(African Sleeping Sickness)
/ Treatment / Bibliography
The history of the Human African Trypanosomes
(HAT) is intimately linked to the African continent. Endemic since
the 14th century, HAT is the only vector-borne disease whose geographical
distribution is limited to the African continent (Pepin, 2000).
Since the 1970's the disease has re-emerged as a epidemic which,
until recently, received little attention from the international
community (Stich, 2002).
According to the World Health Organization
in 1998, there were more than 200 active foci of African trypanosomiasis
in 36 African countries. An estimated 500 million individuals live
in these endemic areas. Only four million of this at risk population
benefit from adequate case surveillance and vector control. All
endemic countries characteristically lack the sufficient financial
and human resources necessary to implement or sustain comprehensive
control programs (Pepin, 2001).
HAT is transmitted by the riparian tsetse flies of the genus
Glossina but can be contracted congenitally and through blood contamination.
The sickness is a result of periods of parasetimia that are induced
by haemoflagellates of the genus Trypanosoma. There are classically
3 subspecies of Trypanosma brucei, only two of which are pathogenic
to humans, including the human sub-species' T. brucei gambiense,
and T.brucei fhodesiense. Transmitted by different Glossina species,
these two subspecies are stratified by their geographical location
in accordance with where they are commonly found, but are morphologically
indistinguishable (Stich, 2002).
Image courtesy of WHO
Humans are only important reservoir of T.b.gambiense, causing the
chronic form of trypanosomiasis in West and Central Africa. The
incidence of T.b.gambiense has reached epidemic proportions in some
foci, challenging numbers infected with HIV. Of the new cases reported
each year, more than 90% are comprised of T.b.gambiense infections
A zoonosis, the incidence of T.b.rhodesiense
remains low, but new epidemics could be triggered by unpredictable
ecological changes (Pepin, 2001). T.b. rhodesiense is a polymorphic
subspecies that causes acute trypanosomiasis throughout East and
Southern Africa. Although many animals can become infrected, antelopes
and domestic animals are the most importane resevoirs. Transmission
to humans only occurs via close interactions with these animals.
Image courtesy of University
of South Carolina
of the two sub-species in relation to their presence in Sub-Saharan
T.b. gambiense is seen in West and Central Africa and T.b. rhodesiense
in East and Southern Africa.
There are two stages of HAT infections. The fist stage begins with
the bite of an infected tsetse fly. Trypanosomes then multiply in
the bloodstream and lymphatic system. This stage may last for years
in the case of gambiense sleeping sickness. At this stage there
are few specific symptoms other than the characteristic swollen
cervical lymph nodes, commonly known as Winterbottom's Syndrome.
Image courtesy of
University of Utah Health Sciences Ctr.
of cervical lymph nodes commonly called Winterbottom's sign.
Parasites next invade all organs of the
body including the heart and central nervous system. The second
stage begins when the parasite crosses the blood-brain barrier and
invades the central nervous system. It is only at this second stage
that the disease presents neurological symptoms and characteristic
signs including alteration of the mental state, sensory disorders,
and coordination problems. Also, the presence of the parasites causes
an alteration of the circadian sleep/wake cycle, endocrinological,
cardiovascular, and renal disorders. The natural progression of
the disease without treatment leads to apathy, tremors, convulsions
and sleepiness, followed by coma. There is rapid weight loss and
death a few months later from malnutrition, heart failure, pneumonia,
or encephalitis (Hunt, 2003).
There are four factors that influence the
potential for infected individuals to transmit T. brucei to others.
They include the duration of infection, the degree of parasitaemia
during exposure to other individuals, the number and distribution
of individuals who are infected, and the intesity of contact the
infected has with the insect vectors. Congenital transmission is
also a factor in infection rates and statistics. The duration of
T.B. gambiense can be anywhere from months to several years. This
form of T. brucei is a much more chronic form of the disease. The
duration of infection with the more acute T.b. rhodiense is much
shorter and serious lasting anwhere from weeks to months (Pepin,
The long duration of infection in humans,
plus the intermittent parasitaemic representation make transmission
and control of this disease very complicated and multifaceted. Even
so, the most reliable means of control available is to be aware
of all infected persons and all at risk individuals in the susceptible
regions, thus screening of endemic populations is crucial to the
maintenance of the disease. During the 1960's, due to the seeming
disappearance of sleeping sickness in Sub-Saharan Africa,there was
a steep decline in the monitoring efforts that had been so dynamic
in the control of the disease. Once the amount of surveillance screening
declined, the presence of the HAT grew to the numbers we are experiencing
There are several methods available for tsetse and trypanosomiasis
control. All of the current methods have limitations based on cost,
capablity of the population to obtain proper tools, systematic use
of the methods, and the sustainability of the constituents and methods.
(Feldmann and Hendrichs, 1998). Parasite Control through the use
of trypanocidal drugs or even livestock that is tolerant to the
parasites. Vector control has been highly successful and is accomplished
through the use of traps and insecticide treated blue colored targets
that are often baited with pheromone derivatives to attract the
tsetse fly. Sterile
insect techinique is also being used as a way to control or
eradicate tsetse populations.
Image courtesy of the BBC
Tsetse fly traps
like these are used to control tsetse presence in areas of
agriculture and development. They
are made produced by the community
and an organized system of education and monitoring have been able
keep tsetse populations in endiemic areas at bay.
Some interventions used in the past, such
as bush-clearing that influence tsetse habitat destruction, the
elimination of wild animals that act as tsetse reservoir hosts,
and aerial spraying are now banned for environmental reasons.
The current control strategies used by the
communities that are endemic to the HAT include regular, active
surveillance that involves both case detection and treatment. This
includes systematic screening of communtities in identified foci
and is also key to identifying any early stage symptoms that may
occur. Increased community education and training have been added
to these screening programs as well as better communication between
resources in the varius foci in which ideas and experiences are
shared and collaborated.
Drug resistance monitoring is a big issue at thecurrent time due
to what seems like increased occurances of parasite resistance to
The major problems that have been brought
on by disease control include, funding, resurgenc and new foci,
regular surveillance not always adequated within misinformed communitites,
population movements due to seasonal migration and refugees, including
cattle, changes in the agrucultral practices that alter tsetse habitat
an may increase human-fly contact, and the need for drugs whose
side effects are not so severe.
· Strengthen the treatment capability of control programs
by looking at drug availability, increasing research capacities,
monitoring drug resistance, and geographical information system
mapping of foci, often there is a lack of funds for purchase of
diagnostic tests and drugs, and some governments accord sleeping
sickness as a low priority until it reaches epidemic proportions.
Political upheaval, civil strife, and wars lead to the breakdown
of healthe services and conttrol programs as monies origianlly allocated
for resources in the surveillance of HAT are lost in the struggle
for limited resources.
All, in all, long term commitment is needed
by the government of endemic countries and the international communitty
to provide reliable, and sufficient support to control programs.
The need for improved case detectio nprocedures and practice is
also a primary factor in control ing this disease. Earlier diagnosis,
is especially important in the case of HAT as time continues, late-stage
treatments, if no new drugs are found, may become obsolete.
The World bank estimated that there were
55,000 deaths per year due to HAT, only 10% of which were detected
cases. The presence of HAT is directly connected to the presence
of human agricultrual activities and game raising. . Information
concerning the presence ofmultiple cases in households has been
recognized. Shared exposure could result from simultaneous contact
with an infective tsetse whose initial blood meal was interrupted
and resumed on a relative, or from members of the same family sharing
an ecological micocosm and bieng similarly exposed to the vector
Sites to look at current events involving HAT:
Against African Trypanosomiasis
Integrated Control of
Pathogenic Trypanosomes and their Vectors
Report on Global Surveillance of Epidemic-prone Infectious Diseases
Fact Sheet on West African Trypanosomiasis
Image courtesy of Aventis
Treatment of the early phase of the disease
is with either pentamidine in West Africa or suramin in Eas tAfrica
and for the late stage of the disease with organic arsenicals (Arsobal,
Melarsoprol, Mel B). The latter treatment is not without danger
and may lead in 5-10% of cases to a fatal encephalopathy. There
are problems related to some if not all of these drugs.
Initial Phase treatments
If detected and treated early, chances for a cure are good. Suramine
and pentamidine affected only one subspecies and have moderate to
severe side effects.
Melarsoprol was discovered in 1949 and until recently was the only
non-species specific drug that could cross the blood brain barrier
to reach the parasite in the later stages of the disease. It is
the last arsenic derivative in existence. Melarsoprol treatment
frequently has severe adverse effects. The most serious complication
of melarsoprol treatment is reactive encephalopathies. They occur
at varying frequencies in 5–10% of treated cases. The reaction
is fatal for about 10–70% of the patients afflicted. There
is also significant drug resistance rising to 30% in some areas
of central Africa. (WHO,2000)(Stich,2002)
Pentamidine (Lomidine) is used only for the early phase of the disease.
It is primarily used against T. gambiense. This
is not recommended anymore since the dose is subcurative and may
mask an underlying infection. The use of pentamidine has provoked
resitance in several areas so the use of this drug is strictly monitored.
The dose for treatment is 4 mg of pentamidine base per kg of body
weight given intramuscularly in a total of 7 injections daily or
on alternating days.
Suramin was been developed in 1916. It is the preferred drug for
use in the infection in East Africa. The drug is administered intravenously
at a dosage of 20 mg/kg. It circulates in the blood and is taken
up slowly by the body. Suramin is treatment involves renal function
and so should not be used in patients with renal problems. Urine
is be checked before and during treatment for proteinuria.
Late Stage Treatment
enter the CNS, late Stage treatment must be implemented to fight
the disease. The drugs are arsenical derivatives.
Melarsoprol, Arsobal, Mel B
This drug has been in use for trypanosomiasis since 1947. It is
very effective in the treatment of both the early and the late stage
of sleeping sickness, however, the drug is used only for the treatment
of the late stage of the disease, both in West and in East Africa.
The usual treatment comprises several series of injections, each
separated by at least one week. Treatment may result in acute encephalopathy
in 5 - 10% of the cases, which may result in paralysis, brain damage,
or death. Melarsoprol is so caustic that it melts regular syringes;
glass ones have to be used. It also burns the skin so that it must
be injected at a different location each time. Once the drug is
diluted in the bloodstream, however, it does not cause this sort
Eflornitine "Ressurrection Drug"
Difluoromethyl ornithine (DFMO) or Eflornithine is a newly developed
drug that is effective in the treatment of both the early and the
late stage of T.b. gambiense, West African sleeping sickness. It
is not effective in the treatment of T. rhodesiense infections in
East Africa. It is an ornithine analogue that inhibits the enzyme
ornithine decarboxylase which is essential in cell division and
in the protection against oxidant accumulation in the parasites.
However, due to rapid excretion of the drug, the compound has to
be given in very large quantities. A full treatment takes 400 grams
of Eflornithine over a total period of two weeks, first as an infusion,
followed by fruit juice containing the drug. This drug is also called
the "resurrection" drug, since comatosed patients may
quickly wake up and resume their activities. (Targets
for chemotherapy of parasitic diseases)
Production of this drug ceased completely
in 1999, because it was unprofitable for the pharmaceutical company
Aventis. A campaign by Medecins Sans Frontieres (Medicine without
Frontiers) and others to bring the drug back succeeded only because
a second drug company, Bristol Myers Squibb, found a potentially
new use for elflornithine as a hair
removal substance for women’s mustaches. Aventis
offered the license to WHO in 2000 and has now agreed to collaborate
with the WHO in financing a 5 year project for $25 million to provide
60,000 doses of the drug (Lewis, 2002).|
As a rule, parasitic infections are chronic and result in morbidity
and suffering. The aim of chemotherapy is to use drugs to exterminate
non-native organisms in humans without injuring the host. Studies
of the modes of action of antimicrobial drugs has led to targets
for the use of chemotherpeuticdrug therapy which is then responsible
fot eh selective toxicity of the drug. The many specializations
of the HAT provides opportunities for future (Decampo, 2002).
Target--> GPI anchors (thiomactylin)
A possible target for chemotherapeutic drugs includes GPI anchors.
The GPI membrane anchor of the T. brucei VSG is unusual in that
its lipid moiety exclusively contains myristate. GPI anchors from
other eukaryotes usually contain fatty acyl or alkyl groups that
are a mixture of species differing in length and degree of saturation
. In the trypanosomes, myristate is incorporated into a precursor
GPI either through fatty acid remodeling or by a myristate exchange
reaction. GPI myristoylation is an attractive target for antitrypanosomal
drugs because it doesn't occur in mammalian cells. The effects of
this type of chemotherapeutic drug have, as of yet, proven to be
too toxic to be used until futher research finds a safer, less toxic
form of a myristate inhibitor (Decampo, 2002).
Target--> Glycolytic enzymes (Glycerol + SHAM,
T. brucei bloodstream forms are entirely dependent on glycolysis
for its production of ATP. Also, T. brucei does not have lactate
dehydogenase. The regeneration of NAD from NADH depends on dihydoxyacetone
phosphate which includes a glycerol-3-phosphate shuttle plus glycerol-3-phosphate
oxidase. So under anaerobic conditions, glycerol-3-phosphate can
be oxidized back to dihydosy acetone phosphate and becomes a accumulated
inside the glycosome. Thus an accumulation of glycerol-3-phosphate
and ADP drives the flycosome to generate flyceol and ATP. Flycerol-3-phosphate
oxidase can be inhibited by salicylhydoxamic acid(SHAM) to bring
T. brucei into an anaerobic condition in which the reversed glycerol
kinase-catalyzed reaction with added glycerol can then stop glycolysis
which can lyse in vitro withinn minutes and effectively suppress
parasetemia in infected animals. Some of the well-known
antitrypanosomal agents (suramin) have been recently found to act
by inhibiting glycolysis.
Target--> Ornithine decarboxylase (DFMO)
Drug resistance has been relatively uncommon in
Gambiantrypanosomiasis despite the majority of treatments being
used for fifty years. Suramin is not often used in the treatment
of Fambian trypanosomiasis. Pentamidine is given throughout Africa.
for early stage of the disease with a
failure rate that reamins areound 7%(Pepin and Khonde, 1996)
Image courtesy of Standford
A woman caring for her comatose
husband who is dying of African trypanosomiasis, Uganda, 1990.
Acosta-Serrano, Alvaro, Morita, Yasu S.,
Englund, Paul T., Bohme, Ulrike, and Cross George A.M. 2001. Virulence
of Trypanosoma brucei strain 427 is not affected by the absence
of glycosylphosphatiylinositol phospholipase C. Molecular and Biochemical
Parasitology 114: 245-247.
African Trypanosmomiasis from the Strategic
Direction for African Trypanosomiasis Research site. Dated Feb.
Aksoy, Shengrong Hao, and Patricia M. Strickler.
2002. What can we hope to gain from trypanosomiasis control form
molecular studies on tsetse biology? Biology and Disease 1:4 <http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=119325>
Atouguia, Jorge and Jose Costa. 1999. Therapy
of Human African Trypanosomiasis: Current Situation. Memorial Institue
of Oswaldo Cruz. Vol. 94(2): 221-4 Mar/April 1999
Feldmann U. and Hendrichs J. (1998). Integrating
the Sterile Insect Technique as a key component of area wide tsetse
and trypansomosis intervention. Insect and Pest Control Section,
Joint FAO/IAEA Division of Nuclear Techniques in Food and Agriculture.
Gibson, Wendy. (2001) Molecular characterization of field
isolates of human pathogenic trypanosomes. Tropical Medicine
and International Health. 6(5):401-406.
Hunt, Richard C. ( 2003) Trypanosomes-Eucaryotic
Cells with a Different Way of Doing Things. Molecular Parasitology.
An Introduction to Molecular Parasitology
Targets for chemotherapy of parasitic diseases
Khonde N. & Mpia B. (1998) Multicentre
comparative study of two treatment durations with eflornithine for
late-stage T. b. gambiense sleeping sickness. WHO Tropical Disease
Research Project no. 960720, 960721, 960722. October
Lewis R. (2002). African Sleeping Sickness: A recurring
Epidemic. The Scientist; 16, 10,26. May
Pepin, Jacques and Honore, A. Meda. (2001)
The Epidemiology and Control of Human African Trypanosomiasis. 49:72-121
Solano, P., Guegan, J.F., Reifenberg, J.M.,
F. Thomas. 2001.Trying to predict and explain the presence of African
Trypanosomes in Tsetse flies. Journal of Parasitology. 87(5): 1058-1063.
Stich, August, Abel, Paulo M., Krishna,
Sanjeev. Clinical Review: Human African trypanosomiasis: The re-emergence
of sleeping sickness presents a major public health problem. 2002.
325 bmj.com Leal, Simone,
African trypanosomiasis from the Strategic
Direction for African Trypanosomiasis Research site at
dated Feb. 2002
Semakula, John Kiwanuka. (2002) No longer
asleep – Africa Sleeping Sickness is back
Zhengrong, Hao, Kasumba, Irene, Lehane, Michael J.,
Gibson, Wendy D., Kwon, Johnny, and Serap Aksoy. (2001) Tsetse immune
responses and trypanosome transmission: Implications for the development
of tsetse-based strategies to reduce trypanosomiasis. Vol 98(22):
/ Treatment / Bibliography
Created by Corliss Harris
as part of a biology senior seminar at Earlham College
Last updated: April 24, 2003