Human African Trypanosomiasis (Sleeping Sickness)

Epidemiology

In 1995, the WHO's Expert Committee on Trypanosomiasis estimated that there were approximately 300,000 new cases of HAT in Africa each year and that less than 10% of these cases were appropriately diagnosed and treated (WHO, ). The number of new cases reported annually has decreased significantly in recent years, with 2009 marking the first time in more than 50 years that less than 10,000 new cases were reported. A further decrease was seen in 2010, with the WHO reporting only 7,139 cases that year. Although there has been a general decrease in disease prevalence, disease transmission is characterized by focal epidemics during periods of political unrest, war, and famine—largely due to decreased surveillance and treatment ( ).

Transmission of HAT requires the presence of a competent vector, the tsetse fly ( Glossina species). These insects are found in warm, shaded areas in a geographic region between 14° North and 19° South of the equator in Africa ( ). They inhabit an area that covers approximately one-third of Africa's landmass and is roughly the size of the United States ( ). The average lifespan of a tsetse fly is between 1 and 6 months, and once a fly is infected, it remains so for life ( ). Although an infected tsetse fly remains a vector for disease transmission for the duration of its lifecycle, the trypanosome undergoes complete transformation in only about 10% of infected flies ( ).

While exclusively endemic to the African continent, there are approximately 50 cases of HAT per year diagnosed outside Africa, mostly in travelers returning from visits to East African game reserves ( ).

Pathogen/Lifecycle

There are two forms of HAT, both of which are transmitted by the bite of the tsetse fly. The disease caused by the species Trypanosoma brucei rhodesiense occurs mostly in Southern and Eastern Africa (and therefore is often referred to as “East African sleeping sickness”) and causes a more rapidly progressive disease, while infection with Trypanosoma brucei gambiense occurs mostly in West and Central Africa (“West African sleeping sickness”) and leads to a more chronic form of disease. In either case, the infected tsetse fly bites its host, thereby injecting metacyclic trypomastigotes into the skin ( ). The trypomastigotes then transform into bloodstream trypomastigotes, allowing them to travel throughout the body, where they multiply by binary fission ( ). To complete the lifecycle, the host must then be bitten by another tsetse fly. During the second ingestion, the trypomastigotes move to the midgut of the fly where they transform and, after approximately 3 weeks, migrate to the salivary gland of the tsetse fly. In the salivary gland, they undergo a final transformation to the infective form, which allows them to be transmitted to another host with the next meal ( Fig. 27.1 ).

The genome of T. brucei was fully sequenced in 2005. It contains approximately 9000 genes, with 10% of these coding for variable surface glycoproteins. The lifecycle of T. brucei involves near continuous modulation of these proteins, which allows the parasite to rapidly switch expression of surface proteins to constantly evade host immune responses, a process known as antigenic shift ( ). As a result, there are typical waves of parasitemia that occur with each antigenic shift, and then subside as the immune system begins to develop a response.

Clinical Manifestations

Trypanosome infection involves both an early, or hemolymphatic, stage and a late stage in which there is central nervous system (CNS) involvement. In T.b. gambiense infection, this is a slowly progressive process marked by indolent symptoms that persist for months to years. In T.b. rhodesiense , there is a more rapid progression, often associated with early onset of CNS involvement ( ) ( Table 27.1 ).

In either form of disease, a trypanosomal chancre may be the herald of infection and typically appears about 5-15 days after a tsetse fly bite. These are well-circumscribed, painful, indurated lesions at the site of the bite and are more common with T.b. rhodesiense than T.b. gambiense infections ( Fig. 27.2 ).

For 1-3 weeks after the initial bite, the trypanosome parasites spread through the bloodstream and lymph nodes in the hemolymphatic stage of infection. It is during this stage that trypomastigotes can be seen on blood smear.

Early symptoms of disease are nonspecific and include fevers, malaise, headaches, and arthralgias. Symptoms may coincide with waves of parasitemia as the trypanosomes undergo antigenic variation, thus evading host immune response. Conversely, symptoms may temporarily subside as the immune system begins to develop a response. This leads to nonspecific polyclonal B cell activation with large production of IgM and resultant enlargement of the spleen and lymph nodes ( ). Diffuse lymphadenopathy, hepatomegaly, and, more commonly, splenomegaly, are often present. Lymphadenitis can occur anywhere, but in the T.b. gambiense form it is classically seen in posterior cervical nodes, with painless enlargement of these mobile nodes referred to as Winterbottom sign ( ). This phase can last up to 3 years in the T.b. gambiense form, whereas T.b. rhodesiense is more rapidly progressive and can lead to death within weeks or months ( ). Other nonspecific symptoms that are recognized include pruritus, rash, weight loss, and facial swelling ( ).

Because the trypomastigotes can pass through blood vessel walls, they easily spread into connective tissue and can enter the cerebrospinal fluid (CSF) ( ). Progression to the second stage of infection (the “late” or encephalitic stage) occurs when parasites cross the blood–brain barrier. This may happen within weeks in T.b . rhodesiense infection or months in T.b. gambiense infection. This stage is defined by increased white blood cells (WBCs) in the CSF.

Clinically, stage II disease manifests as a progressive, diffuse meningoencephalitis, which can have a broad range of features, including headaches, poor concentration, difficulty completing tasks, psychosis, personality change, tremor, and/or ataxia. One of the hallmarks of late disease is alteration in the normal circadian rhythm, with reversal of the sleep–wake cycle, hence the name “sleeping sickness.” Convulsions may occur as the disease progresses, especially in children, though meningismus and focal neurologic signs are often absent ( ). As the disease progresses, there is clinical deterioration until coma or stupor results. Wasting and cachexia are common. Stage 2 disease is universally fatal without treatment.

Testing and Diagnosis

Because clinical features are nonspecific, diagnosis depends on appropriate laboratory testing. Numerous nonspecific laboratory findings are associated with HAT infection. Common findings include anemia, leukocytosis, and thrombocytopenia, likely due to splenic sequestration ( ). Hypergammaglobulinemia with polyclonal IgM is characteristic. Other common findings include elevated erythrocyte sedimentation rate and C-reactive protein, and hypoalbuminemia.

There is neither antigen nor antibody testing for T.b. rhodesiense . Antibody testing is available for T.b. gambiense but is not sufficient for definitive diagnosis. The most frequently used detection method is the card agglutination test for T.b. gambiense (CATT), which relies on the agglutination of trypanosomes and antibodies and has a sensitivity of 94-98% ( ). This test is not available in the United States but is often used in large-scale screening programs in endemic areas. All patients with a positive CATT require further evaluation.

Definitive diagnosis requires detection of parasites in blood, CSF, or lymph node aspirates. Microscopic detection of parasites is relatively straightforward and more widely available than serologic testing. Diagnosis is often made incidentally, with trypanosomes being visualized on a smear done to look for malaria parasites, as HAT is often clinically suspected to be malaria in early stages. Because T.b. rhodesiense disease is often associated with a high parasite load, parasites are usually seen on microscopy. When available, examination of the buffy coat from centrifuged specimens can increase sensitivity if parasite counts are low and organisms are not easily seen ( ). T.b. gambiense is more difficult to detect and has been traditionally tested via biopsy of suspicious enlarged posterior lymph nodes when present. Serologic testing for T.b. gambiense may be useful in screening programs but requires confirmation for definitive diagnosis (see below). If initial testing is negative and clinical suspicion remains high, repeat smears should be collected on subsequent days, as parasitemia fluctuates during the course of disease due to antigenic shift and immune response ( Fig. 27.3 ).

CSF testing is essential in anyone with suspected diagnosis of HAT both to confirm and to stage the disease. Typical CSF findings include pleocytosis, elevated protein, and increased opening pressure ( ). A rare but pathognomonic finding is the presence of eosinophilic plasma cells with high levels of IgM, or so-called morula cells of Mott ( ). It may also be possible to visualize trypanosomes in the CSF. Antitrypanosomal antibody testing has been developed for CSF analysis, but these tests lack sensitivity and it is generally felt that a WBC count >5-6 or high levels of IgM in the CSF are the most sensitive markers for CNS involvement ( ).

Both antigen detection via enzyme - linked immunosorbent assay testing and polymerase chain reaction-based testing methods have been developed but are not yet commercially available. Other clinical tests, such as magnetic resonance imaging and electroencephalo­graphy, may show nonspecific abnormalities but are not yet widely available in endemic areas at this time.