Amebiasis is an infection with the intestinal protozoan Entamoeba histolytica. About 90% of infections are asymptomatic, and the remaining 10% produce a spectrum of clinical syndromes ranging from dysentery to abscesses of the liver or other organs.
LIFE CYCLE AND TRANSMISSION
E. histolytica is acquired by ingestion of viable cysts from fecally contaminated water, food, or hands. Food-borne exposure is most prevalent and is particularly likely when food handlers are shedding cysts or food is being grown with feces-contaminated soil, fertilizer, or water. Besides the drinking of contaminated water, less common means of transmission include oral and anal sexual practices and—in rare instances—direct rectal inoculation through colonic irrigation devices. Motile trophozoites are released from cysts in the small intestine and, in most patients, remain as harmless commensals in the large bowel. After encystation, infectious cysts are shed in the stool and can survive for several weeks in a moist environment. In some patients, the trophozoites invade either the bowel mucosa, causing symptomatic colitis, or the bloodstream, causing distant abscesses of the liver, lungs, or brain. The trophozoites may not encyst in patients with active dysentery, and motile hematophagous trophozoites are frequently present in fresh stools. Trophozoites are rapidly killed by exposure to air or stomach acid, however, and therefore cannot transmit infection.
About 10% of the world’s population is infected with Entamoeba, the majority with noninvasive Entamoeba dispar. Amebiasis results from infection with E. histolytica and is the third most common cause of death from parasitic disease (after schistosomiasis and malaria).The wide spectrum of clinical disease caused by Entamoeba is due in part to the differences between these two infecting species. Cysts of E. histolytica and E. dispar are morphologically identical, but E. histolytica has unique isoenzymes, surface antigens, DNA markers, and virulence properties (Table 115-1). Most asymptomatic carriers, including homosexual men and patients with AIDS, harbor E. dispar and have self-limited infections. These observations indicate that E. dispar is incapable of causing invasive disease, since Cryptosporidium and Isospora belli, which also cause only self-limited illnesses in immunocompetent people, cause devastating diarrhea in patients with AIDS.
However, host factors play a role as well. In one study, 10% of asymptomatic patients who were colonized with E. histolytica went on to develop amebic colitis, while the rest remained asymptomatic and cleared the infection within 1 year. Areas of highest incidence (due to inadequate sanitation and crowding) include most developing countries in the tropics, particularly Mexico, India, and nations of Central and South America, tropical Asia, and Africa. In a 4-year follow-up study of preschool children in a highly endemic area of Bangladesh, 80% of children had at least one episode of infection with E. histolytica and 53% had more than one episode. Naturally acquired immunity did develop but was usually short-lived and correlated with the presence in the stool of secretory IgA antibody to the major adherence lectin galactose N-acetylgalactosamine (Gal/GalNAc). The main groups at risk for amebiasis in developed countries are returned travelers, recent immigrants, homosexual men, and inmates of institutions.
PATHOGENESIS AND PATHOLOGY
Both trophozoites (Fig. 115-1) and cysts (Fig. 115-2) are found in the intestinal lumen, but only trophozoites of E. histolytica invade tissue.The trophozoite is 20–60 μm in diameter and contains vacuoles and a nucleus with a characteristic central nucleolus. In animals, depletion of intestinal mucus, diffuse inflammation, and disruption of the epithelial barrier occur before trophozoites actually come into contact with the colonic mucosa.Trophozoites attach to colonic mucus and epithelial cells by Gal/GalNAc.The earliest intestinal lesions are microulcerations of the mucosa of the cecum, sigmoid colon, or rectum that release erythrocytes, inflammatory cells, and epithelial cells. Proctoscopy reveals small ulcers with heaped-up margins and normal intervening mucosa. Submucosal extension of ulcerations under viable-appearing surface mucosa causes the classic “flask-shaped” ulcer containing trophozoites at the margins of dead and viable tissues.
Although neutrophilic infiltrates may accompany the early lesions in animals, human intestinal infection is marked by a paucity of inflammatory cells, probably in part because of the killing of neutrophils by trophozoites (Fig. 115-3). Treated ulcers characteristically heal with little or no scarring. Occasionally, however, full-thickness necrosis and perforation occur. Rarely, intestinal infection results in the formation of a mass lesion, or ameboma, in the bowel lumen.The overlying mucosa is usually thin and ulcerated, while other layers of the wall are thickened, edematous, and hemorrhagic; this condition results in exuberant formation of granulation tissue with little fibrous-tissue response. A number of virulence factors have been linked to the ability of E. histolytica to invade through the interglandular epithelium. One consists of the extracellular cysteine proteinases that degrade collagen, elastin, IgA, IgG, and the anaphylatoxins C3a and C5a. Other enzymes may disrupt glycoprotein bonds between mucosal epithelial cells in the gut. Amebas can lyse neutrophils, monocytes, lymphocytes, and cells of colonic and hepatic lines. The cytolytic effect of amebas appears to require direct contact with target cells and may be linked to the release of phospholipase A and pore-forming peptides. E. histolytica trophozoites also cause apoptosis of human cells.
Liver abscesses are always preceded by intestinal colonization, which may be asymptomatic. Blood vessels may be compromised early by wall lysis and thrombus formation. Trophozoites invade veins to reach the liver through the portal venous system. E. histolytica is resistant to complement-mediated lysis—a property critical to survival in the bloodstream. In contrast, E. dispar is rapidly lysed by complement and is thus restricted to the bowel lumen. Inoculation of amebas into the portal system of hamsters results in an acute cellular infiltrate consisting predominantly of neutrophils. Later, the neutrophils are lysed by contact with amebas, and the release of neutrophil toxins may contribute to necrosis of hepatocytes. The liver parenchyma is replaced by necrotic material that is surrounded by a thin rim of congested liver tissue.The necrotic contents of a liver abscess are classically described as “anchovy paste,” although the fluid is variable in color and is composed of bacteriologically sterile granular debris with few or no cells. Amebas, if seen, tend to be found near the capsule of the abscess. A study in Bangladeshi schoolchildren revealed that an intestinal IgA response to Gal/GalNAc reduced the risk of new E. histolytica infection by 64%. Serum IgG antibody is not protective; titers correlate with the duration of illness rather than with the severity of disease. Indeed, Bangladeshi children with a serum IgG response were more likely than those without such a response to develop new E. histolytica infection. Studies of animals suggest that cell-mediated immunity may be important for protection, although patients with AIDS appear not to be predisposed to more severe disease.
Intestinal Amebiasis The most common type of amebic infection is asymptomatic cyst passage. Even in highly endemic areas, most patients harbor E. dispar. Symptomatic amebic colitis develops 2–6 weeks after the ingestion of infectious cysts. A gradual onset of lower abdominal pain and mild diarrhea is followed by malaise,weight loss, and diffuse lower abdominal or back pain. Cecal involvement may mimic acute appendicitis. Patients with full-blown dysentery may pass 10–12 stools per day.The stools contain little fecal material and consist mainly of blood and mucus. In contrast to those with bacterial diarrhea, fewer than 40% of patients with amebic dysentery are febrile. Virtually all patients have heme-positive stools. More fulminant intestinal infection, with severe abdominal pain, high fever, and profuse diarrhea, is rare and occurs predominantly in children.
Patients may develop toxic megacolon, in which there is severe bowel dilation with intramural air. Patients receiving glucocorticoids are at risk for severe amebiasis. Uncommonly, patients develop a chronic form of amebic colitis, which can be confused with inflammatory bowel disease. The association between severe amebiasis complications and glucocorticoid therapy emphasizes the importance of excluding amebiasis when inflammatory bowel disease is suspected. An occasional patient presents with only an asymptomatic or tender abdominal mass caused by an ameboma, which is easily confused with cancer on barium studies. A positive serologic test or biopsy can prevent unnecessary surgery in this setting. The syndrome of postamebic colitis—persistent diarrhea following documented cure of amebic colitis—is controversial; no evidence of recurrent amebic infection can be found, and re-treatment usually has no effect. Amebic Liver Abscess Extraintestinal infection by E. histolytica most often involves the liver. Of travelers who develop an amebic liver abscess after leaving an endemic area, 95% do so within 5 months.Young patients with an amebic liver abscess are more likely than older patients to present in the acute phase with prominent symptoms of <10 days’ duration.
Most patients are febrile and have right-upperquadrant pain, which may be dull or pleuritic in nature and may radiate to the shoulder. Point tenderness over the liver and right-sided pleural effusion is common. Jaundice is rare. Although the initial site of infection is the colon, fewer than one-third of patients with an amebic abscess have active diarrhea. Older patients from endemic areas are more likely to have a subacute course lasting 6 months, with weight loss and hepatomegaly. About one-third of patients with chronic presentations are febrile.Thus, the clinical diagnosis of an amebic liver abscess may be difficult to establish because the symptoms and signs are often nonspecific. Since 10–15% of patients present only with fever, amebic liver abscess must be considered in the differential diagnosis of fever of unknown origin (Chap. 9). Complications of Amebic Liver Abscess Pleuropulmonary involvement, which is reported in 20–30% of patients, is the most frequent complication of amebic liver abscess.
Manifestations include sterile effusions, contiguous spread from the liver, and rupture into the pleural space. Sterile effusions and contiguous spread usually resolve with medical therapy, but frank rupture into the pleural space requires drainage.A hepatobronchial fistula may cause cough productive of large amounts of necrotic material that may contain amebas. This dramatic complication carries a good prognosis. Abscesses that rupture into the peritoneum may present as an indolent leak or an acute abdomen and require both percutaneous catheter drainage and medical therapy. Rupture into the pericardium, usually from abscesses of the left lobe of the liver, carries the gravest prognosis; it can occur during medical therapy and requires surgical drainage. Other Extraintestinal Sites The genitourinary tract may become involved by direct extension of amebiasis from the colon or by hematogenous spread of the infection. Painful genital ulcers, characterized by a punched-out appearance and profuse discharge, may develop secondary to extension from either the intestine or the liver. Both these conditions respond well to medical therapy. Cerebral involvement has been reported in fewer than 0.1% of patients in large clinical series. Symptoms and prognosis depend on the size and location of the lesion.
Laboratory Diagnosis Stool examinations, serologic tests, and noninvasive imaging of the liver are the most important procedures in the diagnosis of amebiasis. Fecal findings suggestive of amebic colitis include a positive test for heme, a paucity of neutrophils, and amebic cysts or trophozoites. The definitive diagnosis of amebic colitis is made by the demonstration of hematophagous trophozoites of E. histolytica (Fig. 115-1). Because trophozoites are killed rapidly by water, drying, or barium, it is important to examine at least three fresh stool specimens. Examination of a combination of wet mounts, iodinestained concentrates, and trichrome-stained preparations of fresh stool and concentrates for cysts (Fig. 115-2) or trophozoites (Fig. 115-1) confirms the diagnosis in 75–95% of cases. Cultures of amebas are more sensitive but are not routinely available. If stool examinations are negative, sigmoidoscopy with biopsy of the edge of ulcers may increase the yield, but this procedure is dangerous during fulminant colitis because of the risk of perforation.
Trophozoites in a biopsy specimen from a colonic mass confirm the diagnosis of ameboma, but trophozoites are rare in liver aspirates because they are found in the abscess capsule and not in the readily aspirated necrotic center. Accurate diagnosis requires experience, since the trophozoites may be confused with neutrophils and the cysts must be differentiated morphologically from Entamoeba hartmanni, Entamoeba coli, and Endolimax nana, which do not cause clinical disease and do not warrant therapy. Unfortunately, the cysts of E. histolytica cannot be distinguished microscopically from those of E. dispar.Therefore, the microscopic diagnosis of E. histolytica can be made only by the detection of Entamoeba trophozoites that have ingested erythrocytes. In terms of sensitivity, stool diagnostic tests based on the detection of the Gal/GalNAc lectin of E. histolytica compare favorably with the polymerase chain reaction and with isolation in culture followed by isoenzyme analysis. Serology is an important addition to the methods used for parasitologic diagnosis of invasive amebiasis. Enzyme-linked immunosorbent assays (ELISAs) and agar gel diffusion assays are positive in more than 90% of patients with colitis, amebomas, or liver abscess.
Positive results in conjunction with the appropriate clinical syndrome suggest active disease because serologic findings usually revert to negative within 6–12 months. Even in highly endemic areas such as South Africa, fewer than 10% of asymptomatic individuals have a positive amebic serology. The interpretation of the indirect hemagglutination test is more difficult because titers may remain positive for as long as 10 years. Up to 10% of patients with acute amebic liver abscess may have negative serologic findings; in suspected cases with an initially negative result, testing should be repeated in a week. In contrast to carriers of E. dispar, most asymptomatic carriers of E. histolytica develop antibodies. Thus, serologic tests are helpful in assessing the risk of invasive amebiasis in asymptomatic, cyst-passing individuals in nonendemic areas. Serologic tests also should be performed in patients with ulcerative colitis before the institution of glucocorticoid therapy to prevent the development of severe colitis or toxic megacolon owing to unsuspected amebiasis. Routine hematology and chemistry tests usually are not very helpful in the diagnosis of invasive amebiasis. About three-fourths of patients with an amebic liver abscess have leukocytosis (>10,000 cells/μL); this condition is particularly likely if symptoms are acute or complications have developed. Invasive amebiasis does not elicit eosinophilia.Anemia, if present, is usually multifactorial. Even with large liver abscesses, liver enzyme levels are normal or minimally elevated. The alkaline phosphatase level is most often elevated and may remain so for months. Aminotransferase elevations suggest acute disease or a complication.
Radiographic Studies Radiographic barium studies are potentially dangerous in acute amebic colitis. Amebomas are usually identified first by a barium enema, but biopsy is necessary for differentiation from carcinoma. Radiographic techniques such as ultrasonography, CT, and MRI are all useful for detection of the round or oval hypoechoic cyst. More than 80% of patients who have had symptoms for >10 days have a single abscess of the right lobe of the liver (Fig. 115-4). Approximately 50% of patients who have had symptoms for <10 days have multiple abscesses. Findings associated with complications include large abscesses (>10 cm) in the superior part of the right lobe, which may rupture into the pleural space; multiple lesions, which must be differentiated from pyogenic abscesses; and lesions of the left lobe, which may rupture into the pericardium. Because abscesses resolve slowly and may increase in size in patients who are responding clinically to therapy, frequent follow-up ultrasonography may prove confusing. Complete resolution of a liver abscess within 6 months can be anticipated in twothirds of patients, but 10% may have persistent abnormalities for a year.
The differential diagnosis of intestinal amebiasis includes bacterial diarrheas (Chap. 25) caused by Campylobacter (Chap. 56); enteroinvasive Escherichia coli (Chap. 51); and species of Shigella (Chap. 55), Salmonella (Chap. 54), and Vibrio (Chap. 57). Although the typical patient with amebic colitis has less prominent fever than in these other conditions as well as heme-positive stools with few neutrophils, correct diagnosis requires bacterial cultures, microscopic examination of stools, and amebic serologic testing. As has already been mentioned, amebiasis must be ruled out in any patient thought to have inflammatory bowel disease. Because of the variety of presenting signs and symptoms, amebic liver abscess can easily be confused with pulmonary or gallbladder disease or with any febrile illness with few localizing signs, such as malaria (Chap. 116) or typhoid fever (Chap. 54). The diagnosis should be considered in members of high-risk groups who have recently traveled outside the United States (Chap. 4) and in inmates of institutions. Once radiographic studies have identified an abscess in the liver, the most important differential diagnosis is between amebic and pyogenic abscess. Patients with pyogenic abscess typically are older and have a history of underlying bowel disease or recent surgery. Amebic serology is helpful, but aspiration of the abscess, with Gram’s staining and culture of the material, may be required for differentiation of the two diseases.
AMEBIASIS INTESTINAL DISEASE
(Table 115-2) The drugs used to treat amebiasis can be classified according to their primary site of action. Luminal amebicides are poorly absorbed and reach high concentrations in the bowel, but their activity is limited to cysts and trophozoites close to the mucosa. Only two luminal drugs are available in the United States: iodoquinol and paromomycin. Indications for the use of luminal agents include eradication of cysts in patients with colitis or a liver abscess and treatment of asymptomatic carriers. The majority of asymptomatic individuals who pass cysts are colonized with E. dispar, which does not warrant specific therapy. However, it is prudent to treat asymptomatic individuals who pass cysts unless E. dispar colonization can be definitively demonstrated by specific antigen-detection tests. Tissue amebicides reach high concentrations in the blood and tissue after oral or parenteral administration.
The development of nitroimidazole compounds, especially metronidazole, was a major advance in the treatment of invasive amebiasis. Patients with amebic colitis should be treated with intravenous or oral metronidazole. Side effects include nausea, vomiting, abdominal discomfort, and a disulfiram-like reaction. Another longer-acting imidazole compound, tinidazole, is also effective and was recently approved in the United States.All patients should also receive a full course of therapy with a luminal agent, since metronidazole does not eradicate cysts. Resistance to metronidazole has been selected in the laboratory but has not been found in clinical isolates. Relapses are not uncommon and probably represent reinfection or failure to eradicate amebas from the bowel because of an inadequate dosage or duration of therapy.
AMEBIC LIVER ABSCESS
Metronidazole is the 1075 drug of choice for amebic liver abscess. Longer-acting nitroimidazoles (tinidazole and ornidazole) have been effective as single-dose therapy in developing countries. With early diagnosis and therapy, mortality rates from uncomplicated amebic liver abscess are <1%.The secondline therapeutic agents emetine and chloroquine should be avoided if possible because of the potential cardiovascular and gastrointestinal side effects of the former and the higher relapse rates with the latter. There is no evidence that combined therapy with two drugs is more effective than the single-drug regimen. Studies of South Africans with liver abscesses demonstrated that 72% of patients without intestinal symptoms had bowel infection with E. histolytica; thus, all treatment regimens should include a luminal agent to eradicate cysts and prevent further transmission. Amebic liver abscess recurs rarely.
ASPIRATION OF LIVER ABSCESSES
More than 90% of patients respond dramatically to metronidazole therapy with decreases in both pain and fever within 72 h. Indications for aspiration of liver abscesses are (1) the need to rule out a pyogenic abscess, particularly in patients with multiple lesions; (2) the lack of a clinical response in 3–5 days; (3) the threat of imminent rupture; and (4) the need to prevent rupture of left-lobe abscesses into the pericardium. There is no evidence that aspiration, even of large abscesses (up to 10 cm), accelerates healing. Percutaneous drainage may be successful even if the liver abscess has already ruptured. Surgery should be reserved for instances of bowel perforation and rupture into the pericardium.
Amebic infection is spread by ingestion of food or water contaminated with cysts. Since an asymptomatic carrier may excrete up to 15 million cysts per day, prevention of infection requires adequate sanitation and eradication of cyst carriage. In high-risk areas, infection can be minimized by the avoidance of unpeeled fruits and vegetables and the use of bottled water. Because cysts are resistant to readily attainable levels of chlorine, disinfection by iodination (tetraglycine hydroperiodide) is recommended. There is no effective prophylaxis.
INFECTION WITH FREE-LIVING AMEBAS EPIDEMIOLOGY
Free-living amebas of the genera Acanthamoeba and Naegleria are distributed throughout the world and have been isolated from a wide variety of fresh and brackish water, including that from lakes, taps, hot springs, swimming pools, and heating and air-conditioning units, and even from the nasal passages of healthy children. Encystation may protect the protozoa from desiccation and food deprivation. The persistence of Legionella pneumophila in water supplies may be attributable in part to chronic infection of free-living amebas, particularly Naegleria. Free-living amebas of the genus Balamuthia have only recently been isolated from soil samples, including a sample from a flowerpot linked to a fatal infection in a child.
Primary amebic meningoencephalitis caused by Naegleria fowleri follows the aspiration of water contaminated with trophozoites or cysts or the inhalation of contaminated dust, leading to invasion of the olfactory neuroepithelium. After an incubation period of 2–15 days, severe headache, high fever, nausea, vomiting, and meningismus develop. Photophobia and palsies of the third, fourth, and sixth cranial nerves are common. Rapid progression to seizures and coma may follow. The prognosis is uniformly poor: most patients die within a week. Only a few survivors, treated with high-dose amphotericin B and rifampin, have been reported. Infection is most common in otherwise- healthy children or young adults, who often report recent swimming in lakes or heated swimming pools. The diagnosis of Naegleria infection should be considered in any patient who has purulent meningitis without evidence of bacteria on Gram’s staining, antigen detection assay, and culture.
Other laboratory findings resemble those for fulminant bacterial meningitis, with elevated intracranial pressure, high white blood cell counts (up to 20,000/μL), and elevated protein concentrations and low glucose levels in cerebrospinal fluid (CSF). Diagnosis depends on the detection of motile trophozoites in wet mounts of fresh spinal fluid. Antibodies to Naegleria spp. have been detected in normal adults; serologic testing is not useful in the diagnosis of acute infection.
Granulomatous Amebic Encephalitis Infection with Acanthamoeba species follows a more indolent course and typically occurs in chronically ill or debilitated patients. Risk factors include lymphoproliferative disorders, chemotherapy, glucocorticoid therapy, lupus erythematosus, and AIDS. Infection usually reaches the central nervous system (CNS) hematogenously from a primary focus in the sinuses, skin, or lungs. In the CNS, the onset is insidious, and the syndrome often mimics a spaceoccupying lesion. Altered mental status, headache, and stiff neck may be accompanied by focal findings such as cranial nerve palsies, ataxia, and hemiparesis. Cutaneous ulcers or hard nodules containing amebas are frequently detected in AIDS patients with disseminated Acanthamoeba infection. Examination of the CSF for trophozoites may be diagnostically helpful, but lumbar puncture may be contraindicated because of increased intracerebral pressure. CT frequently reveals cortical and subcortical lesions of decreased density consistent with embolic infarcts. In other patients, multiple enhancing lesions with edema may mimic the computed tomographic appearance of toxoplasmosis (Chap. 121).
Demonstration of the trophozoites and cysts of Acanthamoeba on wet mounts or in biopsy specimens establishes the diagnosis. Culture on nonnutrient agar plates seeded with E. coli may also be helpful. Fluorescein-labeled antiserum is available from the Centers for Disease Control and Prevention (CDC) for the detection of protozoa in biopsy specimens. Granulomatous amebic encephalitis in patients with AIDS may have an accelerated course (with survival for only 3–40 days) because of the difficulty these individuals have in forming granulomas.Various antimicrobial agents have been used to treat Acanthamoeba infection, including pentamidine, trimethoprim-sulfamethoxazole, and fluconazole, but the infection is almost uniformly fatal. Keratitis The incidence of keratitis caused by Acanthamoeba has increased in the past 20 years, in part as a result of improved diagnosis. Earlier infections were associated with trauma to the eye and exposure to contaminated water.
At present, most infections are linked to extendedwear contact lenses, and rare cases are associated with laser-assisted in situ keratomileusis (LASIK). Risk factors include the use of homemade saline, the wearing of lenses while swimming, and inadequate disinfection. Since contact lenses presumably cause microscopic trauma, the early corneal findings may be nonspecific. The first symptoms usually include tearing and the painful sensation of a foreign body. Once infection is established, progression is rapid; the characteristic clinical sign is an annular, paracentral corneal ring representing a corneal abscess. Deeper corneal invasion and loss of vision may follow. The differential diagnosis includes bacterial, mycobacterial, and herpetic infection. The irregular polygonal cysts of Acanthamoeba (Fig. 115-5) may be identified in corneal scrapings or biopsy material, and trophozoites can be grown on special media. Cysts are resistant to available drugs, and the results of medical therapy have been disappointing. Some reports have suggested partial responses to propamidine isethionate eyedrops. Severe infections usually require keratoplasty.
Balamuthia mandrillaris, a free-living ameba previously referred to as a leptomyxid ameba, is an important etiologic agent of amebic meningoencephalitis in immunocompetent hosts. The course is typically subacute, with focal neurologic signs, fever, seizures, and headaches leading to death within 1 week to several months after onset. Examination of CSF reveals mononuclear or neutrophilic pleocytosis, elevated protein levels, and normal to low glucose concentrations. Multiple hypodense lesions are usually detected with imaging studies. This mixed picture of space-occupying lesions with CSF pleocytosis is suggestive of Balamuthia. Detection of an indirect fluorescent antibody response may be helpful in noninvasive diagnosis, but usually a definitive diagnosis is made post-mortem. Fluorescent antibody is available from the CDC.The variety of drugs used to treat the few surviving patients (numbering fewer than five in the United States) include pentamidine, flucytosine, sulfadiazine, and macrolides. The differential diagnosis includes tuberculomas (Chap. 66) and neurocysticercosis (Chap. 127).