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African
Trypanosomiasis African
Sleeping Sickness |
Introduction Pathogenesis Diagnosis Treatment
Vector Epidemiology Prevention
History of Discovery Morphology
Transmission Trends
A group of
young boys attend a funeral in the Ivory Coast for
a woman
believed to have died from African sleeping sickness.[1]
“From
the beginning of Arab and European influence in the hinterland of tropical Africa,
trypanosomiasis of man and animals has curbed the realization of human
ambitions and the mobilization of the continent’s vast resources.” --Herbert S. Gasser [2]
The quotation from Herbert S.
Gasser, a Nobel laureate and former director of the Rockefeller Institute for
Medical Research, profoundly captures the impact of African trypanosomiasis as
being a major barrier to economic and social development in many regions of the
African continent. African trypanosomiasis,
commonly referred to as African sleeping sickness, is the result of a
blood-borne protozoan infection in humans from one of two species—Trypanosoma
brucei gambiense or Trypanosoma brucei rhodesiense. Tryaposoma
belongs to the family Trypanosmatidae of the order Kinetoplastida. Both of these parasites have similar
pathogenic features, including the presentation of indistinguishable clinical
manifestations in infected humans.
However, their epidemiological features differ greatly. Throughout this website a distinction will
be made when information applies to only one of the species. All other information applies to both. If you have questions or concerns, please
feel free to contact the author, John Turnbull, at jht@stanford.edu.
Although the symptoms of
African sleeping sickness were documented by Atkins in 1742, the association of
the clinical syndrome with its etiological agent, the trypanosome, was not
documented until 1902 by Forde.[3] In The
Journal of Tropical Medicine, Forde chronicles his treatment of a 42
year-old European male colonialist who presented to his practice in the Gambia
Colony in May 1901. The patient
complained of fever and malaise, leading Forde to make a preliminary diagnosis
of malaria. He initiated anti-malarial
quinine treatment, but days later the patient’s conditioned had yet to
improve. Slides of the patient’s blood
were prepared. This examination
ruled-out malaria due to a lack of malarial parasites found in the blood. Only later, Dutton, a second physician from
the Liverpool School of Tropical Medicine, made the identification of Trypanasoma
brucei in the patient’s blood.[4] Due to the
probable location of the patient’s inoculation, this case can be attributed to
the species T.b. gambiense.
The identification of T.b.
rhodesiense as another species of trypanosome to cause African sleeping
sickness was not documented until 1910.
Stephens and Fantham describe a strain of trypanosome observed in a blood
smear of a patient who presented with symptoms of African trypanosomiasis. The patient had no history of travel within
a region known to be endemic with T.b. brucei, yet his blood smear
clearly indicated a trypanosomal infection.
The novel morphology was believed to a be a new species of T. brucei. Because the patient was believed to have
been infected in Rhodesia (present day Zimbabwe), the new parasite was thus
named—T.b. rhodesiense.[5]
Experiments published in
1912 by Kinghorn and Yorke proved that T.b. rhodesiense could be
transmitted from human to animals by the tsetse fly. They also concluded through their research that many game animals
in East Africa, including waterbuck, hertebeest, impala, and warhog, served as
reservoirs for T.b. rhodesiense in this region of the continent.[6]
Pathogenesis
of T.b. gambiense & T.b. rhodesiense
A) 
B) 
The above slides are human blood
smears of T. brucei stained with Giemsa stain (A) and a second one with differential
interference contrast, as well, (B) to better visualize the flagellum.[7] Only the Giemsa stain is required to locate
trypanosomes and make a definitive diagnosis of African trypanosomiasis. The two species of T. brucei are
morphologically indistinguishable, but the differential diagnosis of the two
infections can be made based on exposure history and serodiagnostic
testing. These slides highlight the
characteristic organelles of the trypanosome, including the centrally located
nucleus, the anterior kinetoplast—a second DNA-containing organelle, and the
posterior flagellum that arises from a flagellar pocket to protect immunogenic
sites. The parasites range in size
from 14 to 33 μm.
1) Infection
of a human host occurs when a tsetse fly bites a human and transmits from its
salivary glands the metacylic stage (the infective state) of the trypanosome.
2) This
metacylic stage quickly gives way to a blood-borne stage that begins a series
of binary fission divisions at the site of inoculation. This process leads to the formation of a
primary chancre.
3) The
trypanosomes enter the bloodstream via the lymphatics and continue to
multiply. They also enter the CNS from
here.
4) A
subsequent tsetse fly becomes infected by ingesting a blood meal that contains
the trypanosomes from the infected host.
5) In the gut
of the fly, the trypanosomes transform into procyclic trypmastigotes that
divide for 10 days.
6) The
organisms then migrate to the salivary glands and transform into epimastigotes,
which later transform into metacyclic trypanosomes that can infect a new host.
VARIANT SURFACE GLYCOPROTEINS
(VSGs)
T. brucei have a
specialized mechanism to overcome the obstacles of the mammalian immune
system. Days after infection, host
antibodies recognize surface glycoproteins that coat the protozoa—the antigenic
determinants of the organism—and kill the organisms by labeling them
destruction. However a few protozoa
escape destruction via a programmed system that changes their glycoprotein
composition and thus enables them to evade immune recognition. Again, days later the immune system
recognizes this change and mounts an immune response against the new
glycoprotein. This cycle is repeated
with a pattern of high parasite load followed by a period of low parasite load. For this reason, patients exhibit an
irregular pattern of high-grade fevers followed by an afebrile period
throughout the course of a systemic infection.
For this reason, vaccine development has been thwarted.
Incubation Period: The first clinical manifestation of African
trypanosomiasis occurs a few days after infection as a chancre at the site of
tsetse fly inoculation. This is due to
the localized proliferation of the pathogens within the subcutaneous tissue. Incubation period for T.b. rhodesiense
may be two to three weeks, while the incubation period for the Gambian species
may last several weeks to months.
A) 
B)
C)
A
teenage girl in Uganda with sleeping sickness exhibiting the characteristic
chancre on her leg at the site of tsetse fly inoculation (A), and a woman in
Uganda with a partially healed chancre just above her elbow (B). Although (C) may look painful, chancres are
generally painless with some associated tenderness.
Dissemination: With the conclusion of the incubation period, the
organisms have already disseminated into the bloodstream, leading to the
emergence of a characteristic intermittent fever pattern that correlates
directly with high versus low levels of parasitemia. The reason for the oscillating levels of parasite load is linked
to the ability of the organisms to change their variable surface glycoproteins (VSGs) and evade the host’s immune system. Lymphadenopathy, the swelling of lymph
nodes, especially in the posterior cervical nodes (on the back of the neck) is
characteristic sign of African sleeping sickness and is termed Winterbottom’s
sign.
Invasion of the
Central Nervous System: Invasion of the central nervous system (CNS)
occurs within several weeks in the Rhodesian species and months to even years
in the Gambian species of trypanosomiasis.
Symptoms include headache, stiff neck, sleep disturbance, and
depression, followed by progressive mental deterioration, focal seizures,
tremors, and palsies. This progresses
to coma and the ultimate death of the patient often secondary to pneumonia or
sepsis. Without treatment, African
trypanosomiasis is a universally fatal illness.
A) 
B) 
A
male patient in the finals stages of African sleeping sickness, ultimately
ending with his death. (A)
(B)
The neuropathology slide form a patient with encephalitis secondary to African
trypanosomiasis. The dots stained with
purple indicate a highly dense population of lymphocytes, plasma cells and
large macrophages within the blood vessel and diffusing into the surrounding
tissue. This would lead to an
immune-mediated swelling of the central nervous system, ending with death.
A history of travel
within an endemic region and especially a memory of a bite from a tsetse fly
are both key to a clinician’s ability to consider African sleeping sickness
when encountering a patient outside an endemic region. If exposure history has been documented, the
definitive diagnosis of African trypanosomiasis is made by identifying the
protozoa in the patient’s blood, cerebrospinal fluid, or aspirates of the lymph
nodes. Because this is primarily a
tissue-dwelling organism examination of the bone marrow or lymph nodes may
reduce the likelihood of a false negative compared to examination of the
peripheral circulation. To concentrate
the trypanosomes in a sample, centrifugation is often advised. An ELISA may also be used to identify antigens,
as well as a new serodiagnostic tool termed the Card Agglutination Test for
Trypanosomiasis (CATT). Another test
called card Indirect Agglutination Test (CIATT) tests for antigens rather than
antibodies. It has a high sensitivity
and specificity and can distinguish between the two species of
trypanosomes. This latter test will
allow for rapid and reliable data concerning the incidence of African
trypanosomiasis—a key aspect of any prevention and control program.
A) 
B) 
A
doctor performing a spinal tap to examine the cerebrospinal fluid of a patient
suspected to have an infection with African trypanosomiasis (A). The Card Agglutination Test for Trypanosomiasis
(CATT). This inexpensive and rapid
serodiagnostic test identifies those patients with antibodies against the
organisms, indicating infection (B).
Unless treated, African
trypanosomiasis is a fatal illness. The
most effective treatment intervention for this disease must begin before the organism
migrates into the CNS because the most effective drug does not cross the
blood-brain barrier. This drug,
suramin, is administered intravenously and most often results in the full
recovery of the patient. Side effects
include nausea, vomiting, pruritus (itching), uricaria (hives), hypesthesia
(decreased sensitivity), photophobia (increased sensitivity to light), and
peripheral neuropathy. Most of these
symptoms are not dangerous and disappear after a few days of treatment. Pentamidine isethionate is an alternative
therapeutic agent, but also has many side effects.
Melarsoprol is the drug
of choice should the disease have progressed sufficiently to affect the central
nervous system. This drug is toxic and
may lead to myocarditis, renal damage, peripheral neuropathy, encephalopathy, a
Jarisch-Herxheimer reaction (an immune-mediated system reaction). Approximately 5% of patients die from this
treatment, while another 5% relapse.
Success rate may be increased by pretreatment with suramin.[8] More recently,
Difluormethylornithine (DFMO), known as eflornithine, has proven to more safely
and efficaciously eliminate the protozoa from the blood stream and has thus
been termed “the resurrection drug.”[9]
A) 
B) 
C) 
(A) Vials of melarsopral. (B) A 19 year-old girl
dying from late-stage disease
(B) and an adverse reaction to melarsopral. (C)
A man receiving IV treatment with eflornithine.
Two
pictures of Glossina, the tsetse fly and vector of African trypanosomiasis[10]
The vector for both types of African trypanosomiasis
is Glossina, often referred to as the tsetse fly (pictured above). Biologists have identified 23 different
species of Glossina, of which all but three will transmit the
trypanosomal infection to mammals. The
flies generally measure 7 to 14 mm in length.
Currently, this species of flies are restricted to sub-Saharan Africa
north of the Kalahari Dessert, which currently restricts the transmission of
the disease to within this region.
However, with rapid and frequent intercontinental travel, the
introduction of this species to naïve regions poses a threat.
Tsetse flies are haematophagous—dependant on blood
sucking to derive nutrients. Different
species of Glossina have different preferences for the source of their
blood meal with some specifically preferring human blood and are therefore
important vectors of the disease in human populations. Both male and female flies feed on blood and
are both vectors of the parasites.
Geographic
Distribution of African Trypanosomiasis by Country[11]
The distribution of African trypanosomiasis is
completely linked to the range of its vector, the tsetse fly. Due to the tsetse fly’s climatic
restrictions the disease is restricted between the 14th latitude
north and the 29th latitude south on the African continent.[12] According to the World Health Organization, countries where the
disease is currently epidemic include Angola, Democratic Republic of
the Congo, Uganda & Sudan. Countries with high levels endemicity of including Cameroon,
Congo, Cote d’Ivoire, Central African Republic, Guinea,
Mozambique, Tanzania, & Chad. African sleeping sickness can also be found
in low endemic levels in Benin, Burkina-Faso, Gabon, Ghana,
Equatorial Guinea, Kenya, Mali, Nigeria, Togo,
& Zambia. Because of poor disease
surveillance and reporting, epidemiological information in Burundi, Botswana,
Ethiopia, Liberia, Namibia, Rwanda, Senegal,
& Sierra-Leone is poorly understood.
The disease is a threat to more 60 million people
throughout Africa. However, currently
only 3 to 4 million of these people are under surveillance, leading to the
reporting of only 45,000 cases in 1999.
Epidemiologists estimate that between 300,00 and 500,000 cases actually
occurred during that same time period.
Surveillance is not only essential to track disease trends to determine
possible interventions, but also to identify infected individuals so that
treatment may be initiated before the disease progresses to less treatable
state.
There have been three major epidemics in Africa in
the last century. One between 1896 and
1906 in Uganda and the Congo Basin.
Another one in 1920 that incorporated several African countries, and
finally one that started in 1970 and is still in progress across much of
Africa. Noted below is an epidemic curve
from Uganda illustrating this most recent outbreak.
African trypanosomiasis
cases in Uganda by year[13]
TRANSMISSION TRENDS BETWEEN
SPECIES
The different species of human pathogenic
trypanosomes have different epidemiological characteristics, but both depend on
transmission by the tsetse fly. T.b.
gambiense is found only in West Africa and is transmitted solely from
person-to-person via the tsetse fly vector.
The species of tsetse flies that transmit this strain are G. palpalis,
which live near vegetation associated with drainage lines, rivers and other
permanent bodies of water. No
reservoirs exist in this species of the disease. On the other hand, T.b. rhodesiense, which is found in
Eastern and Southern Africa, is transmitted by G. morsitans, G. pallidipes
and G. swynnertoni. It is
primarily transmitted from person-to-animal and then back to person via the
tsetse fly vector. The infection of a
human is probably the result of an ecological disturbance in the environment
that forced an encounter between an infected fly and a human, rather than the
natural animal host and reservoir cycle.
Reservoirs include domestic and wild ungulates, plus other game and
wild-life found on the East African plain.
From an anthropocentric perspective, these animals act as an unlimited
and uncontrollable reservoir for the trypanosomal infection. Control measure are much more difficult to
implement here because solely monitoring the human population is inadequate to
prevent transmission.
A) 
B) 
Two examples of tsetse fly
habitat from West Africa (A) and East Africa (B).
Conversely, if one were to identify and treat every
case of African sleeping sickness in West African humans, theoretically
transmission would fall below the level needed to sustain the pathogen. However, the complete elimination of West
African trypanosomiasis from the human population seems unlikely even in this
idealized situation due to the extreme cost of such a program. The decreased virulence of the Gambian
trypanosome also helps the pathogen’s ability to successfully infect new human
hosts. Remember that someone with T.b.
gambiense will progress to disease and death much more slowly than someone
with the Rhodesian form. This allows
more opportunity for a tsetse fly to bite an infectious host to transmit the
infection to another individual.
Essentially, in this humans asymptomatic humans act as a reservoir of
future infection.
Impact of African Animal Trypanosomiasis
In addition to the parasite’s associated human
morbidity and mortality, various species of trypanosomes, including T.
duttonella vivax, T.d. congolense and T.b rhodesiense, infect
other animals and produce a similar disease as seen in humans. When found in cattle, this disease is called
nagana. African animal trypanosomiasis
has had a profound impact on the ability for parts of Africa to sustain a
highly productive livestock population on the African plains. The Food and Agricultural Organization of
the United Nations states, “Trypanosomiasis is probably the only disease which
has profoundly affected the settlement and economic development of a major part
of a continent.” Of the approximately
7-10 million km2
of land that are infested by tsetse fly, only 20 million cattle are
raised. Under different circumstances,
this land could support more than 140 million cattle and increase meat
production by 1.5 million tons! [14]
Clinical syndromes in animals are similar between
the various species of pathogenic trypanosomes. Infection can lead to death, extreme weight loss, reduced growth
rate in young animals, and organ damage.
Fertility in males may also be decreased due to testicular damage. The impact of this disease extends beyond
the direct associated human morbidity and mortality, as it decreases economic
viability and the nutritional potential of human populations. Sadly, the decrease in nutrition and protein
intake also decreases the overall human health in an endemic region.
Prevention and Control Strategies
Early detection and treatment of infected
individuals is key to prevention and control especially in West Africa where no
non-human reservoirs exist. New
diagnostic tools, including CATT and CIATT, should be used to actively survey a
population for possible infection. Once
a pocket of infection has been identified, every effort must be made to find
all cases and treat them accordingly.
The World Health Organization sponsors a program called The Programme for Surveillance and
Control of African Trypanosomiasis. Its strategies include coordinating one surveillance system for
all endemic countries under and coordinating among various field agencies
surveillance work.
Controversial measures to eradicate the vectors and
reservoirs of infection have been undertaken by various NGOs and governments in
Africa. However, because the reservoirs
serve an important role in the environment for both humans and the overall
ecosystem these measures have been largely avoided. Campaigns to limit human exposure to tsetse flies have been
undertaken in the form of fly traps near human populations. The poisoning and drainage of water sources
in West Africa has also been undertaken, but this too has negative side effects
that many say outweigh the benefit of such a program.
Two tsetse fly traps to aid
in the avoidance of fly-human contact
Centers for Disease Control Parasites Page
Ohio State Trypanosomiasis Page
World Health Organization's Disease Surveillance
World
Health Organization Trypanosomiasis Info
Program Against African Trypanosomiasis (PAAT)
Also refer to footnotes.
A
woman caring for her comatose husband who is dying of African trypanosomiasis,
Uganda, 1990