35-01: African Trypanosomiasis (Sleeping Sickness)

African trypanosomiasis is caused by the hemoflagellates Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. The organisms are transmitted by bites of tsetse flies (genus Glossina), which inhabit shaded areas along streams and rivers. Trypanosomes ingested in a blood meal develop over 18–35 days in the fly; when the fly feeds again on a mammalian host, the infective stage is injected. Human disease occurs in rural areas of sub-Saharan Africa from south of the Sahara to about 30 degrees south latitude. T b gambiense causes West African trypanosomiasis, and is transmitted in the moist sub-Saharan savannas and forests of west and central Africa. T b rhodesiense causes East African trypanosomiasis, and is transmitted in the savannas of east and southeast Africa.

T b rhodesiense infection is primarily a zoonosis of game animals and cattle; humans are infected sporadically. Humans are the principal mammalian host for T b gambiense, but domestic animals can be infected (eFigure 35–1). The number of reported cases increased from the 1960s to the 1990s and has since decreased greatly, although cases are reported from over 20 countries. Total incidence has been estimated at less than 5000 cases per year, mostly due to T b gambiense, with the largest number in the Democratic Republic of the Congo. Infections are rare among travelers, including visitors to game parks.

A. Symptoms and Signs

1. West African trypanosomiasis

Chancres at the site of the bite are uncommon. After an asymptomatic period that may last for months, hemolymphatic disease presents with fever, headache, myalgias, arthralgias, weight loss, and lymphadenopathy, with discrete, nontender, rubbery nodes, referred to as Winterbottom sign when in a posterior cervical distribution. Other common signs are mild splenomegaly, transient edema, and a pruritic erythematous rash. Febrile episodes may be broken by afebrile periods of up to several weeks. The hemolymphatic stage progresses over months to meningoencephalitic disease, with somnolence, irritability, personality changes, severe headache, and parkinsonian symptoms progressing to coma and death.

2. East African trypanosomiasis

Chancres at the bite site are more commonly recognized with T b rhodesiense infection, with a painful lesion of 3–10 cm and regional lymphadenopathy that appears about 48 hours after the tsetse fly bite and lasts 2–4 weeks. East African disease follows a much more acute course, with the onset of symptoms usually within a few days of the insect bite. The hemolymphatic stage includes intermittent fever and rash, but lymphadenopathy is less common than with West African disease. Myocarditis can cause tachycardia and death due to arrhythmias or heart failure. If untreated, East African trypanosomiasis progresses over weeks to months to meningoencephalitic disease, somnolence, coma, and death.

B. Laboratory Findings

Diagnosis can be difficult, and definitive diagnosis requires identification of trypanosomes. Microscopic examination of fluid expressed from a chancre or lymph node may show motile trypanosomes or, in fixed specimens, parasites stained with Giemsa. During the hemolymphatic stage, detection of parasites in Giemsa-stained blood smears is common in East African disease but difficult in West African disease. Serial specimens should be examined, since parasitemias vary greatly over time. Meningoencephalitic (or second stage) disease is defined by the World Health Organization (WHO) as cerebrospinal fluid (CSF) showing at least five mononuclear cells per microliter, elevated protein, or presence of trypanosomes. Concentration techniques can aid identification of parasites in blood or CSF. Serologic tests are also available. The card agglutination test for trypanosomes (CATT) has excellent sensitivity and specificity for West African disease and can be performed in the field, but the diagnosis should be confirmed by identification of the parasites. Field-applicable immunochromatographic lateral flow rapid diagnostic tests that cost less than CATT and are simpler to perform are available; combining tests improves sensitivity and specificity. Molecular diagnostic tests, including PCR and field-friendly loop-mediated isothermal amplification (LAMP) are available, but these are not yet standardized or routinely available.

Detection of trypanosomes is a prerequisite for treatment of African trypanosomiasis because of the significant toxicity of most available therapies. Treatment recommendations depend on the type of trypanosomiasis (Table 35–1), which is determined by geography, and stage of disease, which requires examination of CSF. Eflornithine, nifurtimox, suramin, and melarsoprol are available in the United States from the CDC Drug Service (www.cdc.gov/laboratory/drugservice).

A. West African Trypanosomiasis

Pentamidine (4 mg/kg intramuscularly or intravenously every day or every other day for 7 days) has been used to treat infection that does not involve the central nervous system (CNS). The side effects of pentamidine include immediate hypotension; tachycardia; gastrointestinal symptoms during administration; sterile abscesses; and pancreatic (hypoglycemia), liver, and kidney abnormalities. An alternate drug for early stage infection is eflornithine (100 mg/kg/day intravenously every 6 hours for 14 days).

The treatment of choice for CNS infection has been a combination of intravenous eflornithine (400 mg/kg/day in two doses for 7 days) and oral nifurtimox (15 mg/kg/day in three doses for 10 days), which has improved efficacy and less toxicity than older regimens. Eflornithine, though less toxic than older trypanocidal drugs, can cause gastrointestinal symptoms, bone marrow suppression, seizures, and alopecia. An alternative agent is melarsoprol. Fexinidazole is as effective and safe as eflornithine plus nifurtimox when administered orally over 10 days; this drug has been endorsed by the WHO for both early and CNS infection and will likely replace other therapies for all but advanced CNS disease. Fexinidazole is recommended for persons 6 years of age and older, with body weight at least 20 kg, and a CSF leukocyte count below 100/mcL (evaluation of CSF can be avoided if there is no suspicion of severe CNS disease). The drug has an acceptable safety profile, in particular compared to older therapies, but adverse events include headache, nausea, vomiting, insomnia, anxiety, weakness, tremor, and decreased appetite. For advanced CNS disease (CNS leukocytes more than 100/mcL), eflornithine plus nifurtimox is recommended.

B. East African Trypanosomiasis

Pentamidine and eflornithine are not reliably effective, and early disease is treated with suramin. The dosing regimens of suramin vary (eg, 100–200 mg test dose, then 20 mg/kg [maximum 1 g] intravenously on days 1, 3, 7, 14, and 21 or weekly for five doses). Suramin toxicities include vomiting and, rarely, seizures and shock during infusions as well as subsequent fever, rash, headache, neuropathy, and kidney and bone marrow dysfunction.

Suramin does not enter the CNS, so East African trypanosomiasis involving the CNS is treated with melarsoprol (three series of 3.6 mg/kg/day intravenously for 3 days, with 7-day breaks between the series or a 10-day intravenous course with 0.6 mg/kg on day 1, 1.2 mg/kg on day 2, and 1.8 mg/kg on days 3–10). Melarsoprol also acts against West African disease, but eflornithine plus nifurtimox is preferred due to its lower toxicity. Immediate side effects of melarsoprol include fever and gastrointestinal symptoms. The most important side effect is a reactive encephalopathy that can progress to seizures, coma, and death. To help avoid this side effect, corticosteroids are coadministered (dexamethasone 1 mg/kg/day intravenously for 2–3 days or oral prednisolone 1 mg/kg/day for 5 days, and then 0.5 mg/kg/day until treatment completion). In addition, increasing resistance to melarsoprol is a serious concern.

Individual prevention in endemic areas should include neutral-colored clothes (eg, long sleeve shirts and pants), insect repellents, and mosquito nets. Control programs focusing on vector elimination and treatment of infected persons and animals have shown good success in many areas but suffer from limited resources.