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Amebiasis and other parasitic infections
Amebic liver abscess
History
The earliest report of amebiasis is probably the Sanskrit document Brigu-samhita, written about 3000 bce , referring to bloody mucoid diarrhea. Assyrian and Babylonian texts refer to blood in the feces, suggesting the presence of amebiasis in the Tigris-Euphrates basin before the sixth century bce , and it is possible that hepatic and perianal abscesses described in both Epidemics and Aphorisms in the Corpus Hippocratorum refer to amebiasis. , After the death of Hippocrates in 356 bce , Alexander the Great became king of Macedonia. In Alexander’s eastern campaign, he reached an area where amebiasis was endemic, and he died on the return trip at the age of 33 years, probably of an amebic liver abscess (ALA).
In 1818, Ballingall described a surgical technique to drain liver abscesses. In 1828, James Annesley gave detailed descriptions of “hepatic dysentery.” The connection between amebic dysentery and liver abscesses was described by the English physician William Budd, but Charles Morehead, professor of Medicine and first principal of Grant Medical College, Bombay, India, was the first to report a case of hepatic abscess, in 1848.
Entamoeba histolytica was discovered by Friedrich Lösch in 1873 in Russia. Lösch recognized amebae in the colon and terminal ileum accompanying acute dysentery. He gave descriptions of amebae, including structure, size, motility, intracytoplasmic elements, and drawings. Lösch named the amebae after his patient; Amoeba coli was proved later on sequencing of the genome, and a calreticulin-like protein and Golgi apparatus were detected in the amebae. ,
Stephanos Kartulis, a Greek physician, found amebae in intestinal ulcers in patients from Egypt in 1885 and noted that he never found amebae from nondysenteric cases. In 1890, Osler reported a young physician who died of ALA after an attack of dysentery. The report by William Thomas Councilman and Henri Lafleur, working at Johns Hopkins in 1891, represents a definitive statement about the pathologic processes of amebiasis, amebic dysentery, and ALA at the end of the nineteenth century. Schaudinn did differentiate between harmless Entamoeba coli and pathogenic E. histolytica . In 1901, Harris produced ALAs by intrarectal infection of puppies with E. histolytica cultivated E. histolytica in vitro, introducing the term amebiasis. In 1952, Hoare reported that E. histolytica had three phases. , Species of amebae found in human host— Entamoeba gingivalis, Entamoeba coli, Iodamoeba bütschlii, and Entamoeba hartmanni —were discovered between 1849 and 1919.
A plant alkaloid, concessine, was found to kill E. histolytica . The first effective treatment came from Brazil in the form of ipecac; emetine was isolated from ipecac in the nineteenth century. Leonard Rogers, professor of pathology at Medical College Hospital in Calcutta, India, reported successful treatment of both intestinal and hepatic amebiasis by injectable salts of emetine. The 1930s witnessed the introduction of two important hydroxyquinolines introduced by Anderson and Koch in 1931 and by a number of others. Although largely replaced by imidazoles in the 1980s, hydroxyquinolines remain useful today. In 1966, Powell et al. demonstrated the effectiveness of metronidazole as an amebicidal agent in both intestinal and extraintestinal amebiasis.
Epidemiology
Amebiasis occurs worldwide but predominantly seen in developing countries. Old textbooks often reported one tenth of the world population infected with E. histolytica, with 100,000 deaths per year due to invasive amebiasis. These estimates could be confounded as it dates before the separation of E. histolytica from the morphologically identical, nonpathogenic Entamoeba dispar and Entamoeba moshkovskii . E. dispar infection is ten times more common than infection with E. histolytica . Molecular techniques allow construction of more reliable map of endemic regions of E. histolytica amebiasis around the world, such as on the Asian subcontinent (India, Bangladesh), Africa, Asian Pacific (Thailand, Japan), and South and Central America (Mexico, Colombia). , Infection is common in these countries given poor sanitation and low socioeconomic status. Amebiasis, caused by E. histolytica, is second most common cause of parasite infection-related mortality worldwide and estimated to account for 40,000 to 74,000 deaths annually. More recent data show that amebiasis caused about 55,000 deaths in 2010, down from 68,000 in 1990 worldwide. ,
The exact burden of amebiasis in developing countries is difficult to quantify because of variations in study designs, sample sizes, and sensitivity of diagnostic tests used. Reported seroprevalence of E. histolytica in some rural communities of Mexico is as high as 42%. The annual incidence of amebic dysentery in children in Bangladesh is reported as 11%. In the large Global Enteric Multi-Center Study (GEMS) from various countries, E. histolytica has the highest hazard ratio for death in the second year of life. The annual incidence of ALA averaged 21 cases per 100,000 inhabitants in Hue City, Vietnam. Recent data from 115 cases of liver abscesses from tertiary care center in India showed 88% positivity for E. Histolytica with nested multiplex PCR test.
Infection is becoming more common in developed countries because of increased migration and travel from endemic countries. Although the incidence of amebiasis is low in United states, at least five deaths per year were reported as amebiasis related. In the United States and Europe, patients infected with the human immunodeficiency virus (HIV) have increased risk of amebiasis. Recent reports from other industrialized countries such as Japan, for example, have shown high rates of invasive amebiasis in HIV-infected persons.
Organism
E. histolytica is a protozoan with two forms: trophozoite and cyst. Cysts constitute the infective form through fecal-oral transmission by food, water, or direct person-to-person contact. Cysts survive the acid of the stomach and travel through the small intestine, and within the terminal ileum or colon, trophozoites emerge to complete the life cycle. Cysts can survive for 45 minutes in feces lodged under fingernails and for 1 month in soil at 10°C. They remain infective in fresh water, seawater, and sewage but are destroyed by drying, iodine, and heat. They are not killed by chlorination used to purify drinking water. The genus Entamoeba includes the pathogenic species E. histolytica and nonpathogenic E. hartmanni, E. coli, Entamoeba polecki (in swine), and E. moshkovskii (from sewage). There are four species of human intestinal amebae with identical morphologic characteristics: E. histolytica, E. dispar, E. moshkovskii, and Entamoeba bangladeshi . The study of zymodemes, patterns of the electrophoretic mobility of isoenzymes, genetic differences using RNA and DNA probes, and the use of polymerase chain reaction (PCR) amplification became more reliable in their identification. Encoding genes for transcription factors have been cloned for E. histolytica .
Host factors
The major reservoir for Entamoeba spp. is the human being. Breastfed neonates have a low incidence as a result of the presence of immunoglobin A (IgA) and low iron content in breast milk. A diet rich in iron and carbohydrates predisposes to invasive amebiasis and HLA-DR3 gene expression is an independent risk factor for ALA.
Although immunosuppression is considered an important risk factor for invasive amebiasis in Asian Pacific countries, others mention there is no particular susceptibility for developing invasive forms of amebiasis in immunosuppressed individuals. Nevertheless, some HIV infections have been detected during admission of patients with ALA. On the other hand, the natural history of the disease seems to be the same in immunocompetent patients.
Pathogenesis
The disease course is determined by three virulence factors: lectin (a surface protein), amebapores (small peptides), and cysteine proteases. The virulence of different strains of E histolytica is variable. Trophozoite adhesion to the colonic wall is mediated by lectin, which results in persistent infection, and caspase 3 activation, which is a crucial step in cell necrosis and abscess formation. Amebapores are inserted by the trophozoite into the host cell, where they puncture the lipid bilayer and form a portal of entry into the host. Amebapores result in colloid osmotic lysis of the cell. Cysteine proteases contribute to degradation of the extracellular matrix proteins and disruption of cell monolayers. Other amebic molecules such as lipophosphopeptidoglycan, peroxiredoxin, arginase, and lysine, and glutamic acid-rich proteins are also implicated in the pathogenesis of amoebiasis.
It is anticipated that antiamebic antibodies protective against invasive infection would block lectin binding and neutralize amebapore and cysteine proteases. It has been suggested that the proteophosphoglycans (PPGs) in the amebic glycocalyx may participate in E. histolytica pathogenicity because the closely related, nonpathogenic E. dispar lacks a significant glycocalyx surface layer. Furthermore, antibodies that bind to PPGs neutralize liver abscess formation. PPGs are anchored into the parasite cell membrane by a glycosylphosphatidylinositol (GPI) moiety. Synthesis of the GPI anchor requires a cascade of enzymes, including mannosyltransferase 1 (PIG-M1), whose blockage reduces GPI synthesis and PPGs in trophozoites. In addition, experimental evidence suggests that liver cell necrosis is increased when neutrophils are present along with E. histolytica .
Normal blood flow in the portal vein is about 1.4 L/min, pressure is 12 to 15 mm Hg, and erythrocyte velocity is 8 to 18 cm/sec. In comparison, sinusoidal blood flow is extremely low (3.4–0.16 mL/min), as is red blood cell velocity 0.1 mm/sec (see Chapter 5 ). Forces exerted on a parasite that adheres to the endothelium are thus much lower in the sinusoids and may partly explain why the parasite crosses the endothelium within these structures. Lack of tight junctions in liver sinusoidal endothelial cells can facilitate crossing by the parasite, creating a larger breach when reaching the hepatic parenchyma.
Publication of the E. histolytica genome facilitated transcriptome studies of the parasite. Microarrays have been used to compare virulent and avirulent trophozoites (those unable to form liver abscesses) from the same strain. Overexpression of peroxiredoxin and rubrerythrin genes in virulent parasites is of interest for ALA development because inflammatory cell recruitment and subsequent inflammation are features of liver infection by E. histolytica .
Molecular genetics
Molecular genetics has contributed to better understanding of amebiasis pathogenesis. The Institutes for Genomic Research have recognized that E. histolytica has a small, highly repetitive genome rich in adenosine-thymidine and densely packed sequences, but it lacks introns. Although some regions of the genome encode highly conserved proteins, other areas exhibit high degrees of polymorphism. Sequencing of the E. histolytica genome has revealed at least 44 genes. The purification of trophozoites from different organs of the same patients revealed that their tropism was linked to different genotypes.
Host defense
It has not been definitively established which mechanism is responsible for invasion or recurrence. The first line of defense is the innate immunity that recognizes pathogen-associated molecular patterns (PAMPs) that trigger an inflammatory response. Natural killer T cells activated by E. histolytica are important in the control of ALA. Interferon-γ (IFN-γ) initiates inflammation through macrophage production of tumor necrosis factor (TNF) and nitrous oxide (NO) synthesis by polymorphonuclear cells and macrophages. In vitro, the effects of IFN-γ can be bypassed by the recognition of PPGs of E. histolytica by Toll-like receptors (TLRs) 2 and 4, which results in direct production of TNF and interleukin (IL)-12 and IL-8. This shows the importance of early recognition of PPGs and inflammatory cell recruitment during ALA onset.
Complement cannot prevent invasion because it is absent from gut mucosal secretions, and amebic cysteine proteases degrade C3a and C5a. , Neutrophils fail in initial host defense. The second line of adaptive immune response constituted by activated lymphocytes and macrophages is the important effector mechanism against E. histolytica . E. histolytica infection elicits mucosal IgA and serum IgG response to lectin protein shown to be protective against infection in addition to epitope-specific antibodies that inhibit adherence to target cells. , The galactose/ N -acetyl-d-galactosamine–binding (Gal/GalNAc) lectin isolates from three distinct areas of the world—Bangladesh, Republic of Georgia, and Mexico—retains remarkable sequence conservation, and is recognized as a potential vaccine target. , Serum IgG response to the lectin protein does not provide protection against infection.
Pathology
The development of ALAs is a serious complication of infection by E. histolytica and is the most common extraintestinal form of invasive amoebiasis. Trophozoites that successfully penetrate the colonic mucosal barrier cause invasive disease, enter the portal system, and travel to the liver. Amebic colitis and ALA rarely occur simultaneously, and the colonic lesions are usually silent; direct extension to the liver and lymphatic spread do not occur. The cecum is the most common site of amebic colitis, and the right lobe of the liver is more commonly affected because of drainage of the right portal branch from the right side of the colon. The condition usually starts as diffuse amebic hepatitis; liver cells undergo liquefactive necrosis, starting in the center and spreading peripherally to produce a cavity full of blood ( Fig. 71.1 ) and liquefied liver tissue resembling anchovy sauce; it has no odor and is sterile. The fluid itself is free from any amebae, which may be found at the expanding edge of the abscess cavity with little inflammation. Amebae are known to lyse neutrophils, and the release of neutrophilic mediators may promote hepatocyte death and extension of the abscess. Secondary bacterial infection may occur spontaneously, altering the color, odor, and consistency of the pus. Lack of fibrotic response by the surrounding tissue with centrifugal extension results in extension of the abscess to the Glisson capsule, which is resistant to the amebae. Typically, ALAs are solitary, large, and located in the right liver. Left lobe abscesses are less common, but because of the smaller volume of the left liver, abscesses in this location are more prone to rupture the capsule. Vascular and biliary structures may traverse the abscess cavity; because of the intrahepatic covering of the Glisson capsule, such structures are resistant to the process of liquefactive necrosis. However, these structures can be mistaken for septa within the abscess cavity and fracturing of these strands can lead to hemorrhage or biliary leak, or it can create a communication between the vascular and biliary channels and result in hemobilia and jaundice. The abscess wall is typically ill defined with a minimal host response of fibrous tissue, but long-standing abscesses may develop a fibrous wall and may even calcify. In treated cases, complete resolution is the rule, but it may take 6 months to 2 years or longer than the usual time for pyogenic abscesses to resolve. ,
Clinical presentation
Most E. histolytica infections are asymptomatic or present as mild, “noninvasive” disease. Asymptomatic carriers, or cyst passers, may excrete cysts for a short period, but the majority of these patients clear the infection within 12 months. Patients with confirmed E. histolytica infection, even if they are asymptomatic, should be treated to eliminate the organism and prevent further transmission. The time between penetration of colonic mucosa and damage to hepatic parenchyma is unknown. Active diarrhea usually occurs in less than 30% of patients at any time before presentation despite intestinal infection by E. histolytica. Symptomatic amebic colitis presents as diarrhea with blood and mucus in stools and the presence of hematophagous trophozoites (trophozoites with ingested red blood cells) in stools or tissues. However, in most cases of ALAs, standard stool microscopy results are negative, but in research studies, cultures of stool were positive for E. histolytica in more than 75% of patients with ALA. Although E. dispar is considered to be nonpathogenic, there have been reports of ALA and diarrhea. , Similarly, nonpathogenic E. moshkovskii has been associated with diarrhea. The pathogenicity of E. bangladeshi needs further investigation.
The peak incidence of ALA is between 20 and 60 years of age; thus it is predominantly a disease of young men. ALA is 10 times more common in adults than in children and is 3 to 10 times more common in males. , Children (especially neonates), pregnant women, and women in the postpartum period have an increased risk of severe disease and death. Treatment with steroids, malignancy, malnutrition, alcoholism, men having sex with men, advanced age, and malnutrition could be considered risk factors for severe disease.
Concomitant hepatic abscess is found in only one third of patients with amebic colitis. The duration of symptoms is usually 10 days. In nonendemic regions, such as Western Europe and the United States, patients usually report travel to an endemic area in the previous 2 to 5 months (median, 3 months), although a prolonged latency may occur. , Patients with ALA start reporting nonspecific symptoms such as anorexia, nausea, vomiting, and acute colitic illness. Abdominal pain and fever are the cardinal symptoms of the disease, seen in 90% of patients or more. Other signs and symptoms vary according to the site and the size of the abscess. The chief symptom is typically the abrupt onset of right upper quadrant pain radiating to the right shoulder and scapular area. The pain increases with coughing, deep breathing, and walking. If the abscess is in the left liver, the pain may be epigastric, precordial, or retrosternal and may radiate to the left shoulder. Abscesses located on the inferior aspect of the liver may manifest in a manner similar to peritonitis resulting from any upper abdominal cause. On occasion, the presentation is insidious, lasting 2 or more weeks; in such patients, significant weight loss may occur. One report has suggested that ALAs can be silent and asymptomatic.
Abdominal examination usually reveals a tender, soft hepatomegaly accompanied by overlying muscle guarding and intercostal tenderness. Jaundice is often seen, although it was previously reported to be a prominent feature in only 5% to 8% of patients ; biliary communication of ALA had been reported in up to 27%. , Because the right posterior-superior surface of the liver is the most common site of ALA, it is always accompanied by right basal lung signs as a result of pleural effusion, empyema, or lung abscess. On the other hand, left liver abscess may be complicated by pericardial friction, and abscesses in this location can extend into the pericardium, a sign associated with a very high mortality rate. Hepatic failure, ascites, and splenomegaly may occur in 15% of patients who have multiple abscesses. Hepatic encephalopathy in patients with ALA may result from a combination of right hepatic vein occlusion, pylephlebitis, and occlusion of several portal vein radicles. Clinically, the usual differential diagnosis includes acute cholecystitis, hepatitis resulting from viral or other causes, and pyogenic liver abscess. With atypical presentation, hepatocellular carcinoma, a hepatic hydatid cyst, or a simple cyst may be considered. Approximately three quarters of patients with an ALA have leukocytosis. Eosinophilia is rare, but mild anemia may occur in half of patients and is multifactorial. Hyperbilirubinemia is present in only a small proportion of cases.
In chronic liver abscess, the alkaline phosphatase level tends to be elevated, and the AST level tends to be within normal limits. Chest radiography typically shows elevation of the right dome of the diaphragm with an anterior bulge on the lateral view, atelectasis of the right lung, and pleural effusion. Amebic lung abscess with concurrent lung cancer, but without either a liver abscess or amebic colitis, although extremely uncommon, has been recently reported. ,
Diagnosis
Diagnostic tests for intestinal amebiasis and also used as community screening procedure include (1) microscopic examination of unfixed fecal samples, (2) the Ritchie method of fecal concentration, (3) staining of alcohol-fixed stools, (4) Robinson in vitro culture, (5) stool antigens, (6) serology (indirect hemoagglutination test [IHAT], enzyme-linked immunosorbent assay [ELISA], and immunofluorescence test), (7) isoenzyme electrophoresis of stool for zymodeme identification, and (8) PCR.
Stool microscopy is still by far the most commonly used method for diagnosis of intestinal amebiasis around the world. It can distinguish the E. histolytica cyst (four nuclei, centrally located endosome, and round chromatoidal body) from cysts of other nonpathogenic protozoa but not from cysts of commensals E. dispar and E. moshkovski . Direct microscopic examination is less sensitive than Robinson culture and zymodeme identification, the gold standards.
Stool antigen tests can overcome some of the limitations of microscopy but be reported with variable sensitivity and specificity in low-endemic regions. Benefits of stool antigen tests are rapid, differentiating of pathogenic strains and diagnosis of early infection in endemic areas where serology is less useful.
DNA-based PCR is rapid and sensitive to detect cysts in the stool (<5) and in fluids aspirated from ALA. In 2007, Helmy used nested PCR and restriction enzyme digestion (RED) to distinguish E. histolytica from E. dispar . Currently, a number of PCR assays, such as conventional PCR, nested PCR, real-time PCR (RT-PCR), multiplex PCR, and loop-mediated isothermal amplification assay, are commercially available. These PCR tests are extremely sensitive and considered the gold standard for diagnosis but still largely underused because of cost and requirement for technical expertise.
Serologic tests are very useful when E. histolytica is present in extraintestinal sites. Amebic serology is highly sensitive and specific in the differentiation between pyogenic and amebic hepatic abscess. Currently, ELISA for detection of the galactose-inhibitable adherence protein in serum and feces and IHAT appear to be the most reliable tests, with sensitivity and specificity greater than 95%, with a reversal rate of 82% after 1 week of treatment with metronidazole. , Serology detects antibodies specific for E. histolytica in approximately 70% with active intestinal infection and 10% who are asymptomatic cyst passers. Serologic results becomes positive after 2 weeks of initial infection. Antibody titers peak by the second and third months, decrease to lower levels by 9 months, and revert to negative by 12 months. Because antibodies persists over years, positive serologic findings may not necessary means active infection.
Imaging
Ultrasonography (US) for diagnosis of ALA has an accuracy of 90% (see Chapter 14 ). It will show an abscess located in contact with the liver capsule (see Fig. 71.1 ) as round or oval, with well-defined margins; they are hypoechoic and clearly defined from normal liver parenchyma with distal enhancement ( Figs. 71.2–71.4 ). In 80% of patients, the abscess is single in the right lobe and in 10% in the left lobe; 6% in the caudate lobe are single, and the remaining are multiple abscesses. In early stages, amebic abscess appears as a subtle area of decreased echogenicity, and US diagnosis is not pathognomonic; complicated cysts, hematomas, metastases, and amebic abscesses may mimic each other. Only 40% of patients have typical US features of ALA. The mean resolution time for ALA is 7 months, and complete resolution may take up to 2 years. On occasion, percutaneous diagnostic aspiration may be needed to differentiate amebic from pyogenic liver abscess. Although pyogenic liver abscesses tend to resolve earlier (within 2–4 months), ALAs acquire a more echogenic and fibrous wall in 8 to 16 weeks and begin to resemble, but must be differentiated from an encapsulated tumor. With time, resolution may be complete, or the result may be a residual cystic cavity that resembles a simple cyst of the liver.
Computed tomography (CT) does not add to the diagnostic accuracy of US in acute stages, except in evaluation of imminent rupture of an abscess or for detection of small lesions (see Chapter 14 ). ALAs usually appear on CT with contrast as rounded, well-defined lesions with complex fluid. The most characteristic finding is an enhancing wall with a peripheral zone of edema around the abscess ( Fig. 71.5 ). The abscess cavity may show multiple septa (more with pyogenic abscesses), fluid and debris levels, air bubbles, or hemorrhage. CT may detect extension of ALAs to other organs.
Magnetic resonance imaging (MRI) (see Chapter 14 ) is not superior to CT in the diagnosis of ALA, but it may be useful in differentiating it from a hepatic neoplasm. ALAs appear as heterogeneous cavities that are hypointense on T1-weighted images and hyperintense on T2-weighted images. The abscess margin may show incomplete hyperintense rings with perilesional edema on T2-weighted images. After treatment, the abscess cavity becomes homogeneous, and complete concentric rings appear as a result of periabscess fibrosis and hemosiderin deposits.
Liver scan with gallium citrate and technetium-labeled sulfur colloid radionuclide show ALAs as “cold” spots, whereas pyogenic lesions are seen as “hot” spots. This method is largely limited in diagnosis because of the availability of better imaging modalities.
Role of aspiration
US- or CT-guided aspiration ( Fig. 71.6 ) is often justified on the basis that the diagnosis would be “more certain,” or that the abscess can be “aspirated to dryness” at the time of therapeutic aspiration. PCR may detect E. histolytica DNA in ALA pus as well as in the saliva of patients. , No randomized controlled trial has shown that aspiration is beneficial in survival, length of hospitalization, or time to become afebrile compared with treatment with antiamebic drugs alone, and aspiration may only confuse the diagnosis by revealing atypical pus or blood. , Clinical improvement invariably occurs with antiamebic therapy alone in uncomplicated cases. When the differential diagnosis in a given case includes operable neoplasm or hydatid disease, aspiration is risky and may be contraindicated.
Therapeutic aspiration should be reserved for the following situations:
- 1.
Serology is inconclusive and differential diagnosis is pyogenic liver abscess.
- 2.
A therapeutic trial with antiamebic drugs is deemed inappropriate, as in pregnancy.
- 3.
The liver abscess is secondarily infected (15% of cases) (see Chapter 72 ).
- 4.
Rupture is imminent in an extremely large abscess (>10 cm), especially if pericardial rupture from a left lobe abscess appears likely.
The following factors predict the need for aspiration: (1) age 55 years or older, (2) an abscess 5 cm or more in diameter, and (3) failure of medical therapy after 7 days. In endemic areas, because of late presentation and existence of multiple abscesses, up to 50% of patients may require aspiration. A single aspiration may be sufficient for diagnostic purposes, but it is inaccurate to recommend it because the characteristic “anchovy paste” characteristic of amebic abscess may not be found; when performed as part of therapy, it will likely be inadequate. Percutaneous catheter drainage is better than percutaneous needle aspiration for management of large liver abscesses (>10 cm) in terms of duration to attain clinical relief and duration for which parenteral antibiotics are needed.
Complications
The most common complications of ALA arise from rupture of the abscess into surrounding organs or anatomic spaces. Communication occurs into the peritoneum, viscera, and large vessels on one side of the diaphragm and the pleura, bronchi, lungs, and pericardium on the other.
Peritoneal and visceral involvement
Peritonitis with amebiasis is due to rupture of an ALA in 78% of patients and perforated or necrotizing amebic colitis in the other 22%. , Spontaneous rupture of ALA may occur in 2.7% to 17% of cases. , Adherence of the liver abscess to the diaphragm, abdominal wall, omentum, or bowel tends to confine contamination and lead to rupture into hollow viscera, such as the stomach or colon. Rare complications of amebic colitis include appendicitis, perianal cutaneous amebiasis, and rectovaginal fistulae. ,
A hepatogastric, hepatoduodenal, or hepatocolonic fistula and acute hepatic failure may occur from ruptured ALA. Free rupture into the peritoneal cavity is uncommon and usually occurs only in a nutritionally depleted patient. Bloody diarrhea may occur in colonic rupture, and hematemesis may occur in cases of hepatogastric fistula. US and CT often show a perihepatic fluid collection in cases of ALA that are reactive or with actual leaks from the abscess cavity. Management of abscesses that extended into the peritoneal cavity with aggressive surgical approaches were associated with increased mortality rates and have now been replaced by increasingly successful attempts at percutaneous drainage of the liver abscess and the extravasated pus. , , ,
Absolute indications for laparotomy include a doubtful diagnosis; concomitant hollow viscus perforation with fistulization, resulting in life-threatening hemorrhage or sepsis; and failure of conservative management. At laparotomy, the liver abscess, which usually appears as a tan-colored bulge on the surface, must be handled gently. Septa running across the cavity are usually blood vessels and bile ducts traversing the abscess cavity. Hemorrhage can be difficult to control, and postoperative bile leaks may result. Endoscopic stenting or nasobiliary drainage may be required in cases of biliary communication. Irrigation of the abscess cavity with saline is usually sufficient and may be followed by the installation for 3 to 5 minutes of a solution of 65 mg of emetine hydrochloride in 100 mL of normal saline. Tube drains are inserted and retained as necessary. Hollow viscus perforations must be dealt with on an individual basis, with exteriorization, proximal diversion, or serosal patch closure. Postoperative intravenous metronidazole is combined with broad-spectrum antibiotics, and dehydroemetine is added if no cardiac contraindication exists. The mortality rate of viscus perforation ranges from 12% to 50%.
Thoracic and pleuropulmonary involvement
Pulmonary complications occur in 7% to 20% of patients with ALA. A sympathetic right-sided effusion is the most common pulmonary complication and usually does not require treatment itself. Other thoracic complications include rupture of the abscess into the pleural cavity or into the bronchial tree. This condition manifests as dyspnea and dry cough with right basal crepitations and collapse of the right lung in addition to the abdominal signs. A pleural rub may also be found. Sudden onset of coughing with expectoration of copious quantities of chocolate-colored sputum occurs if the abscess ruptures into bronchi. , There are several routes of pulmonary infection, including direct hematogenous and inhalational amebiasis. Thoracocentesis is the main line of treatment. In case of aspiration and intercostal tube drainage, care is taken to go high on the right lateral side of the chest near the axilla. Ineffective early drainage of the amebic empyema is usually complicated by secondary infection that requires aggressive surgical procedures, such as pulmonary decortication, because the fibrous tissue can be dense enough to complicate thoracoscopic surgical techniques.
Lung abscess rarely occurs, and it is walled off from the pleural and peritoneal cavities; surgical intervention is not required because postural drainage, bronchodilators, and antiamebic drugs may suffice. Metronidazole is effective, but emetine produces a rapid response and may be required in cases of metronidazole resistance.
Vascular and pericardial involvement
Some cases of vascular complications have been reported, such as Budd-Chiari syndrome and right atrial and inferior vena cava thrombosis, complicating multiple large ALAs. Surgical removal of the thrombus may be required.
Abscess rupture into pericardium is rare but serious, occurring in 1.3% to 2% of patients, with mortality rates from 30% to 60%. Abscesses of the left lobe of the liver or those more centrally located are more prone to pericardial complications that range from asymptomatic pericardial effusion to cardiac tamponade. Although left lobe abscesses resolve equally well with antiamebic drugs, as do right-sided abscesses, the detection of pericardial thickening or pericardial effusion may constitute an indication for aspiration of a left-sided ALA. , In cardiac tamponade, pericardiocentesis must be performed, along with drainage of the liver abscess followed by antiamebic drugs, namely metronidazole. Dehydroemetine is used with caution because of its cardiotoxicity.
Chemotherapy
Metronidazole
Metronidazole is the drug of choice for invasive colitis and ALA. The oral dose of metronidazole is 500 to 750 mg three times daily for 7 to 10 days in adults and 35 to 50 mg/kg in three divided doses for 10 days in children, with a cure rate of more than 90%.
Hepatopulmonary amebiasis was found to respond equally to doses of 400 and 800 mg three times daily given over 5 days. The intravenous route is also highly effective at a recommended dose of 500 mg every 6 hours. Metronidazole reaches high concentrations in the liver and intestine and crosses the placenta and the blood–brain barrier. Its use is contraindicated in the first trimester of pregnancy and must be used cautiously in the second and third trimesters; breastfeeding should be discontinued during its use. The response of patients with ALA to metronidazole is profound, with improvement in symptoms within 72 to 96 hours. However, a luminal agent such as paromomycin (30 mg/kg three times daily for 5–7 days), iodoquinol (650 mg orally three times daily for 20 days), or diloxanide furoate (500 mg orally three times daily for 10 days) should also be used to eradicate intestinal colonization.
Over 5 days, an 85% cure rate is achieved, which may increase to 95% after 10 days. From 5% to 15% of patients with ALA may be resistant to metronidazole, but this may not be a major clinical problem ; most reports of “drug resistance” reflect delayed resolution of either clinical symptoms or US findings and not a true resistance documented by drug failure. Experimental resistance may be related to inducing superoxide dismutase in vitro. Alternative to medical therapy, percutaneous aspiration, or surgical intervention usually must be considered in patients who do not respond. In countries where they are available, tinidazole, ornidazole, and nitazoxanide are alternative agents for the treatment of ALA; these drugs are administered for only a few days. One study of a single 2-g dose of either tinidazole or ornidazole gave a success rate of 94% in both treatment arms. Other studies have shown a success rate of almost 100% for patients treated with tinidazole for 2 to 3 days. Secnidazole has a longer half-life, and a single daily dose of 2 g for 5 days is effective. Satranidazole showed lower incidence of side effects and better tolerance than metronidazole in a randomized, single-blind trial of 49 patients with ALA.
Other medications
Emetine hydrochloride is effective against trophozoites and reaches amebicidal concentrations in tissues rather than intestine. Emetine is administered by intramuscular or deep subcutaneous injection in a dose of 1 mg/kg/day (maximum, 60 mg/day) for 10 days. The patient must be placed on complete bed rest. Tissue levels persist for 40 to 60 days, and re-administration should be avoided for 6 weeks. Side effects include myositis at the injection site, hypotension, tachycardia, chest pain, dyspnea, and abnormalities on electrocardiogram, including T-wave inversion and prolonged Q-T interval. The drug is contraindicated in renal, cardiac, and muscular disease and is used cautiously in children and elderly patients. Emetine or dehydroemetine is valuable in treatment of hepatopulmonary amebiasis. , ,
Chloroquine phosphate is antimalarial and is effective in patients with resistance to emetine and pulmonary amebiasis but has no luminal amebicidal activity. Chloroquine is administered orally in a dose of 1 g (600 mg base) per day for 2 days, followed by 500 mg (300 mg base) per day for 2 to 3 weeks. It is contraindicated in patients with retinopathy, but it has been used in pregnant patients. Diloxanide is ineffective in invasive amebiasis and is used for treatment of asymptomatic carriers. Nitazoxanide has shown efficacy in amebic dysentery. The recommended dose is 500 mg three times daily for 10 days. No serious side effects are reported. Further studies are warranted in hepatic amebiasis. Trifluoromethionine is a lead compound, but a single subcutaneous or oral dose prevented the formation of ALA in a rodent model.
Therapeutic strategy
Oral metronidazole is administered as a single drug, with concomitant correction of hypoprothrombinemia, hypoproteinemia, and anemia. If dramatic improvement occurs in 48 to 72 hours, only a complete course of metronidazole treatment is required. A luminal agent, such as diloxanide furoate (500 mg three times daily for 10 days) or paromomycin (30 mg/kg/day in three doses for 10 days), must be administered after metronidazole therapy for eradication of intestinal infection as part of a complete treatment regimen.
In patients who do not respond satisfactorily, emetine or dehydroemetine is added. Evidence of pulmonary, peritoneal, or pericardial extension is an indication for aspiration of the liver abscess with an intercostal tube or catheter drainage. Percutaneous catheter drainage is usually recommended for abscesses larger than 10 cm in diameter and for left lobe liver abscess, failure of medical treatment for 7 days, and failure to differentiate the abscess from a pyogenic abscess. The following are predictive of the need for aspiration: (1) age older than 55 years, (2) abscess greater than 10 cm in diameter, and (3) failure of medical therapy after 7 days. Late presentation with the existence of multiple abscesses may require aspiration, but prompt medical care decreases the need. Laparotomy is usually reserved for patients with suspected peritonitis, fistulization, or secondary infection with sepsis after failure of above measures.
A review of literature reported a mortality rate for patients with ALA of 4%. In patients treated with amebicidal drugs alone, the mortality rate was less than 1%. Independent risk factors for death include serum bilirubin greater than 3.5 mg/dL; encephalopathy; hypoalbuminemia, defined as less than 2 mg/dL; and multiple abscess cavities or total abscess volume greater than 500 mL. , Rupture into the peritoneal cavity and the pericardium is responsible for most deaths. Patients treated with early and aggressive surgery as advocated by some authors did not show a remarkable improvement in mortality rate, although in the series by Balasegaram, the hospital stay was probably reduced. , Ruptured ALA occurs in 2% to 17% of patients, with reported mortality rate of 6% to 50%. These patients usually constitute a major risk for surgery and anesthesia.
Prevention
In addition to regular sanitary measures that include proper washing of vegetables and fruits as well as drinking only bottled water in endemic areas, modern biologic techniques have helped characterize amebic antigens that show great promise in the development of a vaccine. No prophylactic vaccine is currently available for amebiasis, but efforts to better define antigenic candidates and wider use of animal models are encouraging. A codon-optimized DNA vaccine has been tested in a murine model and was found to be useful in stimulating type 1 cellular immune response and serum antibodies. Gal-lectin based vaccinations have conferred some protection in various animal models. Other examples, a serine-rich E. histolytica protein has been expressed in avirulent vaccine strains of Salmonella. A synthetic, enhanced, intranasal lectin-based amebiasis subunit has been extensively studied as attractive candidates for vaccine development. In addition, galactosamine-inhibitable lectin shows promise in animal studies.
Cell-mediated immunity may be sufficient for vaccine protection from intestinal amebiasis with significant IFN-γ, IL-2, IL-12, IL-10, and IL-17 production with recombinant vaccines. Gram-negative bacteria expressing E. histolytica antigens may constitute a suitable oral vaccine carrier against invasive ameobiasis. Thus various amebic proteins associated with virulence have been studied as potential vaccine targets and development of both parental and oral vaccine for human is in progress.
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