AMEBIASIS

AMEBIASIS

Current diagnosis (See also Box 1)

• Amebiasis is transmitted by the ingestion of fecally contaminated water or food and by high-risk sexual behaviors (men who have sex with men [MSM] or oral–anal sexual contact).

• Although self-limiting mild to moderate colitis is the most common disease presentation, various severe illnesses (liver abscess, peritonitis, pleurisy, and pericarditis) can also occur.

• Diagnostic value of microscopic stool or abscess ova and parasite examination (O&P) is low. Antigen detection in stool for intestinal amebiasis and in serum for amebic liver abscess shows high sensitivity. Serology shows high sensitivity but cannot distinguish current infection from past infection, and it is ideally used in conjunction with fecal antigen detection or polymerase chain reaction (PCR).

Current therapy (See also Box 2)

• Infected individuals who are asymptomatic should be treated with a luminal agent, because they can be a source of new infection and also can develop invasive amebiasis after long-term asymptomatic infection.

• Mild to severe colitis and extraintestinal disease require initial treatment with a tissue-active agent followed by a luminal agent.

• Reinfection can occur frequently in endemic settings. The clinician should discuss methods to prevent reexposure to Entamoeba histolytica with treated patients.

Epidemiology and Risk Factors for Acquisition

Amebiasis is transmitted by oral ingestion of the transmissible cyst form of Entamoeba histolytica in human stools. Transmission occurs by the ingestion of fecally contaminated food and water, mainly in developing countries. It also transmits directly from human to human by sexual contact or in institutions for the cognitively impaired. Food- or water-borne infection occurs in settings of poor sanitation. It is estimated to be the second most common cause of parasite infection– related mortality worldwide, accounting for 40,000 to 70,000 deaths annually. In developed countries, people who travel to or immigrate from developing countries are at higher risk for this parasitic disease. In the United States, amebiasis is the second most common cause of diarrhea in returning travelers. Over that last two decades, however, amebic infection has been increasingly reported as a sexually transmitted infection in East Asian developed countries and Australia. In one report from Taiwan, men who have sex with men (MSM) and people engaging in oral–anal sex were more likely to be seropositive for E. histolytica. While older studies from United States had shown that amebiasis in MSM was due to nonpathogenic E. dispar, more recently MSM was shown to be an independent risk factor for amebiasis-related mortality. It is important for primary care physicians to take detailed histories of sexual behavior as well as travel whenever amebiasis is suspected.

Pathophysiology and Susceptible Host Factors to Invasive Diseases

E. histolytica has two different forms: the tissue-invasive “trophozoite form” and the infectious “cyst form,” which is responsible for transmission. Cysts are notable for environmental stability, demonstrating considerable resistance to chlorination and desiccation, with several outbreaks resulting from contamination of drinking water. Once cysts are ingested, excystation occurs at the terminal ileum or large intestine, forming motile trophozoites. Trophozoites bind to the mucous layer and the underlying intestinal epithelial cells via a parasite Gal/GalNAc lectin. Blockade of activity of the Gal/Gal lectin prevents contact-dependent cytolysis. Moreover, it was shown that antilectin IgA in stool or breast milk has a protective effect against future acquisition of amebic infection in cohort studies. These results indicate that the Gal/GalNAc lectin plays a crucial role in amebic infection.

Host factors are also important for susceptibility to amebiasis.

Amebiasis is more common in malnourished children, and the nutritional hormone leptin is protective, with a single nucleotide mutation of leptin receptor the predominant genetic factor controlling amebiasis susceptibility in Bangladeshi children. Amebic liver abscess is 10 times more common in men than in women and uncommon in children. Also, the very young or old, malnourished people, pregnant women, and patients using corticosteroids are at increased risk of severe amebiasis.

Clinical Manifestations and Complications of Amebiasis

Asymptomatic self-limiting infection is the most common disease form of amebiasis. Up to 80% to 90% of people exposed to cysts have no or mild symptoms and clear the infection spontaneously. However, asymptomatic infection persists for a long time in some individuals, who are reported as asymptomatic cyst passers or as fecal occult blood–positive incidentally diagnosed by colonoscopy. These asymptomatically infected individuals can be a source of a new infection in the community. Also, some develop symptomatic invasive diseases after long-term latent infection.

Symptomatic intestinal amebiasis (amebic colitis) generally has a subacute onset. Usually it takes 1 to 3 weeks from disease onset to make a diagnosis. Abdominal symptoms range from mild diarrhea to severe dysentery with abdominal pain, diarrhea, and bloody stools.

Weight loss and fever are common but not universal symptoms. Intestinal fistula or perforation of the large intestine, resulting in peritonitis, is a rare but life-threatening complication of intestinal amebiasis. Toxic megacolon can also be caused by amebiasis. Amebic colitis sometimes mimics acute appendicitis. In this situation appendectomy without amebicidal treatment may result in severe postoperative complications, such as abdominal sepsis, gastrointestinal fistula, or hemorrhage. Periodic acid–Schiff (PAS) stain, or ideally immunoperoxidase with anti-E. histolytica antibodies, in addition to routine hematoxylin and eosin (H&E) stain can help to identify the parasite by the histopathology. Thus, intestinal amebiasis sometimes presents as severe and complicated clinical illnesses.

E. histolytica infection may also have extraintestinal dissemination. Liver abscess is the most common form of extraintestinal amebiasis. Patients usually present with 1 to 2 weeks of fever with or without right upper quadrant abdominal pain. Other common symptoms may include cough, sweating, malaise, weight loss, anorexia, and hiccough.

Two-thirds of patients lack intestinal symptoms. Physical examination reveals hepatomegaly and tenderness over the liver in approximately half of cases. Complications can occur by direct invasion of trophozoites or indirect effect of inflammation. Up to10% of patients with amebic liver abscess have accompanying thoracic amebiasis (pleuritic and pleural effusion). Pericarditis is the next most common form of extraintestinal amebiasis; it may result from rupture of a liver abscess in the left lobe or through extension of pleural amebiasis.

Cerebral amebic abscesses are a rare form of extraintestinal amebiasis; they usually accompany other metastatic lesions, such as liver abscesses and thoracic amebiasis.

Thus, amebiasis can have various clinical presentations. The diagnosis can be very difficult to make in severe cases and in atypical clinical presentations because of secondary bacterial infection at the site of amebic invasion.

Diagnosis

Sensitivity of each diagnostic test is shown in Box 1. Although microscopic stool ova and parasite examination (O&P) is frequently used in many countries including the United States, it has low sensitivity. Identification of trophozoites by microscope in aspirated fluid from amebic abscess is more challenging because trophozoites are present only at the edge of the abscess. Moreover, microscopic examination cannot distinguish pathogenic E. histolytica from nonpathogenic E. dispar or E. moshkovskii by shape.

Box 1
Sensitivity of Tests for Diagnosis of Amebiasis*
Test                                                     Colitis   Liver Abscess
Microscopy (stool) 25–60% 10–40%
Stool antigen detection 80% 40%
Serum antigen detection 65% > 95%
Microscopy (abscess fluid) N/A < 20%
Real time polymerase chain reaction > 95% > 95%
Serologic testing (indirect hemag glutination)
Acute 70% 70–80%
Convalescent > 90% > 90%
Histopathology by biopsy 45% N/A
Modified from Mandell G, Bennett JE, Dolin R, Blaser MJ. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 7th ed. Philadelphia: Elsevier Saunders,   2009.
* Before the initiation of  therapy.

Currently, the combination of antigen detection in stool and/or sera and serologic testing is the best diagnostic pathway. Antigen detection in feces by the TechLab E. histolytica II enzyme-linked immunosorbent assay (ELISA) is rapid to perform (< 2 hours) and can distinguish E. histolytica from E. dispar and E. moshkovskii. In one report, when used on patients’ sera, ELISA showed high sensitivity in amebic liver abscess (ALA) cases but only before metronidazole treatment began. Real-time polymerase chain reaction (PCR) in stool is superior in sensitivity to stool antigen detection, but is still technically complex for diagnostic use in clinical settings. Serologic tests are sensitive (approximately 90% during the convalescent phase) and noninvasive diagnostic tools for amebiasis. Antibodies are detectable in 70% or more of patients within 5 to 7 days of acute infection and persist for years after treatment. Therefore, a negative serologic result is helpful for exclusion of disease, whereas a positive result cannot distinguish between present and previous infection.

Histopathologic examination using biopsy or resected samples is sometimes useful for the diagnosis of intestinal amebiasis. As mentioned, PAS stain in addition to H&E can increase sensitivity in detection of Entamoeba. However, identification of Entamoeba in biopsy specimens is often challenging. About half of cases with gross ulcerative lesions in the large intestine, in which E. histolytica was proven by PCR, had a negative result on histopathology.

Therapy

Recommended treatment regimens are shown in Box 2. Therapy for invasive infection differs from therapy for noninvasive infection.

Noninvasive infections (treatment for asymptomatically infected individuals) require treatment with luminal-active agents: paromomycin (Humatin) is currently recommended because of its high potency in asymptomatic cyst passers.

Box 2
Treatment Recommendations for Amebiasis in Adults
Asymptomatically Infected Individuals

Paromomycin (Humatin) 30 mg/kg/day PO tid × 5–10 days

or

Iodoquinol (Yodoxin) 650 mg PO tid × 20 days

Mild to Severe Intestinal and Extraintestinal  Disease

Metronidazole (Flagyl) 750 mg PO tid × 10 days

or

Tinidazole (Tindamax) 2 g PO once daily × 5 days

Followed by

Paromomycin1 30 mg/kg/day PO tid × 5–10 days

or

Iodoquinol1  650 mg PO tid × 20 days

*Use of intravenous form of metronidazole is limited to patients

who cannot take oral medications.

Modified from Mandell G, Bennett JE, Dolin R, Blaser MJ. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 7th ed. Philadelphia: Elsevier Saunders,  2009.

1 Not FDA approved for extraintestinal amebiasis.

For symptomatic patients, tissue-active agents should be administered before luminal-active agents. Most patients with mild to moderate colitis and uncomplicated liver abscess respond to treatment with tissue-active agents, such as metronidazole (Flagyl) and tinidazole (Tindamax). Tinidazole has the advantage of less frequent dosing than metronidazole. Treatment with tissue-active agents should be followed by luminal-active agents because parasites persist in the intestine in up to 40% to 60% of patients who receive tissue- active agents. Broad-spectrum antibiotics and/or surgical treatment should be added to tissue-active agents in patients with fulminant colitis in which perforation and peritonitis or bacteremia are suspected. Therapeutic needle aspiration or catheter drainage is not routinely required for uncomplicated liver abscesses. Those interventions in addition to medical treatment are recommended if there is clinical deterioration or lack of response to initial medical treatment, or if alternative diagnoses need to be excluded. Also, some reports suggest that clinicians should consider those interventions for patients with a high risk of abscess rupture, as defined by a cavity with a diameter of more than 5 cm or by the presence of lesions in the left lobe, although these criteria were not conclusive in case-control studies.

Symptoms (diarrhea, dysentery, fever, pain, and tenderness) and laboratory markers (white blood cell counts, red blood cell counts, and C-reactive protein) rapidly improve after effective treatment even in patients with extraintestinal lesions. In contrast, radiologic findings, such as abscess size, often remain unchanged for months after completion of treatment.

Monitoring after Treatment and Disease Prevention

Although routine monitoring after treating amebiasis is not recommended, it is well known that reinfection frequently occurs in endemic situations, including both water- or food-borne infections and sexually transmitted infections. In developed countries, in order to prevent reinfection, it is important for the primary physician to inform patients of behaviors that will place them at risk for acquisition of the cyst and how to avoid them, such as avoiding nonsterilized water or food in developing countries, unsafe homosexual contact, and oral–anal sexual contact. In developing countries, more than 1 billion people still have no access to safe food and water, resulting in the urgent need for an effective vaccine. Induction of acquired mucosal immunity is the current goal for vaccine development.

Although there is currently no vaccine in human clinical trials, a vaccine containing the naive or recombinant Gal/GalNAc lectin of E. histolytica has strong immunogenicity and protective effect against amebic colitis and liver abscess in animal models. Continuous effort will be needed to develop an effective vaccine to save the lives of affected people in endemic areas.

References

1.     Barwick R.S., Uzicanin A., Lareau S., et al. Outbreak of amebiasis in Tbilisi, Republic of Georgia 1998. Am J Trop Med Hyg. 2002;67:623–631.

2.     Blessmann J., Tannich E. Treatment of asymptomatic intestinal Entamoeba histolytica infection. N Engl J Med. 2002;347:184.

3.     Chavez-Tapia N.C., Hernandez-Calleros J., Tellez-Avila F.I., et al. Image-guided percutaneous procedure plus metronidazole versus metronidazole alone for uncomplicated amoebic liver abscess. Cochrane Database Syst Rev. 2009;CD004886.

4.    Duggal P., Guo X., Haque R., et al. A mutation in the leptin receptor is associated with Entamoeba histolytica infection in children. J Clin Invest. 2011;121:1191–1198.

5.     Gunther J., Shafir S., Bristow B., et al. Short report: amebiasis- related mortality among United States residents, 1990–2007. Am J Trop Med Hyg. 2011;85:1038–1040.

6.    Haque R., Mollah N.U., Ali I.K., et al. Diagnosis of amebic liver abscess and intestinal infection with the TechLab Entamoeba histolytica II antigen detection and antibody tests. J Clin Microbiol. 2000;38:3235–3239.

7.     Hung C.C., Chang S.Y., Ji D.D. Entamoeba histolytica infection in men who have sex with men. Lancet Infect Dis. 2012;12:729– 736.

8.      Hung C.C., Wu P.Y., Chang S.Y., et al. Amebiasis among persons who sought voluntary counseling and testing for human immunodeficiency virus infection: a case-control study. Am J Trop Med Hyg. 2011;84:65–69.

9.    Kobayashi T., Watanabe K., Yano H., et al. Underestimated Amoebic Appendicitis among HIV-1-Infected Individuals in Japan. J Clin Microbiol. 2016;55:313–320.

10.    Korpe P.S., Liu Y., Siddique A., et al. Breast milk parasite- specific antibodies and protection from amebiasis and cryptosporidiosis in Bangladeshi infants: a prospective cohort study. Clin Infect Dis. 2013;56:988–992.

11.     Leder K, Weller PF. Intestinal and extraintestinal entamoeba histolytica amebiasis. UpToDate. Available at: http://www.uptodate.com/contents/search. [accessed 30.12.15].

12.     Petri Jr. W.A., Haque R. Entamoeba species, including amebic colitis and liver abscess. In: Bennett J.E., Dolin R., Blaser M.J., eds. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. ed 8th Philadelphia: Elsevier Saunders; 2015:3047–3058.

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