Christopher R. Fox MD
Merle A. Sande MD
ENTAMOEBA HISTOLYTICA & ENTAMOEBA DISPAR
Essentials of Diagnosis
General Considerations
It has been estimated that 10% of the world's population is infected with either E histolytica or E dispar. Of those infected, < 10% will manifest symptomatic disease. Infection is prevalent in Central and South America, southern and western Africa, the Far East, and India. Pregnant women, children, those of lower socioeconomic status, and those who live in crowded conditions or areas with poor sanitation are more likely to be infected.
In the United States, the prevalence of E histolytica and E dispar is much lower, approximately 4%. The risk factors for infection are the same as those above. In addition, those who travel to an endemic area, homosexual males, and institutionalized persons are at increased risk of infection.
During acute colitis, trophozoites may be shed into the stool. Unlike the cyst, the trophozoite cannot live outside the host because it is rapidly killed by poor environmental conditions and, if ingested, is degraded in the acid stomach environment.
CLINICAL SYNDROMES
Infection with E histolytica causes multiple syndromes, which range from asymptomatic intestinal infection to fulminant colitis. In addition, E histolytica may cause disease at several nonintestinal sites, including the liver, lung, brain, and genitourinary tract. The clinical syndromes caused by E histolytica are outlined in Box 82-1.
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BOX 82-1 Clinical Features of Amebiasis |
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INTESTINAL DISEASE
Clinical Findings
Acute amebic colitis usually presents with several weeks of lower abdominal pain and diarrhea with frequent loose to watery stools containing blood and mucus. Most patients are afebrile. Significant volume depletion is uncommon.
Chronic amebic colitis is characterized by low-grade inflammation resulting in intermittent bloody diarrhea and abdominal pain over a period of months to years. It is often difficult to distinguish chronic disease from inflammatory bowel disease, and this distinction must be made before corticosteroid or surgical therapy for inflammatory bowel disease, to avoid worsening amebic infection or to perform surgical therapy for a treatable infection.
Patients with fulminant amebic colitis present with fever, diffuse abdominal pain, and bloody diarrhea. This form of the disease is rare and presents most commonly in children. Colonic perforations frequently develop, and the patient may progress to toxic megacolon, particularly in the setting of corticosteroid treatment. Liver abscess is common in patients with fulminant colitis. Mortality in patients with fulminant colitis is high, approaching 50%.
Of patients with intestinal disease, ~ 1% will develop an ameboma. Most common in the cecum or ascending colon, ameboma is a chronic, localized amebic infection. The mass may be entirely asymptomatic or may be painful and tender. It is often confused with malignant lesions on imaging studies, and correct diagnosis can be made by biopsy.
AMEBIC LIVER ABSCESS
Clinical Findings
Exam may reveal abdominal tenderness, tender hepatomegaly, and crackles at the right lung base. Jaundice is uncommon.
Pleuropulmonary amebiasis. Pleuropulmonary disease is the most common complication of amebic liver abscess and usually presents with cough and pleuritic chest pain. Findings may reveal serous effusion, which does not imply disseminated disease. Amebic empyema, with “anchovy paste” material present upon drainage, occurs with rupture of the abscess into the pleural space and has an increased mortality. Consolidation of the lung parenchyma may occur with contiguous spread from a liver abscess. A patient who develops a hepatobronchial fistula will have a cough productive of large amounts of sputum and necrotic material, with the sputum possibly containing detectable amebas.
Peritoneal amebiasis. Peritoneal amebiasis occurs in 2–7% of patients with amebic liver abscess and represents the second most common complication of amebic liver abscess. Presentation may be dramatic enough to simulate a perforated viscus or may be more indolent with a slow leak of organisms into the peritoneal space.
Pericardial amebiasis. Pericardial disease is a rare but serious complication of amebic liver abscess. It usually results from the rupture of an abscess in the left lobe of the liver and presents with fever and chest pain and progresses to congestive heart failure, tamponade, and shock.
Cerebral amebiasis. Cerebral amebiasis is rare, with reports from clinical series of < 0.1% of patients. Autopsy series of patients with known amebiasis show central nervous system involvement of 1–2%. Cerebral abscess should be suspected in a person with known amebiasis who presents with mental status changes or focal neurologic signs.
Genitourinary amebiasis. Renal infection may occur either from direct extension of hepatic disease or by hematogenous or lymphatic spread. Genital lesions typically arise from fistulae from hepatic or colonic disease and present with painful ulcers with profuse discharge.
Diagnosis
The diagnosis of intestinal infection with E histolytica or E dispar is made by demonstration of cysts or trophozoites in the stool or by examination of biopsy specimens of mucosal tissue. Amebic trophozoites are destroyed by many agents, including antibiotics, antidiarrheal agents, barium, and tap water. Therefore, stool specimens should be examined by preparing wet mounts of specimens within 20 min of collection and examining immediately. Staining with iodine and trichrome maximizes the yield of positive specimens. Pathogenic trophozoites of E histolytica may be distinguished from nonpathogenic species by the presence of ingested erythrocytes within the organism.
Serology is useful in diagnosis of E histolytica infection. Antibodies to ameba develop only with infection by E histolytica and do not develop with E disparinfection. With invasive colitis or hepatic abscess, antibodies may be negative initially but become positive by 7–10 days in > 85–95% of patients. Antibodies cannot distinguish current infection from remote infection, as the antibodies may remain positive for years.
Monoclonal antibodies and polymerase chain reaction technology are newer technologies being used for diagnosis of amebic infection and appear to allow differentiation of E histolytica from E dispar. An enzyme-linked immunoabsorbent assay with monoclonal antibodies to a region that contains epitopes unique to E histolytica has been used to make this distinction in preliminary studies.
Amebic liver abscess should be suspected in any patient with an abnormal abdominal exam and appropriate risk factors, such as recent travel to an endemic area. Once a hepatic fluid collection is demonstrated radiographically, it is important to distinguish amebic abscess from pyogenic abscess. Serology once again is useful but may be negative for the first week of the infection. Often, percutaneous sampling of the fluid is required to look for cysts and trophozoites. Amebas may not be found in the liquefaction center of an abscess, but the results of Gram stain, culture, and serology will usually distinguish amebic abscess from other causes.
Diagnosis of other extraintestinal sites of infection requires clinical suspicion in the appropriate setting, such as a patient with known amebic abscess. Demonstration of amebas in these extrahepatic sites is not universally required but is often obtained, because drainage is required for empyema, peritoneal involvement, and, usually, pericardial involvement.
Treatment
Treatment of amebic disease requires both the elimination of the trophozoite form from the intestine or extraintestinal sites and the elimination of cysts from the intestine. If a luminal agent is not used to eradicate cysts, disease may recur.
Metronidazole is the agent of choice for treatment of amebic colitis. Doses of 750 mg three times daily for 5–10 days are extremely effective, and the drug can be given orally or intravenously. Side effects are generally gastrointestinal: nausea, vomiting, and abdominal discomfort. If ingested with alcohol, metronidazole produces a disulfiram-like reaction. The drug carries a potential risk of teratogenicity if used in pregnant women; however, because amebic disease is often more serious in pregnant women, treatment is generally recommended. No teratogenic effects were seen in > 2500 women inadvertently given metronidazole during pregnancy. In Europe, two additional nitroimidazole antibiotics (tinidazole and ornidazole) are available, are effective therapy, and are associated with fewer adverse effects than metronidazole. These drugs are not available in the United States.
Tetracycline or erythromycin is effective therapy for milder cases of colitis. Because these drugs will not eradicate ameba in the liver, their use should probably be restricted to patient who cannot tolerate metronidazole. Emetine and dehydroemetine have relatively high toxicity and must be given in a monitored environment. They offer no benefit over standard metronidazole therapy.
Three luminal agents are available for eradication of cysts after treatment with metronidazole or other agents. Diloxanide furoate has a > 90% efficacy but must be obtained from the Centers for Disease Control and Prevention in the United States. Iodoquinol (diiodohydroxyquin) requires 20 days of therapy and is in limited supply in the United States. Because of its high iodine content, it may interfere with thyroid function tests and should be avoided in those allergic to iodine. Other side effects include gastrointestinal discomfort, fever, and headache. Paromomycin is a nonabsorbable aminoglycoside that may cause loose stools. It is often preferred for circumstances in which systemic absorption is undesirable, such as in pregnancy.
Amebic liver abscess is responsive to medical therapy, and, as with intestinal disease, metronidazole is the preferred agent. Given as a 5- to 10-day treatment, metronidazole has a cure rate of > 95%. The role of aspiration or drainage is unclear but usually is not necessary. Because of the high response rate to medical therapy, aspiration is probably best used only in a few defined circumstances. In the patient who is not clinically improved within 3 days of initiation of therapy, aspiration is used to confirm the diagnosis and to exclude other causes of abscess, such as bacterial infection. Aspiration is also indicated for a ruptured abscess and in an abscess that is in danger of rupture, as characterized by a large fluid collection surrounded by a thin rim of hepatic tissue. If a left-lobe abscess is in danger of involving the pericardium, aspiration should be performed.
Medical therapy is generally sufficient for amebiasis involving the genitourinary tract, central nervous system, and lung parenchyma. Involvement of the pericardium and pleural space may require drainage because of the development of loculations. Treatment of amebiasis is outlined in Boxes 82-2 and 82-3.
Prognosis
Although infection with E histolytica can be debilitating, it is generally not life threatening. Once infection is identified, effective treatment exists. Relapse or reinfection is not unusual. Only a small minority of patients develops severe complications, such as colonic perforation, toxic megacolon, ruptured hepatic abscess, or cerebral amebiasis.
Prevention & Control
Prevention of amebic infection is greatly enhanced by effective sanitation and a clean water supply. Cysts are resistant to destruction by chlorine, but iodine or boiling is sufficient to kill the organism. Health education and public health efforts to identify and treat carriers may limit disease spread (Box 82-4). Travelers to endemic areas should avoid unpeeled fruits and vegetables and should avoid drinking water unless it has been properly treated. Several vaccines to E histolytica are under development and may provide the most effective means of disease control once released.
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BOX 82-2 Treatment of Amebiasis in Adults |
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BOX 82-3 Treatment of Amebiasis in Children |
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BOX 82-4 Prevention of Control of Amebiasis |
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PATHOGENIC FREE-LIVING AMEBAS
ACANTHAMOEBA INFECTION
Amebas of the genus Acanthamoeba live as cysts and trophozoites in soil and in water. They can cause several disease syndromes in human hosts, including encephalitis, keratitis, and infections of the skin that resemble deep fungal infections. In addition, they can infect other human tissues and cause a granulomatous reaction. These amebas may be carried in an asymptomatic nasal carrier state. Immunocompromised patients, such as transplant recipients and HIV-infected persons, are at increased risk of contracting disease. Diving in warm water may increase infection rates.
The encephalitis caused by Acanthamoeba is a chronic, focal, necrotizing infection characterized by granuloma formation (granulomatous encephalitis). Patients usually present with the insidious onset of focal neurological deficits, fevers, headache, meningismus, seizures, and mental status changes. Common focal deficits include visual disturbances and ataxia. Diagnosis is difficult and is often made only at autopsy. Tissue biopsy specimens may provide diagnosis. Cerebrospinal fluid lymphocytosis may be present, but the organism has not been isolated from cerebrospinal fluid. Granulomatous encephalitis leads to death, with an average survival from the onset of symptoms of 40 days. No treatment is effective. Imidazole antifungal agents, amphotericin B, neomycin, flucytosine, sulfonamides, pentamidine, and propamidine have been used without success.
Acanthamoeba species cause keratitis, and > 200 cases have been described in the United States since the early 1970s. Risk factors include use of contact lenses, exposure to contaminated water, and trauma to the cornea. After exposure, patients typically note a foreign body sensation that is followed by eye pain, visual change, tearing, and conjunctivitis. Progression of disease may lead to blindness. The disease is frequently misdiagnosed initially as herpes simplex virus or bacterial keratitis. Correct diagnosis is made by demonstration of the organism on corneal scrapings or biopsy material. Treatment requires surgical débridement followed by a minimum of 3–4 weeks of medical therapy, which consists of topical treatment with propamidine, Neosporin, and miconazole. Other therapies are topical polyhexmethylene biguanide or the combination of topical miconazole and oral itraconazole.
NAEGLERIA FOWLERI INFECTION
Naegleria fowleri is a free-living ameba that causes a primary meningoencephalitis. It may live in warm water areas, including lakes, hot springs, mud puddles, and swimming pools. Most infections are in children or young adults and manifest 5–15 days after exposure to an infected water source. The organism invades the meninges through the cribiform plate, a process facilitated by diving in deep water. Those infected may have a viral prodrome with nausea, vomiting, headache, and malaise and rapidly progress to coma and death within 2–3 days. Most patients have meningeal signs.
Diagnosis must be suspected early, because, even with prompt treatment, there are only four documented survivors of this infection. Primary amebic meningoencephalitis should be considered in those with a viral prodrome rapidly progressing to coma. Patients typically have leukocytosis. Lumbar puncture should be performed with caution, as increased intracranial pressure raises the risk of herniation. Cerebrospinal fluid will show many erythrocytes and typical leukocyte counts of 400–25,000/µL, with 50–100% neutrophils. Protein may be mildly elevated, and glucose is normal to slightly low. If no bacteria are seen on Gram stain of a purulent cerebrospinal fluid, a wet mount should be examined for amebic trophozoites. The specimen should not be refrigerated or centrifuged, because this reduces the ameba's motility and makes trophozoites difficult to distinguish from the many leukocytes.
Treatment of primary amebic meningoencephalitis is generally unsuccessful. The documented survivors received intravenous and intrathecal amphotericin B. One patient also received miconazole, rifampin, and sulfisoxazole. Laboratory studies with a rabbit model have shown synergy between amphotericin B and rifampin or tetracycline. Intrathecal administration of antinaegleria antibody has also improved survival in animal models.
REFERENCES
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Ravdin JI: Amebiasis. Clin Infect Dis 1995;20:1453.
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Reed SL, Wessel DW, Davis CE: Entamoeba histolytica infection and AIDS. Am J Med 1991;90:269.
Seidel J: Primary amebic meningoencephalitis. Pediatr Clin North Am 1985;32:881.
Warhurst DC: Diagnosis of amebic infection. In Rickwood D, Hames BD: Medical Parasitology, A Practical Approach. Oxford University Press, 1995.