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Human African trypanosomiasis 

Human African trypanosomiasis

Human African trypanosomiasis

August Stich



Trypanosoma brucei rhodesiense—clinical differences between stage II patients in Uganda and Tanzania.

Updated on 31 May 2012. The previous version of this content can be found here.
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Human African trypanosomiasis (HAT, sleeping sickness) is caused by two subspecies of the protozoan parasite Trypanosoma brucei: T. b. rhodesiense is prevalent in East Africa among many wild and domestic mammals; T. b. gambiense causes an anthroponosis in Central and West Africa. The disease is restricted to tropical Africa where it is transmitted by the bite of infected tsetse flies (Glossina spp.).

Although well under control in the mid 20th century, HAT has returned to Africa in epidemic proportions since the 1980s, causing a severe public health problem in countries such as the Democratic Republic of Congo, Angola, Sudan, and Uganda. A joint effort by national, international, and nongovernmental organizations, as well as the pharmaceutical industry, is required to reverse this trend.

Clinical features

HAT progresses through distinct clinical stages that invariably lead to death if left untreated. Progress is fast in rhodesiense HAT, often resembling the clinical picture of malaria or septicaemia, and slow—sometimes lasting years—in gambiense HAT.

  1. (1) Trypanosomal chancre—a papule at the site of the bite, surrounded by an intense local erythematous/oedematous reaction and with regional lymphadenopathy, healing without treatment after 2 to 4 weeks.

  2. (2) Haemolymphatic stage (HAT stage 1)—manifests with fever, chills, rigors, headache and joint pains; hepatosplenomegaly and generalized lymphadenopathy are common

  3. (3) Meningoencephalitic stage (HAT stage 2)—insidious onset of headache, sometimes with change in behaviour and personality; convulsions are common; sleep pattern becomes fragmented, eventually leading to somnolence and coma, with inability to drink and eat leading to dehydration and wasting.

Outside Africa, HAT is a rare diagnosis as an imported infection in travellers, but has to be considered in any patient with fever, chronic lymphadenopathy, or neurological changes returning from HAT endemic areas.

Diagnosis, staging, and treatment

Diagnosis—this is established by the detection of trypanosomes (usually by direct microscopy) in chancre aspirate, blood, lymph, or cerebrospinal fluid. Serology is useful for rapid screening under field conditions, but does not necessarily imply overt disease.

Staging—this is crucial for correct management: the cerebrospinal fluid must be examined in every patient found positive for trypanosomes in blood or lymph aspirate.

Treatment—HAT is curable, but many factors make this difficult: the disease is found in remote places, diagnosis is difficult, treatment is costly and complicated, and many drugs are not easily available. Aside from supportive care, specific treatment depends on the trypanosome subspecies and the stage of the disease, including (1) stage 1—pentamidine, and suramin; (2) stage 2—melarsoprol, eflornithine, and nifurtimox. There are no generally accepted recommendations on drug combinations, but—especially in late stages—treatment is difficult and dangerous to the patient; all of the drugs used are toxic and have many side effects, some potentially lethal.


Control can be achieved by a combination of mass screening programmes, treatment of patients, and vector control, which together can lead to a complete break of the transmission cycle. There is no vaccine.


Sleeping sickness or human African trypanosomiasis (HAT) is caused by subspecies of the protozoan haemoflagellate Trypanosoma brucei transmitted to humans and animals by tsetse flies (Glossina spp.). The distribution of the vector restricts sleeping sickness to the African continent between 14° north and 29° south (Fig. Human disease occurs in two clinically and epidemiologically distinct forms, gambiense or West African and rhodesiense or East African sleeping sickness (Table A third subspecies of the parasite, T. b. brucei, causes disease in cattle but is nonpathogenic in humans. In Uganda, the only country where all three forms occur, gambiense and rhodesiense sleeping sickness are currently about to overlap.

Fig. The geographical distribution of human African trypanosomiasis.

The geographical distribution of human African trypanosomiasis.

Table The principal features of West and East African sleeping sickness


West African sleeping sickness

East African sleeping sickness


Trypanosoma brucei gambiense

Trypanosoma brucei rhodesiense


Transmitted by riverine tsetse flies (Palpalis group)

Transmitted by savannah tsetse flies (Morsitans group)

Clinical course

Insidious onset, slow progression, death in stage II after many months or years

Acute onset, chancre frequent, rapid course, death frequently in stage I (cardiac failure)


Parasitaemia scanty, Winterbottom’s sign, serology

Parasitaemia usually higher and easily detectable, serological tests unreliable


See Table


Tendency for endemicity, humans as main reservoir with evidence for several other mammal species, severe public health problem in many West and Central African countries

Wild (antelopes e.g. bushbuck) and occasionally domestic animals as reservoir and source of case clusters and epidemic outbreaks

The first case reports of the disease go back to the 14th century. In the past, its impact on health in Africa has been enormous. Many areas were long rendered uninhabitable for people and livestock. During the early decades of the 20th century, millions may have died in Central Africa around Lake Victoria and in the Congo basin (Fig. The success of control programmes in the 1960s promised the disappearance of sleeping sickness as a public health problem. However, recent epidemics in the Democratic Republic of Congo, northern Angola, southern Sudan, the Central African Republic, Uganda, and other countries have confirmed a major resurgence of HAT. According to estimates by the World Health Organization (WHO) at the turn of the millennium, the achievements in sleeping sickness control during colonial times had been nearly completely reversed. However, recent successes of control programmes run by national institutions and various nongovernmental organizations could again reduce its prevalence and transmission in many accessible areas of central Africa.

Fig. Sleeping sickness patients on an island in Lake Victoria; historical photograph taken during Robert Koch’s research expedition to East Africa.

Sleeping sickness patients on an island in Lake Victoria; historical photograph taken during Robert Koch’s research expedition to East Africa.

Today, about 60 million people in 36 African countries are exposed to the potential risk of HAT. In some 300 currently existing active foci, up to 100 000 people are still believed to be infected, almost all with T. b. gambiense. If left untreated, they are doomed. For tourists and expatriates, sleeping sickness has always been a rare disease, although several clusters of cases have been reported in tourists to Tanzania, Zambia, and Malawi. The role of trypanosomes recently diagnosed in patients in some areas of the Indian subcontinent caused by T. evansi is currently under investigation.


In 1895, Sir David Bruce (1855–1931) suggested an association between trypanosomes and ‘cattle fly fever’, a major problem for livestock in southern Africa. In 1902, Robert M Forde and Everett Dutton from the Liverpool School of Tropical Medicine identified trypanosomes in the blood of a patient during a research expedition in the Gambia (see Fig., and in 1903, Aldo Castellani isolated trypanosomes from the cerebrospinal fluid. In the same year, tsetse flies were identified as the vector.

Fig. (a) Trypanosomes in thin human blood film (Giemsa stain, ×1000). (b) Everett Dutton’s painting of trypanosomes.

(a) Trypanosomes in thin human blood film (Giemsa stain, ×1000). (b) Everett Dutton’s painting of trypanosomes.

Trypanosoma brucei (phylum Sacromastigophora, order Kinetoplastida) is an extracellular protozoal parasite. Like leishmania, it possesses a centrally placed nucleus and a kinetoplast, a distinct organelle containing extranuclear DNA. The kinetoplast is the insertion site of an undulating membrane, which extends over nearly the whole cell length and ends as a free flagellum.

The three subspecies of T. brucei are indistinguishable morphologically. However, they differ considerably in their interaction with their mammalian host and the epidemiological pattern of the diseases they cause. Formerly, T. b. gambiense and T. b. rhodesiense isolates were characterized either by isoenzyme analysis or by animal inoculation. The advent of molecular techniques created expectations of more reliable tools for their differentiation. However, genomic characterization has revealed several more subdivisions than the three that were expected. Whereas West African isolates proved relatively homogeneous, East African isolates from humans and animals did not simply conform to what is still called T. b. rhodesiense and T. b. brucei but showed a complex relationship with evidence of sexual genetic exchange in the vector. Further molecular research may lead to a comprehensive phylogenetic tree and a deeper insight into trypanosomal evolution and biology.


Although congenital, blood-borne, and mechanical transmission have been reported and may play an occasional role, the main mode of transmission is through the bite of infected tsetse flies (Glossina spp., order Diptera; Fig. These are biologically unique insects, which occur only in Africa, with 31 distinct species and subspecies of which less than half are potential vectors of HAT. Their distinctive behaviour, ecology, and chosen habitat explain many epidemiological features of sleeping sickness. Tsetse flies can live for many months in the wild, are viviparous, and give birth to only about eight larvae per lifetime. Both sexes feed on blood. They are fastidious in requiring warm temperatures, shade, and humidity for resting and larviposition and so their distribution is highly localized. Recently, the mapping and monitoring of possible HAT transmission foci has become possible with the use of satellite imaging techniques.

Fig. Adult tsetse fly Glossina morsitans.

Adult tsetse fly Glossina morsitans.

During the blood meal on an infected mammalian host, the tsetse fly takes up trypanosomes (‘short-stumpy form’) into its mid-gut, where they develop into procyclic forms and multiply. After about 2 weeks, they migrate to the salivary glands as epimastigotes where they finally develop into infective metacyclic forms. At the next blood meal, they are injected into a new vertebrate host where they appear as ‘long-slender’ trypomastigotes and multiply by binary fission. In contrast to leishmania and T. cruzi, T. brucei is an exclusively extracellular parasite.

Molecular and immunological aspects

The cyclic changes of the trypanosome into different developmental stages are accompanied by variations in morphology, metabolism, and antigenicity. Several unique metabolic pathways have been described in trypanosomes, distinct from their host and thus qualifying as potential drug targets.

The bloodstream forms of T. brucei are covered with a dense coat of identical glycoproteins with up to about 500 amino acids per molecule. Being highly immunogenic, they stimulate the production of specific antibodies, mainly of the IgM subclass. Once the surface glycoproteins have been recognized by host antibodies, the parasite will be attacked and destroyed through complement activation and cytokine release, giving rise to local and systemic inflammatory reactions.

However, about 2% of T. brucei in each new generation change the expression of their specific surface glycoprotein. The ‘coat’ will then be different in the new clone (thus called variant surface glycoprotein, VSG). This phenotypic switch is done mainly by programmed DNA rearrangements, moving a transcriptionally silent VSG gene into an active, telomerically located expression site. Each T. brucei parasite already has the information for hundreds of different VSG genes, and within a whole trypanosome population, the potential repertoire for such different VSG copies seems to be virtually infinite.

Every new VSG copy is antigenically different, thus stimulating the production of a new IgM population. This antigenic variation is the major immune evasion strategy of the parasite, enabling the trypanosome to persist in its vertebrate host. It also reduces parasite load and prolongs the infection. But the inevitable outcome is immune exhaustion of the host (supported by additional immunosuppressive metabolites of the parasites), penetration of trypanosomes into immune-privileged sites such as the central nervous system, and finally death.

Clinical features

Sleeping sickness is a dreadful disease, causing great suffering to patients, their families, and the affected community. The infection often has an insidious onset, but T. brucei, whether the East or West African subspecies, will invariably kill unless treated in time. The natural course of HAT can be divided into different and distinct stages. Their recognition and differentiation is important for the clinical management of the patient.

Trypanosomal chancre

Tsetse bites can be quite painful, usually leaving a small and self-healing mark. In the case of a trypanosomal infection, the local reaction can be quite pronounced and longer lasting. A small raised papule will develop after about 5 days. It increases rapidly in size, surrounded by an intense erythematous tissue reaction (Fig. with local oedema and regional lymphadenopathy. Although some chancres have a very angry appearance, they are not usually very painful unless they become ulcerated and superinfected. They heal without treatment after 2 to 4 weeks, leaving a permanent, hyperpigmented spot.

Fig. Trypanosomal chancre on the calf of a missionary returning from the Congo.

Trypanosomal chancre on the calf of a missionary returning from the Congo.

Trypanosomal chancres occur in about half the cases of T. b. rhodesiense. In T. b. gambiense, they are much less common and often go undetected in endemic populations.

Haemolymphatic stage (HAT stage I)

After local multiplication at the site of inoculation, the trypanosomes invade the haemolymphatic system, where they can be detected after 7 to 10 days. There they are exposed to vigorous host defence mechanisms, which they evade by antigenic variation. This continuous battle between antigenic switches and humoral defence results in a fluctuating parasitaemia with parasites frequently becoming undetectable, especially in gambiense HAT. The cyclic release of cytokines during periods of increased cell lysis results in intermittent, nonspecific symptoms: fever, chills, rigors, headache, and joint pains. These can easily be misdiagnosed as malaria, viral infection, typhoid fever, or many other conditions. Hepatosplenomegaly and generalized lymphadenopathy are common, indicating activation and hyperplasia of the reticuloendothelial system.

A reliable sign, particularly in T. b. gambiense infection, is the enlargement of lymph nodes in the posterior triangle of the neck (Winterbottom’s sign). Other typical signs are a fugitive patchy or circinate rash, a myxoedematous infiltration of connective tissue (‘puffy face syndrome’), and an inconspicuous periostitis of the tibia with delayed hyperaesthesia (Kérandel’s sign).

In T. b. rhodesiense infection, this haemolymphatic stage is very pronounced with severe symptoms, often resembling falciparum malaria or septicaemia. Frequently, patients die within the first weeks after the onset of symptoms, mostly through cardiac involvement (myocarditis). In the early stage of T. b. gambiense infection, symptoms are usually infrequent and mild. Febrile episodes become less severe as the disease progresses.

Meningoencephalitic stage (HAT stage II)

Within weeks in T. b. rhodesiense and months in T. b. gambiense infection, cerebral involvement will invariably follow; trypanosomes cross the blood–brain barrier.

The onset of stage II is insidious. The exact time of central nervous system involvement cannot be determined clinically. Histologically, perivascular infiltration of inflammatory cells (‘cuffing’) and glial proliferation can be detected, resembling cerebral endarteriitis. As the disease progresses, patients complain of increasing headache, and their families may detect a marked change in behaviour and personality. Neurological symptoms, which follow gradually, can be focal or generalized, depending on the site of cellular damage in the central nervous system. Convulsions are common, usually indicating a poor prognosis. Periods of confusion and agitation slowly evolve towards a stage of distinct perplexity when patients lose interest in their surroundings and their own situation. Inflammatory reactions in the hypothalamic structures lead to a dysfunction in circadian rhythms and sleep regulatory systems. Sleep pattern become fragmented and finally result in a somnolent and comatose state. Progressive wasting and dehydration follows the inability to eat and drink.

In children, HAT progresses even more rapidly towards this meningoencephalitic stage. Parents often notice insomnia and behavioural changes long before the diagnosis is established.

There is no unique clinical sign of late HAT, opening up a wide range of possible neurological and psychiatric differential diagnoses. However, the appearance of the patient with apathy, the typical expressionless face, and swollen lymph nodes at the posterior triangle of the neck, is very suggestive for HAT in endemic areas (Fig.

Fig. Patient with late-stage trypanosomiasis.

Patient with late-stage trypanosomiasis.

Human African trypanosomiasis Clinical features of stage II patients with T. b. rhodesiense infections were compared in two locations in East Africa. Nonspecific signs of infection were more common in Uganda, whereas classic neurological manifestations dominated the clinical picture in Tanzania. Coinfections with malaria and HIV influenced neither clinical presentation nor response to treatment in Tanzania.


HAT can never be diagnosed with certainty purely on clinical grounds alone. Definitive diagnosis requires the detection of the parasite in chancre aspirate, blood, lymph, or cerebrospinal fluid using various parasitological techniques.

Lymph node aspirate

Lymph node aspiration is widely used, especially for the diagnosis of gambiense HAT. Fluid of enlarged lymph nodes, preferably of the posterior triangle of the neck (Winterbottom’s sign), is aspirated and examined immediately at ×400 magnification without additional staining. Mobile trypanosomes can be detected for a few minutes between the numerous lymphocytes.

Wet preparation, thin, and thick blood film

During all stages of the disease, trypanosomes may appear in the blood where they can be detected in unstained wet or in stained preparations. The yield of detection is highest in the thick blood film, a technique widely used for the diagnosis of blood parasites such as plasmodium or microfilaria. Giemsa or Field staining techniques are appropriate (Fig.

Especially in gambiense HAT, parasitaemia is usually low and fluctuating, often even undetectable. Repeated examinations on successive days are sometimes necessary until trypanosomes can be documented.

Concentration methods

To increase the sensitivity of blood examinations, various concentration assays have been developed. Trypanosomes tend to accumulate in the buffy coat layer after centrifugation of a blood sample. The best results have been obtained with the mini anion exchange column technique (mAECT), where trypanosomes are concentrated after passage through a cellulose column, the quantitative buffy coat (QBC) method, which was originally developed for the diagnosis of malaria, or the capillary tube centrifugation (CTC) method, which is widely used in the field.

Nucleic amplification techniques

Several specific primers have been described to detect trypanosomal DNA using the polymerase chain reaction (PCR). They had been successfully applied to samples from blood, lymph, and cerebrospinal fluid, mostly in research laboratory conditions. Although some of these techniques are able to detect fewer than 10 trypanosomes per probe, in the real situation of clinical diagnosis PCR assays are inferior to conventional parasitological techniques.

Serological assays

Serology is a useful tool to detect antibodies against trypanosomiasis. Various test methods have been described, some of them are now commercially available. They are mainly based on the enzyme-linked immunosorbent assay (ELISA) technique or immunofluorescence, but provide reliable results only in gambiense HAT.

For rapid screening under field conditions, the card agglutination test for trypanosomiasis (CATT) is an excellent tool in areas of T. b. gambiense infestation. It is easy to perform and delivers results within 5 min. A visible agglutination in the CATT suggests the existence of antibodies, but does not necessarily imply overt disease. Still, any positive serological result requires parasitological confirmation.

Nonspecific laboratory findings

Anaemia and thrombocytopenia are caused by systemic effects of cytokine release, especially of tumour necrosis factor α‎ (TNFα‎). Hypergammaglobinaemia can reach extreme levels as a result of polyclonal activation of plasma cells. IgM levels detected in HAT are among the highest observed in any infectious disease.

Diagnosis of stage II

Stage determination is crucial for the correct management of a patient. This cannot be done on clinical grounds alone. Cerebrospinal fluid must therefore be examined in every patient found positive for trypanosomes in blood or lymph aspirate. A lumbar puncture should also be performed in all patients in whom HAT is suspected clinically even if peripheral examinations had proved negative. A minimum of 5 ml of cerebrospinal fluid is required to examine for:

  • Leucocytes—cerebral involvement in HAT stage II is accompanied by pleocytosis, mostly lymphocytes, in the cerebrospinal fluid. By convention a number of five cells or more per mm3 cerebrospinal fluid defines central nervous system involvement even if the patient does not (yet) have neurological symptoms. Pathognomonic for HAT is the appearance of activated plasma cells with eosinophilic inclusions in the cerebrospinal fluid, the morular cells of Mott (Fig.

  • Trypanosomes—the chances of detecting trypanosomes in the cerebrospinal fluid increase with the level of pleocytosis and the technique used. The highest yield is obtained by cerebrospinal fluid double centrifugation and rapid microscopy at the bedside.

  • Protein—in patients with HAT, a level of 37 mg of protein per 100 ml cerebrospinal fluid (dye-binding protein assay) or more is highly suggestive of the advanced stage. Stage II HAT is characterized by an autochthonous production of IgM antibodies in the cerebrospinal fluid, which can be selectively detected if suitable laboratory facilities exist (e.g. latex IgM test).

Fig. Morular cell of Mott in a histological brain section of a stage II HAT patient (haematoxylin and eosin stain, ×1000).

Morular cell of Mott in a histological brain section of a stage II HAT patient (haematoxylin and eosin stain, ×1000).


General considerations

HAT is curable, especially if the diagnosis is made at an early stage of the disease. In the stark reality of the African situation, however, there are many major obstacles to successful patient management:

  • Sleeping sickness is a disease of rural, remote places. The active foci of sleeping sickness are usually in faraway and insecure places, which are difficult to reach. Many treatment centres work under emergency conditions with extremely restricted resources. Numerous affected patients, without proper access to health care, are left unattended.

  • The diagnosis is difficult. Initial diagnosis and exact staging of trypanosomiasis requires sophisticated methods that are often dangerous to the patient and justified only in the hands of experienced personnel. Repetitive training programmes, constant supervision, and continuous quality control are necessary but in reality rarely available.

  • The treatment of trypanosomiasis is extremely costly, although the drugs themselves are now covered by a donation programme. Invariably, demand exceeds the locally available resources. External funding and sustainable donor commitments for rural Africa are generally decreasing.

  • The treatment is complicated. Treatment of HAT is dangerous, prolonged, and usually requires hospitalization. Most patients with late-stage trypanosomiasis are severely ill and malnourished. Adverse drug reactions during treatment are difficult to assess because of concomitant pathologies. Their management requires considerable medical skill and good nursing care. Hospitals in rural Africa are often inadequately equipped and staffed to accomplish good patient care.

  • Many drugs are not easily available. Many trypanosomicidal agents are on the verge of disappearance, despite increasing demand. The range of drugs is diminishing, and hardly any new treatments are in sight. This is especially worrying in view of the reported spread of drug resistance.

  • HAT treatment is not standardized. Trypanosomiasis treatment regimens vary considerably between countries and treatment centres. Results from different centres are comparable to only a very limited extent. Few properly conducted and sufficiently powered clinical trials are available to evaluate duration, dosage, and possible combinations of drugs. Sufficient infrastructure for carrying out clinical research exists in only a handful of places.

The price for cure of HAT is high: dangerous drugs with limited availability and prolonged treatment schedules administered in many places by poorly trained personnel in rudimentary medical facilities. Little progress has been achieved in the last 30 years.

Stage I drugs

The treatment of HAT depends on the trypanosome subspecies and the stage of the disease (Table

Table The choice of drugs in the treatment of sleeping sickness

Gambiense sleeping sickness

Rhodesiense sleeping sickness


1st line


1st line


Stage I

2nd line


2nd line



1st line

Eflornithine (+ nifurtimox?)

1st line


Stage II

2nd line


2nd line

Melarsoprol + nifurtimox


Since its introduction in 1937, pentamidine has become the drug of choice for gambiense HAT stage I, achieving cure rates as high as 98%. However, there are frequent failures in rhodesiense HAT. Lower rates of cellular pentamidine uptake in T. b. rhodesiense may explain these differences. Some cures of stage II infections have also been reported, but cerebrospinal fluid drug levels are usually not sufficiently high to guarantee a reliable trypanosomicidal effect in the central nervous system.

Pentamidine is usually given by deep intramuscular injection, often to outpatients. If hospital care and reasonable monitoring conditions are available, an intravenous infusion, given in normal saline over 2 h, might be used instead. The main advantage of pentamidine over other drugs is the short treatment course and ease of administration. Adverse effects are related to the route of administration or its dose and are usually reversible (Table

Table Dosage and principal adverse reactions of antitrypanosomal agents


Dosage regimen

Adverse drug reactions


4mg/kg body weight intramuscular daily or on alternate days for 7 to 10 injections (3 dose regimen currently under investigation)

Hypotensive reaction with tachycardia, dizziness, even collapse and shock, especially after intravenous administration, close monitoring of pulse rate and blood pressure after injection is mandatory

Inflammatory reactions at the site of injection (sterile abscesses, necrosis)

Renal, hepatic, and pancreatic dysfunction

Neurotoxicity: peripheral polyneuropathy

Bone marrow depression


Day 1: Test dose of 4–5 mg/kg body weight

Pyrexia (very common)

Day 3, 10, 17, 24, and 31: 20 mg/kg body weight, maximum

Early hypersensitivity reactions such as nausea, circulatory collapse, urticaria

Dose per injection 1 g

Late hypersensitivity reactions: skin reactions (exfoliative dermatitis), haemolytic anaemia

Renal impairment: albuminuria, cylinduria, haematuria (high renal tissue concentrations); regular urine checks during treatment are mandatory

Neurotoxicity: peripheral neuropathy

Bone marrow toxicity: agranulocytosis, thrombocytopenia


New regimen:

Treatment-induced encephalopathy

Day 1–10: 2.2 mg/kg body weight


Neurotoxicity: peripheral motor or sensory polyneuropathy

Dermatological reactions: pruritus, urticaria, exfoliative dermatitis;


Renal and hepatic dysfunction


Most commonly used dosage regimen:

Gastrointestinal symptoms such as nausea, vomiting and diarrhoea

100 mg/kg body weight at 6-hourly intervals for 14 days

Bone marrow toxicity: anaemia, leucopenia, thrombocytopenia

Alopecia, usually towards the end of the treatment cycle

Neurological symptoms such as convulsions


5mg/kg body weight 3 times daily for 30 days

Abdominal discomfort such as nausea, pains, and vomiting in half of the treated patients, often leading to a disruption of the treatment course

Neurological complications: convulsions,

Impairment of cerebellar function, polyneuropathy

Skin reactions

Pentamidine is also used as second-line therapy for visceral leishmaniasis and especially in the prophylaxis and treatment of opportunistic Pneumocystis jiroveci pneumonia in AIDS. Since the start of the HIV pandemic, the cost of pentamidine has been increased more than tenfold by producers, making it unaffordable by health institutions in low-income countries. After an intervention by WHO, a limited amount of pentamidine is now made available for use in HAT as part of a donation programme.


In the early 20th century, the development of suramin, resulting from German research on the trypanosomicidal activity of various dyes (‘Bayer 205’), was a major breakthrough in the field of tropical medicine. For the first time, African trypanosomiasis, at least in its early stages, became treatable without causing major harm.

Even today, suramin is still used to treat stage I HAT, especially rhodesiense. Like pentamidine, it does not reach therapeutic levels in cerebrospinal fluid. Suramin is injected intravenously after dilution in distilled water.

Adverse effects depend on nutritional status, concomitant illnesses (especially onchocerciasis), and the patient’s clinical condition. Although life-threatening reactions have been described, serious adverse effects are rare (Table

Stage II drugs


Until the systematic introduction of the arsenical compound melarsoprol in 1949, late stage trypanosomiasis was virtually untreatable. Since then, it has remained the most widely used stage II antitrypanosomal drug both for gambiense and rhodesiense infections. It has saved many lives, but has a high rate of dangerous adverse effects. Increasing frequency of relapses and resistance has been reported in some parts of Congo, Angola, Sudan, and Uganda.

Melarsoprol clears trypanosomes rapidly from the blood, lymph, and cerebrospinal fluid. Its toxicity usually restricts its use to late-stage disease. It is given by slow intravenous injection; extravascular leakage must be avoided.

A new, simpler regimen is based on recently acquired knowledge of the drug’s pharmacokinetics (Table The most important adverse effect is an acute encephalopathy, provoked around day 5 to 8 of the treatment course in 5 to 14% of all patients. There are severe headache, convulsions, rapid neurological deterioration, or deepening of coma. Characteristically, the comatose patient’s eyes remain open. Most probably, this is an immune-mediated reaction precipitated by release of parasite antigens in the first days of treatment. The overall case fatality under treatment ranges between 2 and 12%, depending on the stage of disease and the quality of medical and nursing care. Simultaneous administration of glucocorticosteroids (prednisolone 1 mg/kg body weight; maximum 40 mg daily) reduces mortality, especially in cases with high cerebrospinal fluid pleocytosis. However, in areas where tuberculosis, amoebiasis, and strongyloidiasis are highly prevalent, corticosteroids have dangers of their own.

Eflornithine (DFMO)

Initially developed as antitumour agent, eflornithine (α‎-difluoromethylornithine) was introduced in 1980 as an antitrypanosomal drug, in the hope that it might replace melarsoprol for treatment of stage II trypanosomiasis. However, exorbitant costs and limited availability have restricted its use mostly to melarsoprol-refractory cases of gambiense sleeping sickness. T. b. rhodesiense is much less sensitive, because of a much higher turnover rate of the target enzyme ornithine decarboxylase, and therefore cannot be treated with eflornithine.

The drug can be taken orally, but intravenous administration is preferred as it achieves a much higher bioavailability and success rate. Eflornithine should be administered slowly over a period of at least 30 min. Continuous 24-h administration is preferable if facilities allow.

The range of adverse reactions to eflornithine is wide, as with other cytotoxic drugs in cancer treatment. Their occurrence and intensity increase with the duration of treatment and the severity of the patient’s general condition (Table

In the late 1990s no pharmaceutical company produced eflornithine for use against HAT, despite pressure by WHO. The discovery of its therapeutic effect in cosmetic creams against facial hair helped to restimulate production and thus had a beneficial ‘spin-off’ effect for HAT. In 2001 agreements were signed between WHO and two major drug companies which led to a ‘public–private partnership’ (PPP) and helped to assure a sufficient supply of eflornithine and other drugs essential for the treatment of HAT. In 2006, the agreement was prolonged until 2011.


Ten years after its introduction for the treatment of American trypanosomiasis in 1967, nifurtimox was found to be effective in the treatment of gambiense sleeping sickness. It has a place as second-line treatment in melarsoprol-refractory cases or in combination chemotherapies.

Nifurtimox is given orally and generally not well tolerated, but adverse effects are usually not severe. They are dose-related and rapidly reversible after discontinuation of the drug (Table

Combination treatments in HAT

Melarsoprol, eflornithine, and nifurtimox interfere with trypanothione synthesis and activity at different stages. There is also experimental evidence that combinations of suramin and stage II drugs might be beneficial. Therefore, by reducing the overall dosage of each individual component, drug combinations have the potential to reduce the frequency of serious side effects and the development of resistance, which are such common problems in the treatment of sleeping sickness.

Recent prospective clinical trials have shown a beneficial effect of nifurtimox eflornithine combination therapy (NECT). This has the potential to develop into the preferred first-line treatment of stage II gambiense HAT in the future.

Individual protection

Tsetse flies have a very patchy distribution. Infested strips of land are often well known to the local population and should be avoided as far as possible. HAT among tourists and occasional visitors to endemic areas is a rare event. Pentamidine or suramin chemoprophylaxis is historical, and can no longer be recommended. Long-sleeved, brightly coloured clothing and insecticide repellents are the best defence against attacking tsetse flies.

Prevention and control

In the past, tremendous efforts were undertaken to control the threat posed by sleeping sickness to human lives and economic development in rural Africa. Control programmes are based on the five complementary pillars given in Box

The most important strategy is active case finding. This requires mobile teams, which regularly visit villages in endemic areas. Mostly based on the results of CATT screening, patients, preferably in the early stage of the disease, are identified and treated. Gradually, the parasite reservoir is depleted. As glossina is a relatively incompetent vector, with infectivity rates usually below 0.1% and susceptible to control measures such as insecticide application, trapping, or even the release of sterile males, the combination of various approaches can lead to a complete break of the transmission cycle. In the past this was achieved in many places. However, the resurgence of sleeping sickness in areas ridden by war and civil unrest during the last decades of the 20th century, in combination with the decreasing availability of drugs on the international market and the general loss of interest in health issues of the developing world, gives rise to the fear that HAT will always be a problem in many rural parts of Africa (Fig.

Fig. Number of annually reported cases of human African trypanosomiasis.

Number of annually reported cases of human African trypanosomiasis.

(source: WHO Report on Global Surveillance and Epidemic-prone Infectious Diseases); according to WHO, the actual patient numbers are about 10-fold higher.

Trypanosomiasis in the 21st century

There is hardly any other tropical disease that demonstrates more clearly the dichotomy characterizing our modern age. On one side, trypanosomes are kept in culture and studied extensively in numerous research laboratories. Their genome is sequenced, and many molecular, biochemical, and immunological phenomena have been discovered as a result of basic science research.

General interest in this disease is usually restricted only to its research aspects, however. Diagnostic and especially therapeutic tools are increasingly unavailable, because the tens of thousands of infected people in Africa are not commercially viable consumers. The prospects for the fight against trypanosomiasis look grim, although some recent successes have been accomplished usually through the work of committed nongovernmental organizations (e.g. in Sudan and Angola). Global concern about the crisis of human trypanosomiasis in Africa is a question of scientific ethics and international solidarity.

Further reading

Brun R, Balmer O (2006). New developments in human African trypanosomiasis. Curr Opin Infect Dis, 19, 415–20.Find this resource:

Brun R, et al. (2010). Human African trypanosomiasis. Lancet, 375, 148–59.Find this resource:

Burri C (2010). Chemotherapy against human African trypanosomiasis: is there a road to success? Parasitology, 137, 1987–94.Find this resource:

Dumas M, Bouteille B, Buguet A (eds) (1999). Progress in human African trypanosomiasis, sleeping sickness. Springer-Verlag, Paris.Find this resource:

    Jannin J, Cattand P (2004). Treatment and control of human African trypanosomiasis. Curr Opin Infect Dis, 17, 565–70.Find this resource:

    Kuepfer I, et al. (2011). Clinical presentation of T. b. rhodesiense sleeping sickness in second stage patients from Tanzania and Uganda. PLoS Negl Trop Dis, 5, e968.Find this resource:

    Maudlin I (2006). African trypanosomiasis. Ann Trop Med Parasitol, 100, 679–701.Find this resource:

    Pepin J, et al. (1989). Trial of prednisolone for prevention of melarsoprol-induced encephalopathy in gambiense sleeping sickness. Lancet, i, 1246–50.Find this resource:

    Priotto G, et al. (2009). Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial. Lancet, 374, 56–64.Find this resource:

    Stich A, Barrett MP, Krishna S (2003). Waking up to sleeping sickness. Trends Parasitol, 19, 195–7.Find this resource:

    World Health Organization (1998). Control and surveillance of African trypanosomiasis. WHO Technical Report Series 881. WHO, Geneva.Find this resource: