African Trypanosomiasis

African trypanosomiasis is a parasitic infection caused by Trypanosoma brucei subspecies and transmitted by the bite of the tsetse fly. It is endemic to specific regions of sub Saharan Africa.

It comprises two clinically and epidemiologically distinct forms. West African disease (gambiense) is chronic and slowly progressive. East African disease (rhodesiense) is more acute and rapidly progressive. Untreated, both produce the characteristic central nervous system involvement historically named "sleeping sickness".

Disease stage at diagnosis (haemolymphatic versus central nervous system) determines treatment selection. Once the central nervous system is involved, agents that cross the blood brain barrier are required.

Pathophysiology and disease staging

• After the tsetse fly bite, the parasite multiplies in the blood and lymphatic system (the haemolymphatic, or stage one, phase). It then crosses the blood brain barrier to invade the central nervous system (the meningoencephalitic, or stage two, phase).
• Staging is critical to treatment selection. Agents effective against haemolymphatic disease frequently fail to achieve adequate central nervous system penetration to treat established stage two disease.
• Rhodesiense disease has a more acute, aggressive natural history and progresses to central nervous system involvement over weeks.
• Gambiense disease typically progresses more slowly, over months to years.
• Both forms are fatal without treatment once central nervous system involvement is established.

• A painful chancre (trypanosomal chancre) may develop at the site of the tsetse fly bite within one to two weeks. It is more commonly noted in rhodesiense infection, given its typically more prominent local inflammatory response.
• The haemolymphatic stage presents with intermittent fever, headache, arthralgia and lymphadenopathy. Posterior cervical lymphadenopathy (Winterbottom sign) is a classically described and relatively characteristic finding, particularly in gambiense infection.
• Progression to the meningoencephalitic stage produces the features that gave the disease its historical name: progressive daytime somnolence with nocturnal sleep disturbance (an inverted sleep wake cycle). Other neuropsychiatric features include personality change, confusion, tremor and, in advanced disease, coma.
• Rhodesiense infection, given its more acute course, is more likely to cause prominent cardiac involvement (myocarditis) during the haemolymphatic stage. This can cause death before central nervous system involvement develops.
• In gambiense infection the chronic haemolymphatic phase generally allows time for progression to overt central nervous system disease if untreated.

• Parasitological confirmation is the diagnostic reference standard. It is by direct microscopic identification of trypomastigotes on blood film, lymph node aspirate or, for central nervous system involvement, cerebrospinal fluid.
• Blood film is particularly useful in rhodesiense infection, which typically produces higher and more readily detectable parasitaemia.
• Lymph node aspirate is particularly useful in gambiense infection, where the characteristic lymphadenopathy provides an accessible sampling site.
• Cerebrospinal fluid examination is essential in every confirmed case to determine staging. An elevated white cell count (generally above five cells per microlitre) or the presence of trypanosomes indicates stage two, meningoencephalitic disease and determines the treatment regimen.
• Serological screening tests, particularly the card agglutination test for trypanosomiasis, are used for population screening in endemic regions for gambiense infection specifically.
• Any positive screening result needs confirmatory parasitological testing before treatment is initiated, given the significant toxicity of several treatment regimens.

• Treatment selection is determined by the infecting subspecies and, critically, the disease stage, given the fundamental difference in blood brain barrier penetration between agents.
• Stage one (haemolymphatic) gambiense infection is treated with pentamidine, and stage one rhodesiense infection with suramin. Both are effective against haemolymphatic disease but penetrate the central nervous system inadequately, so neither is appropriate for stage two disease.
• Stage two (meningoencephalitic) gambiense infection is increasingly treated with fexinidazole. This oral agent is a significant advance, being considerably more practical than older, more toxic parenteral regimens.
• Nifurtimox eflornithine combination therapy was used historically and is still used in some settings for stage two gambiense infection. Both options need specialist tropical medicine guidance for administration.
• Stage two rhodesiense infection is treated with melarsoprol, an older arsenic based compound with substantial toxicity, including a risk of potentially fatal reactive encephalopathy. Effective options have historically been limited for this form and stage, and research continues toward safer regimens.
• Staging, subspecies specific treatment selection and the toxicity of several agents make management complex. Confirmed or suspected African trypanosomiasis should be managed with specialist tropical medicine and infectious disease input, generally in a specialist centre with relevant experience, given the rarity of this diagnosis outside endemic regions.
• Prevention for travellers to endemic regions centres on tsetse fly avoidance (protective clothing, insect repellent).
• At population level in highly endemic areas, prevention uses vector control programmes and active case detection and treatment campaigns targeting the human reservoir of gambiense infection specifically. This public health investment has historically driven control and, in some regions, near elimination of the disease.