Human African Trypanosomiasis
(African Sleeping Sickness)
Epidemiology / Treatment / Bibliography

Image Courtesy
depts.washington.edu/sgpp/ african_sleeping_sickness.html

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 (Pepin, 2000).

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
Distribution of the two sub-species in relation to their presence in Sub-Saharan Africa.
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.
Characteristic swelling 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, 2001).

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 today.

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 to
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 certain treatments.

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 (Pepin, 2000).

Sites to look at current events involving HAT:
Program Against African Trypanosomiasis
Integrated Control of Pathogenic Trypanosomes and their Vectors
WHO Report on Global Surveillance of Epidemic-prone Infectious Diseases
CDC Fact Sheet on West African Trypanosomiasis
World Bank Statistics

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:
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
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
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
Once parasites 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 of damage.

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).|

Targets for chemotherapy
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, suramin)
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 University
A woman caring for her comatose husband who is dying of African trypanosomiasis, Uganda, 1990.
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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. 2002. http://www.who.int/tdr/diseases/tryp/direction.htm Accessed 2/19/03

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. November.

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. <http://www.med.sc.edu:85/trypanosomiasis.htm> Accessed

An Introduction to Molecular Parasitology and Trypanosomes.
http://tryps.rockefeller.edu/crosslab_intro.html Accessed 3/5/2003.

Targets for chemotherapy of parasitic diseases Accessed 3/5/03
http://www.cvm.uiuc.edu/courses/vp437/biochemicalpeculiarities.html

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
<http://www.who.int/tdr/diseases/tryp/direction.htm> dated Feb. 2002

Semakula, John Kiwanuka. (2002) No longer asleep – Africa Sleeping Sickness is back
<http://medilinks.org/Features/Articles/ june2002/tryps.htm>

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): 12648-12653.

Epidemiology / Treatment / Bibliography

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Created by Corliss Harris as part of a biology senior seminar at Earlham College
Last updated: April 24, 2003