African Trypanosomiasis (Sleeping Sickness)

Practice Essentials

African trypanosomiasis (sleeping sickness) is an illness endemic to sub-Saharan Africa. It is caused by 2 subspecies of the flagellate protozoan Trypanosoma brucei, which are transmitted to human hosts by bites of infected tsetse flies.

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African trypanosomiasis (sleeping sickness). Human trypanosomes blood smear.

Signs and symptoms

Symptoms of stage 1 (early or hemolymphatic stage) disease may include the following:

• Painful skin chancre
• Intermittent fever (refractory to antimalarials and antipyretics)
• General malaise, myalgia, arthralgias, and headache
• Generalized or regional lymphadenopathy
• Facial edema
• Transient urticarial, erythematous, or macular rashes 6-8 weeks after onset
• Skin lesions (trypanids)

Symptoms of stage 2 (late or neurologic stage) disease may include the following:

• Persistent headaches (refractory to analgesics)
• Daytime somnolence followed by nighttime insomnia
• Behavioral changes, mood swings, or depression
• Loss of appetite, wasting syndrome, and weight loss
• Seizures (more common in children)

Physical findings in stage 1 (early or hemolymphatic stage) disease may include the following:

• Indurated chancre at bite site
• Trypanids (skin lesions) in light-skinned patients and irregular rash
• Lymphadenopathy
• Fevers, tachycardia, edema, and weight loss
• Organomegaly, particularly splenomegaly

Physical findings in stage 2 (late or neurologic stage) disease may include the following:

• CNS manifestations (irritability, tremors, increased muscle rigidity and tonicity, ataxia, hemiparesis)
• Kerandel sign (delayed pain on compression of soft tissue)
• Behavioral changes consistent with mania or psychosis, speech disorders, and seizures
• Stupor and coma
• Psychosis
• Sensory disorders

See Presentation for more detail.

Diagnosis

Although general laboratory studies may be helpful, a definitive diagnosis of African trypanosomiasis requires actual detection of trypanosomes.

Significant laboratory abnormalities include the following:

• Anemia
• Thrombocytopenia
• Elevated erythrocyte sedimentation rate (ESR)
• Hypergammaglobulinemia
• Low complement levels
• Hypoalbuminemia

Studies performed to detect trypanosomes include the following:

• Blood smear (unstained or Giemsa-stained)
• Chancre aspiration with microscopy
• Lymph node aspiration with microscopy
• Bone marrow aspiration with microscopy
• Lumbar puncture and CSF assay

CSF assay is also done to measure white blood cell (WBC) counts, protein, and IgM in patients with parasitemia or positive serologies or symptoms.

The following studies also may be considered:

• Computed tomography (CT) of the head
• Magnetic resonance imaging (MRI) of the head
• Electroencephalography (EEG)

See Workup for more detail.

Management

The type of drug treatment used depends on the type and stage of disease, as follows:

• East African trypanosomiasis, stage 1 - Suramin
• East African trypanosomiasis, stage 2 - Melarsoprol
• West African trypanosomiasis, stage 1 - Pentamidine isethionate, suramin, or fexinidazole
• West African trypanosomiasis, stage 2 - Nifurtimox and Eflornithine Combination Therapy (NECT), melarsoprol, or fexinidazole 

No vaccine is available for African trypanosomiasis. Chemoprophylaxis is unavailable.

In both early- and late-stage trypanosomiasis, symptoms usually resolve after treatment, and the parasitemia clears on repeat blood smears.

Patients who have recovered from late-stage East African trypanosomiasis should undergo lumbar punctures every 3 months for the first year. Patients who have recovered from West African trypanosomiasis may no longer need to undergo lumbar punctures every 6 months for 2 years, depending on their treatment regimen.^[1]

See Treatment and Medication for more detail.

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Background

African trypanosomiasis, also referred to as 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 transmitted to human hosts by bites of infected tsetse flies, which are found only in Africa, as follows:

• Trypanosoma brucei rhodesiense (East African or Rhodesian African trypanosomiasis) transmitted by infected tsetse flies (Glossina morsitans).
• Trypanosoma brucei gambiense (West African or Gambian African trypanosomiasis) transmitted by infected tsetse flies (Glossina palpalis).

Tsetse flies inhabit rural areas, living in the woodlands and thickets that dot the East African savannah. In central and West Africa, they live in the forests and vegetation along streams. Tsetse flies bite during daylight hours. Unlike other vector-borne diseases, both male and female flies can transmit the infection.  Even in areas where African trypanosomiasis is endemic, only a very small percentage of flies are infected. Although the vast majority of infections are transmitted by the tsetse fly, other modes of transmission are possible. Occasionally, a pregnant woman can pass the infection to her unborn baby. In theory, the infection can also be transmitted via blood transfusion or sexual contact, but such cases have rarely been documented.

In West African trypanosomiasis, the reservoirs of infection for these vectors are exclusively human. East African trypanosomiasis, however, is a zoonotic infection with animal vectors. African trypanosomiasis is very distinct from American trypanosomiasis, which is caused by Trypanosoma cruzi and has a different epidemiology, vectors, clinical manifestations, and therapies.

The major epidemiological factor in African trypanosomiasis is contact between humans and tsetse flies. This interaction is influenced by an increasing tsetse fly density, changing feeding habits, and expanding human development into tsetse fly–infested areas.

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Pathophysiology and Etiology

Trypanosomes are parasites with a two-host life cycle: mammalian and arthropod. The life cycle starts when the trypanosomes are ingested during a blood meal by the tsetse fly from either a human reservoir (West African trypanosomiasis) or an animal reservoir (East African trypanosomiasis). The trypanosomes multiply over a period of 2-3 weeks in the fly midgut; then, the trypanosomes migrate to the salivary gland.

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Trypanosoma life cycle. Courtesy of the CDC Division of Parasitic Diseases and Malaria [DPDx at https://www.cdc.gov/dpdx/trypanosomiasisafrican/index.....

Humans are infected with T brucei after a fly bite, which occasionally causes a painful skin chancre at the site 5-15 days later. The injected parasites further mature and divide in the blood and lymphatic system, causing malaise, intermittent fever, rash, and wasting. Eventually, the parasitic invasion reaches the central nervous system (CNS), causing behavioral and neurologic changes (eg, encephalitis and coma). Death may occur.

Innate immunity to trypanosomes results from apolipoprotein L-1 (APOL1), which bind to high-density lipoprotein (HDL) in serum. This protein causes lysis of the trypanosomes when taken up through endocytosis. Disease develops when resistance to APOL1 is acquired.

The parasites escape the host defense mechanisms through extensive antigenic variation of parasite surface glycoproteins (major variant surface glycoprotein [VSG]). This evasion of humoral immune responses contributes to virulence and leads to waves of parasitemia. 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. Increased lymphocyte levels in the spleen and lymph nodes infested with the parasite lead to fibrosis but rarely to splenomegaly. Monocytes, macrophages, and plasma cells infiltrate blood vessels, causing endarteritis and increased vascular permeability.

The gastrointestinal (GI) system is also affected. Kupffer cell hyperplasia occurs in the liver, along with portal infiltration and fatty degeneration. Hepatomegaly is rare. A pancarditis may develop secondary to extensive cellular infiltration and fibrosis (particularly in the East African form). Arrhythmia or cardiac failure can cause death before the development of CNS manifestations (including perivascular infiltration into the interstitium in the brain and spinal cord, leading to meningoencephalitis with edema, bleeding, and granulomatous lesions.

In rare instances, parasitic transmission can result from blood transfusions. Accidental transmission in the laboratory has been implicated in a small number of cases.

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Epidemiology

United States statistics

All cases of African trypanosomiasis in the United States are imported from Africa by travelers to endemic areas. Infections among travelers are rare (< 1 case/year among US travelers). Most of these infections are caused by T brucei rhodesiense and are acquired in East African game parks.

International statistics

African trypanosomiasis has steadily decreased since 2000.^[2]  

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The cases of Human African Trypanosomiasis (HAT) have decreased annually from 2000 to 2020. Courtesy of PLoS Neglected Tropical Diseases [Franco JR, C....

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.^[3] The prevalence of African trypanosomiasis outside this area varies by country and region. In 2005, major outbreaks occurred in Angola, the Democratic Republic of Congo, and Sudan.^[4] In the Central African Republic, Chad, Congo, Côte d’Ivoire, Guinea, Malawi, Uganda, and Tanzania, African trypanosomiasis remains a major public health problem.^{[5, 6, 7]}

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Geographical distribution of human African trypanosomiasis. Courtesy of PLoS Neglected Tropical Diseases [Franco JR, Cecchi G, Paone M, et al. The eli....

Fewer than 50 new cases per year are reported in Burkina Faso, Cameroon, Equatorial Guinea, Gabon, Kenya, Mozambique, Nigeria, Rwanda, Zambia, and Zimbabwe.^[8] In Benin, Botswana, Burundi, Ethiopia, Gambia, Ghana, Guinea Bissau, Liberia, Mali, Namibia, Niger, Senegal, Sierra Leone, Swaziland, and Togo, T brucei transmission seems to have stopped, and no new cases of African trypanosomiasis have been reported for several decades.

African trypanosomiasis threatens millions of people in 36 countries of sub-Saharan Africa. The current situation is difficult to assess in numerous 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 transmission of African trypanosomiasis is possible. In 1998, almost 40,000 cases of the disease were reported, but in view of the remoteness of the affected regions and the focal nature of the disease, it was clear that this number did not reflect the true situation. It was estimated that 300,000-500,000 more cases were undiagnosed and thus went untreated.

During some epidemic periods, prevalence reached 50% in several villages in the Democratic Republic of Congo, Angola, and South Sudan. African trypanosomiasis was considered the first or second greatest cause of mortality in those communities, even ahead of HIV infection and AIDS. By 2005, surveillance had been reinforced, and the number of new cases reported throughout the continent had been substantially reduced; between 1998 and 2004, the figures for both forms of African trypanosomiasis together fell from 37,991 to 17,616.

In 2009 the World Health Organization (WHO) indicated that the number of new African trypanosomiasis cases dropped below 10 000 for the first time in 50 years, and in 2019 there were with 992 and 663 cases reported in 2019 and 2020 cases recorded respectively.^[9]

Age, sex, and race-related demographics

Exposure can occur at any age. Congenital African trypanosomiasis occurs in children, causing psychomotor retardation and seizure disorders. African trypanosomiasis has no sexual or racial predilection.

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Prognosis

In early (stage 1) trypanosomiasis, most patients recover fully after treatment. In late (stage 2) trypanosomiasis, the CNS manifestations are ultimately fatal if untreated. The cure rate approaches 95% with drugs that work inside the CNS (eg, melarsoprol).

The symptoms of East African trypanosomiasis develop more quickly (starting 1 month after a bite) than the symptoms of West African trypanosomiasis, which can begin months to a year after the first bite.

Both types of African trypanosomiasis cause the same generalized symptoms, including intermittent fevers, rash, and lymphadenopathy. Notably, individuals 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 precede onset of fevers, rash, and cervical lymphadenopathy. 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 due to aspiration or seizures caused by CNS damage.

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History

Symptoms of stage 1 (early or hemolymphatic stage) African trypanosomiasis (sleeping sickness) include the following:

• Painful skin chancre that appears about 5-15 days after the bite, resolving spontaneously after several weeks (less commonly seen in T brucei gambiense infection)
• Intermittent fever (refractory to antimalarials and antipyretics)
• General malaise, myalgia, arthralgias, and headache; usually 3 weeks after the bite
• Generalized or regional lymphadenopathy - Posterior cervical lymphadenopathy (Winterbottom sign) is characteristic of T brucei gambiense African trypanosomiasis
• Facial edema (minority of patients)
• Transient urticarial, erythematous, or macular rashes 6-8 weeks after onset
• Trypanids (ill-defined, centrally pale, evanescent, annular, or blotchy edematous erythematous macules on the trunk)

Symptoms of stage 2 (late or neurologic stage) African trypanosomiasis include the following:

• 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)

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Physical Examination

Physical findings in stage 1 (early or hemolymphatic stage) African trypanosomiasis include the following:

• Indurated chancre at bite site
• Skin lesions (trypanids) in light-skinned patients, irregular rash
• Lymphadenopathy - Axillary and inguinal lymphadenopathy are more common in East African trypanosomiasis, and cervical lymphadenopathy is more common in the West African form; the classic Winterbottom sign (ie, enlarged, nontender, mobile posterior cervical lymph node) is clearly visible
• Fevers, tachycardia, edema, and weight loss
• Organomegaly, particularly splenomegaly (T brucei gambiense African trypanosomiasis)

Physical findings in stage 2 (late or neurologic stage) African trypanosomiasis include the following:

• CNS manifestations - Onset is slower in West African trypanosomiasis (months to a year), and manifestations may include irritability, tremors, increased muscle rigidity and tonicity, occasional ataxia, and hemiparesis, with overt meningeal signs being rare; East African trypanosomiasis usually has a faster onset (weeks to a month) and does not exhibit a clear distinction between the 2 stages
• Kerandel sign (delayed pain on compression of soft tissue)
• Behavioral changes consistent with mania or psychosis, speech disorders, and seizures
• Stupor and coma (giving rise to the name sleeping sickness)
• Psychosis
• Sensory disorders

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Complications

Complications of African trypanosomiasis may include the following:

• Anemia and fatigue
• Wasting syndrome
• Aspiration pneumonia
• Meningoencephalitis and seizures
• Stupor or coma (sleeping sickness)
• Death
• Perinatal death or abortion (after congenital infection)

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Approach Considerations

Although general laboratory studies may be helpful in the diagnosis of African trypanosomiasis (sleeping sickness), a definitive diagnosis of T brucei infection requires actual detection of trypanosomes in blood, lymph nodes, cerebrospinal fluid (CSF), skin chancre aspirates, or bone marrow. In areas where diagnostic studies are not readily available, however, symptomatic improvement after empiric treatment is the usual confirmatory test.^[10]

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General Blood Studies and Serology

The most significant laboratory abnormalities in African trypanosomiasis include anemia, hypergammaglobulinemia, low complement levels, elevated erythrocyte sedimentation rate (ESR), thrombocytopenia, and hypoalbuminemia (but not eosinophilia or abnormal liver function). In the West African form, the total immunoglobulin M (IgM) level is notably higher in blood and CSF (along with a high CSF protein level).

Serologic antibody detection

Field serology-based diagnosis of African trypanosomiasis has been slow to progress. Although many research tools are available for diagnosis, few are used clinically in endemic areas.^[11]

The standard serologic assay for diagnosing 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.

Antigen detection tests based on enzyme-linked immunosorbent assay (ELISA) technology have been developed. They have shown inconsistent results and are not yet commercially available.

An individual serological rapid diagnostic test for the diagnosis of West African trypanosomiasis was recently developed and commercialized (HAT Sero-K-SeT). Its diagnostic performance was shown to be similar to that of CATT.^[12]

Culture of CSF, blood, bone marrow aspirate, or tissue specimens can be performed in liquid media. Other tests that have been developed but are not frequently used in clinical settings include antibody detection in the CSF and intrathecal space (low sensitivity), polymerase chain reaction (PCR), and serum proteomic tests. Research tools such as isoenzyme analysis and restriction fragment length polymorphism (RFLP) are used for definitive subspecies identification.

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Blood Smear

A wet smear of unstained blood or a Giemsa-stained thick smear (more sensitive) is examined to look for mobile trypanosomes (see the image below).  The organisms remain mobile for only 15-20 minutes. This technique is most sensitive in the early stages of the disease, when the number of circulating parasites is highest (≥5000/mL), particularly in T brucei rhodesiense (East African) trypanosomiasis.  Wright and Leishman stains are inadequate.

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Trypanosoma brucei in a thin blood smear stained with Giemsa. Courtesy of the CDC Division of Parasitic Diseases and Malaria [DPDx at https://www.cdc.....

Better assays now are available, including the hematocrit centrifugation technique for buffy coat examination and the miniature anion-exchange centrifugation technique (mAECT), which filters out the red blood cells (RBCs) but not the trypanosomes. This test can be used to detect serum parasite levels as low as 5 /mL; the test can be repeated on subsequent days to increase the yield when results are negative.

Chancre aspirate can be used as a wet preparation, especially in East African trypanosomiasis, but a blood smear is more sensitive.

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Aspiration of Lymph Node or Bone Marrow

Lymph node aspiration at a high dry magnification (400x) is commonly used as a rapid test for trypanosomes. It requires an immediate search for parasites because, as noted above, the organisms are mobile for only 15-20 minutes. This test has more utility in T brucei gambiense (West African) trypanosomiasis.

Bone marrow aspiration may yield positive results in some patients.

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Lumbar Puncture and CSF Assay

Lumbar puncture should be performed whenever trypanosomiasis is suspected. CSF is examined for the purposes of detecting trypanosomes and measuring white blood cell (WBC) counts, protein, and IgM in patients with parasitemia or positive serologies or symptoms. CSF examination helps to diagnose and stage the disease. However, a negative result does not rule out the diagnosis.

The double centrifugation technique is the most sensitive method for detecting the trypanosomes. Other findings that may be noted on evaluation of the CSF include elevated WBC counts, elevated IgM levels, elevated total protein levels, and raised intracranial pressure. An uncommon characteristic finding is Mott cells, which are thought to be large eosinophilic plasma cells containing IgM that have failed to secrete their antibodies.

Increased intrathecal synthesis of IgM has been found to be the most sensitive indicator of CNS involvement in African trypanosomiasis. CNS disease can manifest early in East African trypanosomiasis.

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Other Studies

Computed tomography (CT) and magnetic resonance imaging (MRI) of the head reveal cerebral edema and white matter enhancement, respectively, in patients with late-stage African trypanosomiasis.

In cases of neurologic involvement, electroencephalography (EEG) usually shows slow wave oscillations (delta waves), a nonspecific finding.

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Approach Considerations

Prehospital care of African trypanosomiasis (sleeping sickness) centers on management of the acute symptoms of fever and malaise in conjunction with close monitoring of the patient’s neurologic status. In the emergency department, if central nervous system (CNS) symptoms are severe, airway management to prevent aspiration becomes important, along with an immediate blood smear, complete blood count (CBC), and lumbar puncture for trypanosome detection.

If late stage disease is present or CNS disease complications and coma occur, intensive care unit (ICU) staff are needed while treatment is administered (ie, melarsoprol for East African trypanosomiasis or eflornithine for West African trypanosomiasis). Potential adverse effects from such drugs, including hematologic, renal, and hepatic function must be monitored.

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Pharmacologic Therapy

The type of drug treatment used depends on the type and stage of African trypanosomiasis.^[13]

Table. Medications Recommended for Treatment of African Trypanosomiasis

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See Table

Since 2009, the WHO has adopted the combination of eflornithine and nifurtimox (NECT) as first-line treatment for second-stage gambiense human African trypanosomiasis in all countries with endemic disease. The combination of both drugs reduces the duration of eflornithine monotherapy treatment and is easier to administer, while improving the level of efficacy and safety.  The guidelines from WHO were updated in 2019 and reflect simplified and safer treatment options.^[14]

In November 2018, the European Medicines Agency (CHMP) adopted a positive opinion for fexinidazole as the first oral-only regimen for the treatment of first–stage (hemolymphatic) and second-stage (meningoencephalitic) human African trypanosomiasis due to T brucei gambiense in adults and children aged 6 years and older and who weigh 20 kg or more.^[15]  

Fexinidazole was approved by the FDA in July 2021. In a randomized trial including 394 patients with late-stage human African trypanosomiasis due to T brucei gambiense treated with fexinidazole or nifurtimox-eflornithine combination therapy (NECT), success at 18 months was noted in 91% of patients treated with fexinidazole versus 98% of patients treated with NECT.^[16]  Two single-arm trials in adults and pediatric patients aged 6-15 years demonstrated efficacy of 98.7% and 97.6% respectively at 12 months.^[17]  

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Prevention

No vaccine is available for African trypanosomiasis. Chemoprophylaxis is unavailable.

Avoidance of travel to areas heavily infested with tsetse flies is recommended. Tsetse flies are attracted to moving vehicles and dark contrasting colors. They are not affected by insect repellants and can bite through lightweight clothing. At-risk travelers are advised to wear wrist- and ankle- length clothing that is made of medium-weight fabric in neutral colors.

Treatment of asymptomatic carriers is possible, and infection can be detected by means of the card agglutination test for trypanosomiasis (CATT) or lymph node aspiration and confirmed with smears.

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Consultations

An infectious disease specialist should be consulted for evaluation of both early- and late-stage African trypanosomiasis in a symptomatic patient with recent travel or suspicious parasitic exposure.

Because African trypanosomiasis is so rarely encountered in the United States, it may be advisable to contact the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, for assistance in the diagnosis and treatment of this disease (Division of Parasitic Diseases, 770-488-7760; Drug Service, 404-639-3670).

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Long-Term Monitoring

In both early and late-stage trypanosomiasis, symptoms usually resolve after treatment, and the parasitemia clears on repeat blood smears.

Patients who have recovered from late-stage East African trypanosomiasis should undergo lumbar punctures every 3 months for the first year. Patients who have recovered from West African trypanosomiasis should undergo lumbar punctures every 6 months for 2 years.

If symptoms return, the CSF WBC count is higher than 20/µL, or trypanosomes are still present in blood or CSF, a relapse is suggested. However, a persistently elevated CSF WBC count may also be observed in recovering patients; thus, the change (increase or decrease) in the WBC count is more diagnostically helpful than the count by itself. If a relapse is noted, repeat treatment with melarsoprol or eflornithine may be considered.

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Guidelines Summary

WHO interim guidelines for the treatment of gambiense human African trypanosomiasis. Geneva: World Health Organization;2019. Licence: CC BY-NC-SA 3.0 IGO.

Executive Summary from the Guideline:

Human African trypanosomiasis (HAT), or sleeping sickness, is a parasitic infection that is almost invariably fatal unless treated. It is a neglected tropical disease that occurs insub-Saharan Africa.

The infection is transmitted to humans through the bite of an infected tsetse fly. The parasite multiplies in the lymph and blood, causing unspecific symptoms and signs(first-stage or haemo-lymphatic stage) and, over time, crosses the blood–brain barrier to infect the central nervous system (second-stage or meningo-encephalitic stage). Brain involvement causes various neurological disturbances, including sleep disorders (hence the name “sleeping sickness”), progression to coma and, ultimately, death.

The disease has 2 forms: the slowly progressing form (gambiense HAT), caused by infection with Trypanosoma brucei gambiense, found in western and central Africa (currently 98% of cases); and the faster progressing form (rhodesiense HAT), caused by infection with T brucei rhodesiense, in eastern and southern Africa (responsible for the remainder of cases). All age groups and both sexes are at risk of both forms of HAT, although prevalence is higher in adults than in children.

The incidence of the disease is declining in response to intensive surveillance andncontrol in endemic areas. As a result, HAT is among the neglected tropical diseases targeted by the World Health Organization (WHO) for elimination. WHO maintains exhaustive records of all declared cases; in 2018, a historically low number of cases(< 1000) was reported.

The remarkable progress in the control of gambiense HAT has relied on case-finding and curative treatment, a strategy that interrupts transmission by depleting the reservoir ofparasites in humans. This has been combined occasionally with vector control activities.The subject of these guidelines, therefore, is of utmost importance for the continuation of progress to eliminate HAT.

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Medication Summary

The type of drug treatment used depends on the type and stage of African trypanosomiasis (sleeping sickness)—that is, whether it is East African or West African and whether it is stage 1 (early/hemolymphatic) or stage 2 (late/neurologic). 

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Pentamidine isethionate (Pentam)

• Dosing, Interactions, etc.

Clinical Context:  Pentamidine isethionate is an antiprotozoal agent typically used for early (stage 1) African trypanosomiasis, as well as for Pneumocystis carinii pneumonia and leishmaniasis. It works by inhibiting dihydrofolate reductase enzyme, thereby interfering with parasite aerobic glycolysis.

Because of poor gastrointestinal absorption, pentamidine is administered IV or intramuscularly and is strongly bound to tissues, including the spleen, liver, and kidneys. Clinical improvement is usually noted within 24 hours of injection, and a cure rate exceeding 90% has been reported. Pentamidine does not penetrate the blood-brain barrier effectively and thus does not treat central nervous system infection.

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Eflornithine (Vaniqa)

• Dosing, Interactions, etc.

Clinical Context:  Eflornithine is recommended for treatment of patients with West African trypanosomiasis, especially in the late (neurologic) stage. It is a selective and irreversible inhibitor of ornithine decarboxylase, which is a critical enzyme for DNA and RNA synthesis. It is used for patients in whom melarsoprol fails and is generally better tolerated and less toxic than arsenic drugs. The initial response time is 1-2 weeks. Eflornithine is available via the World Health Organization.

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Nifurtimox (Lampit)

• Dosing, Interactions, etc.

Clinical Context:  Recommended by the CDC off-label in combination with eflornithine for treatment of African trypanosomiasis (HAT; sleeping sickness) caused by Trypanosome brucei gambiense. 

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Fexinidazole

• Dosing, Interactions, etc.

Clinical Context:  Nitroimidazole antiprotozoal drug indicated for treatment of African trypanosomiasis (HAT; sleeping sickness) caused by Trypanosome brucei gambiense in adults and children aged 6 years and older who weigh at least 20 kg. It is indicated for stage 1 (hemolymphatic) and stage 2 (meningoencephalitic) HAT. 

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Suramin

• Dosing, Interactions, etc.

Clinical Context:  Suramin is an antiparasitic agent given intravenously (IV) in early-stage African trypanosomiasis and onchocerciasis. It is a polysulfonated naphthylamine derivative of urea. Suramin is trypanocidal and works by inhibiting parasitic enzymes and growth factors. It is highly bound to serum proteins and thus crosses the blood-brain barrier poorly. Serum levels are approximately 100 µg/mL. Suramin is more effective and less toxic than pentamidine. The drug is excreted in the urine at a slow rate.

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Melarsoprol

• Dosing, Interactions, etc.

Clinical Context:  Melarsoprol is a CDC anti-infective agent. It is a trivalent arsenical agent used in the late (neurologic) stage of African trypanosomiasis. It is trypanocidal, inhibiting parasitic glycolysis. Melarsoprol is water-insoluble and has a half-life of 35 hours. Serum levels are in the range of 2-5 µg/mL, but CSF levels are 50-fold lower. Melarsoprol is primarily excreted by the kidneys. Clinical improvement is usually observed within 4 days after starting the drug. Parasitemia is cleared in as many as 90-95% of cases. However, the drug can be toxic and even fatal in 4-6% of cases.

Studies have 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; as many as 30% of cases do not respond to the drug.

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Class Summary

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

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