639-3670, Fax (404) 639-3717).

ADJUNCTIVE THERAPY

The rate of rupture of liver abscess appears to be high, on the order of 15-22% (38, 41). Rupture occurs most commonly into the thoracic or peritoneal cavity and less commonly into the pericardium or bowel. Any rupture is a high-mortality event (6-30%), particularly if into the pericardium (1). Therapy for rupture into accessible areas has traditionally included percutaneous or open drainage and if possible liver drainage as well. Some ruptures into the pleura have improved with metronidazole therapy alone. Intravenous metronidazole has been used successfully in the rupture setting (16).

Given the high mortality of abscess rupture, the issue of when to prophylactically drain an abscess arises. One study found that percutaneous aspiration of amebic liver abscess with intralesional antibiotics led to faster resolution of pain than medical therapy or open drainage (13). However other studies indicate routine drainage of amebic liver abscess has conferred no clinical benefit over antibiotics alone (69) and a meta-analysis concluded therapeutic aspiration could not be supported or refuted due to lack of evidence (10). One study showed that failure to respond by 72 hours in terms of prolonged fever, leukocytosis, and hepatomegaly identified a group at high-risk group for abscess rupture (4/7= 57%) (68). We therefore feel that ongoing pain while on appropriate therapy for 72h is a reasonable criteria for drainage, especially with large left lobe abscesses as these are associated with a greater frequency of complications (70).

ENDPOINTS FOR MONITORING THERAPY

At present there are no specific endpoints for monitoring amebic colitis or liver abscess patients other than clinical improvement. Provided serum antigen tests become more widespread this should become a laboratory test worth following. Patients with liver abscess should respond rapidly with therapy.

VACCINES

There are no commercially available vaccines against amebiasis, but the adherence lectin and the SREHP protein are promising candidates in animal systems.

PREVENTION

General

Amebiasis can be prevented by increased sanitation and effective and safe disposal of human excreta. Travelers should avoid unpeeled fresh vegetables and fruits and drink only boiled or bottled water. Avoiding sexual practices that involve fecal-oral contact can reduce infection in homosexuals. In mental institutions recurrent outbreaks of amebiasis can be prevented by routine screening of stool and treating infected patients.

Antiparasitic Agent Prophylaxis

A global traveler surveillance network revealed that amebiasis accounted for 12% of gastrointestinal illnesses in returning travelers (15), however antiparasitic agent prophylaxis is not routinely recommended and has not been studied.

COMMENTS

An important challenge for E. histolytica researchers is to update the epidemiologic literature now that it is accepted that E. histolytica, E. dispar, and E. moshkovskii are distinct species.

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**Table 1. Activity of Antiparasitic Drugs Against E. Histolytica Strain 200 in Axenic Culture**

Drug	ED50 (mg base/l)	(mg base/l)
Lumenal agents
Iodohydroxyquinoline sulfonic acid	33	(30-35)
Diloxanide	0.88	(0.83-0.94)
Paromomycin	0.73	(0.69-0.76)
Tissue amebicides
Metronidazole	0.010	(.0093-0.011)
Tinidazole	0.032	(0.029-0.036)
Ornidazole	0.032	(0.029-0.035)
Chloroquine sulfate	85	(75-96)
Emetine	0.09	(0.07-0.099)
Dehydroemetine	0.25	(0.22-0.29)

Adapted from (40)

**Table 2. Antimicrobial Therapy for E. Histolytica Infection [Download PDF]**

Scenario	Drugs of choice Adult dose (pediatric dose)	Comments	Second-line drugs Adult dose (pediatric dose)
Asymptomatic intestinal colonization	Paromomycin 25-35 mg/kg/d po ¸ tid x 7-10d		Diloxanide 500mg po tid (20mg/kg/d ¸ tid) x 10d Iodoquinol 650mg po tid (30-40 mg/kg/d ¸ tid) x 20d
Amebic colitis	Metronidazole 750mg po tid (35-50mg/kg/d ¸ tid) x 5-10 d or Tinidazole 2g po qd (50mg/kg qd) x 3-5d	Follow with course for asymptomatic colonization
Amebic liver abscess	Metronidazole 750mg po tid (35-50mg/kg/d ¸ tid) x 10 d or Tinidazole 2g po qd (50mg/kg qd) x 5d	If not responding within 72h consider drainage Follow with course for asymptomatic colonization	Dehydroemetine or chloroquine

Scenario

Drugs of choice

Adult dose (pediatric dose)

Comments

Second-line drugs

Adult dose

(pediatric dose)

Asymptomatic intestinal colonization

Paromomycin

25-35 mg/kg/d po ¸ tid

x 7-10d

Diloxanide