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African Health Sciences
Makerere University Medical School
ISSN: 1680-6905 EISSN: 1729-0503
Vol. 7, Num. 2, 2007, pp. 62 - 67
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African Health Sciences, Vol. 7, No. 2, June, 2007, pp. 62 - 67
Cyclosporiasis: an emerging public health concern around the world and in Africa
Robert M. Karanja 1, Wangeci Gatei2* and Njeri Wamae2
1Centre for Biotechnology Research & Development (CBRD), Kenya Medical Research Institute, P.O. Box 54840 City Square,
Nairobi, Kenya;
2Centre for Microbiology Research (CMR), Kenya Medical Research Institute, P.O. Box 19464-00200, Nairobi, Kenya;
Correspondence:
Robert M. Karanja
Centre for Biotechnology Research & Development (CBRD),
Kenya Medical Research Institute,
P.O. Box 54840, Nairobi, Kenya
Email: RKaranja@kemri.org
Code Number: hs07014
Background: Cyclosporiasis is an emerging gastro-enteric disease caused by the coccidia protozoan Cyclospora cayetanensis. It isassociated with diarrhoea among children in developing countries, in the Americas where C. cayetanensis is endemic, traveller’s diarrhoeaand/or food and waterborne outbreaks in the developed countries.
Objectives:The aim of this review is to highlight cyclosporiasis and its relevance to public health in East Africa and Africa at large.
Methods: All literature on Cyclospora, C. cayetanensis,cyclosporiasis in Africa, and endemic cyclosporiasis was searched from libraries,colleagues and internet but only literature on its history, clinical presentation, epidemiology in endemic settings, and occurrence inAfrica were scrutinised.
Results: In Sub Saharan Africa, cyclosporiasis has been reported in at least 3 countries, including Tanzania, in East Africa, occurring inboth immunocompromised and immunocompetent patients. Zoonotic species of Cyclospora have also been identified in East Africanprimates, indicating likely endemicity of this little reported disease in the region. This can be attributed to lack of awareness in thepublic and medical profession concerning the disease, and therefore not routinely checked at the health centres. Cyclosporiasis ischaracterized by intermittent diarrhoea, and secondary conditions or sequelae such as reactive arthritis syndrome (Reiter’s syndrome),have been associated with progression of the disease. Its management is based on antibiotics, an unusual scenario for a protozoa.
Conclusions: Although many aspects of this disease and its transmission remain an enigma, the situation has been rapidly changing since the disease first came to medical attention in the 1970s.
Introduction
Cyclosporiasis and Africa – should we be concerned?
Cyclosporiasis is a diarrhoeal disease caused by
the protozoan pathogen Cyclospora cayetanensis1 . It is
considered an emerging disease of public health concern
primarily in the developed countries where it has been
identified as the cause of several outbreaks in North
America and Europe, and with traveller’s diarrhoea2-6 . In
these countries, cyclosporiasis transmission has primarily
been linked to foods imported from developing
countries adding impetus to the review of food import
regulations with far reaching implications on developing
country economies that depend on North-South trade
in agricultural produce4-9 . The transmission of the disease
in the developing South where C. cayetanensis is endemic,
remains little understood but has been associated with
water and sanitation in Nepal, Guatemala, Nigeria and
Egypt7, 10, 11 .
Ashford is credited with having first identified C. cayetanensis as a human pathogen in 1979 in Papua
New Guinea 12 . Thereafter, the parasite remained largely
uninvestigated and it was not until 1994, when the first
detailed morphological description and naming of Cyclospora cayetanensis was done 1 . Few studies have been
carried out since then to determine the transmission and
epidemiology of cyclosporiasis in Africa and its public
health impact on the continent. The disease has been
reported in Nigeria, Tanzania and Egypt 13-15 . Although it
is thought to be self-limiting in immuno-competent
individuals, cyclosporiasis can cause prolonged diarrhoea
that could be life threatening in immuno-compromised
patients. Moreover, like other coccidian parasites, C.
cayetanensis has been associated with various sequelae
including biliary disease, aculculous cholecystitis,
Guillain-Barré syndrome and reactive arthritis syndrome
following prolonged infection 16-19.
The study of cyclosporiasis is rife with
difficulties that have largely contributed to its
underreporting in Africa and little public awareness 20 . A
key contributor to this is the specialised staining methods
for diagnosis that are not routinely carried out in clinicallaboratories 20-22 . Additionally, efforts to elucidate its transmission
and biology in endemic areas is impeded by lack
of sensitive and specific methods for Cyclospora detection
in the environment, agricultural produce and water bodies
and further compounded by the lack of a suitable
animal-model 23-26 . Cyclosporiasis has therefore remained
a little known disease albeit with potentially far reaching
impact on the health and economy of developing
countries due to its impact on the horticulture industry
as a food borne pathogen. Several publications pertaining
to the methods of diagnosis and detection exist and have
been ably reviewed by others 9 . Our aim is to bring this
disease to the attention of African health researchers and
to highlight potential areas of study in our likely endemic
setting.
History of Cyclosporiasis
According to Lainson 27 , it was Eimer who as early
as 1870 first described an organism in intestines of the
mole Talpa europaea that was eventually characterized and
named Cyclospora caryolytica by Schaudinn in 1902
28 . But C. glomericola, observed in the millipede, was the first
species to be classified as Cyclospora by Schneider who
established the genus in 1881
29 . So far C. glomericola is
the only species out of a total of 19 Cyclospora species
identified to date to be encountered in an invertebrate
host, the rest being found in reptiles (snakes) and
mammals (rodents and non-human primates)
27 .
It was not until the 1970s that cyclosporiasis first
came to medical attention when an un-described
coccidian was associated with diarrhoea in Papua New
Guinea 4, 12 . Thereafter, endemic cases were also reported
in Haiti, Nepal, Peru and linked to Travellers Diarrhoea
in the 1980s, where it was reported variously as
Cryptosporidium muris-like, a flagellate, an unsporulated
coccidian, a large Cryptosporidium, a blue-green alga
(cyanobacterium-like body), or a coccidian-like body 4, 30 . By 1990 the new pathogen was associated with chronic
diarrhoea in acquired immunodeficiency syndrome patients 31 . Nevertheless, it was not until the 1990s that
food and water-borne outbreaks in North America
grabbed public and scientific attention to the emergence
of the disease, after a food or waterborne outbreak of 21
was reported in a Chicago teaching hospital in 1990
32 .
This fuelled efforts to definitively identify and
characterise the pathogen, with the first breakthrough
occurring in 1992 when Ortega et al., reported they had
sporulated and excysted the oocysts, thus ending
speculation on the classification of the parasite and
placing it in the genus Cyclospora 33 . The same group finally
identified and characterised the causative agent as the
coccidian Cyclospora cayetanensis (Apicomplexa: Eimeriidae) using classical morphological methods
1, 30 .
However, molecular techniques have placed the
pathogen closer to Eimeria species, suggesting its classification
as such
34, 35 . Today, C. cayetanensis transmission in
developed countries through food and water borne
outbreaks has been well documented and understood,
however the modes of transmission and risk factors in
endemic areas remain poorly understood 4, 36, 37 .
Life cycle and Biology
Cyclospora cayetanensis is an obligate intracellular
parasite that is normally found in the jejunum. Oocysts
found in the stool can be mistaken for the common
Cryptosporidium spp. infecting humans, but can easily be
distinguished by their larger size (8-10 μm) using an
ocular micrometer
38 . The life cycle begins with the ingestion
of the sporulated oocyst in contaminated water
or food. Unlike Cryptosporidium, this oocyst when freshly
passed in the stool is not sporulated and therefore not
infective 1, 30 . Oocysts require a few days to weeks,
depending on climatic factors, to develop and mature in
the environment into the infective sporulated oocyst,
thus precluding direct fecal-oral transmission
1, 38 .
Temperatures ranging between 25-30ºC are most suitable
for sporulation. Upon being ingested, the oocysts excyst
in the gut, releasing the sporozoites, which proceed to
invade the epithelial cells of the small intestine
39, 40 . The
sporozoites undergo two generations of asexual reproduction
in the cell, whereby they form meronts that
contain numerous merozoites 40 . The first generation
meronts have 8-12 merozoites, whilst the second have
only 4 merozoites, which penetrate new cells to form
gametes. Some of these gametes enlarge to form the
female macrogametes and some microgametes that
undergo meiosis to form numerous flagellated spermlike
microgametes. The mature microgametes leave the
microgametocyte and migrate to fertilize the
macrogamete. The development of a resilient oocyst
wall around the zygote, which contains 2 sporocysts or
small oocysts, makes up the unsporulated oocyst.
Eventually the oocyst is passed out with stool to begin
the process of sporulation. Sporogyny commences in
the presence of higher atmospheric oxygen concentrations
and is complete between 7-12 days 40-43 .
Clinical aspects of C. cayetanensis infection
Presentation:
The clinical presentation of C. cayetanensis may
include gastrointestinal (GI) symptoms such as loose or
watery diarrhoea, nausea, vomiting, abdominal cramps,
loss of appetite, or unintentional weight loss; or
constitutional symptoms such as fever, chills, muscleaches, joint aches, generalized body aches, headache, or
fatigue
8 . Although asymptomatic infections are known
to occur, the onset of symptoms in naïve populations
observed in outbreaks is 1-14 days post exposure and is
often accompanied by a characteristic waxing and waning
of symptoms 6, 40, 41, 44 . In endemic countries, symptoms
begin approximately 5-8 days after and may persist for a
month or more. However, infection without watery
diarrhoea is a common occurrence and has been
observed in Haiti among other areas
45 .
Diagnosis
Detection is based on the identification of
oocysts in stool specimens using modified acid fast
staining, or hot safranin test
21 . Where cyclosporiasis is
suspected, up to 3 stool specimens taken 2 days apart
should be tested to rule out the parasite. A rapid method
of identification is possible on wet mounts using fluorescent
microscopy employing a filter with a wavelength
in the range of 340-380 nm, which reveals the bright,
pale blue oocysts glow
30 . Polymerase chain methods
(PCR) have also been developed for diagnosis and
detection in the environment, but the primers appears
to cross react with Eimeria spp.
26, 35, 46 .
Differential diagnosis of cyclosporiasis includes
all other causes of diarrhoea. Infections with Giardia,
Cryptosporidium, Isospora, Toxoplasma and Microsporidia
should be suspected in cases of persistent diarrhoea that
does not respond to the usual treatment (6, 20, 31, 36, 41, 47).
Cyclosporiasis can also present symptoms closely
resembling celiac disease and irritable bowel syndrome 48.
Sequelae
Like cryptosporidiosis, C. cayetanensis infection
has also been associated with the onset of various extraintestinal
complications that may accompany prolonged
infection, especially in the HIV immunocompromised
patients. These include acalculous cholecystitis
19 ; biliary
disease
18 , Guillian-Barré syndrome
17 , and Reiter or
reactive arthritis syndrome
16 . One case of C. cayetanensis oocysts found in the sputum of 60-year-old HIV negative
male with a history of successfully treated TB has been
reported in Argentina
49 , and a similar case has also been
reported in Egypt where a 45 year-old HIV negative
male with TB history also presented oocysts in the sputum
accompanied with active TB infection
50 . The latter has
prompted calls for the inclusion of cyclosporiasis as a
new causative agent of respiratory disease and as a
differential diagnosis for TB. In both TB negative and
positive cases, the patients presented with loss of weight,
cough with expectoration of purulent sputum and dyspnea. The implications of pulmonary infection to the
biology, life cycle and transmission of C. cayetanensis remains to be evaluated, as does its interaction with TB, a
disease currently on the increase in Africa due to the
HIV/AIDS pandemic
51 .
Treatment
Symptoms resolve with the administration of
Trimethoprim-Sulfamethoxazole, the standard treatment
for cyclosporiasis at 160/800 mg oral dose taken twice
a day for 7 days or 160/800 mg oral dose taken 4 times
a day for 10 days in immunocompromised patients with
AIDS often with symptoms resolving and passage of
oocysts in the stool ceasing within 24-48 hr
52, 53 .
Epidemiology in endemic setting
The first epidemiological studies conducted in
an area endemic for C. cayetanensis, were carried out in
1997-1998 in Guatemala where raspberry exports to
USA were linked to cyclosporiasis outbreaks
10 . Children
of age groups 1.5 to 4 years and 5 to 9 years were found
to be 5 times more likely to be positive for C. cayetanensis in stool samples than adults. Overall infection did not
differ significantly by sex. The infection rates were also
found to fluctuate seasonally, with prevalence peaking in
the rainy season (6.7%) and falling to undetectable levels
in the dry seasons. Drinking of untreated water or
swimming in rivers or springs, having a septic tank as
opposed to municipal sewage, direct contact with the
soil and ownership of dogs, chicken or other fowls, were
all found to significantly increase risk of infection
although cats and pigs did not
10 .
Subsequent epidemiological studies in endemics
areas of Haiti, Nepal and Peru have corroborated higher
infection rates in children, seasonal fluctuation of
prevalence, and risk associated with water source and
ownership of domestic animals, particularly fowl, guinea
pigs and rabbits
37, 54 . However no oocysts were detected
in a survey for C. cayetanensis in domestic animals carried
out for 1.5 years in an endemic area in Haiti, ruling out
domestic animals as a reservoir
24 . Studies in Peru have
also shown that previous infection offers significant protection
against subsequent exposures
54 . This consolation
is however short lived as clinical sequale may still be
linked with asymptomatic infection. Humans are
therefore the only known host for C. cayetanensis, but
the eating of raw or insufficiently cooked bivalves, which
are filter feeders that concentrate pathogens from waters,
has been shown to be a risk factor
55 .
Reports of Cyclospora spp. infecting non-human
primates in the East African countries of Uganda, Kenya,
Tanzania and Ethiopia have led to efforts to conduct studies of non-human primates in order to better
understand the epidemiology and ecology of endemic
cyclosporiasis
25, 56-59 . Host specificity of Cyclospora species
in the different non-human primates, geographic
overlaps of both monkey and parasite species
notwithstanding, corroborated the likelihood of humans
as the sole definitive host of C. cayetanensis 58 . However
the collection of oocyst positive stools from the studied
troops of vervet monkeys, baboons and colobus
monkeys at all times of the year in Kenya, which is notable
for extreme weather patterns, demonstrated a lack
of seasonality in infection contrary to expectations
58 .
Cyclospora the enigma
It is clear that the epidemiology of
cyclosporiasis as we know it today is a study in contradictions,
as the causative agent itself remains shrouded in
mystery. How can a pathogen incapable of direct faecaloral
infection and lacking a zoonotic reservoir or
ubiquitous presence in the environment 38 , be responsible
for so many widespread outbreaks of gastroenteritis all
over the world? Trace amounts of oocyst contamination
in food products indicate that the infective dose of C.
cayetanensis is likely to be very low 38 . However attempts
at experimental infection in both humans and animals
have all proved futile 25, 60 . The lack of an animal model
has therefore made it hard to determine the viability of
oocyst exposed to varying environment conditions that
may impact its transmission 38 . While most outbreaks
have been linked to food sources, just as many
unexplained sporadic cases linked to water/sewage
transmission have been reported in the developed
countries 32, 38, 61 . These cases may signify ubiquitous
endemicity, remaining undetected due to seasonality of
infection, but by what means the parasite survives from
one infection season to the next remains unknown.
Even more puzzling is the dearth of C.
cayetanensis reports in African populations and as a cause
of traveller’s diarrhoea in visitors returning from the
continent. The screening of over 4,800 samples using
modified acid fast staining, and other concerted efforts
in previous years have all failed to determine the presence
of C. cayetanensis in Kenya 62 . In addition to economic
restraints for effective routine diagnosis in health centres
and national/regional surveillance, it has been
postulated that the amount of sulpha drugs administered
in sub Saharan Africa as drugs of choice for malaria and
other infectious diseases may suppress the parasite,
humans being the only reservoir
36 . Could sulfadoxinepyrimethamine
(SP), the now largely ineffective but still
affordable treatment of malaria, be our unlikely saviour?
Or is it the use of trimethoprim (Septrin), which is widely used as a first line of antibiotics and in management of
HIV before ARVs? Significantly higher HIV and malaria
prevalence in sub-Saharan Africa may account for a higher
drug pressure than other parts of the world, however,
the withdrawal of SP as a first line antimalarial due to
resistance and similar use of Septrin in C. cayetanensis endemic Peru and Haiti where 5-11% HIV prevalence
have been documented, makes the dearth of reported
African cyclosporiasis all the more mysterious.
The controversy and questions surrounding C.
cayetanensis are no less intriguing. Whereas there is
compelling molecular evidence for its reclassification as
a mammalian Eimeria species, only C. cayetanensis DNA
sequences and C. colobi, C. cercopitheci and C. papionis from
East African non-human primates are available
27, 34, 36, 57 .
The way forward on the classification of this parasite in
the light of these new developments remains uncharted
waters. The biology of C. cayetanensis in the host is no
less intriguing. The presence of oocysts in HIV negative
TB patients strongly suggests the existence of an extraintestinal
parasite lifecycle and colonization in humans
that is yet unknown
49, 50 . Moreover, more studies are
required to determine whether C. cayetanensis interacts
with TB or has only been observed in TB patients because
it is an acid-fast staining organism like the TB bacillum.
Extra-intestinal stages in the life cycle of Cyclospora talpae in European moles have been demonstrated in the liver
where sexual stages develop in the bile duct epithelial
cells
63, 64 . C. cayetanensis has similarly been shown to
cause biliary disease in HIV/AIDS patients suggesting
possible colonization of the liver
18, 36 . Unfortunately,
the lack of animal/experimental models remains an
impediment to resolving these questions.
Conclusions and recommendations
Cyclosporiasis therefore presents an everbroadening frontier cutting across multiple disciplines of research including clinicians, epidemiologists, parasitologists, veterinarians, environmental scientists among others. As a food-borne disease that impacts on horticulture (the backbone of most developing country economies) and primarily infects children and HIV/AIDS patients, routine surveillance in both the population and environment should be carried out. Surveillance in populations should include sputum samples regardless of TB or HIV status. The role of its interaction with TB and/or HIV should also be elucidated. Use of nonpathogen Cyclospora spp. such as non-human primates cyclosporiasis and C. talpae and mole hosts should be developed as alternative animal models for the study of extra-intestinal colonization and disease. Additionally, the possible role of sulphur drugs in control of cyclosporiasis should be evaluated, in order to address the impact of the disease in Africa.
Acknowledgements
This work was funded by the Centre for Microbiology Research and is published with the permission of Director, Kenya Medical Research Institute.
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