Entamoeba histolytica Infection

Etiology

Entamoeba histolytica is transmitted by the ingestion of amebic cysts through fecal-oral contact, usually through contaminated food or water sources.[3][4]

Epidemiology

Entamoeba histolytica continues to be an important global health issue being the third leading cause of death from parasitic infections.[5] Although 90 percent of E. histolytica infections are asymptomatic, nearly 50 million people become symptomatic, with up to 100,000 deaths yearly.[6] Those infected by Entamoeba are mostly colonized by either E. histolytica or E. dispar. E. histolytica is the pathogenic form and can cause amoebic colitis and extraintestinal amoebiasis.  E. dispar is considered to be nonpathogenic and causes no signs of disease.[2]

Infection occurs worldwide, with a higher prevalence in countries of low socioeconomic status and poor public health. Countries with a high rate of infections include India, Africa, Mexico, and Central and South America. For example, a three-year study conducted in Bangladesh showed that 2.2% of dysentery cases were caused by E. histolytica in preschool children.[7] In rural areas of Mexico, the seroprevalence of E. histolytica has been reported as high as 42%.[8]  Risk factors for infection are mostly related to fecal-oral transmission and have been due to poor hand hygiene, defecation into water sources such as rivers, and being in close proximity with animals. In developed countries such as the United States, amebiasis infections are rare, accounting for at least 5 deaths per year, and are commonly seen in individuals that have had exposure to endemic areas such as immigrants or recent travelers.[8]

Amoebic colitis generally affects males and females of all ages equally. There are reports of increased risk of infection from gay or bisexual males due to the risk of fecal-oral contamination through oral and anal sex.[2] Factors that are associated with increased risk for complicated infection and mortality are associated with the following: pregnancy, corticosteroid treatment, malignancy, malnutrition, and alcoholism. Amoebic liver abscess infections are at least 3 times more likely to affect middle-aged men between the ages of 18 and 50.[2]

Pathophysiology

There are two forms E. histolytica can take: the cyst form, which can survive in the environment for a prolonged period, and the trophozoite stage, which is the active and invasive form. After the ingestion of the cyst form, trophozoites can be formed, which can invade and penetrate intestinal mucosa destroying epithelial cells and inflammatory cells.

The pathogenesis of infection by trophozoites is due to the adherence of colonic epithelial cells through a specific galactose-N-acetylgalactosamine lectin.[2] Through the direct adherence of trophozoites to the colonic epithelial cells, the colonic epithelial cells die off through cytolysis and apoptosis, which results in the release of interleukin-1α and precursor interleukin-1β.  IL-1β activates NF-κB in distal cells to produce cytokines and other inflammatory mediators such as COX-2, interleukin-1, and interleukin-8. Amoebic cysteine proteinases can also convert precursor IL-1β to active IL-1β, which can further facilitate the process. These cytokines and inflammatory mediators subsequently attract neutrophils and macrophages. Neutrophils can be damaged by direct contact with trophozoites which can cause more damage to colonic epithelial cells resulting in the release of more mediators. Macrophages release other mediators as well, such as TNFα, which further contributes to inflammation.

The pathological range includes mucosal inflammation, thickening, ulcers, and necrosis, leading to perforation. Amoebic cysteine proteinases can also contribute to trophozoites' ability to suppress a host’s immune response by being able to cleave and inactivate anaphylatoxins C3a, C5a, IgA, and IgG.[2] Trophozoites can reach other areas of the body, most commonly the liver, which can cause tissue necrosis and abscess formation.[7]

History and Physical

The majority of E. histolytica infections are asymptomatic; however, up to 10% of asymptomatic individuals infected can develop the disease over time.[8] E. histolytica most commonly causes intestinal amoebiasis but can also affect the liver, respiratory tract, heart, and brain. 

Gastrointestinal: Symptoms typically have a gradual onset, usually over one to three weeks.  Common symptoms include diarrhea, bloody stools, weight loss, and abdominal pain.[2]

Liver: Amoebic liver abscess formation is the most common extraintestinal complication. It can be seen in months to years after an individual has had exposure to an endemic area. Symptoms include fever and right upper quadrant pain. Exam findings may include hepatomegaly with hepatic tenderness. Less than 10 percent of patients have jaundice. Common laboratory findings include leukocytosis without eosinophilia, elevated alkaline phosphatase, transaminitis, and elevated erythrocyte sedimentation rate.

Respiratory tract: Pleuropulmonary involvement is a rare complication that causes atelectasis and transudative pleural effusions.  In rare cases, an amoebic liver abscess can rupture into the pleural space causing empyema or hepato-bronchial fistula causing fevers, coughing, and respiratory distress.[2] 

Cardiac infection: Cardiac infection is an even less common complication than pleuropulmonary disease and occurs with a liver abscess ruptures into the pericardium and presents with symptoms of pericarditis or cardiac tamponade.

Brain infection: Amoebic brain abscesses are very rare with sudden onset symptoms such as headache, vomiting, and mental status changes with rapid progression to death.[2]

Evaluation

Historically amoebic infections were diagnosed by microscopy with the identification of trophozoites; however, this method was unable to distinguish between E. histolytica and E. dispar infections.  Now, there are many tools used for diagnosis with stool polymerase chain reaction (PCR) having the highest sensitivity in distinguishing E. histolytica from E. dispar.  Other diagnostic modalities available include stool microscopy, stool antigen detection, serology, stool molecular studies, and colonoscopy with a histologic examination.[2]

Stool microscopy: This diagnostic method is advantageous, being widely available with minimal equipment needed and can be used to screen for other parasites.  Disadvantages include poor sensitivity, reported at <60%, with the inability to differentiate from other Entamoeba species and relies on the experience or skills of the observer.[8][9]  

Stool antigen detection: This method is simple with a quick turnaround time and has the advantage of being able to differentiate between E. histolytica and E. dispar.  There are a wide number of commercially available antigen detection kits using enzyme-linked immunosorbent assay (ELISA), radioimmunoassay, or immunofluorescence that have varying sensitivities of up to 88%.[10][8][9]

Serology: Has high sensitivity and specificity with quick turnaround time but is not helpful in distinguishing between an acute or previous infection.   Antibodies are not detectable in an active infection until at least a week into the infection and will remain detectable in individuals for years.

Stool molecular studies: Considered to be the gold standard with high sensitivity of 92% to 100% and specificity of 89% to 100%.  Testing is becoming more widely available but is considered to be more expensive, requiring appropriate equipment and kits and requiring a skilled technician.

Colonoscopy with histologic examination: Not used for routine diagnosis but can be used to look for other causes of symptoms.  Used to look for characteristic findings of amebic ulcers or erosions with the identification of trophozoites or cysts with biopsy specimens.[8]

Treatment / Management

Due to the risk of spread and the risk of developing extraintestinal manifestations, all E. histolytica infections need to be treated. 

Metronidazole is the first-line treatment for intestinal amebiasis and amebic liver abscess followed by a luminal agent. Typical dosing for metronidazole is 500 to 750 mg orally 3 times a day for 7 to 10 days in adults.[2] Metronidazole can be safely used in children at a dosing of 35 mg/kg to 50 mg/kg per day divided into three doses.[2] Luminal agents include the following: paromomycin, diiodohydroxyquin, or diloxanide furoate. Dosing for paromomycin is 25 mg/kg to 30 mg/kg per day divided into three doses for 7 days, diiodohydroxyquin is 650 mg orally for 20 days, diloxanide furoate is 500 mg orally three times a day for 10 days.[2](B3)

Alternatives to metronidazole include tinidazole, ornidazole, and nitazoaxanide. 

In patients with fulminant amoebic colitis or signs of peritonitis, broad-spectrum antibiotics should be started. Surgical intervention may be required with bowel perforation or toxic megacolon.   

In uncomplicated cases of amebic liver abscess, it has been shown that there is no benefit to drainage in addition to medical therapy.[11] In situations where there is a lack of clinical response to antibiotic therapy, aspiration or catheter drainage may be necessary.[2](A1)

Pleuropulmonary infections should be treated by aspiration of amebic pleural effusion followed by antimicrobial therapy such as metronidazole with a luminal agent.[12]

Differential Diagnosis

The differential diagnosis for E. histolytica intestinal amebiasis includes:

• Bacterial pathogens: Shigella, Escherichia coli, Salmonella, Campylobacter, and Clostridioides difficile
• Inflammatory bowel disease
• Ischemic bowel disease

The differential diagnosis for E. histolytica extraintestinal amebiasis includes:

• Pyogenic liver abscess
• Echinococcal disease
• Malignancy

Prognosis

Uncomplicated infections and early treatment have a mortality rate of less than 1 percent. Risk factors for complicated infections and increased mortality include the following:[13]

• Young age 
• Pregnancy 
• Corticosteroid treatment
• Malignancy 
• Malnutrition 
• Alcoholism 

Fulminant amoebic colitis is associated with 40% mortality.[13] Amebic liver abscess with prompt medical treatment has been highly effective, with mortality rates between 1 and 3 percent.[2]  Pleuropulmonary amebiasis is associated with mortality up to 16%, while cardiac involvement has a mortality of up to 30%.[14]

Complications

Complications of E. histolytica infection can involve any of the following:[2]

• Asymptomatic infection
• Symptomatic noninvasive infection
• Acute proctocolitis
• Fulminant amoebic colitis with perforation
• Toxic megacolon
• Chronic non-dysenteric colitis

Extraintestinal conditions resulting from E. histolytica infection include the following:[2][15][16]

• Liver abscess
• Pleuropulmonary disease
• Brain abscess
• Peritonitis
• Pericarditis
• Genitourinary disease
• Perianal cutaneous amebiasis
• Hepatic vein thrombosis
• Inferior vena cava thrombosis
• Ameboma 
• Appendicitis