Synonyms include: African/Gambian/Rhodesian sleeping sickness, human African trypanosomiasis (HAT)
Human African trypanosomiasis (HAT) is endemic in sub-Saharan Africa. It is caused by a flagellate protozoan called Trypanosoma brucei.
- There are 2 subspecies that cause slightly different diseases. They are:
- Trypanosoma brucei rhodesiense (East African or Rhodesian African sleeping sickness). This is more virulent, deaths often occurring within months. It is a zoonotic infection with animal vectors, primarily game animals (waterbuck, hartebeest, reedbuck, duiker and antelope).
- Trypanosoma brucei gambiense (West African or Gambian African sleeping sickness). Man is the main reservoir, through its chronic form with long latency period, although animals can act as reservoirs but evidence is scanty. Only small numbers of tsetse flies have been shown as necessary to maintain endemic transmission cycles at relatively high levels.
- It is almost invariably spread by bites from infected tsetse flies, but it is rarely transmitted by blood transfusion, or across the placenta. The latter is rare because the disease causes infertility and abortion in women of child-bearing age.
- The tsetse fly is found only in Africa and comprises 3 groups of species, Glossin fusca, or forest tsetse is of little significance to man, G. palpalis, or riverine tsetse, is responsible for the transmission of T. gambiense and G. morsitans, or savannah tsetse is predominantly a vector of T. rhodesiense.
- Tsetse flies are fastidious in terms of conditions and satellite imaging techniques can be used to map potential transmission foci. They are not infected easily, but infection is lifelong (1 to 6 months) and they produce only 6-8 larvae in a lifetime.
- Both male and female flies feed by cutting through the skin, rupturing small blood vessels and feeding on the pool of blood formed, intermittently ejecting saliva, with metacyclic trypanosomes if infected.
- The trypanosomes display antigenic variation in successive generations during host infection. This enables persistence of infection, immune exhaustion, penetration of the central nervous system and eventual death.
South American sleeping sickness or Chagas disease is a totally different disease with a different pathogen and different treatment.
- It is a resurgent disease. Annual reported incidence ranges from 20,000 to 300,000, but under-reporting is likely where there is political instability. A WHO report gives the higher figure and says that 60 million people are at risk, only 4 million are under surveillance and only 10% of cases are treated.
- East African Sleeping Sickness occurs in most countries in East Africa, including Kenya, Tanzania, Malawi, Zambia and Mozambique. They usually report fewer than 200 cases each per year but Uganda may have 1,000 or more. The WHO says that infection covers a total of 36 countries in sub-Saharan Africa.
- West African Sleeping Sickness is endemic around water holes and river areas in Western and Central Africa. The Democratic Republic of Congo reports about 20,000 cases a year, Angola about 2,000 and north western Sudan around 1,500 cases. Senegal, Gambia, Guinea Bissau, Sierra Leone and Ghana do not report any cases, but about 200 to 300 cases are recorded annually in the Ivory Coast, Guinea, Nigeria and Uganda.
- Sleeping sickness claims comparatively few lives annually, but the risk of major epidemics means that surveillance and ongoing control measures must be maintained.
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This is the early or haemolymphatic stage. It occurs about 3 weeks after the bite.
Symptoms tend to be non-specific including:
- General malaise
- Intermittent fever
- Pruritus, urticaria and facial oedema sometimes occur
- A painless, indurated chancre on the skin appears 5 to 15 days after the bite (although this may be absent if the fly has fed from a large enough blood vessel without needing a "pool", the organism going straight into the circulation).
- Lymphadenopathy: Axillary and inguinal lymphadenopathy are more prominent in patients with the East African disease whilst cervical lymphadenopathy is more usual in the West African type. The classical Winterbottom's sign is a clearly visible, enlarged, firm & rubbery, mobile, non-tender, gland of the posterior cervical triangle.
- Fevers, tachycardia, irregular rash, oedema and weight loss
- Multiple organs, including spleen, liver, skin, cardiovascular, endocrine and eyes may be affected.
This is late or CNS stage and is of insidious onset.
- Continuous headaches with a poor response to analgesics
- Daytime somnolence then nocturnal insomnia with upset of the circadian rhythm
- Behavioural changes with mood swings and sometimes depression
- In East African sleeping sickness, CNS signs appear early, presenting in weeks to a month with the 2 stages merging, whereas West African sleeping sickness has a more gradual onset with CNS symptoms taking months to a year.
- Anorexia, wasting and weight loss.
- There is irritability, tremors, increased muscle tone, sometimes ataxia or hemiparesis but rarely meningism.
- Kerandel's sign is deep hyperaesthesia, often delayed, after slight blow on bony projection of body (tibia often quoted).
- Behavioural changes such as mania or psychosis with speech disorders and seizures. Seizures occur in children but rarely in adults.
- Stupor and coma (hence the name sleeping sickness).
- Malaria: where inappropriate antimalarial treatment reduces the fever of sleeping sickness and where the 2 diseases may co-exist
- HIV infection
- Typhoid fever and other enteric fevers
- Other causes of lymphadenopathy such as tuberculosis, cancer and other causes of acute confusional state (eg meningitis)
Blood tests may show:
- FBC shows anaemia and thrombocytopenia. There is no eosinophilia
- Hypergammaglobulinaemia and a raised ESR
- A wet smear of unstained blood to look for mobile trypanosomes and a Giemsa-stained thick smear
More sensitive tests are now available. The haematocrit centrifugation technique for buffy coat examination and the miniature anion-exchange centrifugation technique filter out the red cells but not the trypanosomes.
The standard serological test for West African trypanosomiasis is the card agglutination test for trypanosomiasis (CATT). The CATT can be performed in the field without electricity and results are available in 10 minutes. It has a sensitivity of 96% but is less specific because of cross-reactivity with animal trypanosomes. A similar test for East African disease is being developed.
- Lymph node aspirate is often used in a rapid test for parasites. The specimen is examined dry at high magnification (x400) without delay as parasites are mobile for only 15 to 20 minutes.
- Lumbar puncture should be performed. CNS disease can present early in East African trypanosomiasis.
- CSF is examined for trypanosomes, elevated WBC count, elevated IgM and elevated total protein levels.
- CSF examination by PCR for trypanosome DNA has been used.
- The double centrifugation technique is the most sensitive method to detect the parasites.
- Classically diagnosis requires detection of trypanosomes in lymph nodes but they can be found in blood, CSF, skin chancre aspirates, or bone marrow.
- In rural Africa giving chemotherapy to produce symptomatic improvement is the usual way to confirm the diagnosis.
- Care before hospital admission involves management of the acute symptoms of fever and malaise while closely monitoring the neurological condition.
- Control of the airway may be required to prevent aspiration.
- In severe disease where CNS complications and coma occur, intensive care is needed while treatment is administered.
- Potential adverse effects from drugs require monitoring of haematological, renal and hepatic function.
Treatment is based on 4 main drugs, with nifurtimox under evaluation. Most have been developed in the first half of the 20th century and would probably fail current safety standards:
- East African sleeping sickness:
- Stage 1 - suramin or eflornithine
- Stage 2 - melarsoprol (trivalent organic arsenical - 5% mortality rate from treatment) or eflornithine
- West African sleeping sickness:
- Stage 1 - pentamidine isethionate, suramin or eflornithine .
- Stage 2 - melarsoprol or eflornithine.
- A recent trial has shown that in stage 2 disease,10-days of low-dose melarsoprol-nifurtimox combination is more effective than the standard melarsoprol regimen.
- Following recovery from stage 2 disease a lumbar puncture is required every 3 months for the first year in patients with East African disease and every 6 months for 2 years in patients with West African disease.
- Relapse has occurred if symptoms return, CSF pleocytosis appears, or if trypanosomes are still present in blood or CSF. A persistently elevated CSF white cell count can be found in recovering patients, so a change in white cell count is more helpful as an indicator of relapse.
- If relapse occurs, treatment with melarsoprol or eflornithine should be repeated.
- Anaemia and fatigue
- Wasting syndrome
- Meningoencephalitis with seizures
- Stupor or coma (sleeping sickness)
- Death occurs in untreated disease
- In early or stage 1 disease, most patients recover fully with treatment.
- In late or stage 2 disease, the CNS disease will be fatal if untreated but the cure rate approaches 95% with drugs that cross the blood/ brain barrier such as melarsoprol.
- Treatment usually resolves symptoms and clears parasites on repeat blood smears.
- Without treatment advanced disease is fatal.
- Previous infection does not grant future immunity.
The difficulty of diagnosis in a remote primary care setting, the difficulty and high risk of treatment in late stage disease and the long almost asymptomatic phase (in gambiense infection),and near impossibility of vector control, means that sleeping sickness is one of the few communicable diseases where systematic population screening is necessary. At the beginning of the 20th century, sleeping sickness was "the colonial disease." Recent research has produced control solutions, for the African trypanosomiases of humans and livestock, that are effective, affordable and sustainable by small-holder farmers. Whether these simple solutions are allowed to fulfil their promise and become fully integrated into agricultural practice remains to be seen. After more than 100 years of effort, trypanosomiasis control remains a controversial topic, subject to the tides of fashion and politics.
- Treatment of asymptomatic carriers is possible and infection can be detected by CATT or node aspirate and confirmed with smears.
- There is no vaccine.
- There is no effective prophylaxis.
- Tsetse fly trapping is possible but costly. A WHO report discusses cost effective measures.
- Wear protective clothing of dull colours and use bed nets in areas with tsetse flies.
- Insect repellent is less effective than with other insect-borne diseases.
- Avoid areas where African trypanosomiasis is endemic.
- Molecular genetics to replace susceptible insect phenotypes with refractory counterparts is a possibility in future.
- Sleeping sickness was known to slave traders, who rejected captives with the characteristic swollen cervical glands, recognising that they would die.
- David Livingstone first described "tsetse fly disease" or "nagana" in cattle in 1858.
- Sir David Bruce (of brucellosis fame), who spent his career in the Army Medical Service and the Royal Army Medical Corps, whilst working in a wattle-and-daub hut in northern Zululand in 1894, identified the trypanosome, being the first to prove that an insect carried a protozoan of a pathological kind. He was later head of the Royal Society Sleeping Sickness Commission which published in the BMJ of 1903, that human sleeping sickness was caused by a trypanosome (described earlier by John Dutton and named by him Trypanosoma gambiense) transmitted by one species of tsetse fly, Glossina palpalis. It is perhaps unfortunate for Dutton, that it is Bruce's name that attaches to the trypanosomes, but it recognises Bruce's extensive work on transmission, vectors and animal reservoirs.
- The last century brought 3 severe epidemics, Uganda & Congo basin 1896-1906, 1920s and 1970s onwards. This last followed virtual elimination of the disease by 1960 and must largely be a result of civil disorder, war and poverty, which led to the breakdown of screening and control.
- A major problem in the development of effective drugs for use in poor countries is the lack of financial incentive for pharmaceutical companies to invest in such areas. Of 1,233 new drugs to reach the market between 1975 and 1997, 13 were for tropical diseases. Of these, 6 were developed with support from Tropical Drug Research (TDR), a body set up in 1975 and co-sponsored by the United Nations Children's Fund (UNICEF), the United Nations Development Programme (UNDP), the World Bank and the World Health Organisation (WHO). It aims to help coordinate, support and influence global efforts to combat a portfolio of major diseases of the poor and disadvantaged.
Further reading & references
- African Trypanosomiasis Fact Sheet, World Health Organization
- Martinez LJ; African Trypansomiasis (Sleeping Sickness). eMedicine, January 2007.
- African Trypanosomiasis, Centers for Disease Control & Prevention
- Smith DH, Pepin J, Stich AH; Human African trypanosomiasis: an emerging public health crisis. Br Med Bull. 1998;54(2):341-55.
- No authors listed; Control and surveillance of African trypanosomiasis. Report of a WHO Expert Committee. World Health Organ Tech Rep Ser. 1998;881:I-VI, 1-114.
- African Trypanosomiasis Fact Sheet, World Health Organization
- African Trypanosomiasis. Strategic direction. Overview and strategy for research, World Health Organization
- Lundkvist GB, Kristensson K, Bentivoglio M; Why trypanosomes cause sleeping sickness. Physiology (Bethesda). 2004 Aug;19:198-206.
- Chappuis F, Pittet A, Bovier PA, et al; Field evaluation of the CATT/Trypanosoma brucei gambiense on blood-impregnated filter papers for diagnosis of human African trypanosomiasis in southern Sudan. Trop Med Int Health. 2002 Nov;7(11):942-8.
- Burchmore RJ, Ogbunude PO, Enanga B, et al; Chemotherapy of human African trypanosomiasis. Curr Pharm Des. 2002;8(4):256-67.
- Bisser S, N'Siesi FX, Lejon V, et al; Bisser S, N'Siesi FX, Lejon V, et al; Equivalence trial of melarsoprol and nifurtimox monotherapy and combination therapy for the treatment of second-stage Trypanosoma brucei gambiense sleeping sickness. J Infect Dis. 2007 Feb 1;195(3):322-9. Epub 2006 Dec 21.
- Maudlin I; African trypanosomiasis. Ann Trop Med Parasitol. 2006 Dec;100(8):679-701.
- Kennedy PG; Human African trypanosomiasis of the CNS: current issues and challenges. J Clin Invest. 2004 Feb;113(4):496-504.
- The Special Programme for Research and Training in Tropical Diseases (TDR); Mission statement
|Original Author: Dr Gurvinder Rull||Current Version: Dr Gurvinder Rull|
|Last Checked: 21/05/2010||Document ID: 1782 Version: 22||© EMIS|
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