REVIEW

CURRENT
OPINION Intestinal protozoan infections in the
immunocompromised host
Luis A. Marcos and Eduardo Gotuzzo

Purpose of review
Intestinal protozoa are becoming increasingly recognized as significant pathogens in immunocompromised
hosts. However, pathogenesis of infection is still poorly understood, diagnostic tests remain insensitive, and
management continues to pose a challenge.
Recent findings
Invasion by intestinal protozoa can be facilitated by impaired host T-cell immune response,
although the exact pathogenesis at the cellular level is unclear. HIV-infected and transplant
patients have been reported to have the highest risk for developing severe disease. Cryptosporidium is the
most common parasite encountered in the immunocompromised host, followed by Cyclospora and
Isospora. In recent years, Microsporidia and Blastocystis have also emerged as important players,
due in part to improved molecular diagnostic assays. Effective drugs against these parasites in
immunocompromised patients have not been reported in recent years. When possible, reducing the level of
immunosuppression seems to be the most effective treatment strategy in combination with adjunctive
antiparasitic therapy.
Summary
Despite that intestinal protozoan infections cause greater morbidity and mortality in the
immunocompromised host, their pathogenesis in the setting of immunosuppression is poorly understood and
efforts to develop new therapeutic agents are rather limited. Improving detection and identification of
species or subtypes by PCR will result in improved management decisions and a better understanding of
the epidemiology of intestinal protozoa. Favorable clinical outcomes can be achieved by early detection
and effective treatment of the infection. Further research on key aspects of pathogenesis at the cellular level
in humans is needed.
Keywords
HIV, immunocompromised, intestinal parasites, protozoa, transplant

INTRODUCTION globally as the number of immunocompromised

Intestinal protozoan infections are frequently
encountered in clinical practice in low-income
countries and remain a public health challenge in
many parts of the world. Although their impact in
developed countries is less pronounced, these
organisms have been responsible for large outbreaks
of disease. At least 199 waterborne outbreaks associ-
ated with intestinal protozoan infections were
reported in Australia, North America and Europe
from 2004 to 2010 [1].
Certain immunocompromised patient popu-
lations (e.g. HIV/AIDS, solid and bone marrow trans-
plantation, malnutrition) are at greater risk for
developing abrupt, severe and explosive diarrhea
associated with intestinal protozoan infection than
are immunocompetent individuals [2]. Morbidity
caused by these parasites affects millions of people
individuals has risen to astronomic numbers. An
estimated 33 million people worldwide were living
with HIV in 2008 (http://www.unaids.org/en/data
analysis/epidemiology/2009aidsepidemicupdate/;
accessed 6 February 2012). In the United States
alone, more than 180 000 individuals were living
with a transplant in 2007 (http://www.ustrans
plant.org/annual_reports/current/Chapter_I_AR_CD.
htm; accessed 6 February 2012). Over the past
Institute of Tropical Medicine Alexander von Humboldt, Universidad
Peruana Cayetano Heredia, Lima, Peru
Correspondence to Luis A. Marcos, MD,
#4 Medical Blvd. Hattiesburg,
Mississippi, USA. Tel: +1 601 579 5444; fax: +1 601 579 3083; e-mail:
marcoslrz@yahoo.com
Curr Opin Infect Dis 2013, 26:295–301
DOI:10.1097/QCO.0b013e3283630be3

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Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 Infections of the immunocompromised host
KEY POINTS
 Transplant patients are at high risk of developing
intestinal protozoa infections.
 One of the most effective therapies to ameliorate
diarrhea caused by intestinal protozoa infections is
reduction of immunosuppression when feasible.
 Blastocystis and microsporidia are emerging pathogens
in the immunocompromised host.
decade, almost 792 million people have struggled
with malnutrition (http://www.who.int/water_sani
tation_health/diseases/malnutrition/en/; accessed
on 6 February 2012). With increased globalization,
travelers represent an emerging population at risk for
intestinal protozoan infection. Parasitic infections
are now the second most common cause of acute
diarrhea in returned travelers [3]. Travelers with
underlying immunodeficiency are at even greater risk
of acquiring an infection [4]. Transplant tourism in
developing countries represents another avenue of
acquiring a parasitic infection [5]. It has been specu-
lated that intestinal protozoan infections have been
underestimated in several parts of the world due to
lack of access to sensitive diagnostic tests and special
staining techniques (e.g., modified Kinyoun’s acid-
fast method for Cryptosporidium, Cyclospora and
Isospora). Worldwide increase in immunocompro-
mised individuals, travel, medical tourism, and
immigration will inevitably be accompanied by a
greater burden of intestinal protozoan infections
globally.
We will review the most common intestinal
protozoa that infect immunocompromised patients,
including Cryptosporidium, Cyclospora, Isospora,
microsporidia and Blastocystis, focusing on their
pathogenesis (Fig. 1), diagnosis, and management
(Table 1).
WHY ARE INTESTINAL PROTOZOA MORE
COMMONLY SEEN IN
IMMUNOCOMPROMISED HOSTS?
Immunocompromised hosts are at higher risk for
acquiring intestinal protozoan infections particu-
larly in the setting of impaired or deficient T-cell
function [6]. The immune response against parasites
is divided into two broad categories: innate immun-
ity, which alone seldom eliminates the parasite; and
adaptive immunity, which is better suited to thwart-
ing the infection [7]. Intestinal protozoa usually
trigger a strong adaptive immune response medi-
ated by T cells [8]. However, the immune response
may not always be effective. These parasites have
296 www.co-infectiousdiseases.com
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developed mechanisms to evade the immune
response and survive within the host [9]. For
instance, parasites can modulate the effector
response by inducing regulatory T cells [10], which
in turn can suppress antiparasitic effector cells. The
underlying mechanisms by which the intestinal
parasites invade and cause infection in the immuno-
compromised host remain poorly understood [11].
CRYPTOSPORIDIUM
Two species of Cryptosporidium infect humans,
C. parvum and C. hominis. Pathogenesis relies on both
cellular and humoral immune responses. Specifi-
cally, a depletion in CD4þ T cells is associated with
a greater risk for developing cryptosporidiosis (e.g.,
in HIV/AIDS). A recent novel biology molecular
method, ribosome display, has identified a specific
adhesion protein, Cp20, that is involved in sporo-
zoite invasion of host cells and is now being studied as
a potential candidate gene for a vaccine [12].
Despite efforts to control the HIV epidemic
using antiretroviral therapy (ART) in many parts
of the world, prevalence rates of Cryptosporidium
in HIV-infected patients remain high and associated
morbidity is significant. For example, C. parvum
infection has been reported in 44 and 20% of
HIV-infected patients in Ethiopia and Thailand,
respectively [13,14]. In India, 66.6% of patients with
AIDS (CD4 cell count 200cells/ml) and acute diar-
rhea have demonstrable Cryptosporidium in their
stool, as do up to a third of HIV-infected patients
(CD4 cell count 200cells/ml) with diarrhea [15].
Other populations at risk for diarrhea associated
with Cryptosporidium infection include solid organ
[16] and hematopoietic stem cell transplant (HSCT)
patients [17]. In one study, 21% of 33 solid trans-
plant patients were found to have Cryptosporidum as
the most likely causative agent of diarrhea [18].
Another study involving allogeneic HSCT patients
showed that the prevalence of Cryptosporidium
associated with diarrhea was about 9.6% (n ¼ 52)
with a median time to presentation of 503 days after
transplantation [19]. Patients with primary immu-
nodeficiencies including hyper-IgM syndrome type
1 and primary CD4 lymphopenia may also be at
increased risk for developing cryptosporidiosis [20].
Diarrhea associated with Cryptosporidium can be
indistinguishable from graft-versus-host disease
(GVHD) in allogeneic HSCT recipients. Reduction
in immunosuppression often resolves diarrhea
associated with Cryptosporidium. Apart from intesti-
nal disease, sclerosing cholangitis associated with
Cryptosporidium has been reported in at least
one patient with a liver transplant [21]. Manage-
ment consists of a combination of antibiotics (e.g.,
Volume 26  Number 4  August 2013
 Intestinal protozoan infections Marcos and Gotuzzo

Intestinal protozoa Immune response Intestinal epithelial cells

Method: ribosome
Cyst Sporozoite Cp20
Cryptosporidium display

Finding: specific adhesion
spp. proteins (i.e. Cp20)

Impact: candidate gene
for vaccine
At greater risk, those with:
Cyclospora •Depletion of T cells
cayetanensis •CD4
Adaptive immunity
•AIDS, transplant is essential (T-cell
response)

Specific host—
parasite interactions
Isospora belli poorly understood

Antigens (?)

Induces:
Microsporidia •
Th1 response

Strong CD8+T-cell
E. bieneusi •Strong CD8+T-cell response
PTP1
response: protective
E. intestinalis •Unknown CD4 role immunity against E.
Population at risk cuniculi
E. cuniculi
•AIDS and transplant
Polartube protein 1
E. hellem
(PTB1) induces strong T-cell
response in E. cuniculi
Virulent factors
•Cysteine proteases
Induces:

Unknown
•
interferon-γ surface
Blastocystis •
IL-12 Invasion
proteins or
subtypes 1–9 Unknown CD4 role
hyaluronidase specific
Immunocompromised hosts: immune
HIV/AIDS and transplant response

FIGURE 1. Pathogenesis of intestinal protozoa.

azithromycin, paramomycin, nitazoxanide) and,

Table 1. Management of Intestinal protozoan
more importantly, reduction in immunosuppres-
parasitic infections in immunocompromised
sion. Antibiotics alone may not necessarily decrease
population the symptoms associated with Cryptosporidium
Intestinal protozoa Therapy infection. In HIV-infected children with cryptospor-
idiosis, a randomized clinical trial using 28 days of
Cryptosporidium Decrease immunosuppression nitazoxanide demonstrated no difference in eradi-
spp. Nitazoxanide 500 mg twice a day for cation of infection or reduction of symptoms com-
14 days
pared with placebo [22]. Furthermore, a Cochrane
Paramomycin 500 mg four times a day for review of several randomized clinical trials focusing
14 days
on treatment or prevention of cryptosporidiosis in
Cyclospora Trimethoprim–sulfamethoxazole
immunocompromised individuals concluded that
cayetanensis (160 mg/800 mg) twice a day for 7 days
no effective treatment is available for the manage-
Ciprofloxacin 500 mg twice a day for
7 days
ment of cryptosporidiosis [23], but reduction in
immunosuppression was strongly recommended.
Isospora belli Trimethoprim–sulfamethoxazole
(160 mg/800 mg) twice a day for 10 days Similarly, in HIV-infected individuals, a key step
Ciprofloxacin 500 mg twice a day for 7 days
in controlling diarrhea associated with Cryptospori-
dium is the initiation of ART [24] by reducing
Microsporidia Decrease immunosuppression
the immunosuppression.
Albendazole 400 mg twice a day for
28 days
Blastocystis spp. Metronidazole 500 mg three times a day for CYCLOSPORA
10 days
Furazolidone and tinidazole
Nineteen species of Cyclospora have been identified
worldwide but only C. cayetanensis has been

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 Infections of the immunocompromised host
described as a pathogen in humans [25]. Surpris-
ingly, few reports describe cyclosporiasis in immu-
nosuppressed patients in the United States even
though there were 1110 laboratory-confirmed
sporadic cases of cyclosporiasis from 1997 to 2008
[26]. The prevalence rate of Cyclospora is lower than
that of Cryptosporidium infections in the HIV-
infected population. In one study, 5% of HIV
patients in Thailand harbored Cyclospora in their
stools [14]. In India, prevalence rates from 0.7 to
24% of Cyclospora have been described among HIV-
infected patients [15,27].
Molecular assays on stool specimens allow accu-
rate and rapid identification of Cylcospora [28]. A
study using multiplex PCR showed a sensitivity of
87% for detection of Cyclospora in stools [29,30].
These DNA-based tests can be especially helpful in
improving diagnostic yield during outbreaks [31]
and they may eventually identify the source of
contamination in the environment.
In terms of management, trimethoprim–sulfa-
methoxazole (160/800 mg) twice a day is more effec-
tive than ciprofloxacin for cyclosporiasis in HIV
patients [31]. Those already taking trimethoprim–
sulfamethoxazole for Pneumocystis jiroveci prophy-
laxis are protected to a degree against Cyclospora
infection.
ISOSPORA
Isospora belli is an intestinal protozoan that is fre-
quently seen in HIV-infected individuals in tropical
and subtropical regions. Prevalence rates ranging
from 4 to 15% have been reported in HIV-infected
patients from Ethiopia, Peru, Malaysia and Brazil
[13,32–34]. Though few reports of Isospora infection
in transplant patients exist, improvements in diag-
nostic techniques and an increase in immunocom-
promised individuals worldwide have unveiled
several new cases in recent times. Isospora has been
identified in the stool of a liver transplant patient
with diarrhea in Turkey [35]. Another case was ident-
ified in a patient with an intestinal transplant who
developed profuse diarrhea during the first 3 months
of profound immunosuppression [36]. Molecular
diagnostic tests have been developed in recent years,
with one PCR-based assay demonstrating a sensitivity
of 93% [28]. Excellent clinical response has been seen
after treatment with trimethoprim–sulfamethoxa-
zole [36], which continues to be the drug of choice.
MICROSCOPORIDIA
Microsporidia are obligate intracellular eukaryote
pathogens that are phylogenetically related to fungi,
specifically zygomycetes [37]. Out of 14 species,
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Enterocytozoon bieneusi and Encephalitozoon intestina-
lis are common human pathogens [38], followed by
Encephalitozoon cuniculi and Encephalitozoon hellem
&
[39 ]. Genetic characterization of new species by
analysis of the small unit of rRNA may contribute
to the discovery of new species infecting humans
&
[40 ]. Microsporidia can cause a variety of clinical
syndromes, either localized or disseminated, includ-
ing hepatitis, peritonitis, encephalitis, myositis,
urethritis, prostatitis, nephritis, sinusitis, kerato-
conjunctivitis, cystitis, diarrhea and cellulitis [38].
E. cuniculi infection induces a strong CD8þ cyto-
toxic T-lymphocyte response that restricts parasite
growth by lysing infected cells via a perforin-depend-
ent mechanism [41]. Recent attempts to identify
immune response triggers specific to E. cuniculi have
uncovered polar tube protein 1, a highly conserved
major polar protein, that is capable of eliciting a
strong CD8þ T-cell response with no effect on the
CD4þ T-cell subset [42]. The role of CD4þ T cells in
E. cuniculi infection remains unclear.
Cases of microsporidia infection were rare
before the global HIV pandemic. An increase in cases
was observed initially during the early years of the
pandemic but decreased after the introduction of
&
ART [43 ]. In regions where antiretrovirals are not
available, the prevalence of microsporidia remains
high. In fact, the prevalence rate of microsporidia in
HIV patients from Thailand has been reported to be
as high as 81% [14]. HIV-infected individuals are
three times more likely to have microsporidia in
their stools than non-HIV-infected patients, with
a prevalence of 8.5 vs. 2.9%, respectively [44]. Micro-
sporidia can also affect transplant patients. Among
solid organ recipients, E. bieneusi is the most com-
mon species of microsporidia reported. Two renal
transplant recipient patients with explosive diarrhea
were reported with microsporidia infection. One
responded clinically to albendazole but spores were
still detected by PCR in stools after therapy, whereas
the other case improved after suspending immuno-
suppressants [45]. Diarrhea caused by microsporidia
can present within months to years of transplan-
tation. Disseminated E. cuniculi infection has been
reported in a renal transplant [46]. Notoriously,
microsporidia infection has been associated with
higher mortality in immunosuppressed individuals
[45,46].
Further studies are needed to elucidate the
modes of transmission of microsporidia. One hypo-
thesis is that humans are an asymptomatic carrier
and that infection only occurs in the setting of
acquired immunodeficiencies such as HIV/AIDS or
transplant immunosuppression [41]. Patients with
cancer may also be at heightened risk for developing
infection. A study showed that up to 11% of patients
Volume 26  Number 4  August 2013

with hepatocellular carcinoma with chronic diar-
rhea had E. intestinalis in their stools, compared with
1.4% of asymptomatic healthy individuals [47].
Microsporidia keratitis is another presentation of
disease in severely immunocompromised patients
[48]. Identification of environmental sources,
modes of transmission and clinical presentations
may contribute to a better understanding of this
uncommon (or underestimated) parasite and aid the
development of preventive strategies in high-risk
populations.
Stool PCR is a promising diagnostic tool that has
improved detection compared with routine micro-
scopic examination. PCR sensitivity for E. bieneusi
has been reported to be about 95% [31].
Reduction of immunosuppression is an effective
management strategy. In HIV patients with low CD4
cell count, the initial use of antiretrovirals is recom-
mended to control the symptoms [24], similar to
the management of Cryptosporidium infection. In
addition, albendazole has been recommended as
initial therapy for microsporidiosis, except in cases
of E. bieneusi or Vittaforma corneae infection, both of
which seem to be intrinsically resistant to albenda-
zole [24]. Itraconazole in combination with alben-
dazole may be indicated for disseminated disease,
whereas topical fumagillin is recommended for
ocular infections [24].
BLASTOCYSTIS
Blastocystis spp. has become an important protozoa
in clinical practice around the world because of its
potential pathogenic role in humans. Immunocom-
promised individuals are more likely to develop
symptoms associated with Blastocystis, whereas
healthy individuals can have a self-limited disease
[49]. In terms of susceptible populations, both HIV
and transplant patients are at greater risk of devel-
oping symptoms associated with Blastocystis. For
example, the most common parasite associated with
diarrhea found in a cohort of liver/kidney transplant
patients in Brazil was Blastocystis (14%) [50]. About
11% of patients with AIDS in Ethiopia have been
found to have Blastocystis in their stools in contrast
to 0% in non-HIV-infected patients [13]. Similar
results were found in HIV-infected patients in
Thailand [14].
Currently, it has been suggested that the patho-
genesis of Blastocystis may be dependent upon sub-
type. At least nine subtypes of Blastocystis spp. can
infect humans [51], as identified though analysis of
the subunit ribosomal RNA gene. Subtype 3 is the
most common and has a cosmopolitan distribution;
followed by subtypes 1, 2, and 4 [49]. One study has
postulated a possible pathogenic mechanism for
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Intestinal protozoan infections Marcos and Gotuzzo
invasion with subtype 3 through the action of
cysteine proteases released by the parasite in the
intestines [52]. Cysteine proteases have been shown
to induce production of interleukin (IL)-8, as an
inflammatory marker, in human colonic epithelial
cells through a NF-kB-dependent mechanism [53].
Another study has demonstrated that Blastocystis
may invade the intestinal cells as evidenced by a
significant increase in the urinary levels of hyalur-
onidase, IL-6, and IL-8 in infected rats compared
with controls [54], which indicates that tissue
destruction and inflammation occurred in the
infected animal.
Blastocystis subtype 4 has also been described to
cause intestinal inflammation, as demonstrated by
induction of goblet cell hyperplasia and upregula-
tion of interferon-g expression, IL-12, and tumor
necrosis factor a in the cecal mucosa of rats [55].
Humoral immunity has been found to play a role in
this parasitic infection. A study demonstrated a
strong immune response in the form of increased
levels of IgA and IgM in intestinal secretions and
serum in orally infected mice [56]. During infection,
nitric oxide (NO) induces apoptosis-like cell death in
Blastocystis [57], but this parasite can evade the host
defense by depressing host NO production [58]. In
summary, at least Blastocystis spp. subtypes 3 and
4 have been demonstrated to produce inflammation
by invading the tissue of the host, in animal models.
Further research is needed to link these subtypes to
human disease.
Although infection by Blastocystis may be self-
limited, and not all subtypes are known to cause
disease, a careful evaluation should be performed in
patients with persistent symptoms as they may
benefit from treatment. Antimicrobials that have
been shown to be clinically effective against Blasto-
cystis include metronidazole, paramomycin, cotri-
moxazole, iodoquinol, ketoconazole, furazolidone,
tinidazole, nitazoxanide and Saccharomyces boulardii
&&
[59 ], but further randomized clinical trials are
needed.
CONCLUSION
The epidemiology of intestinal parasites has evolved
in recent years thanks to globalization, immigra-
tion, worldwide travel, and increased use of immu-
nosuppression for a number of medical conditions,
among others things. Intestinal protozoan infec-
tions are more commonly encountered in the
immunocompromised host, especially in those with
impaired T-cell function. The immune response to
these infections is complex and pathogenesis in
humans is poorly understood. Stool examination
by routine tests are insensitive, and special staining
www.co-infectiousdiseases.com 299
 Infections of the immunocompromised host
is needed to improve sensitivity. Molecular diagnos-
tic tests, including PCR, are highly sensitive tools for
identifying infection but are seldom available in
resource-poor countries. As few successful thera-
peutic approaches have been described in recent
years, the most important goal in the management
of these infections remains decreasing immunosup-
pression when possible. In conclusion, intestinal
protozoan infections are more prevalent in immu-
nocompromised hosts and management continues
to pose a serious challenge for clinicians.
Acknowledgements
We thank Dr Stephen Liang for help with editing and
review of this article.
Conflicts of interest
There are no conflicts of interest.
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An outstanding article that describes a complete overview of Blastocystis in
humans including management data.
www.co-infectiousdiseases.com 301