Intestinal Entamoeba histolytica amebiasis

INTRODUCTION — Intestinal amebiasis is caused by the protozoan Entamoeba histolytica. There are four species of intestinal amebae with identical morphologic characteristics: E. histolytica, E. dispar, E. moshkovskii, and E. bangladeshi [1,2]. Most symptomatic disease is caused by E. histolytica; E. dispar is generally considered nonpathogenic. Reported infections with E. moshkovskii are becoming more frequent, with increasing evidence of its potential pathogenicity emerging [3]. The pathogenic potential of E. bangladeshi remains unclear [3,4].

Issues related to intestinal E. histolytica infection will be reviewed here; issues related to extraintestinal E. histolytica infection are discussed separately. (See "Extraintestinal Entamoeba histolytica amebiasis".)

EPIDEMIOLOGY

Geographic distribution — Amebiasis occurs worldwide; the prevalence is disproportionately increased in resource-limited countries because of poor socioeconomic conditions and sanitation levels. Areas with high rates of amebic infection include India, Africa, Mexico, and parts of Central and South America. The overall prevalence of amebic infection may be as high as 50 percent in some areas [1].

In resource-rich countries, amebiasis is generally seen in migrants from and travelers to endemic areas. E. histolytica is not a common cause of travelers' diarrhea, and gastrointestinal infection is uncommon in travelers who have spent less than one month in endemic areas. In one prospective study of German travelers to the tropics, only 0.3 percent had pathogenic E. histolytica infection [5]. Institutionalized patients and in some areas, sexually active men who have sex with men, are also at increased risk of infection [6]. In the United States and Europe, the prevalence of E. histolytica among men who have sex with men (MSM) is relatively low; such individuals are principally colonized with nonpathogenic E. dispar [1,7]. However, in areas where E. histolytica is much more prevalent, it does occur among MSM, and invasive, extraintestinal amebiasis (eg, hepatic abscesses) is more frequent in immunosuppressed patients with HIV [1,8-10].

Transmission — The parasite exists in two forms, a cyst stage (the infective form) and a trophozoite stage (the form that causes invasive disease) (figure 1). Infection occurs following ingestion of amebic cysts; this is usually via contaminated food or water but can be associated with sexual transmission through fecal-oral contact, so infection can occur in nonendemic areas among individuals who have never traveled abroad [6,11]. Cysts can remain viable in the environment for weeks to months, and ingestion of a single cyst is sufficient to cause disease.

Risk factors for severe disease — Worldwide, approximately 50 million people develop colitis or extraintestinal disease, with over 100,000 deaths annually [12]. Factors that influence whether infection leads to asymptomatic or invasive disease include the E. histolytica strain and host factors such as genetic susceptibility, age, and immune status [1,13]. Risk factors for severe disease and increased mortality include young age, pregnancy, corticosteroid treatment, malignancy, malnutrition, and alcoholism [14-16]. A systematic review of patients with amoebic colitis who received steroids for initially misdiagnosed colitis noted that rapid progression of disease following steroid therapy was common, and 25 percent of patients died [17].

PATHOGENESIS — Infection with E. dispar occurs approximately 10 times more frequently than infection with E. histolytica, although symptoms are more likely to result from E. histolytica [1]. The host-parasite interaction is complex, and the virulence of different strains of E. histolytica is variable [18,19]. After ingestion of a cyst, the cyst passes through the stomach to the small intestine, where it excysts to form a trophozoite. The trophozoites can invade and penetrate the mucous barrier of the colon, causing tissue destruction and increased intestinal secretion and can thereby ultimately lead to bloody diarrhea [20]. The trophozoite is able to kill both epithelial cells and inflammatory cells, which is thought to occur through a number of different mechanisms, including:

●Secretion of proteinases by the trophozoites

●Lysis of target cells via a contact-dependent mechanism

●Killing of mammalian cells by apoptosis (programmed cell death)

●Formation of amebapores, a family of small peptides that can form pores in lipid bilayers, resulting in cytolysis of infected cells

●Changes in intestinal permeability, probably via disruption of tight-junction proteins

The pathogenicity of amebic trophozoites is facilitated by adherence to colonic epithelial cells via a specific lectin (the galactose-N-acetylgalactosamine lectin) [14]. Mammalian cells without N-terminal galactose or N-acetylgalactosamine residues are resistant to adherence by amebic trophozoites, which is consistent with an important role for the lectin in adhesion. This lectin also plays a role in immunity, since mucosal immunity against the lectin seems to mediate some degree of protection from invasive disease following colonization. One study from Bangladesh showed that children with a mucosal IgA response against the lectin had 86 percent fewer new infections during a one-year period than children without this response [21] and, when reinfected, had a lower incidence of symptomatic disease over a four-year follow-up period [22]. Other amebic molecules such as lipophosphopeptidoglycan, peroxiredoxin, arginase, and lysine, and glutamic acid-rich proteins are also implicated in the pathogenesis of amoebiasis [23].

CLINICAL MANIFESTATIONS — Clinical manifestations can vary from asymptomatic infection to acute fulminant colitis in rare circumstances. Most infection is asymptomatic; clinical manifestations include amebic dysentery and extraintestinal disease [20,24]. Extraintestinal manifestations include amebic liver abscess and other rarer manifestations such as pulmonary, cardiac, or brain involvement; these are discussed separately.

●Asymptomatic infection – The majority of entamoeba infections are asymptomatic; this includes 90 percent of E. histolytica infections. E. dispar is generally considered to be nonpathogenic, although there have been reports describing E. dispar as a potential cause of amebic liver abscess [25,26] and chronic diarrhea [27]. While E. moshkovskii was traditionally thought to be nonpathogenic, it has also been associated with diarrhea [28,29]. The pathogenicity of E. bangladeshi remains to be investigated [30].

Amebic colitis has been recognized in asymptomatic patients. Among 5193 asymptomatic individuals in Japan undergoing colonoscopy for evaluation of positive fecal occult blood tests, for example, four were found to have amebic ulcerative lesions in the cecum or ascending colon [31].

●Clinical acute and subacute disease – Clinical amebiasis generally has a subacute onset, usually over one to three weeks. Symptoms range from mild diarrhea to severe dysentery, producing abdominal pain (12 to 80 percent), diarrhea (94 to 100 percent), and bloody stools (94 to 100 percent), to fulminant amebic colitis. Chronic non-dysenteric colitis is the most frequent form of amebiasis in people of all ages [32]. Rarely, acute fulminant necrotizing amebic colitis presents with life-threatening lower gastrointestinal bleeding without diarrhea [33]. Weight loss occurs in about half of patients, and fever occurs in up to 38 percent.

Amebic dysentery consists of diarrhea with visible blood and mucus in stools and the presence of hematophagous trophozoites (trophozoites with ingested red blood cells) in stools or tissues [34]. Stool specimens are frequently positive for blood in the setting of invasive intestinal amebic disease. The presence of ingested erythrocytes is not pathognomonic for E. histolytica infection (picture 1); ingested erythrocytes may also be observed with E. dispar. Fecal leukocytes are not always present since white cells may be destroyed by the organisms. In one study of travelers and migrants, clinical features of E. histolytica infection included blood in stool (sensitivity and specificity 30 and 100 percent, respectively), mucus in stool (sensitivity and specificity 22 and 100 percent, respectively), and abdominal cramps (sensitivity and specificity 44 and 90 percent, respectively) [35]. Neither watery diarrhea nor fever were significantly associated with diagnosis of E. histolytica.

Fulminant colitis with bowel necrosis leading to perforation, and peritonitis has been observed in approximately 0.5 percent of cases; associated mortality rate is more than 40 percent [36-38]. Toxic megacolon can also develop.

●Chronic diarrhea – Rarely, intestinal amebiasis may present as a chronic syndrome of diarrhea, weight loss, and abdominal pain without dysentery, lasting for years and mimicking inflammatory bowel disease.

●Other intestinal manifestations – Uncommonly, localized colonic infection resulting in a mass of granulation tissue forming an ameboma can occur, mimicking colon cancer [39,40]. Patients with amebomas usually are found to have a tender palpable mass. Other rare complications of amebiasis include appendicitis, perianal cutaneous amebiasis, and rectovaginal fistulae [41,42].

DIAGNOSIS

When to suspect intestinal amebiasis — Intestinal amebiasis is generally suspected in the setting of acute to subacute diarrhea (especially if the diarrhea is bloody) and relevant epidemiologic exposure (residence in or travel to an area where E. histolytica is prevalent). Intestinal amebiasis should also be suspected in patients with persistent diarrhea in whom the initial workup was negative, especially in those with risk factors (eg, institutionalized individuals, sexually active MSM).

Diagnostic evaluation — The diagnosis of intestinal amebiasis can be made by stool microscopy, stool antigen testing, or stool PCR [43]. The test of choice is usually determined by availability. When available, we prefer stool PCR because of its high sensitivity and specificity and its ability to distinguish E. histolytica from E. dispar and E. moshkovskii. If PCR is not available, stool antigen is the next best choice as it is also able to distinguish between various Entamoeba strains. Stool microscopy is labor intensive and has limited sensitivity; however this may be the only tool available in some settings. If stool microscopy is used, we prefer to send at minimum three different specimens on different days to optimize detection of organisms. This approach detects 85 to 95 percent of infections. Stool microscopy is not able to differentiate between Entamoeba strains, requires specialized expertise, and is subject to operator error [44].

Serology is not very helpful in diagnosing an E. histolytica infection, especially in endemic areas, as antibodies can persist for years after infection.

Approach to incidental cysts found on screening — Occasionally, amebic cysts may be detected incidentally on Papanicolaou smears, stool microscopy, or during a sigmoidoscopy or colonoscopy. If entamoebic cysts are detected, we proceed with sending either a stool antigen or PCR to distinguish E. histolytica infection from that of E. dispar or E. moshkovskii. If neither stool antigen nor PCR is available, we evaluate for any clinical signs of infection. Treatment is reasonable in those with symptoms consistent with E. histolytica infection. (See 'Treatment' below.)

If Entamoeba cysts are detected on a cervical pap smear, this is likely to be Entamoeba gingivalis, rather than Entamoeba histolytica. Entamoeba gingivalis is non-pathogenic; no further evaluation or treatment is warranted.

Diagnostic tests — Tools for diagnosis of intestinal amebiasis include stool microscopy, stool and serum antigen detection, stool polymerase chain reaction (PCR), serology, and colonoscopy with histologic examination. Serologic testing cannot distinguish between acute, currently active infection and previous infection.

●Stool microscopy – The demonstration of cysts or trophozoites in the stool suggests intestinal amebiasis, but microscopy cannot differentiate between E. histolytica and E. dispar or E. moshkovskii strains. In addition, microscopy requires specialized expertise and is subject to operator error [44].

Organism excretion can vary; a minimum of three specimens on separate days should be sent to detect 85 to 95 percent of infections. Specimens can be concentrated and stained with iodine to detect cysts. To look for trophozoites, a saline wet mount and a fresh smear stained with iron hematoxylin and/or Wheatley's trichrome should be performed; fixation with polyvinyl alcohol for delayed staining is often useful.

●Antigen testing – Antigen detection is sensitive, specific, rapid, easy to perform, and can distinguish between E. histolytica and E. dispar. Stool and serum antigen detection assays that use monoclonal antibodies to bind to epitopes present on pathogenic E. histolytica strains (but not on nonpathogenic E. dispar strains) are commercially available for diagnosis of E. histolytica infection [45]. Antigen detection kits using enzyme-linked immunosorbent assay (ELISA), radioimmunoassay, or immunofluorescence have been developed [43,46]. Antigen detection has many advantages, including ease and rapidity of the tests, capacity to differentiate between strains, greater sensitivity than microscopy, and potential for diagnosis in early infection and in endemic areas (where serology is less useful).

A number of commercial assays with variable reported sensitivities and specificities have been developed [43]. The TechLab E. histolytica stool antigen test is an ELISA test that is specific for E. histolytica. The assay detects the E. histolytica-derived Gal/GalNAc lectin in stool specimen; it has a sensitivity of 87 percent and a specificity of >90 percent compared with culture [47,48]. A study comparing the TechLab E. histolytica-specific antigen detection test with PCR assays showed comparable sensitivities when performed directly on fresh stool specimens [48].

●Molecular methods – Detection of parasitic DNA or RNA in stool via probes can also be used to diagnose amebic infection and to differentiate between the three different strains.

A number of commercial PCR tests that can detect E. histolytica in stool specimens are available [49-51]. These include conventional PCR, nested PCR, real-time PCR, multiplex PCR, and loop-mediated isothermal amplification assay [43]. Most of the commercial PCR assays have close to 100 percent sensitivity and specificity [43,52,53], and PCR is about 100 times more sensitive than stool antigen tests [54]. In addition, PCR can differentiate between pathogenic and nonpathogenic amebae [55-57], and many of the PCR tests allow the simultaneous detection of multiple pathogens.

●Serology – E. histolytica infection results in the development of antibodies; E. dispar infection does not. Antibodies are detectable within five to seven days of acute infection and may persist for years. Approximately 10 to 35 percent of uninfected individuals in endemic areas have antiamebic antibodies due to previous infection with E. histolytica [1]. Therefore, negative serology is helpful for exclusion of disease, but positive serology cannot distinguish between acute and previous infection, especially in endemic settings.

Indirect hemagglutination (IHA) is the most sensitive serologic assay; it is positive in approximately 90 percent of patients with symptomatic intestinal infection [1]. Agar gel diffusion and counterimmunopheresis are less sensitive than IHA but usually only remain positive for 6 to 12 months, which may make them more useful in endemic areas. A commercially available ELISA that has a sensitivity of 93 percent compared with IHA has also been developed.

●Visual inspection of the colon – Sigmoidoscopy and/or colonoscopy can be performed to make the diagnosis of amebiasis and to exclude other causes of symptoms. However, colonoscopy is not appropriate as a routine diagnostic test since presence of amebic ulcerations increase the likelihood of perforation during instillation of air to expand the colon.

Cecum and colon are the most common sites of involvement [58]. In one study, endoscopic findings of amebic colitis (including discrete ulcers or erosions) were observed in the cecum, rectum, ascending colon, transverse colon, sigmoid colon, and descending colon (93, 45, 28, 25, 20, and 15 percent, respectively) [59]. Typical findings include diffuse wall thickening, skip lesions, or pancolitis [60].

Scrapings or biopsy specimens, best taken from the edge of ulcers, may be positive for cysts or trophozoites on microscopy, and antigen testing for E. histolytica may be positive. Colonic lesions in amebic dysentery range from nonspecific mucosal thickening and inflammation to classic flask-shaped amebic ulcers (picture 2 and image 1).

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of E. histolytica amebiasis includes other causes of acute diarrhea or bloody stools, particularly bacterial pathogens including Shigella, Escherichia coli, Salmonella, Campylobacter, Clostridioides difficile, and some Vibrio species. These are distinguished based on culture results or molecular diagnostic assays. Intestinal tuberculosis should also be considered. Noninfectious etiologies include ischemic bowel and inflammatory bowel disease.

TREATMENT

Entamoeba histolytica — The goals of antimicrobial therapy of intestinal amebiasis are to eliminate the invading trophozoites and to eradicate intestinal carriage of the organism.

Asymptomatic infection — E. histolytica may be found incidentally in the course of screening or evaluation of other conditions. All E. histolytica infections should be treated even in the absence of symptoms, given the potential risk of developing invasive disease and the risk of spread to family members [1,20]. Patients without any symptoms or signs of active disease should be treated with an intraluminal agent (eg, paromomycin or diloxanide furoate).

Intraluminal agents include paromomycin (25 to 30 mg/kg per day orally in three divided doses for 7 days) or diloxanide furoate (500 mg orally three times daily for adults and 20 mg/kg per day in three divided doses for children for 10 days). Choice of agent largely depends on local drug availability. Availability of these medications, particularly diloxanide furoate, is limited. Paromomycin is safe in pregnancy. (See 'Special considerations in pregnant patients' below.)

Nitazoxanide has been proposed as an alternative luminal amoebicide agent [32].

Symptomatic infection — Patients with symptomatic infections require systemic therapy, followed by an intraluminal agent.

●All symptomatic patients – Intraluminal elimination is similar to those with asymptomatic infections and is discussed above. (See 'Asymptomatic infection' above.)

Approach to systemic therapy in patients with symptomatic disease is as follows:

•Mild to moderate disease – Patients exhibiting mild to moderate disease (eg, diarrhea, abdominal pain) require systemic treatment with metronidazole (alternative therapies include tinidazole, ornidazole, secnidazole, and nitazoxanide). A 10-day course of metronidazole eliminates intraluminal infection in many cases, but subsequent treatment with an intraluminal agent is still warranted [61].

•Fulminant colitis/peritonitis/toxic megacolon – Severe presentations and complications of severe disease require empiric broad-spectrum antibiotics for possible superimposed bacterial infection (ie, metronidazole plus treatment for gram-negative enteric organisms). Occasionally, surgical intervention, such as a colectomy, is required in the setting of toxic megacolon. Management of intra-abdominal infections is discussed elsewhere. (See "Antimicrobial approach to intra-abdominal infections in adults" and "Overview of gastrointestinal tract perforation".)

•Extraluminal disease – Patients with infection outside of the colon, such as amebic liver abscess, require metronidazole, along with site-specific management. (See "Extraintestinal Entamoeba histolytica amebiasis".)

Dosing for metronidazole is 500 to 750 mg by mouth three times daily in adults and 35 to 50 mg/kg per day in three divided doses in children for 7 to 10 days. Shorter duration of metronidazole is generally not recommended [62,63]. Metronidazole is well absorbed from the gastrointestinal tract; intravenous therapy offers no significant advantage as long as the patient can take oral medications and has no major defect in small bowel absorption.

Alternatives to metronidazole include other nitroimidazoles, such as tinidazole (2 g by mouth daily for 3 days), ornidazole (500 mg by mouth daily in adults and 40 mg/kg daily dose in children for 3 days), and secnidazole (2 g/day in adults and 30 mg/kg/day in children for 1 to 3 days). Efficacy and comparative data are limited, thus, choice of agent largely depends on drug availability and cost [34,62,63]. Tinidazole cure rates of 90 to 93 percent have been observed [62-64]. In a systematic review, treatment with tinidazole was associated with a 72 percent reduction in clinical failures compared with metronidazole [34]. Tinidazole is also better tolerated than metronidazole. However, cost and lack of availability prohibit its use in many settings.

Special considerations in pregnant patients — Severe amebic colitis due to E. histolytica can cause significant morbidity and potential mortality during pregnancy. It is important to confirm E. histolytica as the causative pathogen. (See 'Diagnosis' above.)

●For pregnant women with mild to moderate amebic colitis due to E. histolytica without evidence of extraluminal disease, we favor treatment with paromomycin to avoid the teratogenic toxicity of metronidazole [65]. Paromomycin is an oral aminoglycoside with poor intestinal absorption. Diloxanide is not recommended in pregnancy. If there is no clinical improvement, further treatment with metronidazole could be considered after determining the risks and benefits to mother and fetus.  

●For pregnant women with severe amebic colitis due to E. histolytica, we suggest metronidazole rather than paromomycin. Paromomycin should be avoided in the setting of severe amebic colitis, given that in this setting, there may be breakdown of the intestinal barrier with risk for systemic absorption. Paromomycin alone is also unlikely to be effective in setting of severe disease [66]. However, we acknowledge that use of metronidazole in pregnancy is controversial; it crosses the placenta and rapidly enters the fetal circulation. There are no well-controlled studies demonstrating safety of metronidazole in pregnancy. Therefore, it should be used only in the setting of severe illness (eg, if the risks to the mother associated with deferring treatment outweigh potential harm to the fetus).

Entamoeba moshkovskii — The need for treatment of E. moshkovskii is uncertain; although data are very limited, we suggest treatment for symptomatic infection, using the same approach as for symptomatic E. histolytica. (See 'Symptomatic infection' above.)

Entamoeba dispar — E. dispar infections are thought to be nonpathogenic and therefore do not require treatment. In countries where amebic infections are endemic, asymptomatic patients incidentally found to have stools positive for amebae are frequently presumed to have infection with E. dispar and are not further evaluated or treated. As antigen tests that can differentiate between E. dispar and E. histolytica become more widely available in these countries, this practice may change.

PREVENTION — Prevention of amebic infection in travelers to endemic areas involves avoidance of untreated water in endemic areas and uncooked food, such as fruit and vegetables that may have been washed in untreated water. Amebic cysts are resistant to chlorine at the levels used in water supplies, but disinfection with iodine may be effective. Avoiding sexual practices that may lead to fecal-oral contact is also advisable. (See "Travel advice", section on 'Behavioral precautions'.)

Vaccine development — There is some evidence of partial acquired immunity to the organism. Protection from invasive disease has been associated with mucosal IgA antibodies to the amebic adherence lectin [21,22], and Gal-lectin based vaccinations have conferred some protection in various animal models against E. histolytica infections [67]. However, recurrent intestinal infection and persistent colonization may occur despite detectable antiamebic antibodies [68]. Thus, it seems probable that acquired, but incomplete, immunity against infection occurs, and a vaccine that can reduce infection and/or invasive disease may therefore be feasible.

The relative importance of systemic and mucosal, cellular, and humoral immunity is unclear. Several amebic proteins associated with virulence have been identified and are being studied as potential vaccine components. Development of both parenteral and oral vaccines for humans is in progress [69].

SUMMARY AND RECOMMENDATIONS

●Epidemiology

•Intestinal amebiasis is caused by the protozoan Entamoeba histolytica. There are four species of intestinal amebae with identical morphologic characteristics: E. histolytica, E. dispar, E. moshkovskii, and E. bangladeshi. E. dispar is nonpathogenic and does not cause clinical disease; most symptomatic disease is caused by E. histolytica. The pathogenic potential of E. moshkovskii remains unclear. (See 'Introduction' above and 'Epidemiology' above.)

•Amebiasis occurs worldwide; the prevalence is disproportionately increased in resource-limited countries because of poor socioeconomic conditions and sanitation levels. Areas with high rates of amebic infection include India, Africa, Mexico, and parts of Central and South America. In resource-rich countries, amebiasis is generally seen in migrants from and travelers to endemic areas. (See 'Epidemiology' above.)

●Clinical manifestations – Clinical amebiasis generally has a subacute onset, usually over one to three weeks. Symptoms range from mild diarrhea to severe dysentery, producing abdominal pain, diarrhea, and bloody stools. Fulminant colitis with bowel necrosis leading to perforation and peritonitis can occur, as can toxic megacolon. Amebic colitis has been recognized in asymptomatic patients as well. (See 'Clinical manifestations' above.)

●Diagnosis

•When to suspect intestinal amebiasis – Intestinal amebiasis is generally suspected in the setting of acute to subacute diarrhea (especially if the diarrhea is bloody) and relevant epidemiologic exposure (residence in or travel to an area where E. histolytica is prevalent). Intestinal amebiasis should also be suspected in patients with persistent diarrhea in whom the initial workup was negative, especially in those with risk factors (eg, institutionalized individuals, sexually active MSM). (See 'When to suspect intestinal amebiasis' above.)

•Approach to diagnosis – Diagnosis is generally made by microscopy, antigen testing, or PCR methods. Advantages of antigen testing and PCR are that they are sensitive and can distinguish between E. histolytica and E. dispar infections. When available, we prefer stool PCR because of its high sensitivity and specificity and its ability to distinguish E. histolytica from E. dispar and E. moshkovskii. (See 'Diagnostic evaluation' above.)

●Treatment – All E. histolytica infections should be treated, even in the absence of symptoms, given the potential risk of developing invasive disease and the risk of spread to family members. The goals of antibiotic therapy of intestinal amebiasis are to eliminate the invading trophozoites and to eradicate intestinal carriage of the organism. (See 'Entamoeba histolytica' above.)

•For all infections, regardless of the presence of symptoms, we suggest treatment with paromomycin to eliminate intraluminal cysts (Grade 2C). Dosing is outlined above.

•For symptomatic infections, we suggest either metronidazole or tinidazole rather than an intraluminal agent alone (Grade 2C). Treatment with an intraluminal agent follows systemic treatment.

•In cases of severe or fulminant infection (eg, fulminant colitis/peritonitis/toxic megacolon), empiric broad spectrum antibiotics to treat gram-negative enteric organisms is also appropriate. (See "Antimicrobial approach to intra-abdominal infections in adults", section on 'High-risk community-acquired infections'.)

●Prevention – Prevention of amebic infection in travelers to endemic areas involves avoidance of untreated water in endemic areas and uncooked food, such as fruit and vegetables, which may have been washed in untreated water. Amebic cysts are resistant to chlorine at the levels used in water supplies, but disinfection with iodine may be effective. (See 'Prevention' above.)