Current Diagnosis & Treatment in Infectious Diseases

Section VII - Parasitic Infections

82. Pathogenic Amebas

Christopher R. Fox MD

Merle A. Sande MD

ENTAMOEBA HISTOLYTICA & ENTAMOEBA DISPAR

Essentials of Diagnosis

  • Patient living in or having traveled to endemic area increases risk.
  • Frequent loose stools with blood and mucus.
  • Demonstration of cyst or trophozoite on stool wet mount or in biopsy specimen.
  • Serology positive within 7–10 days of infection, may remain positive for years after infection resolved.
  • Monoclonal antibodies and polymerase chain reaction emerging; may help differentiate E histolyticaand E dispar.

General Considerations

  • Epidemiology.There are numerous distinct species of ameba within the genus Entamoeba, and the majority of these do not cause disease in humans. E histolytica is a pathogenic species that is capable of causing disease, such as colitis or liver abscess, in humans. E dispar is prevalent and is indistinguishable from E histolytica by conventional laboratory methods. E dispar exists in humans in only an asymptomatic carrier state and does not cause colitis.

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.

  • Microbiology.E histolytica exists in one of two forms, a cyst or a trophozoite. Infection is generally through fecal-oral spread with ingestion of the cyst form, which is resistant to killing by the low pH of the stomach. Within the small bowel, the cyst divides into trophozoites, which then colonize the large intestine. The trophozoites may subsequently encyst and be shed into the stool. Once shed, they may remain viable for weeks to months.

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.

  • Pathogenesis.E histolytica infection is enhanced by the production of several virulence factors. Production of proteolytic enzymes allows the trophozoite to disrupt tissue planes and invade the colonic epithelium. The trophozoite may ascend the portal venous structures to produce hepatic infection, and obstruction of the portal vessels by the trophozoites may produce hepatic necrosis. The trophozoites are able to lyse neutrophils through a contact-dependent mechanism that protects the trophozoite from ingestion and causes local tissue damage by release of the neutrophil's enzymes. Trophozoites are also resistant to complement-mediated lysis and produce adherence lectins that aid in the binding of the trophozoite to colonic epithelium, thereby facilitating invasion of the epithelium. These adherence proteins also aid in the contact-dependent lysis of tissue and white cells.

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.

BOX 82-1 Clinical Features of Amebiasis

 

Intestinal

Hepatic

Extrahepatic

More Common

·  Asymptomatic > (90%)

·  Frequent loose stools with blood and mucus

·  Abdominal pain

·  Right–upper–quadrant pain, right shoulder pain, or both

·  Fever in first 2 weeks

·  Weight loss

·  Cough, even in absence of pulmonary disease

·  Pleuropulmonary (cough, pleuritic chest pain, “anchovy paste” effusion)

·  Peritoneal (abdominal pain—ranges from mild to acute)

Less Common

·  Fever

·  Volume depletion

·  Ameboma

·  Megacolon

·  Perforation

·  Diarrhea

·  Hepatomegaly

·  Pericardial (fever, chest pain, congestive heart failure, tamponade)

·  Cerebral (change in mental status, focal neurologic deficits)

·  Genitourinary (painful ulcers with profuse discharge)

 

INTESTINAL DISEASE

Clinical Findings

  • Signs and Symptoms.Of patients infected with E histolytica, > 90% are asymptomatic carriers who are colonized with the organism and pass cysts in the stool. This carrier state often resolves without treatment, although relapses and reinfection are common.

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.

  • Laboratory Findings.Laboratory findings in intestinal amebiasis are nonspecific, and there are no characteristic laboratory findings that should prompt a search for the organism. The stool is usually positive for erythrocytes. Fecal leukocytes are often not present, secondary to lysis by the parasite, despite invasion of the intestinal mucosa.
  • Imaging.The most useful imaging study for amebiasis is endoscopy. Colonoscopy or flexible sigmoidoscopy allows for direct visualization of the intestinal mucosa and provides an opportunity for mucosal biopsy. Endoscopy typically reveals inflamed mucosa with punctate, hemorrhagic ulcers interspersed with normal-appearing mucosa.
  • Differential Diagnosis.Acute intestinal amebiasis must be distinguished from bacterial dysentery caused by Salmonella, Shigella, Campylobacter, enteroinvasive E coli, and Yersinia spp. Amebiasis, particularly chronic infection, may be confused with inflammatory bowel disease.
  • Complications.Complications from amebic intestinal disease are rare, because the majority of patients are asymptomatic. Those complications that do occur include peritonitis, colonic perforation, stricture formation, and hemorrhage. Toxic megacolon, a serious complication of amebic colitis, occurs rarely, but its incidence is increased in persons treated with steroids during the course of their infection.

 

AMEBIC LIVER ABSCESS

Clinical Findings

  • Signs and Symptoms.Amebic liver abscess is the most common extraintestinal manifestation of amebiasis. Patients may note right-upper-quadrant pain that is either dull or pleuritic in nature. Often pain is referred to the right shoulder. Less than 50% of patients have an enlarged liver. In the acute setting, patients typically manifest fever. If symptoms have been present for > 2 weeks, fever is present in less than half of patients. Respiratory symptoms, such as cough, can occur even in the absence of pulmonary disease and may be the only complaint. In the subacute setting, weight loss is common. Diarrhea is found in less than one-third of patients with amebic liver abscess.

Exam may reveal abdominal tenderness, tender hepatomegaly, and crackles at the right lung base. Jaundice is uncommon.

  • Laboratory Findings.Patients with amebic liver abscess may have leukocytosis without eosinophilia, elevated alkaline phosphatase, and mild anemia. The transaminases are elevated in severe disease. Other findings include a high erythrocyte sedimentation rate and proteinuria.
  • Imaging.Ultrasound of the liver may show a round or an oval hypoechoic area contiguous with the liver capsule and without significant wall echoes. This is often a single lesion in the right hepatic lobe. Computer tomographic scanning and magnetic resonance imaging are sensitive studies for hepatic involvement, but the finding of a mass is not specific for amebic abscess. Each of these studies allows definition of the number of lesions as well as their size, and this information may be used to monitor a patient's course.
  • Differential Diagnosis.An amebic liver abscess needs to be differentiated from other mass lesions of the liver, which include bacterial abscess, echinococcal cyst, hepatoma, and metastatic cancer.
  • Complications.Amebic liver abscesses may rupture and thereby extend into surrounding tissues, including the pleural space, lung parenchyma, and pericardium. Pleural effusion may be present without frank rupture of the abscess.

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.

BOX 82-2 Treatment of Amebiasis in Adults

 

Asymptomatic Cyst Passage

Intestinal Disease

Hepatic

Extrahepatic

First Choice

·  Luminal agent—diloxanide furoate, 500 mg PO three times daily × 10 d
OR

·  Paromomycin, 500 mg PO three times daily × 10 d
OR

·  Iodoquinol, 650 mg PO three times daily × 20 d

·  Metronidazole, 750 mg PO three times daily × 10 d

·  Followed by luminal agent

·  Metroindazole, 750 mg PO three times daily or 500 mg IV every 6 h × 10 d

·  Followed by luminal agent

·  Drug therapy is the same as for hepatic disease

·  Consider drainage

Alternative

 

·  Tetracycline, 250 mg three times daily × 10 d

·  Erythromycin, 500 mg PO four times daily × 10 d

·  Tinidazole, 50 mg/kg per day × 3 d (not available in the United States)

·  Followed by luminal agent

·  Tinidazole or ornidazole, 2 g PO once (not available in the United States)

·  Followed by luminal agent

 

BOX 82-3 Treatment of Amebiasis in Children

 

Asymptomatic Cyst Passage

Intestinal Disease

Hepatic

Extrahepatic

First Choice

·  Luminal agent—diloxanide furoate, 20 mg/kg/d in 3 divided doses × 10 d
OR

·  Paromomycin, 30 mg/kg/d in 3 divided doses × 10 d
OR

·  Iodoquinol, 20–40 mg/kg/d in 3 divided doses × 20 d

·  Metronidazole, 30–50 mg/kg/d in 3 divided doses × 5–10 d

·  Followed by luminal agent

·  Metronidazole, 30–50 mg/kg/d in 3 divided doses PO or IV × 5–10 d

·  Followed by luminal agent

·  Drug therapy is the same as for hepatic disease

·  Consider drainage

Alternative

·  Alternative drugs and dosages not established

BOX 82-4 Prevention of Control of Amebiasis

Prophylactic Measures

·  Effective sanitation and clean water suply

·  Cysts resistant to chlorine, killed by boiling water and iodine

·  Travelers to endemic areas should avoid unpeeled fruits and vegetables and untreated water

Isolation Precautions

·  Vaccines under development

 

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.

 

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