HIV Medicine (2000) 1, 194199

2000 British HIV Association

REVIEWS IN OPPORTUNISTIC INFECTIONS

Management of protozoal diarrhoea in HIV disease

YM Miao and BG Gazzard*
Department of HIV/GUM, Chelsea and Westminster Hospital, London, UK
Summary
Since the rst reported case of HIV infection in 1981, many HIV-seropositive patients have died
as a result of diarrhoea induced by opportunistic protozoal infections: pathogens that would
normally cause only a transient illness in immunocompetent individuals. The introduction of
highly active antiretroviral therapy (HAART) in 1996 has been associated with a signicant
decline in incidence and mortality arising from infections such as cryptosporidia and
microsporidia. Previously, there were no chemotherapeutic agents known to be effective in
eradicating these parasites, but since the availability of HAART, the memory of the emaciated
terminally ill patient with advanced AIDS suffering from refractory diarrhoea will hopefully be a
thing of the past. Signicant advances in the knowledge of the pathogenesis of HIV disease,
earlier detection and thus treatment of the virus, and availability of improved diagnostic
techniques and HAART have transformed the way HIV-associated diarrhoea is managed. In this
review, we look specically at the management of protozoa-induced diarrhoea.

Received: 12 April 2000, accepted 24 June 2000

Introduction

Diarrhoea

Diarrhoea has been a common problem in patients with

advanced HIV. Up to two-thirds of patients have suffered
with this symptom at some time during the course of their
illness [1]. Symptoms arise from a wide range of pathogens
[2]. Protozoal infections such as cryptosporidia (Cryptosporidium parvum) and microsporidia (Enterocytozoon
bieneusi and Encepha-litozoon intestinalis) were among
the most common causative organisms and contributed to
the signicant morbidity and mortality seen in advanced
stages of HIV illness [3].
Since the introduction of combination antiretroviral
therapy in 1996 there has been a signicant reduction
in the number of HIV-seropositive patients with
refractory diarrhoea. The incidence of cryptosporidial
and microsporidial infection is declining in conjunction
with the general reduction in morbidity and mortality
witnessed following successful viral suppression with
highly active antiretroviral therapy (HAART) [4].
This article reviews the current management of patients
with protozoal-induced diarrhoea in HIV-seropositive
patients.

Diarrhoea is a very common complaint; however, perception of what is true `diarrhoea' varies widely among
patients [5]. Complaints may vary, from the passage of
abnormal stool consistency to urgency of defecation or to
an increase in frequency of motion.
Mostgastroenterologists woulddene chronicdiarrhoeaas
an increase in frequency of defecation (greater than three
motions per day) and passing more than 200 g/day of stool
weight for a minimum of 1 month as being abnormal [5].

Aetiology
The causes of diarrhoea in the HIV-seropositive population
have changed in recent years. In the past, intestinal
spore-forming protozoa such as cryptosporidia (C. parvum)
and microsporidia (E. bieneusi and E. intestinalis) were
among the most common infective agents [6]. Other
protozoal organisms commonly affecting HIV-seropositive individuals include giardia (Giardia lamblia),
amoeba (Entamoeba histolytica) and, less commonly,
isospora (Isospora belli) and cyclospora (Cyclospora
cayetanensis).
Since the Department of Health issued guidelines in 1994
[7], advising immunocompromised patients to boil all

Correspondence: Professor B.G. Gazzard, Department of HIV Medicine, St

Stephen's Centre, Chelsea and Westminster Hospital, 369 Fulham Road,
London SW10 9NH, UK.

194

Management of protozoal diarrhoea in HIV disease 195

drinking water and thus to minimize exposure to the

cryptosporidia found in the water supplies, the incidence of
cryptosporidiosis has declined. This trend has continued
with the introduction of HAART, with a similar trend seen
in those with microsporidial infections [8].
Currently, both conditions are rarely seen in the wellmanaged HIV patient. Previous studies indicated that
long-standing cryptosporidiosis or microsporidiosis was
unusual in patients with a CD4 count above 200 cells/mL
[9,10]. Infection with cryptosporidia tended to be selflimiting with spontaneous resolution within 23 weeks,
and was extremely unusual with microsporidia.
Currently, HIV-seropositive patients are routinely offered
follow-up and tend to be treated with HAART before their
CD4 count falls below 200 cells/mL. Protozoal diarrhoea,
however, must still be remembered in individuals presenting with diarrhoea as their initial AIDS-presenting
diagnosis.

Pathogenesis
The pathogenesis of diarrhoea is incompletely understood.
In HIV patients, the presence of malabsorption features
associated with small bowel villous atrophy and impairment of gut permeability are often found [11]. These
ndings in symptomatic patients with no causative
organism detected were grouped previously into those
with `HIV-induced enteropathy'. However, similar but
milder features can also be seen in asymptomatic HIV
patients [12]. Previous studies have shown disproportionate
reductions in the numbers of CD4 T-cell lymphocytes in the
lamina propria compared to circulating levels of CD4 in the
plasma [13,14]. The number and functional capacity of CD4
cells may be important in controlling villous height [15].
Opportunistic enteroparasites such as cryptosporidia and
microsporidia can produce profound villous atrophy, and
are known to be associated with very low levels of CD4
lymphocytes in the lamina propria [16,17]. Recent
prospective follow-up studies in patients following
HAART showed that, with successful viral suppression,
redistribution of T cells occurs, and results in an increase in
CD4 numbers both in the circulation and in the gut [18,19].
For those patients with a gut pathogen, activated memory
CD4 cells high in CD44 (a migratory adhesion molecule)
increase in the gut and improvements in villous height with
normalization of functional gut permeability, as measured
by sugar absorption tests, are seen [1820].
It is thought that after invasion of the enterocyte by
spore-forming protozoal organisms, the epithelial cells
release cytokines that activate the resident phagocytes and
recruit new phagocytes into the lamina propria from the
blood pool [21]. The activated leucocytes then release

2000 British HIV Association HIV Medicine (2000) 1, 194199

cytokines that increase the secretion of chloride and water,

and also inhibit absorption [21]. Research into the role of
cytokine production is currently ongoing. Previous studies
have shown that resolution of primary cryptosporidiosis in
the immunocompetent patient is associated with the
production of interleukin (IL)-15 by intra-epithelial lymphocytes. In previously sensitized individuals, re-infection
is associated with production of g-interferon and IL-4 by
lamina propria lymphocytes [22,23]. In follow-up studies
before and after HAART, expression of IL-15 g-interferon
and IL-4 were found to be absent prior to treatment, with
the reappearance of these cytokines following therapy [23].
The release of these cytokines from activated CD4 T-cell
lymphocytes in the gut may be important for the
eradication of opportunistic protozoal infections.
Alternative mechanisms for the cause of diarrhoea
includes functional motility abnormalities resulting from
HIV-induced autonomic neuropathy [24]. Patients with
protozoal infection have decreased intestinal transit times,
but it is unclear whether this is due to a primary motility
defect or results from malabsorption secondary to villous
atrophy [24].

Investigations
The most important investigation is stool analysis. Light
microscopy and culture of stool is required for routine
pathogens; however, special stains such as the modied
Ziehl-Nielsen [25], Calcouor [26] and trichrome stains
[27] should be requested for immunocompromised patients.
Stool light microscopy and culture are highly specic but
not particularly sensitive tests and therefore at least three,
and preferably six, different stool samples should be sent
for examination [6]. Newer polymerase chain reaction
(PCR) techniques are available, but these tests are costly
and time-consuming and therefore not routinely available
in hospital practice [28,29]. The sensitivity of PCR
techniques for both cryptosporidia and microsporidia
may be much better than currently available techniques.
In the case of cryptosporidia, the threshold for detection is
50 oocysts per gram of stool, compared to a threshold of
50 000 oocysts per gram of stool with routine light
microscopy [30,31]. For microsporidia the threshold for
PCR detection is 100 spores per gram of stool, compared
with light microscopy where the detection threshold is
between 104 and 106 spores per gram of stool [29]. Thus,
some of the individuals formerly diagnosed with pathogennegative diarrhoea may have been infected with these
organisms.
Gut biopsy is an important tool in the investigation of
diarrhoea. Ten per cent of those with cryptosporidial
infections may be detected by gut biopsy, despite stool

196 YM Miao and BG Gazzard

samples remaining negative [32]. Identication of microsporidia in the small bowel at light microscopy may be
difcult due to the intracellular nature of the organism and
its poor staining properties with routine histological stains.
Previously electron microscopy was the `gold standard' and
the only reliable method for species identication [33]. This
was particularly relevant as certain microsporidia species
(E. intestinalis) respond better to treatments such as
albendazole when compared to others [34]. PCR analysis
of either gut or stool samples can also help to identify the
type of microsporidia species that was undertaken previously by electron microscopy [35].
Endoscopic examination can also help to exclude other
more rare causes of diarrhoea seen in late-stage AIDS, such
as lymphomas, the frequency of which have been less
affected by the introduction of HAART [36].

Management of diarrhoea
For those patients presenting with diarrhoea as their initial
AIDS-presenting diagnosis, the most important goal is to
identify any treatable infections or neoplasms. History of
the illness may give valuable clues to the aetiology.
Patients with low-volume diarrhoea tend to resolve
spontaneously or can be controlled with antimotility
agents, a response that is also seen in patients with irritable
bowel syndrome [5].
In HIV-seropositive patients, the single most important
factor governing the severity of disease and prognosis is the
degree of immune suppression in individual patients. A CD4
count of above 200 cells/mL normally indicates that although
opportunistic infections such as cryptosporidiosis and
microsporidiosis can occur, they tend only to be transient
illnesses [37], with the immune system still being able to
eradicate the parasites through a cellular immune response.
For those with CD4 counts below 200 cellls/mL the
treatment of choice is initiation of HAART, but the
diagnosis of other associated pathogens with readily
available treatments is also important. Aside from cryptosporidiosis and microsporidiosis, HIV patients also have a
higher incidence of other gut pathogens, including
bacterial organisms such as salmonella and campylobacter;
atypical mycobacteria such as Mycobacterium aviumintracellulare (MAI); viral causes such as Cytomegalovirus
(CMV); other parasites such as giardia and amoeba; and
fungal infections such as candida.
In patients with advanced immunosuppression, prevention is better than cure. Simple advice to drink only boiled
water reduces exposure to cryptosporidiosis. Standard
ltration or chlorination processes are not effective in
eradicating these protozoa from water supplies [38].
Boiling drinking water for 12 min kills the organisms

and reduces the risk of infection [21]. Successful combination antiretroviral therapy is, however, the only treatment
available which has been shown to eradicate opportunistic
enteroparasites through a process of host-immune reconstitution [8,28].
In those patients who are acutely unwell through a
combination of fevers, dehydration and diarrhoea, quinolones such as ciprooxacin should be effective against
associated bacterial causes of diarrhoea. Supportive
measures with either oral or intravenous rehydration are
important to correct electrolyte imbalances quickly. For
those patients who do not respond to antiretroviral therapy,
symptomatic measures such as the liberal use of antidiarrhoeals (loperamide and codeine phosphate) and, in some
patients, opiates may be needed.
Treatment with subcutaneous somatostatin analogues
such as octreotide may help patients by reducing intestinal
motility and by blocking the secretory mechanism of
diarrhoea. These drugs work via inhibiting intestinal
secretion stimulated by calcium, AMP and GMP and
enhance water and electrolyte reabsorption [39]. Use of
somatostatin analogues can result in dramatic reductions
in stool volume, and in some patients help alleviate
symptoms of nocturnal incontinence, although randomized
controlled trials have shown only limited value. Newer
longer-acting somatostatin analogues, which require only
fortnightly or monthly injections, have made this option
easier to administer.
Specic therapies for cryptosporidia and microsporidia,
such as paromomycin [40] and albendazole [33,34], can
alleviate symptoms by reducing parasite load and reducing
stool volume; however, the organisms are not eradicated.
Recently newer antimicrosporidial agents such as the
water-insoluble antibiotic, fumagillin, have been used
successfully in the treatment of supercial keratitis
secondary to microsporidial infection [41]. However,
systemic use is limited by toxicity. TNP-470, a newer
semisynthetic analogue of fumagillin, is currently being
assessed in vitro [42]. Recent results suggest that these
newer agents can inhibit replication of microsporidia by up
to 70%; however, studies in vivo are still awaited [42]. To
date, no similarly promising compounds have been
identied against cryptosporidial infections. Discrepancies
between drug assays in vitro, in animal models and in
human trials still frustrate efforts to identify any effective
anticryptosporidial agents [43].
Other therapies such as human bovine colostrum [44]
and letrazuril [40] have been tried in the past. Although
they may have helped to reduce symptoms, they did not
effect a cure. Thalidomide has been used with some success
in alleviating diarrhoeal symptoms of microsporidial
infection [45]. It has a number of potential actions,

2000 British HIV Association HIV Medicine (2000) 1, 194199

Management of protozoal diarrhoea in HIV disease 197

including being a simple constipating agent, and it is also

thought to reduce tumour necrosis factor-a (TNF-a).
TNF-a is a pro-inammatory cytokine associated with
cachexia and is increased in stool samples of patients with
HIV-associated diarrhoea [46].
For isospora, which is a common cause of diarrhoea in
South America and a more rare cause of diarrhoea in
HIV-infected individuals, a course of cotrimoxazole may
eradicate the parasite. However, isospora recurrence is
common and secondary prophylaxis may be required,
particularly in those patients who fail to respond to
HAART [47]. Cyclospora has been reported in HIV
patients, but more commonly causes travellers' diarrhoea
and is prevalent in India. Patients respond to treatment
with cotrimoxazole [48]. For giardia or amoeba, standard
treatment with metronidazole or tinidazole should result in
the complete eradication of both parasites [49].

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Summary
Refractory diarrhoea secondary to opportunistic protozoal
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