Amebiasis
Amebiasis is defined as
infection with Entamoeba histolytica, regardless of associated symptomatology.
In resource-rich nations, this parasitic protozoan is seen primarily in
travelers to and emigrants from endemic areas. Infections range from asymptomatic
colonization to amebic colitis and life-threatening abscesses. Importantly,
disease may occur months to years after exposure. Although E histolytica was
previously thought to infect 10% of the world's population, two morphologically
identical but genetically distinct and apparently nonpathogenic Entamoeba
species are now recognized as causing most asymptomatic cases. To avoid
unnecessary and harmful therapies, clinicians should follow the diagnostic and
treatment guidelines of the World Health Organization.
Advances in molecular technologies have
revolutionized our understanding of this organism.3 Most notably, two
additional Entamoeba species that are morphologically indistinguishable from E
histolytica have been recognized in humans. As our knowledge of the global
epidemiology and pathogenicity of Entamoeba increases, new clinical algorithms
are developed. The latest nomenclature
and recommendations, although unfamiliar and confusing to many, are important
for appropriate patient care. Our review discusses what is known about these
Entamoeba and clarifies the currently accepted recommendations for diagnosis
and treatment.
THE “NEW” ENTAMOEBA SPECIES:
ENTAMOEBA DISPAR AND ENTAMOEBA MOSHKOVSKII
It is a long-held
misconception that 10% of the world's population is infected with E
histolytica. In fact, most of these infections should be attributed to the
morphologically identical but nonpathogenic E dispar. Emile Brumpt first
proposed the existence of two indistinguishable Entamoeba, one pathogenic and
one nonpathogenic, in 1925. However, not until 1978 was evidence for the
existence of two separate entities provided by new technology (isoenzyme
analysis). More recent studies using methodologies capable of distinguishing
the two species suggest that E dispar is up to ten times more prevalent in
asymptomatic patients than E histolytica in endemic regions. Little is currently known about their
epidemiology in resource-rich nations, where the incidence of both is rare, but
previous reports of infection with E histolytica based only on morphology represent
E dispar.
The discovery of a third
morphologically identical Entamoeba further complicated our understanding of
the epidemiology of E histolytica. The new species, named E moshkovskii, was
first recognized as a ubiquitous free-living organism in 1941; it has been
reported in humans from both resource-rich and resource-poor nations. Although largely nonpathogenic, some recent
evidence suggests that it may have a role in human intestinal disease. Much
remains unknown regarding the pathogenicity and epidemiology of E moshkovskii.
THE DEFINITIVE PATHOGEN: E
HISTOLYTICA
E histolytica is the
pathogenic species responsible for amebic colitis throughout the world. It
infects people of both sexes and all ages; however, populations at risk may
vary with geographic location, host susceptibility, and differences in organism
virulence. People in highly endemic areas probably have recurrent asymptomatic
infections, thus accounting for the high reported prevalence. In developed countries, amebic colitis is most
found in travelers to or emigrants from endemic countries, institutionalized
persons, and patients infected with human immunodeficiency virus. Men who have
sex with men were previously thought to have an increased incidence of
infection, but this supposition was based on morphologic studies. New evidence
suggests that these men were colonized primarily with E dispar rather than E
histolytica.
The simple life cycle of E
histolytica begins when infectious cysts are ingested in fecally contaminated
food or water.21 This association with poor sanitation explains why resource-poor
nations carry the bulk of the world's disease. After ingestion and passage
through the stomach, the organism excysts and emerges in the large intestine as
an active trophozoite. Trophozoites multiply by simple division and encyst as
they move further down the large bowel. Cysts are then expelled with the feces
and may remain viable in a moist environment for weeks to months. Amebae typically subsist on a diet of
intestinal bacteria and partially digested host food but are capable of tissue
invasion and dissemination. Most infections (≥90%) remain asymptomatic,
suggesting that tissue invasion is an aberration rather than a typical
behavior.
Invasive intestinal disease
may occur days to years after initial infection and is characterized
classically by abdominal pain and bloody diarrhea. Watery or mucus-containing diarrhea,
constipation, and tenesmus may also occur. This clinical picture corresponds
histologically with trophozoites invading and laterally undermining the
intestinal surface to form the so-called flask-shaped ulcers (Figure 1). The
right side of the colon is commonly involved.4 Severe cases of amebic colitis
are characterized by copious bloody diarrhea, diffuse abdominal pain, and
(rarely) fever. Extensive fulminant necrotizing colitis, the most severe form
of intestinal disease, is often fatal. Patients at increased risk of severe disease
include those who are very young, very old, malnourished, or pregnant and those
who are receiving corticosteroids. Some evidence suggests that patients infected
with human immunodeficiency virus are at increased risk of severe disease, but
this is not universally accepted. Complications of intestinal disease include
stricture, rectovaginal fistulas, formation of an annularintraluminal mass
(ameboma), bowel obstruction, perianal skin ulceration, toxic megacolon,
perforation, peritonitis, shock, and death. Chronic intestinal amebiasis is also well
described; patients with this condition can have years of intermittent
abdominal pain, diarrhea, and weight loss.
FIGURE 1“Flask-shaped” ulcer
of invasive intestinal amebiasis (hematoxylin-eosin, original magnification
×50). Note that the apex of the ulcer at the bowel lumen is narrower than the
base, accounting for the flask shape. This is formed as trophozoites invade
through the mucosa and move laterally into the submucosa (direction of ulcer
expansion is marked by arrows). Microscopically, trophozoites are localized to
the advancing edges of the submucosal ulcer. Image courtesy of John Williams,
CBiol, MIBiol, London School of Hygiene and Tropical Medicine.
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On rare occasions, E
histolytica trophozoites enter the bloodstream and disseminate to other body
sites, most commonly the liver via spread from the intestine through the portal
vein. The right lobe is 4 times more likely to be involved than the left
because it receives the bulk of the venous drainage from the right colon. Adult men aged 20 to 40 years are most
frequently affected, although people of both sexes and all ages may develop an
amebic liver abscess (ALA). Disease can occur years after exposure and may
follow the onset of immunosuppression.
Hepatic invasion by amebic
trophozoites results in marked tissue destruction with neutrophil recruitment,
cellular necrosis, and formation of microabscesses that gradually coalesce. Most patients (65%-75%) present with a single
abscess; however, multiple abscesses may also be formed. Abscesses consist of soft, necrotic, acellular
yellow-brown debris, described as “anchovy paste.” Amebae are seldom identified
in aspirates because they are located at the periphery of the lesion.18 White
blood cells are also not usually seen, presumably because they have been
destroyed by the amebic trophozoites.
Clinical presentation of ALA
is highly variable and commonly includes tender hepatomegaly and pain in the
right upper quadrant.18 Unlike amebic colitis, ALA is commonly accompanied by
fever,three as well as by rigors, chills, and profuse sweating.18 Most patients
do not have concurrent colitis and cysts, and trophozoites are not always seen
on fecal smears,3 posing an important diagnostic challenge. Jaundice is not
typically present; elevated bilirubin levels are seen in less than 50% of
patients, but elevated alkaline phosphatase levels are common. Complications include secondary bacterial
infection; perforation into peritoneal, pleural, and pericardial cavities;
septic shock; and death.4, 18
The most serious
complication is amebic metastasis from the liver. Rarely, trophozoites end up
in other regions of the body, such as the brain, spleen, lungs, and
genitourinary tract, through hematogenous or direct spread. Brain abscesses are
extremely rare and are associated with high mortality rates. Like patients with
ALA, those with disseminated disease do not usually have concomitant amebic
colitis. Disseminated disease is not an
adaptive mechanism for the parasite because its life cycle cannot be completed
outside the intestine.
RADIOLOGIC AND ENDOSCOPIC
FEATURES OF INTESTINAL AND EXTRAINTESTINAL DISEASE
When amebiasis is suspected,
radiologic and endoscopic examination may lend further support for a diagnosis.
Colonoscopy can provide a wide spectrum of findings, from rare large-bowel
ulcers in mild disease to diffuse mucosal ulceration, hemorrhage, colonic
stricture, and presence of an ameboma. Grossly, these findings may resemble
those seen with inflammatory bowel disease; therefore, correlation with
histopathology and laboratory results is essential. Endoscopy is contraindicated in patients with
evidence of peritonitis, severe dehydration, or shock.
Radiologic studies may also
be helpful in evaluating a patient with possible ALA. Chest and abdominal
radiography often reveal a pleural effusion and raised hemi-diaphragm overlying
the involved liver lobe.18 Ultrasonography reveals lesions that are typically
hypoechoic and well defined with rounded edges. Computed tomography and
magnetic resonance imaging can further characterize an abscess and allow for
better detection of smaller lesions. All three techniques may facilitate guided
needle biopsy and drainage if indicated. An abscess can usually be
distinguished from solid lesions and biliary tract disease, but the
differentiation between bacterial and amebic abscesses is less clear. Gallium
scans may have a role in this differential diagnosis because amebic abscesses
are usually “cold” on scan because of the lack of white blood cells in the
abscess, whereas bacterial abscesses are typically “hot.”
DEFINITIVE DIAGNOSIS OF E
HISTOLYTICA, E DISPAR, AND E MOSHKOVSKII INFECTIONS
Clinically, it is desirable
to definitively distinguish E histolytica from E dispar and E moshkovskii
because, of the three, it is the only proven human pathogen. The diagnosis of invasive amebiasis is usually
suggested by the patient's presenting symptoms, exposure history, and
radiologic findings but should be confirmed with microbiological laboratory
results. Many laboratory methods exist for identification of E histolytica, E
dispar, and/or E moshkovskii, and the clinician should be aware that tests vary
considerably in price, sensitivity, specificity, and the ability to
definitively differentiate among the three species.
Light microscopic
examination of fecal specimens (i.e., “ova and parasite” examination) is often
the first step in diagnosis3; the characteristic trophozoites and cysts can
often be identified through direct, concentrated, and/or permanently stained
smears Because organisms may appear intermittently,
current recommendations call for submission of 3 stool specimens on different
days during a period of 10 days.3 As mentioned previously, stool specimens from
patients with disseminated disease may not contain cysts and trophozoites,
despite repeated examinations.
FIGURE 2Classic cyst
morphology of Entamoeba histolytica/disbar/moshkovskii (iron hematoxylin stain
of fecal sample, original magnification ×1000). Cysts range from 10 to 16 μm in
diameter (mean, 12.5 am) and contain up to four nuclei, each with a central
irregular dot and peripheral rim of chromatin. As seen above, all 4 nuclei are
rarely visible in the same plane of focus. Chromatoid bodies (crystallized
ribosomes) are also commonly seen (dark staining mass; arrow). Although this morphology
allows for identification of these three organisms, exact speciation requires
further testing. Image courtesy of Professor John Williams, London School of
Hygiene and Tropical Medicine.
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If stool cannot be examined
in the fresh state (within 15 minutes) for motile trophozoites, then it should
be placed immediately in an appropriate fixative to prevent deterioration of
organisms. Unfortunately, microscopy alone cannot
differentiate E histolytica from E dispar and E moshkovskii; additional tests
are required for definitive speciation. The rare exception is when trophozoites
containing ingested red blood cells are identified; they are strongly (but not
definitively) indicative of invasive amebiasis. Trophozoites may also be
identified in intestinal biopsy specimens, scrapings, or aspirates, allowing a
diagnosis of amebiasis to be made if mucosal invasion and ulceration are also
observed.
When only examination of
stool specimens is available, the WHO/PAHO recommends that morphologically
consistent cysts and trophozoites receive the nonspecific diagnosis E
histolytica/E dispar,one which could now be augmented to include E moshkovskii.
The clinician must then interpret this laboratory result in the context of the
individual patient and determine whether treatment is warranted.
When possible, E histolytica
should be definitively identified. Identification methods include biopsy,
serology, antigen detection, and molecular assays. Culture may be performed by
some large specialty laboratories but is technically challenging and
time-consuming. Furthermore, a negative culture result from intestinal samples
does not exclude E histolytica1 because sensitivity is less than 100%. Culture
followed by isoenzyme analysis is the criterion standard in diagnosis; however,
it will be replaced by molecular assays in the near future.
Serologic
tests detect the presence of species-specific antibodies in the patient's
serum. They are particularly useful in nonendemic countries where prevalence is
low and have a good sensitivity and specificity for detecting invasive
intestinal disease. They are also the test of choice for ALA because titers are
typically high and test sensitivities and specificities exceed 95% with most
assays. The primary disadvantage of
serologic tests is that they cannot distinguish between past and current
infection unless IgM is detected; IgM antibodies to E histolytica are
short-lived and rarely detected. In contrast, IgG antibodies are long-lived but
highly prevalent in endemic settings because of past exposure. Serologic
assays, which are also less sensitive in asymptomatic infection, take 7 to 10
days to appear in the bloodstream, resulting in possible false-negative
results. Enzyme-linked immunosorbent assay is the most popular test in the
diagnostic setting because of its speed and ease of use.
Fecal antigen detection
tests use specific monoclonal or polyclonal antibodies to detect E histolytica
antigens. They are rapid, overly sensitive, and widely used in the diagnostic
laboratory. Antigen tests are useful for
confirming microscopic findings and providing a diagnosis in patients with
negative fecal smear results. They are also helpful for interpreting positive
results on amebic serology in patients from endemic countries because positive
results on an antigen test indicate current rather than past infection. Some antigen detection kits can also be used
on serum and material obtained from aspirated abscesses, offering greater
sensitivity than microscopy for extraintestinal disease.18 Not all commercial
kits are capable of speciation; some demonstrate cross-reactivity between E
histolytica and E disbar. Antigen detection methods are also not as sensitive
as polymerase chain reaction assays. and may have low specificity in nonendemic regions. Clinicians should be familiar with the
specifications of the kits used in their laboratory and confirm a suspected
diagnosis if indicated.
The highest sensitivity and
specificity for the diagnosis of E histolytica are offered by DNA-based tests. Many
assays are available, including conventional and real-time polymerase chain
reaction formats; however, they are currently used primarily by research and
reference laboratories. Like most molecular amplification assays, they remain
impractical for resource-limited settings because of their equipment,
personnel, and facility requirements.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis
of amebic colitis must include bacterial (e.g., Salmonella and Shigella spp,
Mycobacterium tuberculosis), parasitic (e.g., Schistosoma mansoni, Balantidium
coli), and noninfectious (e.g., inflammatory bowel disease, carcinoma, ischemic
colitis, diverticulitis) causes of dysentery.
When present, amebomas may mimic carcinoma, tuberculosis, or an
appendiceal mass. Diagnostic tests in
the work-up of patients with dysentery might include stool cultures for
bacteria, ova, and parasites (other than E histolytica) and assays for
bacterial toxins. Biopsy specimens of intestinal ulcers are useful for
confirming the presence of trophozoites and for excluding other etiologies.
Given its varied clinical
presentation and delay of onset, the diagnosis of ALA may not be
straightforward. The differential diagnosis includes bacterial abscess,
echinococcal cyst, tuberculosis, and primary or metastatic tumor, all which
would have vastly different treatments. Radiology can differentiate between
many noninfectious and infectious etiologies; however, bacterial, and amebic
abscesses may appear remarkably similar. In comparison with bacterial abscesses,
ALAs are more likely to be solitary, subcapsular, and located in the right lobe
of the liver, but these findings are not always reliable. Occasionally, ALA may cause a pneumonia-like
presentation with pleuritic pain, cough, and dyspnea. Radiologic imaging,
clinical history, findings on physical examination, and serologic results are
essential for including or excluding the diagnosis of ALA.
TREATMENT
The WHO/PAHO recommendations
state that, when possible, E histolytica should be differentiated from
morphologically similar species and treated appropriately. Given the small but
substantial risk of invasive disease and the potential to transmit the
infection to others, WHO/PAHO recommends treating all cases of proven E
histolytica, regardless of symptoms. If E disbar is the only species
identified, then no treatment should be given, and other causes should be
sought as appropriate.
In resource-poor countries,
the standard but less optimal approach is to treat all patients with cysts and
trophozoites identified on stool examination without additional testing for
speciation.3 This method results in vast overtreatment and may hasten the
development of drug resistance in E histolytica. Thus, WHO/PAHO recommends
withholding treatment from asymptomatic patients when only a morphologic
diagnosis by stool examination is available (i.e., E histolytica/E dispar/E
moshkovskii), unless another reason to suspect E histolytica infection exists.
Even if patients diagnosed as being infected with E histolytica/E dispar/E
moshkovskii have symptoms, other causes of disease, such as bacterial colitis,
should not be excluded until further testing is done. Prophylaxis for E histolytica infection with
amebicides is not recommended under any circumstances.
The medications recommended
to treat confirmed amebiasis vary with clinical manifestation. Asymptomatic
intestinal infection with E histolytica should be treated with luminal
amebicides, such as paromomycin and diloxanide furoate. These medications will eradicate the luminal
amebae and prevent subsequent tissue invasion and spread of the infection
through cysts. Paromomycin, more widely
available in the United States, has the advantage of not being absorbed in the
bowel. Abdominal cramps and nausea are
the most reported adverse effects. A 10-day course at 30 mg/kg per day (divided
into three daily doses) is typical. Some recommend follow-up stool examination
to confirm eradication of cysts.
Compared with asymptomatic
infection, intestinal and extraintestinal invasive disease are aerobic
processes and should be treated with tissue amebicides, such as
5-nitroimidazoles (e.g., metronidazole), which are readily absorbed into the
bloodstream. Metronidazole (750 mg, 3 times a day, for 5-10 days) is the most
commonly used drug in the United States for invasive amebiasis. Because little
metronidazole reaches the lumen of the colon, treatment should be followed by
administration of a luminal agent to eradicate any potential intestinal
reservoirs. Most uncomplicated cases
respond to a 5-day course of metronidazole; however, a 10-day course is useful
in severe cases. Metronidazole may also
be given parenterally to critically ill patients and can be supplemented with
an antibiotic to cover secondary sepsis with bowel flora. The most common
adverse effects of metronidazole are abdominal discomfort and nausea; most
patients, however, are able to complete a full 5- to 10-day course. Serious
adverse drug reactions include confusion, ataxia, and seizures.
A promising new regimen for
invasive amebiasis is a 3-day course of nitazoxanide. This drug is effective
against both luminal and invasive forms and has the added benefit of
eliminating other intestinal parasites, including helminths. Surgery may be necessary in cases of
perforation, abscess, obstruction, stricture, or toxic megacolon. However,
given the friable nature of the inflamed mucosa, bowel repair is risky and
should be avoided when possible.
Like amebic colitis, ALA
typically responds well to a 5- to 10-day course of metronidazole, which should
also be followed with a luminal amebicide.
Metronidazole is the drug of
choice in this setting, given its fast intestinal absorption, excellent
bioavailability in tissue, and good abscess penetration. Surgical or percutaneous drainage of ALAs is
generally not recommended because of the risk of content spillage and/or
bacterial superinfection; exceptions are cases of imminent rupture, failure to
respond to treatment after 4 to 5 days, and secondary bacterial infection. After treatment, ultrasonography may be used
to monitor abscess regression, which occurs slowly during a period of 3 to 12
months.4 Small cystic defects may remain indefinitely.
Amebae rarely disseminate
beyond the portal circulation. Given the small number of cases, no definitive
treatment guidelines are available for management of extraintestinal,
extrahepatic disease. As mentioned previously, infections with E dispar do not
require treatment. Less is known about E moshkovskii, but it is likely that
this infection also would not require treatment in most cases.
CONCLUSION
Recent discoveries have
revolutionized our understanding of the epidemiology of Entamoeba spp
infections and have led to important treatment and diagnostic recommendations.
To avoid unnecessary and possibly harmful therapies, clinicians should follow
the precise guidelines promulgated by the WHO/PAHO in 1997, including
definitive differentiation of E histolytica from morphologically identical
nonpathogenic species. Such definite differentiation is especially important in
countries with adequate sanitation measures, where the predominant organism
identified from morphologic stool examination will be E dispar. Because they
have the highest sensitivity and specificity, molecular technologies offer the
greatest diagnostic potential for laboratories in resource-rich countries at
this juncture; however, some antigen detection tests can also provide reliable
speciation. When speciation is impossible, we recommend using the phrase “E
histolytica/E dispar/E moshkovskii” to describe the morphologically identical
species seen on stool examination. Continued use of new technologies will be
crucial in elucidating the true epidemiology and pathogenesis of Entamoeba spp,
including the less well-studied E moshkovskii. Continued development of
affordable, sensitive, and specific diagnostic tools will be required for use
in resource-poor settings, where the incidence of disease is highest.
Jan Ricks Jennings
Senior Consultant
Senior Management,
Resources
Jan.Jennings@EagleTalons.net
JanJenningsBlog.Blogspot.com
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June 4, 2022
