Sleeping sickness, or human African trypanosomiasis (HAT), is caused by flagellated protozoan parasites that belong to the T. brucei complex and are transmitted to humans by tsetse flies. In untreated patients, the trypanosomes first cause a febrile illness that is followed months or years later by progressive neurologic impairment and death.
The Parasites and Their Transmission
The East African (rhodesiense) and the West African (gambiense) forms of sleeping sickness are caused, respectively, by two trypanosome subspecies: T. b. rhodesiense and T. b. gambiense. These subspecies are morphologically indistinguishable but cause illnesses that are epidemiologically and clinically distinct (Table 213-1). The parasites are transmitted by blood-sucking tsetse flies of the genus Glossina. The insects acquire the infection when they ingest blood from infected mammalian hosts. After many cycles of multiplication in the midgut of the vector, the parasites migrate to the salivary glands. Their transmission takes place when they are inoculated into a mammalian host during a subsequent blood meal. The injected trypanosomes multiply in the blood (Fig. 213-2) and other extracellular spaces and evade immune destruction for long periods by undergoing antigenic variation, a process driven by gene switching in which the antigenic structure of the organisms′ surface coat of glycoproteins changes periodically.
Table 213-1 Comparison of West African and East African Trypanosomiases |Favorite Table|Download (.pdf)
Table 213-1 Comparison of West African and East African Trypanosomiases
|Point of Comparison||West African (Gambiense)||East African (Rhodesiense)|
|Organism||T. b. gambiense||T. b. rhodesiense|
|Vectors||Tsetse flies (palpalis group)||Tsetse flies (morsitans group)|
|Primary reservoir||Humans||Antelope and cattle|
|Human illness||Chronic (late CNS disease)||Acute (early CNS disease)|
|Duration of illness||Months to years||<9 months|
|Diagnosis by rodent inoculation||No||Yes|
|Epidemiology||Rural populations||Workers in wild areas, rural populations, tourists in game parks|
Trypanosoma brucei rhodesiense parasites in rat blood. The slender parasite is thought to be the form that multiplies in mammalian hosts, while the stumpy forms are nondividing and are capable of infecting insect vectors (Giemsa, 1200×). (Courtesy of Dr. G. A. Cook, Madison, WI; with permission.)
Pathogenesis and Pathology
A self-limited inflammatory lesion (trypanosomal chancre) may appear a week or so after the bite of an infected tsetse fly. A systemic febrile illness then evolves as the parasites are disseminated through the lymphatics and bloodstream. Systemic HAT without central nervous system (CNS) involvement is generally referred to as stage I disease. In this stage, widespread lymphadenopathy and splenomegaly reflect marked lymphocytic and histiocytic proliferation and invasion of morular cells, which are plasmacytes that may be involved in the production of IgM. Endarteritis, with perivascular infiltration of both parasites and lymphocytes, may develop in lymph nodes and the spleen. Myocarditis develops frequently in patients with stage I disease and is especially common in T. b. rhodesiense infections.
Hematologic manifestations that accompany stage I HAT include moderate leukocytosis, thrombocytopenia, and anemia. High levels of immunoglobulins, consisting primarily of polyclonal IgM, are a constant feature, and heterophile antibodies, antibodies to DNA, and rheumatoid factor are often detected. High levels of antigen-antibody complexes may play a role in the tissue damage and increased vascular permeability that facilitate dissemination of the parasites.
Stage II disease involves invasion of the CNS. The presence of trypanosomes in perivascular areas is accompanied by intense infiltration of mononuclear cells. Abnormalities in cerebrospinal fluid (CSF) include increased pressure, elevated total protein concentration, and pleocytosis. In addition, trypanosomes are frequently found in CSF.
The trypanosomes that cause sleeping sickness are found only in sub-Saharan Africa. After its near-eradication in the mid-1960s, sleeping sickness underwent a resurgence in the 1990s, primarily in Uganda, Sudan, the Central African Republic, the Democratic Republic of the Congo, and Angola. Although a subsequent increase in control activities reduced the incidence in many endemic areas, the World Health Organization estimated that there were 50,000–70,000 new cases in 2004, the vast majority of which were caused by T. b. gambiense. Approximately 50 million persons are at risk of acquiring HAT.
Humans are the only reservoir of T. b. gambiense, which occurs in widely distributed foci in tropical rain forests of Central and West Africa. Gambiense trypanosomiasis is primarily a problem in rural populations; tourists rarely become infected. Trypanotolerant antelope species in savanna and woodland areas of Central and East Africa are the principal reservoir of T. b. rhodesiense. Cattle can also be infected with this and other trypanosome species but generally succumb to the infection. Since risk results from contact with tsetse flies that feed on wild animals, humans acquire T. b. rhodesiense infection only incidentally, usually while visiting or working in areas where infected game and vectors are present. Roughly one or two imported cases of HAT acquired in East African parks are reported to the CDC each year.
A painful trypanosomal chancre appears in some patients at the site of inoculation of the parasite. Hematogenous and lymphatic dissemination (stage I disease) is marked by the onset of fever. Typically, bouts of high temperatures lasting several days are separated by afebrile periods. Lymphadenopathy is prominent in T. b. gambiense trypanosomiasis. The nodes are discrete, movable, rubbery, and nontender. Cervical nodes are often visible, and enlargement of the nodes of the posterior cervical triangle, or Winterbottom's sign, is a classic finding. Pruritus and maculopapular rashes are common. Inconstant findings include malaise, headache, arthralgias, weight loss, edema, hepatosplenomegaly, and tachycardia. The differential diagnosis of stage I HAT includes many diseases that are common in the tropics and are associated with fevers. HIV infection, malaria, and typhoid fever are common in populations at risk for HAT and need to be considered.
CNS invasion (stage II disease) is characterized by the insidious development of protean neurologic manifestations that are accompanied by progressive abnormalities in the CSF. A picture of progressive indifference and daytime somnolence develops (hence the designation “sleeping sickness”), sometimes alternating with restlessness and insomnia at night. A listless gaze accompanies a loss of spontaneity, and speech may become halting and indistinct. Extrapyramidal signs may include choreiform movements, tremors, and fasciculations. Ataxia is frequent, and the patient may appear to have Parkinson's disease, with a shuffling gait, hypertonia, and tremors. In the final phase, progressive neurologic impairment ends in coma and death.
The most striking difference between the gambiense and rhodesiense forms of HAT is that the latter illness tends to follow a more acute course. Typically, in tourists with T. b. rhodesiense disease, systemic signs of infection, such as fever, malaise, and headache, appear before the end of the trip or shortly after the return home. Persistent tachycardia unrelated to fever is common early in the course of T. b. rhodesiense trypanosomiasis, and death may result from arrhythmias and congestive heart failure before CNS disease develops. In general, untreated T. b. rhodesiense trypanosomiasis leads to death in a matter of weeks to months, often without a clear distinction between the hemolymphatic and CNS stages. In contrast, T. b. gambiense disease can smolder for many months or even for years.
A definitive diagnosis of HAT requires detection of the parasite. If a chancre is present, fluid should be expressed and examined directly by light microscopy for the highly motile trypanosomes. The fluid also should be fixed and stained with Giemsa. Material obtained by needle aspiration of lymph nodes early in the illness should be examined similarly. Examination of wet preparations and Giemsa-stained thin and thick films of serial blood samples is also useful. If parasites are not seen initially in blood, efforts should be made to concentrate the organisms, which can be done in microhematocrit tubes containing acridine orange. Alternatively, the buffy coat from 10–15 mL of anticoagulated blood can be examined directly under a microscope. The likelihood of finding parasites in blood is higher in stage I than in stage II disease and in patients infected with T. b. rhodesiense rather than T. b. gambiense. Trypanosomes may also be seen in material aspirated from the bone marrow; the aspirate can be inoculated into liquid culture medium, as can blood, buffy coat, lymph node aspirates, and CSF. Finally, T. b. rhodesiense infection can be detected by inoculation of these specimens into mice or rats, which—when positive—results in patent parasitemias in a week or two. Although this method is highly sensitive for the detection of T. b. rhodesiense, it does not detect T. b. gambiense because of host specificity.
It is essential to examine CSF from all patients in whom HAT is suspected. Abnormalities in the CSF that may be associated with stage II disease include an increase in the CSF mononuclear cell count as well as increases in opening pressure and in levels of total protein and IgM. Trypanosomes may be seen in the sediment of centrifuged CSF. Any CSF abnormality in a patient in whom trypanosomes have been found at other sites must be viewed as pathognomonic for CNS involvement and thus must prompt specific treatment for CNS disease. In patients with CSF pleocytosis in whom parasites are not found, tuberculous meningitis and HIV-associated CNS infections such as cryptococcosis should be considered in the differential diagnosis.
A number of serologic assays, such as the card agglutination test for trypanosomes (CATT) for T. b. gambiense, are available to aid in the diagnosis of HAT, but their variable sensitivity and specificity mandate that decisions about treatment be based on demonstration of the parasite. These tests are of value for epidemiologic surveys. PCR assays for detecting African trypanosomes in humans have been developed, but none is commercially available.
Treatment: Sleeping Sickness
The drugs used for treatment of HAT are suramin, pentamidine, eflornithine, and the organic arsenical melarsoprol. In the United States, these drugs can be obtained from the CDC. Therapy for HAT must be individualized on the basis of the infecting subspecies, the presence or absence of CNS disease, adverse reactions, and occasionally drug resistance. The choices of drugs for the treatment of HAT are summarized in Table 213-2.
Table 213-2 Treatment of Human African Trypanosomiasesa |Favorite Table|Download (.pdf)
Table 213-2 Treatment of Human African Trypanosomiasesa
|Causative Organism||I (Normal CSF)||II (Abnormal CSF)|
|T. brucei gambiense (West African)|
|T. brucei rhodesiense (East African)||Suramin||Melarsoprol|
Suramin is highly effective against stage I rhodesiense HAT. However, it can cause serious adverse effects and must be administered under the close supervision of a physician. A 100- to 200-mg IV test dose should be given to detect hypersensitivity. The dosage for adults is 20 mg/kg on days 1, 5, 12, 18, and 26. The drug is given by slow IV infusion of a freshly prepared 10% aqueous solution. Approximately 1 patient in 20,000 has an immediate, severe, and potentially fatal reaction to the drug, developing nausea, vomiting, shock, and seizures. Less severe reactions include fever, photophobia, pruritus, arthralgias, and skin eruptions. Renal damage is the most common important adverse effect of suramin. Transient proteinuria often appears during treatment. A urinalysis should be done before each dose, and treatment should be discontinued if proteinuria increases or if casts and red cells appear in the sediment. Suramin should not be given to patients with renal insufficiency.
Pentamidine is the first-line drug for treatment of stage I gambiense HAT. The dose for both adults and children is 4 mg/kg per day, given IM or IV for 7–10 days. Frequent, immediate adverse reactions include nausea, vomiting, tachycardia, and hypotension. These reactions are usually transient and do not warrant cessation of therapy. Other adverse reactions include nephrotoxicity, abnormal liver function tests, neutropenia, rashes, hypoglycemia, and sterile abscesses. Suramin is an alternative agent for stage I T. b. gambiense disease.
Eflornithine is highly effective for treatment of both stages of gambiense sleeping sickness. In the trials on which the FDA based its approval, this agent cured >90% of 600 patients with stage II disease. The recommended treatment schedule is 400 mg/kg per day, given IV in four divided doses, for 2 weeks. Adverse reactions include diarrhea, anemia, thrombocytopenia, seizures, and hearing loss. The high dosage and duration of therapy required are disadvantages that make widespread use of eflornithine difficult. A randomized trial comparing the standard eflornithine regimen (400 mg/kg per day infused over 6 h for 14 days) with nifurtimox-eflornithine combination therapy (oral nifurtimox, 15 mg/kg per day for 10 days; plus eflornithine, 400 mg/kg per day infused over 12 h for 7 days) in adults with stage II gambiense HAT showed improved efficacy and reduced adverse effects with combination therapy, making it suitable for first-line use.
The arsenical melarsoprol is the drug of choice for the treatment of rhodesiense HAT with CNS involvement and is an alternative agent for stage II gambiense disease. For rhodesiense disease, the drug should be given to adults in three courses of 3 days each. The dosage is 2.0–3.6 mg/kg per day, given IV in three divided doses for 3 days and followed 1 week later by 3.6 mg/kg per day, also in three divided doses and for 3 days. The latter course is repeated 7 days later. In debilitated patients, suramin is administered for 2–4 days before therapy with melarsoprol is initiated; an 18-mg initial dose of the latter drug, followed by progressive increases to the standard dose, has been recommended. For children, a total of 18–25 mg/kg should be given over 1 month. An IV starting dose of 0.36 mg/kg should be increased gradually to a maximum of 3.6 mg/kg at 1- to 5-day intervals, for a total of 9 or 10 doses. The regimen for gambiense disease is 2.2 mg/kg per day, given IV for 10 days.
Melarsoprol is highly toxic and should be administered with great care. To reduce the likelihood of drug-induced encephalopathy, all patients receiving melarsoprol should be given prednisolone at a dose of 1 mg/kg (up to 40 mg) per day, beginning 1–2 days before the first dose of melarsoprol and continuing through the last dose. Without prednisolone prophylaxis, the incidence of reactive encephalopathy has been reported to be as high as 18% in some series. Clinical manifestations of reactive encephalopathy include high fever, headache, tremor, impaired speech, seizures, and even coma and death. Treatment with melarsoprol should be discontinued at the first sign of encephalopathy but may be restarted cautiously at lower doses a few days after signs have resolved. Extravasation of the drug results in intense local reactions. Vomiting, abdominal pain, nephrotoxicity, and myocardial damage can occur.
HAT poses complex public-health and epizootic problems in Africa. Considerable progress has been made in some areas through control programs that focus on eradication of vectors and drug treatment of infected humans. People can reduce their risk of acquiring trypanosomiasis by avoiding areas known to harbor infected insects, by wearing protective clothing, and by using insect repellent. Chemoprophylaxis is not recommended, and no vaccine is available to prevent transmission of the parasites.