Version May 2024
INTRODUCTION — Human African trypanosomiasis (HAT), also known as sleeping sickness, is caused by protozoan parasites [1-3]. There are two forms of the disease: an acute form occurring mainly in East and Southern Africa and caused by Trypanosoma brucei rhodesiense (rhodesiense HAT) and a more chronic form occurring mainly in West and Central Africa caused by Trypanosoma brucei gambiense (gambiense HAT) (table 1) [3]. These two T. brucei parasite subspecies have identical morphologic appearances and both are transmitted by tsetse flies (Glossina). However, the two forms of HAT differ in epidemiology, clinical presentation, and management.
Other salivarian trypanosomes cause animal trypanosomosis, including Trypanosoma brucei, Trypanosoma evansi, Trypanosoma equiperdum, Trypanosoma vivax, and Trypanosoma congolense.
The epidemiology, pathogenesis, clinical manifestations, and diagnosis of HAT will be reviewed here. The treatment and prevention of HAT are discussed separately. (See "Human African trypanosomiasis: Treatment and prevention".)
EPIDEMIOLOGY
Disease distribution — There are two forms of HAT: a typically acute form occurring mainly in East and Southern Africa and caused by T. b. rhodesiense (rhodesiense HAT), and a more chronic form occurring mainly in West and Central Africa caused by T. b. gambiense (gambiense HAT) [3]. Gambiense HAT primarily affects humans in endemic areas, whereas rhodesiense HAT is primarily a zoonosis that only occasionally affects humans. Wild animals are the main reservoir for T. b. rhodesiense infection.
Sleeping sickness is endemic in 36 sub-Saharan African countries within the distribution of the tsetse fly [4]. There are an estimated 55 million people at various levels of risk for infection; cases have been mapped at the village level since 2000 (figure 1) [5-8]. Countries particularly affected include the Democratic Republic of Congo, South Sudan, Angola, Guinea, and the Central African Republic (all of which have gambiense HAT); Uganda (which has both gambiense and rhodesiense HAT, but in different zones); and Tanzania, Malawi, and Zambia (which have rhodesiense HAT) [9-13]. In 2022, rhodesiense HAT re-emerged in Ethiopia after 31 years.
The disease distribution differs between the countries and is markedly focal in different parts of a single country. From 2018 to 2022, the distribution was as follows [14]:
●Around 60 percent of cases occur in the Democratic Republic of the Congo.
●The following countries had 10 to 100 new reported cases: Angola, Central African Republic, Chad, Congo, Gabon, Guinea, Malawi, and South Sudan.
●The following countries have had sporadic cases (<10 per year): Burkina Faso, Cameroon, Côte d'Ivoire, Equatorial Guinea, Ethiopia, Ghana, Kenya, Nigeria, Uganda, United Republic of Tanzania, Zambia, and Zimbabwe.
●The following countries have had no new reported cases for over a decade: Benin, Botswana, Burundi, , The Gambia, Guinea Bissau, Liberia, Mali, Mozambique, Namibia, Niger, Rwanda, Senegal, Sierra Leone, Swaziland, and Togo.
HAT mainly affects marginalized and poor communities in remote areas. Such populations are exposed to the tsetse fly through daily activities on rivers, agriculture, animal husbandry, or hunting. The occurrence of HAT in a region often reflects war, civil unrest, and lack of a reliable presence of state authority. Therefore, nearly by definition, HAT as a public health problem occurs in areas where there is no research infrastructure; thus, many important questions of clinical and operational research remain unanswered.
Additional risk groups include (1) individuals who have resided in endemic areas for extended periods (eg, during a business stay, forestry work, or humanitarian mission) and (2) migrants and refugees; these individuals may present several years after leaving an endemic area, due to the slow progression of gambiense HAT [15].
Between 2000 and 2010, 94 cases of HAT were reported in nonendemic countries; of these, 72 percent were cases of rhodesiense HAT imported from Tanzania, Malawi, Zambia, Zimbabwe, and Uganda [15,16]. Most affected individuals were short-term tourists exposed in national parks, game reserves, or areas near Lake Victoria. Reports have described clusters of infection among European tourists [17-19], highlighting the potential for emergence of this disease in international travelers. If a case of rhodesiense HAT is identified in a group of tourists, special attention should be given to the occurrence of additional cases in the group given the likelihood of shared exposure [15].
Epidemics — In the last century, there have been three severe epidemics of HAT [4]: one between 1896 and 1906 (mostly in Uganda and the Congo Basin), one in the 1920s (in several Central African countries; arrested with systematic screening of at-risk individuals by mobile teams), and one that began in 1970 and lasted until the late 1990s.
The disease practically disappeared between 1960 and 1965, and surveillance was relaxed. Civil wars, displacement of people, economic difficulties, and slackening in vector control measures allowed re-emergence of disease in several foci. In 1998, almost 40,000 cases of HAT were reported, with an estimate of 300,000 additional undiagnosed cases [4,5,20]. Major efforts of the national control programs, with the support of the World Health Organization (WHO), bilateral co-operations, and nongovernmental organizations have led to a significant decline of HAT cases since the beginning of the 21st century [4]. In 2009, the number of reported cases was below 10,000 for the first time in 50 years. HAT (mostly gambiense HAT [>87 percent]) occurrence fell below 1000 cases in 2018, remaining below that threshold as of 2022. [7,8,14] (figure 2).
Life cycle — Humans are the main reservoir for T. b. gambiense; this species can also be found in some animals, including pigs. It is possible that animal reservoirs and latent human infections contribute to maintaining the gambiense reservoir [21]. Wild game animals and cattle are the main reservoir of T. b. rhodesiense.
During a blood meal, an infected tsetse fly injects trypomastigotes into the host skin tissue (figure 3). A painful chancre (local inflammatory reaction) can develop at the site of inoculation.
The parasites enter regional lymphatics and then disseminate in the bloodstream, where the metacyclic trypomastigotes differentiate to long, slender forms that measure 15 to 35 microns. These can be seen on blood smear examination (picture 1 and picture 2) and are characterized by a flagellum and a kinetoplast (an organelle associated with the mitochondrion containing extranuclear DNA). Trypomastigotes can pass through the walls of blood and lymphatic vessels into connective tissues and thereby enter the cerebrospinal fluid and the brain. The skin may serve as a reservoir for trypanosomes [22,23].
When ingested by a tsetse fly during a blood meal, trypomastigotes move to the midgut, transform into procyclic trypomastigotes (with different developmental, morphologic, and metabolic characteristics) and undergo replication. They migrate to the salivary gland, where they develop into epimastigotes, and finally, about three weeks after initial infection of the fly, develop into new metacyclic trypomastigotes ready to be transmitted to another host.
Transmission — HAT is transmitted to humans via the bite of a tsetse fly (Glossina spp). Tsetse flies tend to be found in warm, shaded areas and have an average lifespan of one to six months. Once trypanosomes have colonized the salivary glands, the fly remains infective for life. Flies are attracted by large moving objects and are especially drawn to dark colors [24]. Tsetse flies are restricted to the African continent where they occur in 31 species and subspecies, though not all tsetse flies play a role in the transmission of sleeping sickness. T. b. gambiense is transmitted via tsetse flies mainly of the Glossina palpalis group, and T. b. rhodesiense is transmitted via tsetse flies mainly of the Glossina morsitans group. These flies are found in tropical Africa between 14° north and 19° south of the equator, which defines the geographic range for transmission of HAT.
The G. palpalis vector requires humidity as encountered in dense riverine habitats, plantations, and mangroves in West and Central Africa. Humans are exposed to bites during daily activities including fishing, bathing, washing in small rivers or pools of water in rural areas, or while working in coffee or cocoa plantations.
The G. morsitans vector lives in drier and more open areas of woodlands and savannas in East and Southern Africa. These flies mainly feed on wild animals such as antelope (bushbucks) or on domestic animals such as cattle and goats. They do not bite humans frequently, but individuals who enter woodland areas and thickets where flies breed (such as farmers, honey gatherers, firewood collectors, hunters, poachers, fishermen, game wardens, and tourists to national parks and game reserves) are at risk of incidental infection.
Other means of transmission are considered to be rare; these include transmission via blood transfusion (theoretical), laboratory inoculation, and congenital infection [25]. The risk of congenital infection is unknown, but is regarded to be more common than recognized [25,26]. Urban and peri-urban transmission events are rare but have been described in Libreville (Gabon) and Kinshasa (the Democratic Republic of Congo) [27].
It has been proposed that individuals with asymptomatic infection may carry skin-dwelling trypanosomes and act as parasite reservoirs [28].
Elimination — The WHO targeted HAT for elimination as a public health problem by the year 2020 (defined as <2000 reported cases per year and 90 percent reduction in at-risk areas reporting ≥1 case per 10,000 people annually) [6,29]. Additional 2030 targets include elimination of gambiense HAT transmission (resulting in zero cases reported) and elimination of rhodesiense HAT as a public health problem (no area reporting ≥1 case per 10,000 people annually) [7]. The goal for rhodesiense HAT is more complex due to its predominance in animal reservoirs.
PATHOGENESIS — During the lifecycle of T. brucei, there is modulation of the exposed surface antigens of the parasite. Metacyclic trypanosomes in the tsetse fly and bloodstream forms in mammalian and human hosts have proteins on their surface known as variant surface glycoprotein (VSG), which are highly immunogenic. Each trypanosome is covered with approximately 10 million copies of a single VSG [30].
Innate immunity — Innate immunity against T. brucei and other animal trypanosomes is due to the trypanolytic activity of apolipoprotein L-I (APOL1), which is bound to high-density lipoproteins in human serum [31]. This protein is taken up in the parasite by endocytosis and triggers osmotic swelling of the lysosomal compartment with subsequent cell death [32]. The importance of the APOL1 protein in innate immunity has been demonstrated by permissiveness of human infections when parasites otherwise not infective to humans (see above) have acquired resistance to APOL1 [31] or conversely when susceptible patients have mutations in the APOL1 gene [33]. However, both T. b. rhodesiense and T. b. gambiense resist APOL1-mediated lysis [34]. T. b. rhodesiense expresses the serum resistance-associated protein, which binds to APOL1 and thereby inactivates its trypanolytic activity. T. b. gambiense resists through a combination of mechanisms, including reduced APOL1 uptake, faster APOL1 degradation, and membrane stiffening mediated by the T. b. gambiense-specific glycoprotein. Other innate immune mechanisms (eg, polymorphisms of genes encoding tumor necrosis factor or interleukins 6 and 10) may modulate the risk of latency in T. b. gambiense infections [21]. The G2 variant of APOL1 gene is a risk factor for renal disease in African Americans but it may confer a degree of protection against T. b. rhodesiense infections [35].
Evasion of host defense — T. brucei parasites can evade destruction by the mammalian host humoral immune response in the bloodstream by periodically switching their VSG, a phenomenon known as antigenic variation [36,37]. This results in characteristic waves of parasitemia during HAT infection. Trypanosomes express a different VSG during each successive wave of parasitemia and change their surface VSG each time the host begins to mount an effective immune response. In this way, the parasite is able to stay one step ahead of the host's antibody response [38].
Immune response — Antigenic variation leads to nonspecific polyclonal B cell activation during infection and immunoglobulin (Ig)M is produced in large quantities. This can induce false positivity in antibody-based tests used to diagnose other infections [16]. Immune complexes form and secondary hyperplasia of the reticuloendothelial system occurs, particularly involving the spleen and lymph nodes. This process may lead to downregulation of the immune system. Therefore, generalized suppression of humoral and cellular immune responses may be seen in advanced stages of the disease [39].
The relative contribution of immune complex deposition, inflammatory infiltrates, vascular infiltration, and direct parasite invasion to organ damage in HAT is uncertain; it is likely that the pathogenesis of HAT reflects a complex combination of these mechanisms [40].
CLINICAL MANIFESTATIONS — The clinical presentation of HAT is dependent on the parasite subspecies, the disease stage, and host factors. In general, the clinical manifestations of gambiense and rhodesiense HAT differ with respect to their frequency, severity, and progression (table 2).
Disease stages — The incubation period of rhodesiense HAT is less than three weeks. The incubation period of gambiense HAT is variable, with a range of weeks or months prior to onset of systemic symptoms [41].
There are two stages of infection: the first stage, in which trypanosomes penetrate the skin and circulate in the blood and lymphatics, and the second stage, in which there is central nervous system (CNS) involvement. There is overlap in the clinical manifestations of the two stages and distinguishing between them on clinical grounds is usually not possible; lumbar puncture may be required to guide treatment. (See "Human African trypanosomiasis: Treatment and prevention".)
Gambiense HAT is usually slowly progressive, with an oligosymptomatic phase that may last months or years. Patients usually present indolently with fever, neurologic manifestations, weight loss, and lymphadenopathy. The estimated average duration of first stage is 526 days (95% CI 357-833) and the estimated average duration of second stage is 252 days (95% CI 171-399) [42,43].
Rhodesiense HAT is usually rapidly progressive within weeks. Patients often present fulminantly with a severe acute febrile illness, often with signs of hemodynamic instability. Patients may be critically ill, with multiorgan involvement, thrombocytopenia, and disseminated intravascular coagulopathy leading to bleeding [44].
First stage: Hemo-lymphatic disease — First-stage HAT consists of no CNS involvement, defined by cerebrospinal fluid (CSF) white blood cell (WBC) count ≤5 cells/microL and no trypanosomes in the CSF. (See 'Cerebrospinal fluid' below.)
The first sign of HAT infection may be the trypanosomal chancre; when present, it typically appears approximately after one week at the site of the tsetse bite. A typical chancre has a marked and painful erythema, about 2 to 5 cm in diameter, which later becomes indurated, with a considerable variation in appearance (picture 3 and picture 4) [44]. The chancre can ulcerate, with later peripheral desquamation and hyperpigmentation, and usually resolves spontaneously after several weeks. Chancres are observed more frequently in travelers (rhodesiense HAT 88 percent; gambiense HAT 56 percent) than residents of endemic areas (rhodesiense HAT 5 to 26 percent; gambiense HAT <5 percent) (table 2) [26,45].
Following skin penetration, trypanosomes travel to regional lymphatics, where they proliferate and cause lymphadenitis. In T. b. gambiense infection, lymphadenopathy typically occurs in the posterior cervical nodes but can develop at any site. Painless enlargement of the soft, mobile posterior cervical nodes is classically referred to as "Winterbottom's sign" (picture 5). This finding is easily overlooked. In T. b. rhodesiense infection, lymphadenopathy occurs less frequently. When present, it occurs more commonly in the submandibular, axillary, or inguinal regions than in the cervical region [46].
Early symptoms of HAT infection include intermittent fever, headache, malaise, and musculoskeletal pain; these symptoms may correspond with successive waves of parasitemia and antibody production. The pattern of fever is irregular and remittent, although such patterns tend not to be diagnostically useful. Fever is more pronounced in the first stage than in the second stage [47]. Hepatomegaly and particularly splenomegaly may be observed, and generalized lymphadenopathy may be present.
Neurologic or psychiatric symptoms (such as headache, behavioral change, sleeping disorder) may be observed. Other nonspecific symptoms may be present including pruritus, weight loss, gastrointestinal symptoms (such as nausea, vomiting, abdominal pain, diarrhea), and facial swelling [26]. Neuroendocrine disturbances (leading to amenorrhea in women or impotence in men) may also occur.
Cardiac involvement can be observed by electrocardiographic alterations in gambiense HAT; rarely, cardiomyopathy causes severe congestive heart failure [48]. In rhodesiense HAT, myocarditis or pancarditis is more severe and can be fatal in some cases [49,50].
Second stage: Meningo-encephalitis — Second-stage HAT consists of systemic HAT with CNS involvement, defined by CSF WBC count >5 cells/microL with or without trypanosomes in the CSF. (See 'Cerebrospinal fluid' below.)
For gambiense HAT, an additional sub-category, severe second-stage disease, was established in the World Health Organization 2019 guidelines; this is defined as ≥100 WBC/microL in CSF (with or without trypanosomes in CSF) [1]. Such staging is important for guiding management, since fexinidazole is less efficacious in patients with CSF WBC ≥100 cells/microL. Clinical manifestations consistent with severe second-stage HAT are summarized in the table (table 3). (See "Human African trypanosomiasis: Treatment and prevention".)
CNS symptoms include headache, difficulty in concentrating, difficulty completing complex operations (2- or 3-stage tasks), personality changes, psychosis, sensory disorders, tremor, and ataxia [26]. Sleep disorder is one of the most striking characteristics of second-stage HAT; for this reason the disease is also called "sleeping sickness." Alteration of the circadian sleep/wake cycle leads to daytime somnolence, which may already be prominent in the first stage. Meningismus and focal neurologic signs may occur but are unusual. The patient gradually deteriorates to a stuporous or comatose state. Convulsions may occur. Cachexia, wasting, and malnutrition develop as patients are too drowsy to eat. Patients are at risk for complications such as aspiration pneumonia and other secondary bacterial infections.
In one series including more than 2500 patients with second-stage gambiense HAT, the following symptoms and signs were most frequent [47]: headache (79 percent), sleep disorder (74 percent), lymphadenopathy (56 percent), pruritus (51 percent), motor weakness (35 percent), malnutrition (25 percent), unusual behavior (25 percent), disturbed appetite (23 percent), walking difficulties (22 percent), tremor (21 percent), fever (16 percent), speech disorder (13 percent), and abnormal movements (11 percent).
Most of the neuropsychiatric signs and symptoms can be treated successfully; however, depending on the severity of the disease at the time of therapy, irreversible sequelae may occur [26]. In the absence of treatment, second-stage HAT is fatal [51].
Neurologic or psychiatric signs may be also mild or absent at the time of diagnosis [52].
Relapse — Relapse may occur up to 24 months after completion of treatment. For patients who present >24 months after completion of treatment with diagnostic evidence of trypanosomiasis, this is usually interpreted as reinfection. (See "Human African trypanosomiasis: Treatment and prevention", section on 'Approach to relapse'.)
Travelers from non-endemic areas — Clinical features among returning travelers may differ from clinical features among individuals in endemic settings (table 2) and misdiagnosis outside endemic areas is common [15,44,45]. Among travelers, rhodesiense HAT is observed more frequently than gambiense HAT, mainly after visits to game parks (see 'Epidemiology' above). In rhodesiense HAT, timely diagnosis is critical given rapid disease progression.
A history of a painful tsetse fly bite may be reported [44]. In both forms of HAT, patients typically present acutely with fever [45]. For rhodesiense HAT, the incubation period is less than three weeks and may be as short as a few days. For gambiense HAT, the incubation period is frequently less than one month [53], whereas for individuals living in nonendemic countries, late presentations after several years may occur [15,25].
Dermatologic manifestations include:
●Trypanosomal chancre − A trypanosomal chancre is a key finding that may be overlooked or misinterpreted (picture 3 and picture 4) [44,45]. Chancres are observed more frequently in travelers (rhodesiense HAT 88 percent; gambiense HAT 56 percent) than in residents of endemic areas (rhodesiense HAT 5 to 26 percent; gambiense HAT <5 percent) [26,45]. (See 'First stage: Hemo-lymphatic disease' above.)
Chancre aspiration may be diagnostic. (See 'Tissue aspirate' below.)
●Trypanosomal rash − Following the initial episode of fever, a trypanosomal rash develops in approximately one-third of travelers; it is characterized by nonpruritic, blotchy, irregular, erythematous macules mainly on the trunk. Frequently, the rash develops a central area with normal colored skin, with a circinate or serpiginous appearing outline (picture 6). The rash is evanescent and reappears in other locations over a period of several weeks [25,45,53].
In travelers, these dermatologic manifestations may be observed in first-stage and/or second-stage disease.
In patients with severe disease due to rhodesiense HAT, clinical features may include hemodynamic instability, disseminated intravascular coagulopathy, multiorgan failure, and myocarditis [44].
Among travelers, sleep disorders and neuropsychiatric signs are observed less frequently, as patients are more likely to be diagnosed and treated during the first stage [45].
Patients with HIV infection — Thus far, it is uncertain whether the natural history of HAT is influenced by HIV infection, and it is uncertain whether patients with HIV infection may be at increased risk for treatment failure [54].
Laboratory findings — A number of nonspecific laboratory findings may be associated with HAT. Anemia is common (present in more than half of patients) and may be due in part to immune-mediated hemolysis [45] and cytokine-related bone marrow depression [55]. Leukocytosis and thrombocytopenia may be present, possibly related to splenic sequestration and massive cytokine release. Hypergammaglobulinemia, largely related to raised levels of polyclonal IgM, is also characteristic and can give rise to false-positive results on serologic tests for other diseases. Hypoalbuminemia, hypocomplementemia, elevated erythrocyte sedimentation rate, and elevated C-reactive protein are frequently observed.
DIAGNOSIS
Clinical approach — A definitive diagnosis of HAT requires demonstration of trypanosomes in body fluids (blood and/or cerebrospinal fluid [CSF]) or tissues (lymph node or chancre aspirate) via microscopy [56].
Gambiense HAT — In endemic areas, the diagnosis of gambiense HAT should be suspected in individuals with epidemiologic exposure (residence in an endemic area (figure 1)). In these areas, HAT is most frequently diagnosed in the context of screening; patients may or may not be symptomatic.
Outside endemic areas, the diagnosis of gambiense HAT should be suspected in individuals with epidemiologic exposure (travel to an endemic area (figure 1)) in the setting of relevant signs or symptoms (early symptoms of fever, trypanosomal chancre or rash, headache, arthralgia, and lymphadenopathy; later symptoms of neurologic manifestations). A high degree of clinical suspicion is necessary for a timely diagnosis.
Diagnostic evaluation begins with serologic assessment using a rapid diagnostic test; these include the card agglutination test for trypanosomiasis (CATT) or rapid lateral flow tests (algorithm 1) (see 'Serologic tests' below). Patients with a positive serologic test should undergo confirmatory testing. Those with lymphadenopathy warrant lymph node aspiration with examination for parasites. If there is no lymphadenopathy, or the lymph node aspirate does not demonstrate trypanosomes, patients should undergo blood examination using a concentration technique; tools include microhematocrit centrifugation technique (mHCT) and mini anion-exchange centrifugation technique (mAECT). Indications for CSF examination depend on findings of initial diagnostic evaluation, clinical manifestations, and the available treatment options. (See "Human African trypanosomiasis: Treatment and prevention".)
Rhodesiense HAT — The diagnosis of rhodesiense HAT should be suspected in individuals with epidemiologic exposure (travel to or residence in an endemic area (figure 1)), in the setting of relevant signs or symptoms (early symptoms of fever, trypanosomal chancre or rash, headache, arthralgia, lymphadenopathy; later symptoms of neurologic manifestations).
The diagnosis of rhodesiense HAT can often be made via blood smear or chancre fluid; additional blood examination may be helpful in some cases (algorithm 2).
Diagnostic tools
Serologic tests
Gambiense HAT — Serologic screening is the starting point for diagnosis of gambiense HAT (algorithm 1). Serologic tests may be used for surveillance among asymptomatic individuals as well as the clinical evaluation of symptomatic patients.
Rapid diagnostic tests (RDTs) for diagnosis of gambiense HAT include the CATT and rapid lateral flow tests for detection of antibodies against purified variant surface glycoproteins:
●CATT is based upon agglutination of freeze-dried trypanosomes in the presence of a variant-specific antibody in blood, plasma, or serum. It is well suited for HAT surveillance in populations at risk [57]. The sensitivity is generally 94 to 98 percent; the specificity depends in part upon whether whole blood (97 percent specificity) or plasma/serum dilutions are used (further increasing specificity) [58]. The specificity may be reduced by cross-reactivity with antibodies against nonpathogenic animal trypanosomes.
●Rapid lateral flow tests detect antibodies against native variant surface glycoproteins [59,60] or against a combination of recombinant invariant and variant surface glycoproteins [61]. These tests are generally used for initial screening of symptomatic patients; they are well suited for individual diagnosis of HAT. In general, their sensitivity is 90 to 100 percent (with some reports of lower sensitivity [61]). Test specificity of available rapid tests is lower than of CATT, and their specificity is usually ≥85 percent [59,60,62-64].
Serologic tests that require laboratory facilities include enzyme-linked immunosorbent assay (ELISA) and inhibition ELISA [65], indirect fluorescent antibody test (IFAT), and the trypanolysis test [66]. The sensitivity and specificity for IFAT varies depending on the antigen used (75 to 95 percent and >95 percent, respectively) [67-69]. The sensitivity and specificity of ELISA and inhibition ELISA are 95 to 100 percent and 97 to 100 percent, respectively [65,70-73]. The sensitivity and specificity for the trypanolysis test are 95 percent and 100 percent, respectively [59,66].
Additional information on use of these tools for surveillance is presented separately. (See "Human African trypanosomiasis: Treatment and prevention", section on 'Surveillance'.)
Rhodesiense HAT — For diagnosis of rhodesiense HAT, no rapid tests are available. Serologic tests that require laboratory facilities include ELISA [74,75] or IFAT using whole parasites or crude trypanosome extracts [76-78] (algorithm 2). The sensitivity (71 to 92 percent) and specificity of such tests rhodesiense HAT are generally lower than those reported for gambiense HAT, given the acuity of illness due to rhodesiense HAT and the use of crude extracts for antibody detection.
Parasite detection — Trypanosomes may be visualized in tissue (lymph node or chancre aspirate) or body fluids (blood or cerebrospinal fluid). The morphologic appearances of T. b. rhodesiense and T. b. gambiense are identical; in general, the infections are differentiated based on geographic exposure.
Tissue aspirate — A lymph node aspirate is a traditional diagnostic and screening tool for gambiense HAT, which is more commonly associated with lymphadenopathy than rhodesiense HAT. If enlarged cervical lymph nodes are present, we favor pursuing aspiration (picture 5); the technique is relatively simple and may be diagnostic even if blood examination is unrevealing.
The lymph node aspirate may demonstrate motile parasites on direct microscopy of a wet mount with ground-glass illumination; trypanosomes may also be seen after fixation and staining with Giemsa. The sensitivity of this technique is variable (19 to 77 percent) but highest during early infection [79-82].
For patients with a trypanosomal chancre (more common among travelers than among individuals in endemic areas), chancre aspirate may demonstrate trypanosomes before they are detectable in blood; either wet preparation or fixation and staining may be performed.
Blood examination
Direct smear — Trypanosomes may be visualized on direct thin blood smear preparations or on Giemsa-stained thin or thick smears (picture 1 and picture 2). However, the sensitivity of a smear is much lower than that of a concentrated specimen.
For diagnosis of gambiense HAT, a smear should be performed only if concentration techniques are not available. The sensitivity of thick smears is 27 to 35 percent; the sensitivity of thin smears is 4 to 22 percent [79,80]. This is because gambiense HAT is generally associated with a lower level of parasitemia (often below the detection limit of 5000 parasites/mL for thick smears). Specimen concentration may be used to increase the likelihood of diagnosis. (See 'Concentrated specimens' below.)
For diagnosis of rhodesiense HAT, trypanosomes are usually readily detected in stained thin or thick films or wet preparations of blood [44]. The sensitivity of smears for diagnosis of rhodesiense HAT is not well studied. In the setting of persistent symptoms but absence of trypanosomes on serial blood smears, clinical suspicion for rhodesiense HAT should be diminished and alternative diagnoses should to be considered.
Some cases of smear-negative, culture-positive HAT have been observed [83]; however, culture of trypanosomes in liquid culture medium remains a research tool.
There is no role for serial smears to monitor for clearance of parasitemia.
Concentrated specimens — The sensitivity of microscopy may be improved by concentrating the specimen. This approach is most useful for diagnosis of gambiense HAT (given relatively low parasitemia with this species) and in the context of elimination programs in endemic areas [84-86]. Concentration techniques are rarely used for diagnosis of rhodesiense HAT since direct smear is usually sufficient for diagnosis. (See 'Direct smear' above.)
Tools for concentration include anion exchange centrifugation, hematocrit centrifugation, and buffy coat separation:
●Mini anion-exchange centrifugation technique (mAECT) − mAECT is a method for separation of red blood cells and trypanosomes; the charge difference around a pH of 8 allows chromatographic separation on diethylaminoethyl cellulose [87,88]. The technique is demonstrated in an online video. Blood for mAECT should be collected in heparin; the charge of other anticoagulants may inhibit binding of red blood cells to the cellulose.
The sensitivity of mAECT for diagnosis of gambiense HAT is 75 to 85 percent and may reach more than 90 percent by applying the buffy coat obtained after centrifuging ≤10 mLs of blood [79-82]. Ready-to-use mAECT columns are produced in the Democratic Republic of Congo and Côte d’Ivoire for use in endemic areas; outside these areas, mAECT is performed only in specialized laboratories.
●Microhematocrit centrifugation technique (mHCT) − To perform mHCT, blood is centrifuged in capillary tubes for 5 minutes at 12,000 rpm, resulting in separation of the red blood cells from white blood cells and trypanosomes. The buffy coat layer consists of white blood cells; trypanosomes are localized within or on top of this layer. The trypanosomes may be recognized under the microscope by their characteristic movement. When performed by an experienced microscopist, the sensitivity of this technique for diagnosis of gambiense HAT is approximately 50 percent [79,80,82]. The cost of this technique is relatively low and it is commonly used in T. b. gambiense endemic areas.
●Quantitative buffy coat technique − The quantitative buffy coat technique is a variation of the mHCT. It utilizes acridine orange in the capillary tube, which binds to the trypanosomes kinetoplast and nucleus, resulting in improved parasite visualization [84]. This technique is rarely used in endemic areas due to cost.
Cerebrospinal fluid — For patients with established HAT, CSF examination may be needed to guide the management approach (algorithm 3) (see "Human African trypanosomiasis: Treatment and prevention"):
●For gambiense HAT in settings where fexinidazole is available, CSF examination is warranted for patients with symptoms and signs consistent with severe second-stage disease (table 3) [1]. CSF examination is also warranted for all patients <6 years or <20 kg.
●For gambiense HAT in settings where fexinidazole is not available, CSF examination is warranted to differentiate between first-stage (defined by ≤5 white blood cell (WBC)/microL of CSF and no trypanosomes in CSF) and second-stage disease (>5 WBC/microL of CSF or trypanosomes in CSF).
●For rhodesiense HAT, CSF examination is needed to differentiate between first-stage (≤5 WBC/microL of CSF and no trypanosomes in CSF) and second-stage disease (>5 WBC/microL of CSF or trypanosomes in CSF).
Given that trypanosomes are commonly detected on blood smear in the setting of rhodesiense HAT, a dose of suramin is often administered prior to lumbar puncture to reduce parasitemia and minimize the theoretic risk of iatrogenic introduction of trypanosomes into the CSF (in case of a traumatic lumbar puncture) [89].
Trypanosomes are generally scanty in CSF but may be observed on direct examination or following concentration by centrifugation [90]. In gambiense HAT, the sensitivity of direct trypanosome detection in CSF (by observation in the cell counting chamber or on smears) is around 10 percent; this is a reflection of the relatively low parasitemia observed for this species [79]. Following CSF centrifugation, a diagnostic sensitivity of 18 to 79 percent has been observed [82,90].
For patients with suspected gambiense HAT (based on the combination of epidemiologic exposure, clinical manifestations, serologic screening, and other diagnostic test results if available, but unremarkable lymph node aspirate and concentrated blood specimen), CSF examination may be used to detect trypanosomes and establish a definitive diagnosis of HAT. While the sensitivity of CSF examination may appear low, CSF centrifugation followed by visualization of CSF trypanosomes has facilitated diagnosis of gambiense HAT in patients with negative blood examinations in a small number of cases (4 to 8 percent) [79,82].
Second-stage HAT is usually associated with CSF WBC counts below 200 cells/microL (typically lymphocyte predominant, with occasional eosinophils); however, levels as high as 2000 cells/microL may be observed. A correlation between CSF WBC (especially ≥100 WBC/microL) and occurrence of neurologic signs and symptoms has been described [47].
There is often a moderate elevation in protein concentration (overall range approximately 350 mg/L up to 2000 mg/L) [91,92], which may be observed in first-stage or second-stage HAT [93]. Glucose is typically normal or only modestly decreased. Elevated intracranial pressure may develop.
Intrathecal synthesis of IgM in second stage results in a characteristic 40-fold increase in CSF IgM (up to 300 mg/L), and three- to fourfold elevations in IgG and IgA [93]. A characteristic CSF finding associated with second-stage HAT is the presence of Mott cells (picture 7); these are large activated plasma cells with IgM-containing eosinophilic inclusions [92,94,95]. The CSF lactate concentration is normal to slightly increased (<3.5 mmol/L).
Neopterin, a marker for cellular immune activation, is largely a research tool and intrathecal inflammation in second-stage gambiense HAT may be accompanied by a rise in neopterin (>14.3 nmol/L) [56,92,96,97].
Additional tools outside endemic areas — Additional tools outside endemic areas include radiographic imaging, electroencephalogram (EEG), and molecular tests:
●Data on magnetic resonance imaging (MRI) findings of HAT are limited [98-100]. In some cases, T2-weighted MRI scans show hyperintense signals in frontal cortical and periventricular white matter, together with involvement of basal ganglia and cerebellum [98]. Another report noted multiple lesions in white and central gray matter and cortex [99]. Resolution of radiographic abnormalities may take many months or longer.
●Patients with neurologic involvement often have abnormal EEGs, usually demonstrating slow wave oscillations (delta waves) [40]. However, this is a nonspecific finding [40].
●Molecular techniques for HAT diagnosis include polymerase chain reaction and loop-mediated isothermal amplification. The sensitivity and specificity of these tests in research laboratories is around 90 percent [101-104]; their diagnostic performance in the context of a clinical laboratory requires further evaluation [105]. Newly emerging and promising molecular tools include reverse transcriptase quantitative polymerase chain reaction, multiplexing, and specific high-sensitivity enzymatic reporter unlocking [106-108]. These molecular tools are rarely used in most endemic settings; they are costly, time consuming, and require specialized equipment and personnel. In settings where available, it may be used to complement serologic or parasitologic diagnosis to increase suspicion for HAT [109].
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of HAT includes:
●Bacterial meningitis – Meningitis is characterized by acute onset of fever, nausea, vomiting, headache, confusion, and myalgia. In meningococcal infection, nonblanching purpuric rash may be observed. The infection is transmitted by person-to-person contact and occurs worldwide; the highest rate of meningococcal infection is in the meningitis belt of sub-Saharan Africa (from Senegal in the west to Ethiopia in the east). The incubation period is 2 to 10 days, and the diagnosis is established via culture of blood or spinal fluid, agglutination tests, or polymerase chain reaction. (See "Clinical features and diagnosis of acute bacterial meningitis in adults".)
●Malaria – Malaria is characterized by fever, malaise, nausea, vomiting, abdominal pain, diarrhea, myalgia, and anemia. Cerebral malaria is an encephalopathy that presents with impaired consciousness, delirium, and/or seizures; focal neurologic signs are unusual. Malaria is transmitted by Anopheles mosquitoes. The incubation period of malaria due to Plasmodium falciparum is usually 7 to 30 days (but may be longer). The diagnosis of malaria is established by visualization of parasites on peripheral smear and/or rapid antigen tests. (See "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children" and "Laboratory tools for diagnosis of malaria".)
●HIV infection – Acute HIV infection is commonly characterized by fever, lymphadenopathy, sore throat, rash, myalgia/arthralgia, and headache. The infection is transmitted sexually, and infection occurs worldwide. The incubation period is two to four weeks. The diagnosis is established via immunoassay and assessed using viral load. (See "Acute and early HIV infection: Clinical manifestations and diagnosis".)
●Tuberculosis – Tuberculosis (TB) is characterized by cough >2 to 3 weeks' duration, lymphadenopathy, fevers, night sweats, and weight loss. Manifestations of TB involving the central nervous system (CNS) include headache, malaise, and altered mental status; late manifestations include cranial nerve palsies, seizures, and coma. Transmission is human to human, and infection occurs worldwide. The incubation period is at least three months. Diagnostic evaluation begins with chest radiography, followed by sputum acid-fast bacilli smear and nucleic acid amplification testing. The diagnosis of CNS TB is established by spinal fluid examination. (See "Diagnosis of pulmonary tuberculosis in adults" and "Central nervous system tuberculosis: An overview".)
●Cryptococcal meningitis – Cryptococcal meningitis often presents subacutely and may be associated with cranial neuropathies. Immunosuppression (due to HIV infection or other causes) is an important risk factor. The cerebrospinal fluid (CSF) profile classically demonstrates elevated opening pressure, low white blood cell count with a mononuclear predominance, slightly elevated protein concentration, and low glucose concentration. Definitive diagnosis is made by CSF culture; a positive cryptococcal antigen in the CSF or serum strongly suggests the presence of infection. (See "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV" and "Clinical manifestations and diagnosis of Cryptococcus neoformans meningoencephalitis in patients without HIV".)
●Toxoplasmosis – Cerebral toxoplasmosis is the most common CNS infection in patients with HIV/AIDS and CD4 <100 cells/microL who are not receiving appropriate prophylaxis. Clinical manifestations include headache, altered mental status, fever, focal neurologic deficits, and seizures. Transmission is via ingestion of infectious oocysts or undercooked meat from an infected animal. The diagnosis is usually presumptive in the setting of CD4 <100 cells/microL, positive Toxoplasma gondii serology, and ring-enhancing lesions on brain imaging. (See "Toxoplasmosis in patients with HIV".)
●CNS lymphoma – HIV-related primary CNS lymphoma is an AIDS-defining malignancy that is strongly related to Epstein-Barr virus infection and immunosuppression. Symptoms may include headache, blurred vision, motor difficulties, and personality changes. The diagnosis is established by biopsy. (See "HIV-related lymphomas: Primary central nervous system lymphoma".)
●Neurosyphilis – Forms of neurosyphilis include meningitis and meningovascular disease; infection may be asymptomatic in some cases. Symptomatic syphilitic meningitis is typically manifested by headache, confusion, nausea and vomiting, and stiff neck. Visual acuity may be impaired and/or cranial neuropathies may be present. Syphilitic meningitis can cause an infectious arteritis that may affect vessels in the subarachnoid space resulting in thrombosis, ischemia, and stroke. The diagnosis is established with serum treponemal testing and spinal fluid examination with CSF Venereal Disease Research Laboratory test. (See "Neurosyphilis".)
●Enteric fever – Enteric fever refers to both typhoid fever (caused by Salmonella enterica serotype Typhi [formerly S. typhi]) and paratyphoid fever (caused by S. enterica serotype Paratyphi A, B, and C worldwide). Enteric fever is characterized by abdominal pain, fever, and chills. Classic manifestations include relative bradycardia, pulse-temperature dissociation, and "rose spots" (faint salmon-colored macules on the trunk and abdomen). Hepatosplenomegaly, intestinal bleeding, and perforation may occur, leading to secondary bacteremia and peritonitis. Patients with severe enteric fever may develop "typhoid encephalopathy," with altered consciousness, delirium, and confusion. Transmission is fecal-oral; the incubation period is 6 to 30 days. The diagnosis is established via culture of blood, stool, or other specimens. (See "Enteric (typhoid and paratyphoid) fever: Epidemiology, clinical manifestations, and diagnosis".)
●Psychiatric illness – HAT may be misdiagnosed as psychiatric illness, especially in individuals living in nonendemic countries, when epidemiologic exposure is not recognized.
●Viral hemorrhagic fever – Viral hemorrhagic fevers include Lassa, Ebola, Marburg, Crimean-Congo hemorrhagic fever, and yellow fever. In general patients present abrupt onset of nonspecific symptoms and signs, such as fever, malaise, headache, and myalgias. Vomiting and diarrhea may occur, often leading to significant fluid loss. Patients with worsening disease display hypotension and electrolyte imbalances leading to shock and multiorgan failure, sometimes accompanied by hemorrhage. These manifestations may occur in the setting of rhodesiense HAT. (See related topics).
●Other dermatologic conditions − A trypanosomal chancre may be misidentified as an insect or arachnid bite, bacterial cellulitis, or eschar. A trypanosomal chancre is not associated with necrosis and is usually larger than the eschar observed in the setting of African tick bite fever. (See "Insect and other arthropod bites" and "Cellulitis and skin abscess: Epidemiology, microbiology, clinical manifestations, and diagnosis" and "Other spotted fever group rickettsial infections", section on 'R. africae (African tick bite fever)'.)
SUMMARY
●Epidemiology – Human African trypanosomiasis (HAT), also known as sleeping sickness, is caused by protozoan parasites transmitted by tsetse flies. There are two forms of the disease: an acute form occurring mainly in East and Southern Africa and caused by Trypanosoma brucei rhodesiense (rhodesiense HAT) and a more chronic form occurring mainly in West and Central Africa caused by Trypanosoma brucei gambiense (gambiense HAT) (table 1 and figure 1). (See 'Introduction' above and 'Epidemiology' above.)
●Disease stages – The incubation period of gambiense HAT is variable, with a range of weeks or months; the disease is usually slowly progressive, with an oligosymptomatic phase that may last months or years. The incubation period of rhodesiense HAT is less than three weeks, and the disease is usually rapidly progressive within weeks. There are two stages of HAT infection. (See 'Disease stages' above.)
•First stage – In the first stage, trypanosomes penetrate the skin and circulate in the blood and lymphatics. The first sign of HAT infection may a chancre at the site of the tsetse bite. In gambiense infection, lymphadenopathy typically occurs in the posterior cervical nodes. In rhodesiense infection, lymphadenopathy occurs less frequently; when present, it occurs more commonly in the submandibular, axillary, or inguinal regions than in the cervical region. Additional early HAT symptoms include intermittent fever, headache, malaise, and musculoskeletal pain. (See 'First stage: Hemo-lymphatic disease' above.)
•Second stage – The second stage consists of central nervous system involvement, defined by cerebrospinal fluid (CSF) white blood cell (WBC) count >5 cells/microL. For gambiense HAT, an additional subcategory, severe second-stage disease, was established in the World Health Organization 2019 guidelines; this is defined as ≥100 WBC/microL in CSF (with or without trypanosomes in CSF). Such staging is important for guiding management, since fexinidazole is less efficacious in patients with CSF WBC ≥100 cells/microL. Clinical manifestations consistent with severe second-stage HAT are summarized in the table (table 3). (See 'Second stage: Meningo-encephalitis' above.)
●Clinical approach to diagnosis – A definitive diagnosis of HAT requires demonstration of trypanosomes in body fluids (blood and/or CSF) or tissues (lymph node or chancre aspirate) via microscopy. (See 'Clinical approach' above.)
•In endemic areas, the diagnosis of gambiense HAT should be suspected in individuals with epidemiologic exposure; in such cases, HAT is most frequently diagnosed in the context of screening; patients may or may not be symptomatic. Outside endemic areas, the diagnosis of gambiense HAT should be suspected in individuals with epidemiologic exposure (travel to an endemic area) in the setting of relevant signs or symptoms (early symptoms of fever, trypanosomal chancre or rash, headache, arthralgia, and lymphadenopathy; later symptoms of neurologic manifestations). (See 'Gambiense HAT' above.)
•Diagnostic evaluation for gambiense HAT begins with serologic assessment using a rapid diagnostic test; these include the card agglutination test for trypanosomiasis or rapid lateral flow tests (algorithm 1). Patients with a positive serologic test should undergo confirmatory testing. Those with lymphadenopathy warrant lymph node aspiration with examination for parasites. If there is no lymphadenopathy, or the lymph node aspirate does not demonstrate trypanosomes, patients should undergo blood examination using a concentration technique; tools include microhematocrit centrifugation technique and mini anion-exchange centrifugation technique. Indications for CSF examination depend on findings of initial diagnostic evaluation, clinical manifestations, and the available treatment options. (See 'Gambiense HAT' above.)
•The diagnosis of rhodesiense HAT should be suspected in individuals with epidemiologic exposure (travel to or residence in an endemic area), in the setting of relevant signs or symptoms (early symptoms of fever, trypanosomal chancre or rash, headache, arthralgia, lymphadenopathy; later symptoms of neurologic manifestations). The diagnosis of rhodesiense HAT can often be made via blood smear or chancre fluid; additional blood examination may be helpful in some cases (algorithm 2). (See 'Rhodesiense HAT' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Dr. Karin Leder, MBBS, FRACP, PhD, MPH, DTMH, Dr. Peter Weller, MD, MACP, and Dr. August Stich, MD, MSc, DTMH, who contributed to earlier versions of this topic review.
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