Human African trypanosomiasis in non-endemic areas: review
on pathogenesis, clinical manifestation and therapy of cases
published in the last 20 years
Masters Thesis
Stephanie Migchelsen, MSc student
Biomedical Sciences, Universiteit Utrecht
Supervisors:
Dr Emily Adams- Koninklijk Instituut voor de Tropen- Biomedical Research
Prof Dr IM Andy Hoepelman- Head, Dept of Internal medicine and Infection disease, UMC Utrecht
Human African Trypanosomiasis (HAT), also known as African HAT, is caused by two subspecies of
the flagellate protozoan Trypanosoma brucei. Trypanosomes are single-celled eukaryotic parasites and
members of the Kinetoplastida order. These parasites are characterized by a kinetoplast, a granule containing
DNA within the mitochondria and associated with movement of the flagella [1]. Other members of the
kinetoplasts include the causative agents for Chagas disease (American trypanosomiasis), caused by T. cruzi [2]
and the many species of leishmania (Leishmania donovani, L. viannia) that cause visceral and cutaneous
leishmaniasis [3]. T. brucei is endemic to sub-Saharan Africa, where it is a major threat to public health in 36
countries [4]. Only two subspecies of T. brucei [5] are pathogenic to humans; T. b. gambiense causes a chronic
form of HAT in West and Central Africa, while T. b. rhodesiense is the pathogenic agent for the more acute
form of the disease and is endemic to Eastern Africa [1, 6]. The countries most at risk are Angola, Central
African Republic, Chad, Congo, Democratic Republic of the Congo, and Sudan in Central Africa; Côte d’Ivoire
and Guinea in West Africa and Uganda, Malawi and Tanzania in East Africa [7].
Fig 1. Map of HAT. From [4]
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EPIDEMIOLOGY AND TRANSMISSION
Up until the mid-2000s, there was a steady increase in the number of cases for a number of reasons: civil
unrest had disrupted public health systems responsible for control programmes in endemic regions [5], changes
in vegetation and climate, and migration of cattle herds [8]. Recently, the number of cases has gone down as
vector control programmes are re-established in endemic areas [6, 7]. These programmes aim to reduce the
number of HAT cases by controlling the tsetse fly population. Tsetse flies (Glossina) transmit trypanosomes
and can be found in endemic foci in sub-Saharan Africa. It is estimated that Glossina fuscipes and the two
related subspecies of G. palpalis and G. morsitans are responsible for over 90% of HAT cases [9]. Depending
on the species, tsetse flies can be found along rivers and in swamps in western Africa and in the savannahs of
eastern Africa [10]. These regions are roughly divided by the Great Rift Valley [6], although it has been
reported that the two strains may have become sympatric in Uganda [11].Tsetse flies are not endemic outside of
sub-Saharan Africa, making the disease relatively unknown in the developed world. Vector control is one of
the most efficient methods of preventing HAT, both locally in villages and regionally across larger areas [9].
Blue and black targets [9] and traps baited with artificial scents, such as acetone [12], have been proven to be
simpler and, some would argue, more cost-effective than the release of sterile males [13].
Fig 4. Tsetse trap. From [1]
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With the re-establishment of vector control programmes in endemic areas, it should be possible to use these
relatively low-tech and inexpensive methods to control and eliminate the tsetse flies.
The WHO reports that approximately 17, 600 new cases are diagnosed each year, with a cumulative rate of
50,000- 70,000 cases. A totally of 60 million people remain at risk and 48,000 people die from HAT [14] (both
forms combined), despite restored access to endemic areas, increased access to therapeutic drugs, the
commitment of non-governmental organizations to combat the disease, and increased international awareness
of the disease [15]. It is estimated that in endemic areas, HAT results in 1.78 million disability-adjusted life
years (DALYs) lost [16]. With an average treatment cost of only US$17 per DALY averted, it is highly
attractive [16] to treat cases of HAT, based on the rule of thumb that a cost of US$25 per DALY averted is
highly attractive [17]. These figures do not take into account the estimated tens of thousands of cases that go
unreported every year, which may be as high as 50,000 cases per year [16].
PATHOGENESIS
The parasites are transmitted through the bites of infected tsetse flies [8], and undergo complex changes during
their life cycle, which varies from the gut of the insect vector to the blood stream of the human host. The tsetse
fly takes a blood meal from an infected vertebrate (animal or human) reservoir, ingesting bloodstream
trypomastigotes. The parasites multiply in the fly’s midgut as metacyclics, transform then travel to the salivary
glands where they multiply again. When the fly takes its next blood meal, the parasites are transferred and the
new host is infected. The parasites once again transform into trypomastigotes and multiply by binary fission in
body fluids such as blood, lymph and spinal fluid [18].
HAT can be identified in two stages, depending on whether parasites have passed crossed the blood-brain
barrier (BBB) into the cerebrospinal fluid (CSF) [6]. After the parasites are inoculated into man, they
proliferate at the infection site, causing an inflammatory nodule, also known as a trypanosomal chancre. This
ulcer can be seen in approximately half of all patients infected with T. b. rhodesiense [19]; however it is rarely
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seen in T. b. gambiense infections, possibly because most infections are detected after the chancre has
disappeared [20].
Fig. 2 Typical trypanosomal chancre. From [21]
Parasites then spread to the lymph nodes and reach the blood stream which marks the beginning of the
hemolymphatic stage [5]. Up to 50% of European patients will develop a rash on the torso and most patients
will have swollen, palpable lymph nodes [22]. The patient suffers from fever, headache, pruritus and
generalized edema and malaise. Patients suffering from west HAT will show generalized lymphadenopathy,
usually on the back of the neck, a condition known as Winterbottom’s sign. Parasites can, at this stage, be
microscopically detected in blood, lymph and aspirates.
5
Fig 3. Trypomastigotes (“stumpy form”) among blood cells. From [5]
Signs and symptoms may subside after the acute first stage. In the meningoencephalitic stage, parasites enter
into the organs, including the CNS [5, 23]. Disease stage can be determined by the presence of trypanosomes
in the CSF. As this requires a lumbar puncture, this is usually performed after an initial dose of suramin, to
reduce the possibility of contaminating the CSF samples with trypomastigotes from the blood stream [24]. The
trypanosomes cross the blood-brain barrier near intracellular junctions and is an active process [25].This
process is quite rapid in T. b. rhodesiense infections, taking only a few weeks, but lasting a few months or even
years in T. b. gambiense infection. As the disease progresses, the classical signs of HAT arise [26]: severe
headaches, a disruption of the circadian rhythm, with night time insomnia and daytime somnolence, altered
mental functions and personality changes may arise while generalised meningoencephalitis may lead to coma
and death [8]. Other symptoms include anorexia, altered endocrine functions [27], demyelination and
leukoencephalitis are also typical [28].
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DIAGNOSIS
Parasite numbers of less than 100 trypanosomes/mL can be difficult to detect with microscopy alone [20].
Concentration methods such as microhematocrit centrifugation [29], quantitative buffy-coat analysis [30-32] or
mini-anion exchange columns [33] can be used to concentrate the parasites for easier microscopic detection. In
West Africa, many endemic screening programmes rely on the card-agglutination test for trypanosomiasis
(CATT), which tests the agglutination of trypanosomes in the presence of specific antibodies, is a sensitive
assay to detect T. b. gambiense antibodies in serum [34, 35]. T. b. gambiense antibodies can also be detected by
ELISA or immunofluorescence [36-38] although these are not the most practical methods to be used in the field
due to their energy and reagent requirements. CATT is not effective for detecting T. b. rhodesiense infections
and microscopic visualization should always be performed to confirm a positive test. Molecular techniques,
such as PCR, have been developed and evaluated but have yet to be adopted in the field, due to the need for
trained technicians, the proper equipment, a constant source of power, and the required storage methods for the
supplies [1, 8]. Furthermore, the tests must also be standardized and validated in a clinical setting [20]. Some
researchers report prolonged positivity after successful treatment, which could be misinterpreted as a continued
infection [39, 40]. Recent innovations such as a with a novel loop-mediated amplification (LAMP) have led to
the development of techniques for the detection of trypanosomes and may prove to be a useful alternative to
PCR [41]. LAMP has no need for a thermocycler, with the whole reaction taking place between 60-65ºC, have
a high specificity thanks to a complex set of primers and the products are easily detectable using fluorescent
dyes and UV light [41].
Trypanosomes are encapsulated in a variant surface glycoprotein (VSG) that protects the parasite from lytic
factors in plasma [42]. After infection, the VSG is recognized by the host’s immune system, which leads nonspecific B-cell activation and to the production of IgM and IgG antibodies to neutralise the parasites in an
attempt to decrease parasitemia [43]. A small percentage of trypanosomes, however, will have different surface
coats and will escape detection, continuing to proliferate until new coat-specific antibodies are produced by the
host’s immune system. This is termed “antigenic variation”. It is suspected that there are over 2000 VSG genes,
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including pseudogenes, although only one gene is expressed at a time [44, 45]. This high degree of antigenic
variation means that a vaccine will be extremely difficult to produce [46], and that a high level of IgM can
usually be detected in the patient. This elevated measurement is considered a good indication of trypanosomal
infection [28].
TREATMENT
There are only four licensed drugs for the treatment of HAT [47]. Pentamidine and suramin are available to
treat the disease before parasites invade the CNS. Pentamidine is the recommended drug for treatment of firststage west HAT. It is administered intramuscularly for one week and is generally well-tolerated [48].
Complications that arise from intramuscular injections include pain and swelling at the injection site,
abdominal pain or gastrointestinal problems [49]. Suramin is recommended for treatment against first-stage
west HAT. Nephrotoxocity, peripheral neuropathy and thrombocytopenia are frequent but mild side effects and
can easily be treated. Because hypersensitivity is also quite common, it is recommended that a low test dose be
administered [50] prior to beginning the rather long (30 days) and complex drug course [51].
To fully treat trypanosomal infection in the CNS, the drug must be able to cross the blood-brain barrier [8]; two
such drugs are recommended. For treatment of second-stage HAT, melarsoprol remains the most widely-used
drug; it is the only drug available to treat rhodesiense-caused HAT, is the most economical but requires a
lengthy and complex treatment regimen, and can be highly toxic. This organoarsenic compound causes
frequent adverse reactions that can be quite severe and even life-threatening. Post-treatment reactive
encephalopathy (PTRE) occurs in 20% of all patients receiving melarsoprol and two to 12% of those receiving
treatment die as a result of complications [52, 53]. Patients must be carefully monitored during the course of
treatment and diazepam or dexamethasone are recommended to manage the encephalopathy [49]. The onset of
headaches and fever can be indicative of possible complications [54]. The cause of PTRE remains unknown,
although many hypotheses exist. These include: (i) sub-curative chemotherapy; (ii) immune complex
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deposition; (iii) aberrant immune response to glial cell-associated antigens; (iv) autoimmune mechanisms; and
(v) arsenical toxicity [55-59].
Eflornithine is the most recent of the treatments against African trypanosomiasis [14]. It has a much lower
mortality than melarsoprol and therefore it is recommended as the drug of choice to treat second-stage
gambiense-disease [60-62]. It is however, a very expensive drug and its prescription and use may underline the
disparity in access to required pharmaceuticals that exists between first world and developing countries [63]. T.
b. rhodesiense shows an innate reduced susceptibility against eflornithine and thus treatment with melarsoprol
is recommended [64]. Treatment with eflornithine requires 2 weeks of injections repeated 4 times per day;
bacterial infection at the site of the catheter can lead to sepsis but can easily be prevented with proper care [20].
Other potential side effects include anemia, gastrointestinal symptoms and convulsions [65]. Recently the
Drugs for Neglected Diseases initiative (DNDi)recommended a combined nifurtimox-eflornithine treatment
combining 7 days eflornithine (2 infusions per day) followed by 10 days of nifurtimox taken as an oral dose
[14] thereby reducing the number of injections.
Trials are on-going to make more efficient use of existing drugs; combination therapies with known
trypanocides [66] as well as shorter treatment regimens of eflornithine and melarsoprol are being tested [67,
68]. Shorter drug regimens should translate to reduced admission times and greater patient adherence. For
optimal treatment, skilled medical personnel are required, preferably ones familiar with the possible
complications and treatment of HAT. While medical staff experience in dealing with HAT may be difficult to
come by in non-endemic areas, patients are more likely to receive a more thorough treatment, including proper
nutrition and complete monitoring [1].
Due to the fact that HAT is classified as a neglected tropical disease (NTD) [7, 69], there is little incentive for
pharmaceuticals to invest in research, development or production of new anti-trypanosomal compounds. Those
most in need of the drug are not able to pay for treatment and thus there is little financial enticement to produce
these drugs. Recently the WHO, along with several international and non-governmental organizations [70-72]
convinced Aventis, the pharmaceutical company that manufactures these drugs, to guarantee a gratis production
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of pentamidine, melarsoprol and eflornithine [73], as well as support for research into new drugs and other
means of control. Storage and transport of the drugs is to be overseen by Médecins Sans Frontières (MSF).
Bayer has also agreed to provide gratis production of suramin and also to continue production of nifurtimox.
Long-term availability of all trypanocides is still uncertain [21].
Cases of HAT are found only where tsetse flies are located, however some travelers have been reported as
being HAT positive. Here, the non-endemic cases of HAT are reported as well as their frequency and outcome
in an effort to raise awareness about this NTD. The effects of HAT are wide reaching, not only in Africa where
it is an endemic disease, but also in non-endemic, developed areas.
CLINICAL CASES FOUND IN LITERATURE
A recent search of PubMed and ProMED Mail resulted in 59 reported cases of human African trypanosomiasis.
The search was limited to the past 20 years (2010-1990). Many articles published before 1990 proved difficult
to obtain through an academic journal subscription. ProMED Mail archives can be searched dating back to
1994, when it was founded; a search for “trypanosomiasis” returned 184 reports. In total, 8 cases were reported
only on ProMED which were not encountered via the PubMed search. Many of these cases were also reported
on TropNetEurop (http://www.tropnet.net/special_reports/tryps_ex_serengeti.pdf), a European surveillance
network for imported infectious diseases.
The other 51 cases were found through a PubMed search (search terms: “trypanosoma OR HAT OR African
trypanosomiasis NOT Chagas NOT animal NOT reservoir”) and through a bibliographic search of articles.
While it is apparent that not all cases will have been reported and/or published, we are confident that a large
number of non-endemic cases have been included in this review. Migration, tourism, and military presence in
areas at risk may lead to an increase in the number of cases seen in non-endemic areas [22]. For this reason, it
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is important that clinicians and physicians be made aware of the risk of HAT, a disease that is fatal if left
untreated.
WEST AFRICAN TRYPANOSOMIASIS
Fourteen cases of west HAT were detected in a literature search (Table 1). All the cases were either immigrants
from endemic regions who had migrated to Europe or North America [74-77], or cases of ex-patriots who had
been stationed in endemic regions [78-83]. Three reported cases did not specify the reason for exposure [8385]. All of the cases encountered were diagnosed after a significant amount of time had passed after the initial
infection, which is typical for the chronic form of HAT as symptoms may subside while the immune system
reduces the parasitic load [5]. Of the 14 cases in this review, 8 cases were diagnosed in the first stage and 6
were diagnosed in the second stage. Some interesting points arise from a review of these cases.
A New Zealand man who was posted in Nigeria and Gabon and was treated in the United Kingdom [78], but
was initially diagnosed with Loa loa and Schistosomiasis and was treated; however splenomegaly,
lymphadenopathy and elevated IgM levels persisted. Two months after his initial presentation at the hospital,
he returned and trypanosomes were detected in a blood smear and lymph node aspirates. He was treated and
cured with suramin and difluoromethylornithine. Individually, these parasitic infections are rarely seen in nonendemic regions; for one patient to be diagnosed with all three seems “most improbable” [78]. It is important to
remember that travelers to endemic regions may be exposed to many possible parasitic infections. Although
one disease may be diagnosed, physicians should consider other possible infections, especially if atypical
symptoms are present.
It has previously been mentioned that it can be difficult to obtain the required pharmaceuticals to treat a patient.
Bisoffi et. al. (2005) reported a case in which eflornithine for stage 2 west HAT was obtained from the WHO
but was subsequently delayed by 9 days while the drugs were held at Italian customs [85]. Luckily symptoms
abated once eflornithine treatment was begun; lymphadenopathy resolved and a normal neurologic status were
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reported after the treatment. The patient had reported feeling unwell for over 6 months before seeking
treatment; while it is unlikely that a 9-day delay caused any significant damage, this case does highlight the
importance of having timely access to the required pharmaceutical treatment. Had the patient been suffering
from the more acute east HAT, it is likely that this 9-day delay could have had severe ramifications, including
coma or even death.
One common problem across most of the cases in non-endemic regions is an initial misdiagnosis. Western
HAT is difficult to diagnose; its chronic nature is characterized by low parasitemia and may remain
undiagnosed and unrecognized for years [22, 81]. Clinical signs and symptoms are generally non-specific.
Many patients are initially diagnosed and/or presumptively treated for malaria [84-86], however as symptoms
persist there is a need to reassess the diagnosis. Another possible misdiagnosis is Epstein-Barr virus (EBV).
EBV presentation is variable and in cases wherein no trypanosomes are initially detected EBV can indeed seem
like an appropriate diagnosis [80]. In one particular case [80], the patient was incorrectly diagnosed with EBV
and the correct diagnosis of HAT wasn’t obtained until after emergency hospitalization 6 months later.
Patients with west HAT have been reported to have antibodies against Toxoplasma gondii, Strongyloides
stercoralis [76], Epstein-Barr virus, cytomegalovirus [74], Plasmodium fieldi, Plasmodium brasiliana and
Borrelia burgdorferi [87], further complicating diagnosis and reinforcing the shortcomings of serological
testing and emphasizing the need for better and more sensitive means of detection in blood and CSF [88, 89].
In only one reported case of west HAT was a trypanosomal ulcer, or chancre, noted [79]. This wound at the site
of infection is more common in cases of east HAT rather than west HAT. In a review of trypanosomal cases
between 1904 and 1963, Duggan and Hutchison reported that only 19 of 84 patients infected with T. b.
gambiense had chancre [19], however no description of the lesions are included. Tatibouet et. al. (1982)
reviewed 12 cases of west HAT recorded in France between 1967 and 1979 and reported that 42% exhibited
chancres, describing them as circumscribed, red, indurated nodules between 4-10 cm in diameter [90].
Chancres appear much more often in patients suffering from East African trypanosomiasis, with lesions in 7012
90% of cases appearing 5 to 10 days after being bitten by the infected tsetse fly, at around the same time as
fever and detectable parasitemia in the blood [19].
Of the fourteen published cases of west HAT in non-endemic regions, only 4 were regarding infected
immigrants from endemic areas. Prior to 1990, 5 imported cases were seen in the United States, all African
nationals living abroad [21]. Of the four cases since 1990, two were seen in the Netherlands [75, 77] and a third
was seen in France [74] and the fourth was treated in Canada [76]. All were successfully treated although the
correct diagnosis was sometimes difficult to come to.
EAST AFRICAN TRYPANOSOMIASIS
East African trypanosomiasis is distributed throughout eastern and south-eastern Africa, an area encompassing
Tanzania, Uganda, Kenya, Zambia, Zimbabwe and Rwanda, among others, countries that are receiving an
increasing number of tourists from the developed world [91]. HAT due to T. b. rhodesiense is most likely to be
seen in travelers to national parks or game parks, where the ungulate animals so popular with safari tourists,
serve as a reservoir for the parasite [83]. Unlike west HAT, east HAT is a much more acute form of the disease;
death can occur in less than 2 weeks after being bitten by an infected tsetse fly [92]. The most typical signs are
the trypanosomal chancre at the sight of infection and high grade fever. Substantial parasitemia can be detected
in the blood. Incubation can be a little as 3 days, although is most typically between 6-10 days. Approximately
20,000- 40,000 people are currently infected with east HAT in Africa [93]. More foreigners travel to areas
endemic for east HAT than west HAT and thus more are infected with east HAT and more cases are seen by
physicians in non-endemic areas.
Because east HAT is endemic to areas popular with tourists, an increase in the number of cases seen in
travelers returning to non-endemic areas may serve as a warning of a potential outbreak in the region.
Such was the case in 2001, when nine cases of HAT were detected in Europe through TropNetEurop, a sentinel
surveillance network of clinics in Europe PROMEDMAIL [53, 94, 95]. Although prior to the early 1990s the
number of tourists infected with HAT has been very low, the area is endemic for the disease. All nine patients
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had traveled to Serengeti and Tarangire National Parks in Tanzania, among other destinations. Ranging in age
from 27 to 68, all but one (from South Africa) were from Europe. All showed fever and most of the patients
showed the trypanosomal chancre. Microscopy of thick and thin blood smears showed trypanosomes. Six
patients were treated with suramin during the early stage, however 3 had multiorgan failure and showed signs
of cerebral involvement; these patients were treated with either pentamidine or melarsoprol. Specific
pharmaceuticals were difficult to obtain and were not chosen for the specific disease stage of the patient, but
rather availability [53]. One patient, a 53-year-old Dutch woman succumbed to the disease [95, 96]. This
patient was treated with a single dose of suramine in South Africa and after trypanosomes were detected in the
CSF, melarsoprol treatment was begun. The patient continued with her travels through South Africa. She
continued to suffer from headaches, fever and neurological deterioration. Five days after the last dose of
melarsoprol, the patient became paralyzed, went into a coma and required artificial ventilation. She was
repatriated from South Africa to the Netherlands and died approximately 4 months after the on-set of
symptoms.
Similar to the problems faced obtaining pentamidine and eflornithine to treat cases of T. b. gambiense HAT,
many physicians face difficulties acquiring suramin or melarsoprol to treat their patients suffering from T. b.
rhodesiense HAT. In cases of east HAT, it is imperative that patients be treated as soon as possible, due to the
acute nature of the infection.
Within a one-week period in 2000, two patients were admitted to the Hospital for Tropical Diseases in London
[97, 98]. Two men returning from safaris in Zambia and Tanzania, within days of each other, had been bitten
several times by mosquitoes and tsetse flies. Both suffered from diarrhea, vomiting and fever. Upon admission
to hospitals, numerous trypomastigotes were detected in microscopic examination of blood smears. Neither
patient had any CNS involvement; both were treated with suramin in London. Treatment was generally
uncomplicated but significant effort went into obtaining the drugs. The drug was not available at the hospital’s
pharmacy or from regional infectious or tropical disease units in the United Kingdom, France or Belgium. A
small supply was finally obtained from the Liverpool School of Tropical Medicine which sufficed until a more
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complete course was provided by the CDC. These cases highlight the need for physicians involved in the
management of patients from tropical regions to have easy access to the drugs required to treat the potentially
life-threatening diseases these patients may encounter [97].
Even with rapid treatment, patients can face complications. Melarsoprol is an arsenical trypanocide that is used
only for stage 2 treatment because of its numerous side effects. It must be administered using a propylene
glycol solvent; both the drug and the solvent are highly irritating [21]. Cutaneous irritations, fever, vomiting,
diarrhea and polyneuropathy are all common however the most severe reaction is post-treatment reactive
encephalopathy (PTRE) which is lethal in approximately 5% of patients. Arsenical encephalopathy can present
with convulsions, cerebral edema, coma, or mental disturbances [52]. The mechanisms underlying this
complication is still unknown [96]; HAT-related encephalopathy is characterized by multifocal lesions in the
deep white matter [99]. MRIs can be a valuable tool in the management of encephalopathic HAT; treatment
should continue if the scan shows features of trypanosomal encephalopathy rather than melarsoprol-induced
encephalopathy [96, 99].
A 30-year-old man was admitted to the Institute of Tropical Medicine in France after an insect bite while on
vacation in Rwanda left him with a severe headache and anorexia [99]. Examination showed
hepatosplenomegaly, lymphadenopathy and purpura. Trypanosomes were detected in blood, marrow and CSF
smears, confirming CNS involvement. An MRI was performed and revealed a thickening of the meninges.
Treatment with prednisolone and melarsoprol were initiated but twitching and encephalopathy developed after
the second course of melarsoprol. A CT scan indicated lesions of the internal capsules. As previously
mentioned, neurological abnormalities during HAT can be due to brain infection by the parasites or posttherapeutic reactive encephalopathy (PTRE), as the parasites cross the blood-brain barrier or diffuse lesions as
a result of hypoxia caused by an unknown mechanism [52], respectively.
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In the United States, the Centre for Disease Control and Prevention (CDC) provides all the pharmaceuticals to
treat HAT. As such, it maintains records of all HAT patients treated. The disease is virtually unknown in the
United States [100]; only 14 cases were diagnosed and treated between 1968 and 1985 [101] and less than ten
were reported during the two-decade period of this search [21, 24, 43, 102-104]. With such a centralized system
for the distribution of medication, any trends in cases would hopefully become immediately apparent.
CONCLUSIONS
Here, the cases of east and west HAT in non-endemic areas have been reviewed. HAT, in both its forms, is
rarely encountered in the developed world; without experience and expertise required there will continue to be
difficulties in the diagnosis [22]. Physicians should be made aware of the disease and always consider HAT if
their patient has traveled to an endemic area. The above cases are an important example of a tropical disease
brought to a non-endemic country by immigration and tourism.
Non-endemic cases encountered over the past 20 years have been imported largely due to North Americans and
Europeans traveling to endemic areas for various reasons, such as military training or tourism in game parks;
also, cases are observed in immigrants arriving from endemic areas, or in ex-patriots returning from postings
abroad. Interestingly, the epidemiology of HAT seen in non-endemic areas is the opposite of the disease
epidemiology seen in Africa: of the estimated 50,000- 70, 000 cases in endemic areas of Africa, more than 90%
of these cases are due to T. b. gambiense [4], while the remaining cases are due to T. b. rhodesiense. According
to the WHO (J Jannin, unpublished), approximately 20 cases (40%) of T. b. gambiense cases and 30 T. b.
rhodesiense cases (60%) are diagnosed yearly outside of endemic areas [22].T. b. gambiense is most commonly
seen in migrants arriving from and expatriates living in or returning from rural areas in western Africa, whereas
T. b. rhodesiense is most often seen in travelers returning from safari in east African game parks [83]. In the
cases presented below, we found approximately 25% of cases were due to west HAT and 75% were due to east
HAT.
In cases such as the above-mentioned 2001 cluster of HAT in European travelers [43], travelers from nonendemic countries may act as a sentinel or surveillance tool for tropical diseases. They tend to travel widely,
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exposing themselves to may types of diseases. Most often they return home, to a medical system capable of
rapid and definitive diagnosis, during the incubation period of the infectious agent, although the medical
systems may not readily recognize the symptoms and may lack the diagnostic tools and drugs. In this manner,
potential outbreaks can be detected and a warning can be sent to developing countries that might not otherwise
be aware of the situation due to a lack of rapid diagnosis [105]. Information from this cluster of cases was
passed on to the Tanzanian government to increase surveillance in the affected region, which lead to an
increase in vector control programmes [53].
It is interesting to compare African trypanosomiasis to its South American counterpart, Chagas disease. Chagas
disease is well known for being transmissible- both vertically from mother to child as well as through infected
blood or organs [2]. Chagas disease is a silent disease; once it enters the indeterminate phase, the parasites lives
asymptomatically in its human host, replicating in the blood and organs and only 20-30% of those infected will
enter the chronic stage, characterized by involvement of the heart or digestive system [2]. Many of those
infected are unaware of their situation [106]. As such, they may migrate to non-endemic regions, unknowingly
bringing the disease with them.
Vertical transmission of Chagas disease, from mother to infant, has been well documented in North America
and Europe [106-111]. Studies have also shown that unknowing immigrants have already infected donated
blood and organs that have resulted in other contracting the disease, sometimes leading to fatal cases of Chagas
[2, 110, 112-114]. In December 2006, the Food and Drug Administration (FDA) licensed the first test to screen
for T. cruzi infections in potential blood and organ donors [115], however studies have shown that the
seroprevalence of T. cruzi in select donor populations may range between 0-0.48% [116]. Many countries
specifically screen migrants from countries endemic for Chagas disease [106, 110, 115, 117].
Conversely, only one case each of transfusion-mediated HAT [118] and vertically-transmitted case of African
trypanosomiasis [119] have been reported in literature. Without treatment, HAT is 100% fatal [20]. Those
infected with the fast-acting, east HAT likely wouldn’t even be able to pass on the parasites via blood
transfusion or organ transplant. And while west HAT can go undetected and diagnosed for months or even
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years, it too is unlikely to be transmitted person-to-person due to the fragile life cycle of the parasite [120].
Given the low incidence of cases in North America and Europe, both from returning travelers and immigrants
from endemic areas, as well as high fatality level if not treated, it is unlikely that HAT will ever pose a threat to
the blood supply in the way that Chagas disease does.
One salient feature of the cases encountered in this study is that few trends are apparent. The age of infected
patients ranges from 9 years old [121] to 72 [82]. A number of cases presented in the United Kingdom, the
Netherlands, the United States and France, but also in Germany, Italy, Australia, Switzerland, Norway, Canada,
Sweden, Mexico and South Africa. Despite the occasional difficulty in obtaining medication, only 2 fatalities
were reported: both middle-aged European women [53, 83, 92, 95, 96, 122]. Both were initially treated in
Africa and later succumbed to the disease in the Netherlands; one was Dutch while the other was German.
Meanwhile the death rate in Africa is approximately 48,000 [14]. Perhaps one reason to explain the high rate of
survival in non-endemic patients is their general good health. The patients who were treated in the above cases
were from developed nations where, one can assume, they had access to nutritious food and general health care;
many treating physicians specifically noted that their patients were in excellent health other than the
trypanosomal infection [21, 53, 83, 85, 97, 123]. Only one of the patients had a co-infection (with
Schistosomiasis and Loiasis, both readily treatable) [78]; none suffered from tuberculosis, malaria or
HIV/AIDS, unlike many trypanosomiasis patients in endemic regions [51, 89]. Hospitals and medical teams in
developed nations are better able to provide a holistic treatment of the patient, with round-the-clock monitoring,
no shortage of general medical supplies as well as access to drugs to treat complications that may arise.
All diagnoses were based on symptoms and microscopic detection of parasites in blood and/or lymph and/or
CSF. In only two cases was PCR used to confirm diagnosis [76, 124], showing that molecular or serological
techniques have yet to replace classic parasitological techniques [6], both in Africa for those diagnosed abroad
as well as in hospitals in non-endemic areas. This however, doesn’t decrease the need for more sensitive and
rapid diagnostic methods. Any new methods should taken into account the challenges posed by working in the
field in remote areas; new methods should not be limited to hospitals or clinics.
18
Before embarking on travel to endemic areas, travelers should be warned of possible risks, not only for
trypanosomiasis but also for any other endemic diseases that they may encounter. General recommendations to
prevent tsetse fly bites include wearing light-coloured clothing that fully covers arms and legs [43] as well as
the use of personal insecticides, although cases have shown that tsetse flies may not be completely averse to
insecticides [123].
Without a doubt, the most effective means for preventing trypanosomiasis, both in travelers and in those living
in endemic areas, is the control and reduction of vectors and reservoirs. Significant success was had with
rudimentary control methods in the mid 20th century [1]. With the civil unrest present in sub-Saharan Africa in
the late 1990s, vector control programmes fell by the wayside and resurgence in cases was seen in Africa, as
well as in travelers who returned to the area after political stability was re-established [53].
Such data should serve to remind that while Westerners are only occasionally at risk of trypanosomiasis, 60
million people remain at risk in Africa [7] and that further research must be undertaken to treat this disease.
Knowing that simple methods such as traps and targets, have proven very effective, and continue to be
effective, should spur further investment in the disease. Even relatively small amounts of funding are likely to
have disproportionately large returns [6]. With increased funding, it should be possible to eradicate the disease
by 2015, as predicted by the WHO [7]. This goal requires that not only are reservoirs and parasites controlled,
but also that effective and economical drugs are made available to those most in need.
ACKNOWLEDGEMENTS
The author would like to thank Dr Emily Adams of the Koninklijk Instituut voor de Tropen- Biomedical
Research, Amsterdam, the Netherlands and Prof Dr IM Andy Hoepelman, head of the Department of Internal
medicine and Infectious disease UMC Utrecht, the Netherlands for their supervision and critical revision. Many
thanks also to Joanne Brathwaite for critical revision of the manuscript.
19
Table 1. Reported non-endemic cases of west HAT. CSF= cerebrospinal fluid, T. b. g.= T. b. gambiense, S= suramin, E= eflornithine, M= melarsoprol, P= pentamidine
Age
Sex
Nationality
Country of
exposure
Year
Clinical
Features/symptoms
Diagnosis
Stage
Sub
species
Treatment
Ref
Nigeria,
Gabon
1991
lesion, rash, fever,
lymphadenopathy,
splenomegaly, elevated IgM,
lymph, blood
I
T. b. g.
S, difluoromethylornithine
[78]
Angola
1992
fever, insomnia, elevated IgG
and IgM
-
II
T. b. g.
E
[74]
CSF
blood
blood
II
I
I
T. b. g.
T. b. g.
T. b. g.
S,M
E
P
[75]
[84]
[79]
CSF, blood
II
T. b. g.
E
[80]
blood
I
T. b. g.
P
[81]
blood, CSF,
PCR
II
T. b. g.
E
[76]
blood, CSF
II
T. b. g.
E
[83, 85]
blood
I
T. b. g.
P, E
[83, 85]
blood, lymph
I
T. b. g.
P
[82, 83]
blood
I
T. b. g.
P
blood
I
T. b. g.
P
[82, 83]
[83,
125]
32
M
young
M
New Zealander
(ex-pat)
French
(immigrantAngola)
52
32
45
F
M
M
Dutch
(immigrant Cameroon)
Italian (-)
French (ex-pat)
Cameroon
Zaire
Gabon
1995
1996
1999
-
M
French (ex-pat)
Guinea
2000
53
M
Guinea
2000
42
M
French (ex-pat)
Canadian
(immigrantZaire)
Zaire
2002
44
M
Italian (-)
Gabon
2005
54
F
Italian (-)
C. African
Rep.
2005
37
M
French (ex-pat)
Gabon
2007
72
M
French (ex-pat)
Gabon
2007
50
M
French (ex-pat)
Gabon
2009
rash (neck, shoulders), elevated
IgM
fever, malaise
lesion, fever, elevated IgM,
weakness, sweats, vomiting,
myalgia, weight loss,
splenomegaly, fever,
elevated IgG and IgM, lesion
lesion, chills, weakness, fever,
lymphadenopathy,
hepatosplenomegaly, elevated
IgG and IgM
insomnia, anorexia, fatigue,
headaches,lymphadeopathy,
elevated IgM, fever
fever, headache, weakness,
anorexia, lymphadenopathy,
hepatosplenomegaly
fever, headache, insomnia,
fatigue, splenomegaly
fever, fatigue, anorexia,
headache, insomnia, rash,
lymphadenopathies
pruritus, fever, weakness,
anorexia, lymphadenopathy,
elevated IgG and IgM
fever, fatigue, lesion,
lymphadenopathy
27
F
Dutch
(immigrantAngola)
Angola
2009
fatigue, insomnia, anorexia,
depression, coma
21
CSF
II
T. b. g.
E
[77]
Table 2. Reported non-endemic cases of east HAT. CSF= cerebrospinal fluid, T. b. r.= T. b. rhodesiense, S= suramin, E= eflornithine, M= melarsoprol, P= pentamidine
Age
Sex
Nationality
Country of
exposure
Year
-
M
Swiss (tourist)
Rwanda
1990
-
M
Swiss (tourist)
Rwanda
1990
1991
1994
Clinical Features/symptoms
"clinical signs of sleeping
sickness"
"clinical signs of sleeping
sickness"
fever, lesion,
lymphadenopathy, chills,
sweat, anorexia, malaise,
diarrhea
meningoencephalitis
1994
49
-
M
M
American (tourist)
French (solider)
Tanzania,
Kenya,
Rwanda
Rwanda
-
M
French (solider)
Rwanda
57
30
41
54
49
47
51
M
M
M
F
M
F
M
Mexico (tourist)
French (tourist)
American (tourist)
American (tourist)
Kenya
Rwanda
Tanzania
Tanzania
American (tourist)
Tanzania
German (tourist)
Zambia,
Zimbabwe,
Tanzania
British (tourist)
Zambia
Diagnosis
Stage
Sub
species
Treatment
Ref
blood, CSF
II
T. b. r.
M
[83, 126]
blood
I
T. b. r.
S
[83, 126]
I
II
T. b. r.
T. b. r.
P, S
M
[43]
[127]
major inflammatory syndrome
blood
CSF
blood,
medulla
II
T. b. r.
M
[127]
1996
fever, headache, lesion,
hepatic dysfunction,
respiratory distress
blood, lesion
exudate, CSF
II
T. b. r.
P, M
[128]
1997
headache, weight loss, fever,
hepatosplenomegaly,
lymphadenopathy
blood,
marrow, CSF
II
T. b. r.
M
[99]
1999
1999
weakness, headache, fever,
chills, sweats, anorexia,
lesion, lymphadenopathy,
fever, sweats, chills, myalgia,
blood, CSF
blood
II
I
T. b. r.
T. b. r.
S, M
S
[102]
[24]
1999
malaise, drowsiness,
insomnia, fever, chills, sweats,
headache, myalgia, lesion
blood
I
T. b. r.
S
[24]
2000
fever, insomnia, jaundice,
lesion, lymphadenopathy,
mucosal hemorrhage,
splenomegaly, ascites
blood,
marrow
I
T. b. r.
S
[129]
2000
lesion, myalgia, diarrhea,
fever, vomiting, headache,
rigors, sweats,
blood
I
T. b. r.
S
[97, 98]
22
30
30
M
F
32
M
British (tourist)
Australian (tourist)
- (treated in
Antwerp)
Kenya,
Tanzania
Tanzania
2000
2000
Tanzania
2001
lesion, fever, diarrhea,
vomiting
fever, rigor, headache
fever, chancre, headache,
jaundice, hepatosplenomegaly
33
M
Italian (tourist)
Tanzania
2002
30
M
Italian (tourist)
Tanzania
2002
fever, headache, nausea,
vomiting, skin lesion,
lymphadenopathy
skin lesion, local edema,
fever, mild jaundice,
multiorgan failure,
hepatomegaly
American (tourist)
Tanzania
(Kenya,
Zimbabwe)
2002
fever, lesion, headache,
fatigue, myalgia, vomiting,
rash,
Tanzania
Tanzania
Tanzania
2002
2002
2002
Tanzania
2002
lesion, fever
lesion, fever
fever, renal failure, acidosis,
jaundice
Tanzania
Tanzania
Tanzania
2002
2002
2002
lesion, fever
fever
lesion, fever, headache
37
7
patients
44
41
M
68
M
27
60
55
F
M
F
F
M
American/Canadian
British (tourist)
Swedish (tourist)
South African
(tourist)
Norwegian
(researcher)
Dutch (tourist)
Dutch (tourist)
2002
Dutch (tourist)
Tanzania
Kenya,
Tanzania
British (tourist)
Tanzania
2004
lesion, fever, headache,
intracerebral manifestations,
coma, death
fever, headache, myalgia,
vertigo
lesion, fever, dry cough,
vomiting
2004
abdominal pain, fever, lesion,
dry cough, vomiting,
lymphadenopathy
53
F
Dutch (tourist)
28
M
9
M
14
M
British (tourist)
Tanzania
2003
23
blood
blood
I
I
T. b. r.
T. b. r.
S
P, S
[97, 98]
[131]
blood
I
T. b. r.
S
[132]
blood
I
T. b. r.
P, S
[53, 94]
blood
I
T. b. r.
P
[53, 94]
blood
I
T. b. r.
S
[21]
-
II
I
T. b. r.
T. b. r.
T. b. r.
P
S
[11]
[43]
[43]
-
II
T. b. r.
M
[43]
blood
blood
I
I
I
T. b. r.
T. b. r.
T. b. r.
S
S
S
[43]
[43, [95]
[43, 94]
blood
II
T. b. r.
S, M
[53, 83, 95,
96]
blood
lesion
aspirate
I
T. b. r.
S
[130]
I
T. b. r.
S
[121]
blood, lesion
aspirate
I
T. b. r.
S
[121]
26
M
British (solider)
Malawi
2006
62
F
American (tourist)
Africa
2006
insomnia, lethargy, vomiting,
chancre,
lymphadenopathy, fever,
rigors
fever, lesion, elevated IgM,
rash
4
patients
-
Canadian, British,
Australian
Malawi
2007
thrombocytopenia,
hallucinations
38
M
British (tourist)
Namibia,
Mozambique,
Malawi,
South Africa
44
F
German (tourist)
Tanzania
2009
25
F
Dutch (tourist)
Tanzania
2009
61
M
Polish (tourist)
Uganda,
Rwanda
2009
2007
i) fever, lymphadenopathy,
hepatomegaly
ii) somnolence, myalgia,
headache, sweats
iii) somnolence, headache,
fevers, nerve palsy
lesion, fever, myalgia,
malaise, diarrhea,
convulsions, death
fever, lymphadenopathy,
lesion, headache
fever, multi-organ failure,
asthenia, lesion, chills,
jaundice, respiratory distress,
hepatosplenomegaly, mucosal
hemorrhage
24
blood
I
T. b. r.
S
[83, 123]
blood
II
T. b. r.
P, S, M
[103, 104]
blood
I
T. b. r.
S
[133]
[124]
blood, CSF
II
T. b. r.
i) S, M
ii) E
iii) S, M, P
blood
II
T. b. r.
S, M
[83, 122]
blood
I
T. b. r.
S
[134]
blood
I
T. b. r.
P
[135]
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