GASTROINTESTINAL INFECTIONS

Protozoal
gastrointestinal infections

Whats new ?
Entamoeba dispar, which is morphologically identical
to E. histolytica, is non-pathogenic but can be
distinguished by molecular genetic techniques

Michael J G Farthing

Nitazoxanide is now the treatment of choice for

cryptosporidiosis in adults and children

Paul Kelly

HIV-associated protozoal infections, particularly with

intracellular organisms (Cryptosporidium parvum,
microsporidia) are best treated with combination
antiretroviral therapy

Human intestinal protozoal infections are found worldwide, in both

developing and industrialized countries. Protozoa produce diarrhoeal disease by infecting the small or large intestine, or both.
Intestinal protozoal infections (Figure 1) occur most commonly in developing countries, where they are responsible for
a substantial burden of disease. The small intestinal protozoa
Giardia intestinalis (G. lamblia) and Cryptosporidium parvum are
important causes of diarrhoea in children; the latter is particularly
associated with growth failure and malnutrition. They also cause
water-borne and food-borne outbreaks. Food-borne outbreaks
may also be caused by Cyclospora cayetanensis. The importance
of intestinal protozoa has increased with the HIV/AIDS pandemic,
which has led to the recognition of new protozoal pathogens (e.g.
microsporidia, Cyclospora). Intestinal protozoa are difficult to identify, and diagnostic laboratories may have to perform additional
procedures to identify specific infections.

The life cycles of E. histolytica and E. dispar are simple ingested cysts develop to form trophozoites (Figure 2). In an unknown
proportion of E. histolytica infections, trophozoites become invasive and phagocytic, secreting a range of lipases and proteases
and producing human disease. Humans are the main reservoir of
E. histolytica and E. dispar; transmission is mainly faeco-oral, but
can occur directly from person to person, including during sexual
contact.
Clinical features: the clinical spectrum of amoebiasis ranges
from the asymptomatic carrier state to acute colitis, which may
be fulminant and may result in intestinal perforation.
Amoebic colitis is usually insidious in onset, with intermittent
abdominal discomfort and diarrhoea, often with rectal bleeding.
Endoscopic examination of the rectum and colon usually reveals
small ulcers; the intervening mucosa appears relatively normal. In
its most severe form, fulminant amoebic colitis is indistinguishable
from severe ulcerative colitis and may be accompanied by toxic
megacolon.
Amoebic liver abscess is most commonly found in men. Only
10% have a concurrent history of diarrhoea or dysentery. Upper
abdominal pain and fever usually begin abruptly; the pain may
radiate to the right shoulder and may be exacerbated by respiratory movements. The abscess can rupture into the peritoneal,
pericardial or pleural cavity. Complicated amoebic liver abscess
carries high morbidity and mortality.

Amoebiasis
Understanding of amoebiasis has advanced considerably in recent
years, with the identification of a new species, Entamoeba dispar. It
has long been recognized that only a small proportion of individuals carrying infection with amoebic cysts develop clinical illness.
Molecular characterization has established that most infections
that were previously thought to be E. histolytica are an exclusively
non-pathogenic form, now called E. dispar. True E. histolytica infections are less common and are responsible for all cases of invasive
colitis and hepatic amoebiasis. However, non-invasive carrier states
of E. histolytica are also common. These two organisms cannot
be differentiated by microscopy, and much of the epidemiology
of this infection should be reconsidered.

Diagnosis: serology is the most sensitive and specific diagnostic

test. The E. histolytica immunofluorescent antibody test is positive in more than 80% of patients with amoebic colitis and 90%
of those with hepatic amoebiasis. Hepatic amoebiasis is usually
diagnosed using ultrasonography. Trophozoites or cysts may be
detected in faeces, exudate from amoebic ulcers or colonic biopsies.
Trophozoites survive for only short periods of time and therefore
fresh stool specimens should be examined.

Michael J G Farthing is Professor of Medicine at St Georges Hospital

Medical School, London, UK. His research interests include the
pathogenesis of intestinal infection, particularly the role of the enteric
nervous system in enterotoxin-mediated intestinal secretion. Conflict of
interests: received a research grant from Romark for clinical studies into
the efficacy of nitazoxanide in the treatment of HIV-related diarrhoea.

Management: two classes of drug are used in the treatment of

amoebic infection.
Luminal amoebicides (e.g. diloxanide furoate) act on organisms
in the intestinal lumen and are ineffective against organisms in
tissue.
Tissue amoebicides (e.g. metronidazole, dehydroemetine,
chloroquine) are effective in the treatment of invasive amoebiasis
but less effective against organisms in the bowel lumen.

Paul Kelly is Reader and Wellcome Trust Senior Fellow at Barts and
the London School of Medicine, London, UK. His research interests are
intestinal immunology, infection and nutrition. Conflict of interests: none.

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GASTROINTESTINAL INFECTIONS

Important human intestinal protozoa

Sarcodina (amoebae)

Pathogenic
Entamoeba histolytica

Mastigophora (flagellates)

Giardia intestinalis

Ciliophora (ciliates)
Coccidia

Balantidium coli
Cryptosporidium parvum
Isospora belli
Cyclospora cayetanensis
Sarcocystis spp.
Enterocytozoon bieneusi
Encephalitozoon intestinalis

Microspora

Non-pathogenic
Entamoeba dispar
Entamoeba coli
Entamoeba moshkovskii
Entamoeba hartmanni
Entamoeba chattoni
Endolimax nana
Iodamoeba butschlii
Trichomonas hominis
Chilomastix mesnili
Embadomonas intestinalis
Enteromonas hominis

Unclassified

Uncertain

Dientamoeba fragilis

Blastocystis hominis

which the organism produces disease has not been established;

partial villous atrophy, microvillous disruption, mucosal inflammation, inhibition of pancreatic enzyme activity and disruption
of bile salt metabolism have all been implicated.

Intestinal infection and amoebic liver abscess are usually treated

with metronidazole, 800 mg t.d.s. for 10 days, followed by diloxanide furoate, 500 mg t.d.s. for a further 10 days. Asymptomatic
carriers can be treated with diloxanide furoate alone.

Clinical features: the clinical spectrum is diverse, ranging from

asymptomatic carriage to persistent diarrhoea with intestinal
malabsorption. Abdominal discomfort is uncommon. Chronic
infection may lead to weight loss and retardation of growth and
development in infants and young children.

Giardiasis
Giardiasis is found in travellers, children in day-care centres, and
those with immunoglobulin deficiency states who have visited
endemic areas. The parasite does not commonly produce severe
diarrhoea in patients with HIV/AIDS. G. intestinalis is a flagellate
that exists as a motile trophozoite but can survive outside its mammalian host as a cyst. It is a luminal parasite; trophozoites reside
predominantly in the proximal small intestine. The mechanism by

Diagnosis is often based on clinical features and a history of travel

to an endemic area. Empirical treatment may be given on this basis.
Microscopic examination of faeces reveals cysts in about 7080%
of infected individuals, though at least three stool samples may
be required. Duodenal aspiration and/or biopsy complements
stool examination by detecting a further 1020% of cases. Faecal
antigen tests including enzyme-linked immunosorbent assay are
now available for giardiasis.
Management: the drugs of choice for giardiasis are the nitroimidazole derivatives metronidazole, 2 g single dose on 3 days, or
tinidazole, 2 g single dose. Second-line drugs such as albendazole
and mepacrine may be required when initial treatment fails.

Balantidiasis
Balantidiasis is an uncommon disease. Balantidium coli is the only
ciliate that infects humans. It is the largest protozoan enteropathogen; in pigs (its favoured host), trophozoites may reach 200 m in
length, and are visible with a hand-lens and sometimes with the
naked eye. Human infection is common only in communities that
live in close proximity to pigs (e.g. in Central and South America,

2 Scanning electron micrograph of Entamoeba histolytica trophozoite in

culture.

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Microsporidia are important contributors to AIDS-related

diarrhoea and sclerosing cholangitis worldwide. Diagnosis is
difficult and requires special fluorescent stains or trichrome to
detect the small spores. Two species are known to infect humans;
Encephalitozoon intestinalis responds well to albendazole, 400 mg
b.d. for 1 month.
C. cayetanensis causes food-borne and travellers diarrhoea,
particularly in Nepal and Central America. Diagnosis is with
modified ZiehlNeelsen stain and treatment with co-trimoxazole,
960 mg b.d. for 1 week.
Dientamoeba fragilis the pathogenicity of this organism is
in doubt. It is transmitted simultaneously with Enterobius vermicularis. There are reasonable grounds to believe that, when no
other cause is apparent, a trial of treatment may be worthwhile.
Diagnosis is difficult, but treatment with metronidazole, 800 mg
t.d.s. for 10 days, is usually effective.

Iran, Papua New Guinea and the Philippines). The organism can
survive outside its mammalian hosts as a cyst, by which the disease is transmitted.
Clinical features: trophozoites produce an illness that clinically
resembles amoebic colitis.
Management is with tetracycline, 500 mg q.d.s. for 10 days. The
organism is sensitive to other antibiotics, including ampicillin and
metronidazole.

Cryptosporidiosis
Human cryptosporidiosis was first described in 1976, but the
HIV/AIDS pandemic gave it prominence. There are several settings
in which cryptosporidiosis is a major contributor to morbidity
and mortality.
In HIV/AIDS, cryptosporidiosis is generally found in patients
with low CD4 counts (< 200/l); the lower the CD4 count, the
more severe the clinical illness.
Water-borne outbreaks have been described in many parts of
the world; the largest, in Wisconsin, USA in 1993 affected 400,000
individuals.
Children with cryptosporidiosis in developing countries have
associated malnutrition, and mortality is increased. Of all the
agents associated with endemic diarrhoea in the developing world,
cryptosporidiosis has the poorest outcome.
In developed countries, day-care centres and swimming pools
have been reported as foci of cryptosporidiosis outbreaks.
C. parvum is sometimes responsible for travellers diarrhoea.

Protozoal infections in AIDS

A feature of the immunosuppression seen in AIDS is selective
susceptibility to different infections. For example, the HIV pandemic has been associated with a major increase in infection
with Mycobacterium tuberculosis but not M. leprae, though the
immunology of these infections has much in common. This is
also true of the intestinal protozoa; cryptosporidiosis, isosporiasis
and microsporidiosis are more common and more severe in AIDS
patients than in immunocompetent hosts, but the amoebae and
flagellates are not more common or more pathogenic in AIDS.
The reasons for this are not clear, but it seems that AIDS patients
are particularly vulnerable to persistent intracellular infections,
particularly with coccidia.
Management of HIV-positive patients with coccidial infection is
challenging. These patients are often severely unwell with persistent diarrhoea and malnutrition. Management must include fluid
and electrolyte repletion, treatment of other bacterial infections,
micronutrient repletion, specific treatment for the protozoal infection, then macronutrient support, in that order. For isosporiasis
and cyclosporiasis, treatment is with co-trimoxazole for 10 days,
followed by secondary prophylaxis thrice weekly. Cryptosporidiosis should probably be treated with prolonged courses (at least
14 days) of nitazoxanide. The most difficult question is when to
initiate antiretroviral therapy, and there are currently no trials to
guide this decision.

Clinical features: the clinical illness varies from asymptomatic

carriage to severe, life-threatening diarrhoeal disease. Most cases
are indistinguishable from other types of infectious diarrhoea, but
AIDS patients not on highly active antiretroviral therapy sometimes
(10% in one series) develop fulminant disease with high mortality. AIDS patients may also develop a sclerosing cholangitis-like
disease that presents with right upper quadrant abdominal pain
and/or jaundice or abnormal liver biochemistry.
Diagnosis is based on microscopy of stool smears stained with
auramine or modified ZiehlNeelsen stain. Faecal immunofluorescence testing and faecal antigen tests are also available.
Serology and polymerase chain reaction-based tests are research
tools only.
Management is difficult, but there has been progress. In HIVnegative children and in adults, nitazoxanide, 100 mg b.d. for
3 days in children, 500 mg b.d. in adults, has been shown to
be effective.1 In AIDS, it is important to establish antiretroviral
therapy (see below).

REFERENCE
1 Amadi B C, Mwiya M, Musuku J et al. Effect of nitazoxanide on
morbidity and mortality in Zambian children with cryptosporidiosis:
a randomised controlled trial. Lancet 2002; 360: 137580.
FURTHER READING
Farthing F, Cevallos A-M, Kelly P. Enteric protozoan infections.
In: Cook G, Zumla A, eds. Mansons tropical diseases. 20th ed.
London: Saunders, 2003: 1397410.
Kelly M P, Farthing M J G. Intestinal protozoa. In: Schlossberg D, ed.
Current therapy for infectious diseases. 2nd ed. Philadelphia: Mosby,
2000: 6902.

Other protozoa
Isospora belli is an uncommon cause of travellers diarrhoea,
but is often found in AIDS-related diarrhoea in Sub-Saharan Africa.
Diagnosis is by microscopy of modified ZiehlNeelsen-stained
stool smears, as for C. parvum. The infection is treated with cotrimoxazole, 960 mg q.d.s. for 10 days.

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2005 The Medicine Publishing Company Ltd