AUTHOR AND EDITOR INFORMATION

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• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Human African trypanosomiasis (HAT), or sleeping sickness, is an illness endemic to sub-Saharan Africa. It is caused by the flagellate protozoan, Trypanosoma brucei, which exists in 2 morphologically identical subspecies: Trypanosoma brucei rhodesiense (East African or Rhodesian African trypanosomiasis) and Trypanosoma brucei gambiense (West African or Gambian African trypanosomiasis). Both of these parasites are transmitted to human hosts by bites of infected tsetse flies (Glossina species), which are found only in Africa. The reservoirs of infection for these vectors are exclusively human in West African trypanosomiasis. However, East African trypanosomiasis is a zoonotic infection with animal vectors. African trypanosomiasis is distinct from American trypanosomiasis, which is caused by Trypanosoma cruzi and has different vectors, clinical manifestations, and therapies.

The major epidemiology factor in African trypanosomiasis is the human-tsetse fly contact. This interaction is influenced by an increasing tsetse fly density, changing feeding habits, expanding human development into tsetse fly–infested areas, and an increasing number of immunologically naïve persons in previously endemic areas. Major outbreaks from 1920-1950 led to extensive treatment and, apparently, immunity for 50 years. Now, infection is occurring again as the same populations lose their immunity.

Trypanosomes are parasites with a 2-host life cycle: mammalian and arthropod. The life cycle starts when the trypanosomes are ingested during a blood meal by the tsetse fly from a human reservoir in the West African trypanosomiasis or an animal reservoir in the East African form. The trypanosome multiplies over a period of 2-3 weeks in the fly midgut; then, the trypanosomes migrate to the salivary gland where they develop into epimastigotes. The metacyclic trypomastigotes infect humans.

Pathophysiology

Humans are infected following a fly bite, which occasionally causes a skin chancre at the site. These injected trypomastigotes further mature and divide in the blood and lymphatic system, causing symptoms of malaise, intermittent fever, rash, and wasting. Eventually, the parasitic invasion reaches the central nervous system (CNS), causing behavioral and neurologic changes, such as encephalitis and coma. Death may occur.

The parasites escape the initial host defense mechanisms by extensive antigenic variation of parasite surface glycoproteins. This evasion of the humoral immune responses contributes to parasite virulence. During the parasitemia, most pathologic changes occur in the hematologic, lymphatic, cardiac, and central nervous systems. This may be the result of immune-mediated reactions against antigens on red blood cells, cardiac tissue, and brain tissue, resulting in hemolysis, anemia, pancarditis, and meningoencephalitis.

A hypersensitivity reaction causes skin problems, including persistent urticaria, pruritus, and facial edema. An increase in lymphocytes in the spleen and lymph nodes infested with the parasite leads to fibrosis but rarely hepatosplenomegaly. Monocytes, macrophages, and plasma cells infiltrate blood vessels, causing endarteritis and increased vascular permeability.

The gastrointestinal system is also affected. Kupffer cell hyperplasia occurs in the liver, along with portal infiltration and fatty degeneration. Hepatomegaly is rare. More commonly in East African trypanosomiasis, a pancarditis affecting all heart tissue layers develops because of extensive cellular infiltration and fibrosis. Death can occur from arrhythmia or cardiac failure prior to the development of CNS manifestations. CNS problems include perivascular infiltration into the interstitium in the brain and spinal cord leading to meningoencephalitis with edema, bleeding, and granulomatous lesions.

Frequency

United States

All cases of African trypanosomiasis are imported from Africa by travelers to endemic areas. Infections among travelers are rare, and less than 1 case per year is reported among US travelers. Most of these infections are caused by T brucei rhodesiense and are acquired in East African game parks.

International

African trypanosomiasis is confined to tropical Africa between latitudes 15°N and 20°S, or from north of South Africa to south of Algeria, Libya, and Egypt.

The prevalence of the disease differs from one country to another and varies within a single country. In 2005, major outbreaks were observed in Angola, the Democratic Republic of Congo, and Sudan.

In Central African Republic, Chad, Congo, Côte d'Ivoire, Guinea, Malawi, Uganda, and United Republic of Tanzania, sleeping sickness remains an important public health problem.

Countries such as Burkina Faso, Cameroon, Equatorial Guinea, Gabon, Kenya, Mozambique, Nigeria, Rwanda, Zambia, and Zimbabwe are reporting fewer than 50 new cases per year.

Transmission seems to have stopped and no new cases have been reported for several decades in countries such as Benin, Botswana, Burundi, Ethiopia, Gambia, Ghana, Guinea Bissau, Liberia, Mali, Namibia, Niger, Senegal, Sierra Leone, Swaziland, and Togo.

Sleeping sickness threatens millions of people in 36 countries of sub-Saharan Africa. The current situation is difficult to assess in a number of endemic countries because of a lack of surveillance and diagnostic expertise.

In 1986, a panel of experts convened by the World Health Organization (WHO) estimated that 70 million people lived in areas where disease transmission could take place. In 1998, almost 40,000 cases were reported, but this number did not reflect the true situation. Between 300,000 and 500,000 more cases were estimated as remaining undiagnosed and therefore untreated. During recent epidemic periods, in several villages in the Democratic Republic of Congo, Angola, and Southern Sudan, prevalence has reached 50%. Sleeping sickness was considered the first or second greatest cause of mortality in those communities, even ahead of HIV and AIDS. By 2005, surveillance had been reinforced and the number of new cases reported throughout the continent had substantially reduced; between 1998 and 2004, the figures for both forms of the disease together fell from 37,991 to 17,616. The estimated number of cases is currently between 50,000 and 70,000.

Mortality/Morbidity

• In East African trypanosomiasis, patients become more acutely symptomatic (starting 1 mo after bite), compared to patients with West African trypanosomiasis, whose initial symptoms can start months to a year after the first bite.
• Both types have the same generalized symptoms, including intermittent fevers, rash, and lymphadenopathy. Notably, the patients with the East African form are more likely to experience cardiac complications and develop CNS disease more quickly, within weeks to a month. The CNS manifestations of behavioral changes, daytime somnolence, nighttime insomnia, stupor, and coma result in death if untreated.
• In West African trypanosomiasis, the asymptomatic phase may occur before the fevers, rash, and cervical lymphadenopathy develop. If unrecognized, the symptoms then progress to weight loss, asthenia, pruritus, and CNS disease with a more insidious onset. Meningismus is rare. Death at this point is usually from aspiration or seizures from CNS damage.

Race

No racial predilection exists.

Sex

No sex predilection exists.

Age

Exposure can occur at any time. Congenital African trypanosomiasis occurs in children, causing psychomotor retardation and seizure disorders.

CLINICAL

Section 3 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• Stage 1 (early, or hemolymphatic, stage)
• • Painless skin chancre that appears about 5-15 days after the bite
  • Intermittent fever (refractory to antimalarials), general malaise, myalgia, and headache usually 3 weeks after bite
  • Generalized lymphadenopathy
  • Pruritus, urticaria, and facial edema (minority of patients)
• Stage 2 (late, or CNS, stage)
• • Persistent headaches (refractory to analgesics)
  • Daytime somnolence followed by nighttime insomnia
  • Behavioral changes, mood swings, and, in some patients, depression
  • Loss of appetite, wasting syndrome, and weight loss
  • Seizures in children (rarely in adults)

Physical

• Stage 1 (early, or hemolymphatic, stage)
• • Indurated chancre at bite site
  • Skin lesions (trypanids) in light-skinned patients
  • Lymphadenopathy: Axillary and inguinal lymphadenopathy are noted more often in patients with the East African form. Cervical lymphadenopathy is more commonly observed in patients with the West African form. The classic Winterbottom sign is clearly visible (ie, enlarged, nontender, mobile posterior cervical lymph node).
  • Fevers, tachycardia, irregular rash, edema, and weight loss
• Stage 2 (late, or CNS, stage)
• • Patients with West African trypanosomiasis have a slower onset of the CNS symptoms, ie, months to a year.
  • Symptoms include irritability, tremors, increased muscle rigidity and tonicity, occasional ataxia, and hemiparesis but rarely overt meningeal signs.
  • Patients with East African trypanosomiasis usually have a faster onset, ie, weeks to a month, and do not experience a clear distinction between the 2 stages.
  • Kerandel sign, including delayed pain on compression of patient's soft tissue
  • Behavioral changes consistent with mania or psychosis, speech disorders, and seizures
  • Stupor and coma (giving rise to the name sleeping sickness)

Causes

• Tsetse fly bite (see Pathophysiology)
• Blood transfusions are a rare cause of parasitic transmission.

DIFFERENTIALS

Section 4 of 11  

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Other Problems to be Considered

Stage 1 (early) African trypanosomiasis symptoms

Recurrent fever differentials include malaria, HIV, borreliosis, brucellosis, typhoid fever, and other enteric fevers.

Lymphadenopathy differentials include tuberculosis (TB) lymphadenitis, HIV, and cancer.

Stage 2 (late) African trypanosomiasis symptoms

Mental status change differentials include TB, meningitis, and HIV-related opportunistic infections, including cryptococcal meningitis.

WORKUP

Section 5 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• General
• • In African trypanosomiasis, the most significant abnormalities are anemia, hypergammaglobulinemia, elevated erythrocyte sedimentation rate (ESR), thrombocytopenia, and hypoalbuminemia, but not eosinophilia or abnormal liver function.
  • In the West African form of the disease, the total immunoglobulin M (IgM) level is notably higher in blood and CSF (along with high CSF protein).
  • A definitive diagnosis of infection requires actual detection of trypanosomes in blood, lymph nodes, CSF, skin chancre aspirates, or bone marrow. However, empiric treatment with subsequent symptomatic improvement is the usual confirmatory test in areas where diagnostic studies are not readily available.
• Lymph node aspirate is commonly used as a rapid test for trypanosomes at a high dry magnification (X 400). It requires immediate search for parasites because they are mobile for only 15-20 minutes.
• Blood smear
• • A wet smear of unstained blood or Giemsa-stained thick smear (more sensitive) is used to observe the mobile trypanosomes, again for 15-20 minutes. Wright and Leishman stains are inadequate.
  • Better assays are now available, including the hematocrit centrifugation technique for buffy coat examination, and the miniature anion-exchange centrifugation technique, which filters out the red cells but not the trypanosomes.
• Chancre aspirate can be used as a wet preparation, especially in the East African form of the disease, but a blood smear is more sensitive.
• CSF assay
• • Lumbar puncture should always be performed in patients with parasitemia or lymphadenopathy.
  • The double centrifugation technique is the most sensitive method to detect the trypanosomes.
  • Other CSF findings include elevated WBC count, elevated IgM, and elevated total protein levels.

Imaging Studies

• CT scanning and MRI of the head: Both head CT scanning and MRI reveal cerebral edema and white matter enhancement, respectively, in those patients with late-stage disease.

Other Tests

• General: Field diagnosis of African trypanosomiasis based on serology has seen slow to progress over the past decades. Although many research tools for diagnosis are available, few are used clinically in endemic areas.
• Serologic antibody detection
• • The standard serologic assay to diagnose West African trypanosomiasis is the card agglutination test for trypanosomiasis (CATT).
  • The CATT can be conducted in the field without electricity, and results are available in only 10 minutes. It is highly sensitive (96%) but less specific because of cross-reactivity with animal trypanosomes.
  • Commercial antibody tests for Eastern African trypanosomiasis are not available.
• Other tests developed but not frequently used clinically include antibody detection in the CSF and intrathecal space, enzyme-linked immunoassay (ELISA), polymerase chain reaction (PCR), and serum proteomic tests.

Procedures

• Lumbar puncture: CSF fluid is used to detect trypanosomes and measure WBC counts, protein, and IgM levels in a patient with parasitemia or positive serologies or symptoms. Importantly, CNS disease can manifest early in East African trypanosomiasis.

TREATMENT

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Medical Care

• Prehospital care centers on management of the acute symptoms of fever and malaise while closely monitoring patient neurologic status.
• In the emergency department, if CNS symptoms are severe, then airway management to prevent aspiration becomes important, along with an immediate blood smear, CBC count, and lumbar puncture for trypanosome detection.

Consultations

• Consult an infectious disease specialist for evaluation of both early- and late-stage disease in a symptomatic patient with recent travel or suspicious parasitic exposure.
• Contact the Centers for Disease Control and Prevention (CDC) in Atlanta, Ga for expertise in the diagnosis and treatment of this disease because it is rarely observed in the United states (Division of Parasitic Diseases: 770-488-7760 or Drug Service: 404-639-3670).

MEDICATION

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The type of drug treatment used depends on the type and stage of African trypanosomiasis. The table below outlines the recommendations in The Medical Letter on Drugs and Therapeutics in March, 2000.

Table 1. Medications Recommended for Treatment of African Trypanosomiasis

Trypanosomiasis	Medications Stage 1 (Hemolymphatic Stage)	Medications Stage 2 (Neurologic [CNS] Stage)
East African Trypanosomiasis Trypanosoma brucei rhodesiense	Suramin 100-200 mg IV test dose, then 1 g IV on days 1, 3, 7, 14, 21 or Eflornithine 400 mg/kg/d IV in 4 divided doses for 14 d	Melarsoprol 2-3.6 mg/kg/d IV for 3 d; after 1 wk, 3.6 mg/kg/d for 3 d; after 10-21 d, repeat the cycle or Eflornithine 400 mg/kg/d IV in 4 divided doses for 14 d
West African Trypanosomiasis Trypanosoma brucei gambiense	Pentamidine isethionate 4 mg/kg/d IM for 10 d or Suramin 100-200 mg IV test dose, then 1 g IV on days 1, 3, 7, 14, 21 or Eflornithine 400 mg/kg/d IV in 4 divided doses for 14 d	Melarsoprol 2-3.6 mg/kg/d IV for 3 d; after 1 wk, 3.6 mg/kg/d for 3 days; after 10-21 d, repeat the cycle or Eflornithine 400 mg/kg/d IV in 4 divided doses for 14 d

Drug Category: Anthelmintics

Parasite biochemical pathways are sufficiently different from the human host to allow selective interference by chemotherapeutic agents in relatively small doses.

Drug Name	Melarsoprol (Melarsen Oxide-BAL, Mel B, RP 3854)
Description	Trivalent arsenical used in the late or CNS stage of African trypanosomiasis. Trypanocidal, inhibiting parasitic glycolysis. Water insoluble and has a half-life of 35 h. Serum levels range from 2-5 mcg/mL, but CSF levels are 50-fold lower. The drug is primarily excreted by the kidneys. Clinical improvement is usually observed within 4 d after starting the drug. Therapy is as high as 90-95% successful in clearing the parasitemia. However, it can be toxic and even fatal in 4-6% of cases. Studies have now demonstrated the effectiveness of 10-day melarsoprol treatments for late-stage African trypanosomiasis. In addition, melarsoprol resistance has become a concern in the Congo and Uganda; up to 30% of cases do not respond to the drug.
Adult Dose	2-3.6 mg/kg/d IV for 3 d; after 1 wk, 3.6 mg/kg/d IV for 3 d; after 10-21 d, repeat the cycle; always administer each dose slowly on an empty stomach
Pediatric Dose	0.36 mg/kg IV initially; increase gradually to a maximum 3.6 mg/kg at intervals of 1-5 d for a total of 9-10 doses; average dosing is 18-25 mg/kg over 1 mo
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in renal, cardiac, or hepatic disease; encephalopathy may occur in up to 10% cases 2 d to 2 wk after starting melarsoprol unrelated to dose or dosing frequency; prednisolone can reduce risk of encephalopathy and is administered 1-2 d prior to and during melarsoprol therapy, starting with 1 mg/kg/d, up to 40 mg/d, and tapering quickly after last injection; a Herxheimer reaction with fever and chills may also occur, resulting from trypanosome destruction

Drug Name	Eflornithine (Ornidyl)
Description	Recommended for treatment of patients with West African trypanosomiasis, especially late (or CNS) disease. Selective and irreversible inhibitor of ornithine decarboxylase, which is a critical enzyme for DNA and RNA synthesis. Generally tolerated better and is less toxic than arsenic drugs. Available via World Health Organization. Initial response time is 1-2 wk. Used for patients in whom melarsoprol fails.
Adult Dose	100 mg/kg IV q6h for 14 d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	May reduce effects of immunization with live and rotavirus vaccines
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in coexisting bone marrow suppression or hematologic abnormalities; myelosuppression, pancytopenia, decreased hearing, and seizures may occur

Drug Name	Pentamidine isethionate (Pentam 300, Pentacarinat, NebuPent)
Description	Antiprotozoal agent usually used for early (or stage 1) African trypanosomiasis as well as Pneumocystis carinii pneumonia and leishmaniasis. Works by inhibiting dihydrofolate reductase enzyme, thereby interfering with parasite aerobic glycolysis. Because of poor GI absorption, the drug is administered IV/IM and is strongly bound to tissues, including spleen, liver, and kidney. Clinical improvement usually noted within 24 h of injection. Reported to have a >90% cure rate. Pentamidine does not penetrate the blood-brain barrier effectively and, therefore, does not treat CNS infection.
Adult Dose	4 mg/kg/d IM/IV for 10 d
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Coadministration with cidofovir may cause nephrotoxicity; hypocalcemia may occur with foscarnet; prolonged QTc observed with grepafloxacin and sparfloxacin; pancreatitis reported with zalcitabine
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Can cause leukopenia, anemia, hypotension, arrhythmia, rash, renal failure, and pancreatitis; caution in diabetes mellitus, hypertension or hypotension, hepatic dysfunction, hypoglycemia, leukopenia, and thrombocytopenia

FOLLOW-UP

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Further Inpatient Care

• If late or CNS disease complications and coma occur, then intensive care unit (ICU) staff are needed while treatment is administered (ie, melarsoprol for the East African form or eflornithine for the West African form). Monitor potential adverse effects from such drugs, including hematologic, renal, and hepatic functions.

Further Outpatient Care

• For early- and late-stage disease, treatment usually results in resolution of symptoms and clearance of parasitemia on repeat blood smears.
• For patients who have recovered from late-stage disease, perform lumbar punctures every 3 months for the first year in patients with East African trypanosomiasis and every 6 months for 2 years in patients with West African trypanosomiasis. A relapse is suggested if symptoms return, the CSF WBC count is above 20 cells/mm³, CSF pleocytosis occurs, or if trypanosomes are still present in blood or CSF. A persistently elevated CSF WBC count can be observed in recovering patients, however, so the change (increase or decrease) in WBC count is more helpful diagnostically. If a relapse is noted, then consider repeat dosing with melarsoprol or eflornithine.

Deterrence/Prevention

• A vaccine is not available.
• Chemoprophylaxis in not available.
• Avoidance of travel to areas of heavy infestation with tsetse flies is recommended. Tsetse flies are attracted to moving vehicles and dark contrasting colors.
• Tsetse flies are not affected by insect repellants and can bite through lightweight clothing. The CDC recommends that travelers at risk should be advised to wear clothing of wrist and ankle length that is made of medium-weight fabric in neutral colors.
• Treatment of asymptomatic carriers is possible, and infection can be detected with CATT or node aspirate and confirmed with smears.

Complications

• Anemia, fatigue
• Wasting syndrome
• Meningoencephalitis, seizures
• Stupor or coma (sleeping sickness)
• Death

Prognosis

• In early, or stage 1, disease, most patients experience full recovery following treatment.
• In late, or stage 2, disease, the CNS manifestations are ultimately fatal if untreated. The cure rate approaches 95% with drugs that work inside the CNS (eg, melarsoprol).

MISCELLANEOUS

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Medical/Legal Pitfalls

• Failure to obtain adequate travel history
• Delay in diagnosis, especially in a patient with late or CNS disease
• Failure to monitor for toxicities from drug therapies

MULTIMEDIA

Section 10 of 11  

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• Multimedia
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Media file 1:  African trypanosomiasis (sleeping sickness). Human trypanosomes blood smear.
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Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
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• Clinical
• Differentials
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• Follow-up
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• Multimedia
• References

• Abramowicz M. Drugs For Parasitic Infections. In: Abramowicz M, ed. The Medical Letter on Drugs and Therapeutics. New Rochelle, NY:. The Medical Letter, Inc;March, 2000: 1-12.:[Full Text].
• Barrett MP. The fall and rise of sleeping sickness. Lancet. Apr 3 1999;353(9159):1113-4. [Medline].
• Brun R, Balmer O. New Developments in human African trypanosomiasis. Current Opinions in Infectious Diseases. 2006;19:415-420.
• Centers for Disease Control and Prevention. Trypanosomiasis Fact Sheet. CDC. May, 2000;[Full Text].
• Hide G. History of sleeping sickness in East Africa. Clin Microbiol Rev. Jan 1999;12(1):112-25. [Medline].
• Kozarsky PE, Arguin PM, Navin AW. African Trypanosomiasis (African Sleeping Sickness). Travelers' Health: Yellow Book. Health Information for International Travel, 20. 2005-2006;[Full Text].
• Legros D, Evans S, Maiso F, et al. Risk factors for treatment failure after melarsoprol for Trypanosoma brucei gambiense trypanosomiasis in Uganda. Trans R Soc Trop Med Hyg. Jul-Aug 1999;93(4):439-42.
• Micromedex. Antiparasitic drug information. Micromedex electronic database. May, 2000.
• Pepin J, Milord F, Guern C. Trial of prednisolone for prevention of melarsoprol-induced encephalopathy in gambiense sleeping sickness. Lancet. Jun 3 1989;1(8649):1246-50. [Medline].
• Pepin J. African Trypanosomiasis. In: Strickland GT, ed. Hunter's Tropical Medicine. 7th ed. Philadelphia, Pa:. WB Saunders;1998:643-53.
• Schmid C, Richer M, Bilenge CM, et al. Effectiveness of a 10-day melarsoprol schedule for the treatment of late-stage human African trypanosomiasis: confirmation from a multinational study (IMPAMEL II). J Infect Dis. Jun 1 2005;191(11):1922-31.
• Sinha A, Grace C, Alston WK. African trypanosomiasis in two travelers from the United States. Clin Infect Dis. Oct 1999;29(4):840-4. [Medline].
• Smith DH, Pepin J, Stich AH. Human African trypanosomiasis: an emerging public health crisis. Br Med Bull. 1998;54(2):341-55. [Medline].
• Turner CM. Antigenic variation in Trypanosoma brucei infections: an holistic view. J Cell Sci. Oct 1999;112 (Pt 19):3187-92. [Medline].
• World Health Organization. Control and surveillance of African trypanosomiasis. Report of a WHO Expert Committee. World Health Organ Tech Rep Ser. 1998;881:I-VI, 1-114. [Medline].
• World Health Organization. WHO fact sheet on African Trypanosomiasis. WHO fact sheets. Revised August 2006;Fact sheet N°259:[Full Text].

Article Last Updated: Jan 5, 2007