African trypanosomiasis is an insect-borne parasitic infection of humans and other animals caused by the protozoan species Trypanosoma brucei, which is transmitted by the bite of an infected tsetse fly. Human African trypanosomiasis (HAT) is also known as sleeping sickness. Humans are infected by two subspecies of T. brucei: T. brucei gambiense is primarily transmitted between humans and causes over 92% of cases, while T. brucei rhodesiense is zoonotic, with animals such as cattle serving as reservoirs.NCBI. Human African Trypanosomiasis. 2024.
During the first stage of the disease, T. brucei parasites replicate in the blood and lymph, causing fever, headache, itchiness, and joint pains about one to three weeks after the bite. Weeks to months later, the parasite crosses the blood–brain barrier and the second stage begins with neurological symptoms including confusion, poor coordination, numbness, and trouble sleeping. Without treatment, African trypanosomiasis almost always results in death. Diagnosis involves detecting the parasite in a blood smear or lymph node fluid. A lumbar puncture is often needed to tell the difference between first- and second-stage disease. T. brucei gambiense causes chronic infection that can take months to years to develop symptoms, while T. brucei rhodesiense infection causes symptoms within weeks to months.
Prevention involves avoiding tsetse fly bites, for example by the use of insect repellents and protective clothing. Vector control measures, such as spraying insecticides and releasing sterilized tsetse flies in endemic areas, have significantly reduced the incidence of disease. Screening the at-risk population with blood tests for T. brucei gambiense can prevent the development of severe disease. Treatment is easier when the disease is detected early and before neurological symptoms begin. The use of pentamidine or suramin treats the first stage of T. brucei infection, but if the disease progresses to the neurological stage, dosages of eflornithine or a combination of nifurtimox and eflornithine are the preferred treatment. Fexinidazole is a more recent treatment that can be taken by mouth for either stage of T. brucei gambiense. While melarsoprol works for both types of sleeping sickness, it is typically used only for T. brucei rhodesiense, due to its serious side effects.
The disease occurs regularly in some regions of sub-Saharan Africa with the population at risk being about 70 million in 36 countries. An estimated 11,000 people are currently infected with 2,800 new infections in 2015. In 2024, there were 583 confirmed cases recorded. In 2015, it caused around 3,500 deaths, down from 34,000 in 1990. More than 80% of these cases are in the Democratic Republic of the Congo. Three major outbreaks have occurred in recent history: one from 1896 to 1906 primarily in Uganda and the Congo Basin, and two in 1920 and 1970, in several African countries. It is classified as a neglected tropical disease. Other animals, such as cows, may carry the disease and become infected in which case it is known as nagana or animal trypanosomiasis.
Risk factors Risk factors include living in or traveling to rural areas of sub-Saharan Africa where tsetse flies are present. Occupations such as farming, fishing, and hunting increase exposure risk.WHO. Sleeping sickness fact sheet. 2023.
Signs and symptoms African trypanosomiasis symptoms occur in two stages: 1) the hemolymphatic stage and 2) the neurological or meningoencephalitic stage. The hemolymphatic stage is to the period when parasites are present in the blood and lymphatic system, prior to central nervous system involvement. The neurological stage, also called the meningoencephalitic stage, begins when Trypanosoma parasites cross the blood–brain barrier and invade the central nervous system. In addition to the hemolymphatic stage neurological symptoms can still present themselves, resulting in a difficulty in distinguishing the two stages based on clinical features alone.
The disease has been reported to present with atypical symptoms in infected individuals who originate from non-endemic areas (e.g., travelers). In such persons, the infection is said to present mainly as fever with gastrointestinal symptoms (e.g., diarrhea and jaundice) and with lymphadenopathy rarely developing. An earlier study noted a greater dominance of the neurological symptoms, and also reported the presence of jaundice. The reasons for this are unclear and may be genetic or linked to a lack of previous exposure to forms of trypanosomes not pathogenic to humans. The low number of such cases may also have skewed findings. These symptomatological differences have resulted in delayed or missed diagnosis.
Trypanosomal ulcer
Systemic disease is sometimes presaged by a trypanosomal ulcer developing at the site of the infectious fly bite within 2 days of infection. The ulcer is most commonly observed in T. b. rhodesiense infection and rarely in T. b. gambiense infection, where ulcers are more common in persons from non-endemic areas.
Hemolymphatic stage The incubation period is 1–3 weeks for T. b. rhodesiense, and longer (but less precisely characterised) in T. b. gambiense infection. The first/initial stage, known as the hemolymphatic stage, is characterized by non-specific, generalised symptoms like: fever (intermittent), headaches (severe), joint pains, itching, weakness, malaise, fatigue, weight loss, lymphadenopathy, and hepatosplenomegaly.
Diagnosis may be delayed due to the vagueness of initial symptoms. The disease may also be mistaken for malaria (which may occur as a co-infection).
Intermittent fever
Fever is intermittent, with attacks lasting from a day to a week, separated by intervals of a few days to a month or longer. Episodes of fever become less frequent throughout the disease.
Lymphadenopathy
Invasion of the circulatory and lymphatic systems by the parasite is associated with severe swelling of lymph nodes, often to tremendous sizes. Posterior cervical lymph nodes are most commonly affected; however, axillary, inguinal, and epitrochlear lymph node involvement may also occur. Winterbottom's sign is a clinical finding involving swollen lymph nodes at the base of the skull or along the back of the neck, particularly characteristic of T. b. gambiense infections.
Other features
Those affected may additionally present with: skin rash, haemolytic anaemia, hepatomegaly and abnormal liver function, splenomegaly, endocrine disturbance, cardiac involvement (e.g., pericarditis and congestive heart failure), and ophthalmic involvement.
Neurological stage The second stage of the disease, the neurological stage (also called the meningoencephalic stage), begins when the parasite invades the central nervous system by passing through the blood–brain barrier. Progression to the neurological stage occurs after an estimated 21–60 days in case of T. b. rhodesiense infection, and 300–500 days in case of T. b. gambiense infection.
In actuality, the two stages of African trypanosomiasis—the hemolymphatic stage and the neurological stage—often overlap, and their clinical features can be nonspecific or evolve gradually, making it difficult to distinguish them based on symptoms alone. While signs such as enlarged lymph nodes and intermittent fever are more characteristic of the early stage, and neuropsychiatric symptoms such as sleep disturbances, confusion, or motor abnormalities suggest progression to the later stage, these indicators are not definitive. Consequently, to accurately determine the stage of the disease, specifically to determine central nervous system involvement, a lumbar puncture is performed to analyze the cerebrospinal fluid (CSF). The detection of trypanosome parasites in the CSF confirms that the infection has progressed to the neurological stage. This assessment is crucial because treatment protocols differ depending on whether or not the central nervous system has been affected. In the later stage, more intensive drugs that can cross the blood-brain barrier are necessary to eliminate the parasites from the brain and spinal cord.
Sleep disorders Sleep-wake disturbances are a leading feature of the neurological stage and give the disease its common name of "sleeping sickness". Infected individuals experience a disorganized and fragmented sleep-wake cycle. Those affected experience sleep inversion resulting in daytime sleep and somnolence, and nighttime periods of wakefulness and insomnia. Additionally, those affected also experience episodes of sudden sleepiness.
This sleeping impairment is also related to disruptions of circadian rhythm, the body's internal clock, which regulates rhythmic behavior, including metabolic patterns in cells. Studies indicate T. brucei alters the oscillatory expression of clock genes in the suprachiasmatic nuclei (SCN), among other brain regions, charged with circadian regulation. This alteration of expression may be moderated by the host's immune responses, such as parasitic activity and inflammation resulting from elevated TNF-α levels.
Neurological symptoms
Neurological symptoms include: tremor, general muscle weakness, hemiparesis, paralysis of a limb, abnormal muscle tone, gait disturbance, ataxia, speech disturbances, paraesthesia, hyperaesthesia, anaesthesia, visual disturbance, abnormal reflexes, seizures, and coma. Parkinson-like movements might arise due to non-specific movement disorders and speech disorders.
Psychiatric symptoms
Individuals may exhibit psychiatric symptoms, which can sometimes dominate the clinical presentation. These symptoms include aggressiveness, apathy, irritability, psychotic reactions and hallucinations, anxiety, emotional lability, confusion, mania, attention deficit, and delirium.
Advanced disease and outcomes Without treatment, the disease is invariably fatal, with progressive mental deterioration leading to coma, systemic organ failure, and death. An untreated infection with T. b. rhodesiense will cause death within months whereas an untreated infection with T. b. gambiense will cause death after several years. Damage caused in the neurological stage is irreversible.
Circadian rhythm interactions
Circadian rhythm, an intrinsic clock that mediates rhythm of biological function, is affected by African trypanosomiasis. T. brucei alters the rhythmic activity of clock genes in basal forebrain, hypothalamus, thalamus, locus coeruleus, brainstem, etc. . Both parasitic activity and inflammation induced by elevated TNF-α levels impairs oscillatory expression within the host. These disruptions to regulate circadian gene expression are evidenced to contribute to key symptoms of African trypanosomiasis, such as fragmented sleep, temperature changes, and abnormal hormone release.
Effect on circadian rhythm Most organisms implement internal timing mechanisms to regulate the homeostasis of the body with the environment. These mechanisms, called circadian clocks, regulate pathways in core processes, where in mammals the primary circadian clock is the suprachiasmatic Nucleus (SCN). The SCN's ability to serve as the organism's primary internal clock and send signals to adjacent clocks to collectively synchronize them can be affected by a variety of factors. Certain factors that induce inflammation, such as viruses, bacteria, or parasites, can disrupt the interactions between a cell's circadian clock and the central pacemaker. In the case of Trypanosoma brucei, the parasite attacks the internal clock of the cells.
African sleeping sickness mainly disrupts the sleep/wake cycle alongside body temperature and hormonal regulation. After treatment, the sleep-wake cycle can revert to normal, indicating that the parasites are responsible for circadian rhythm alteration rather than neuronal damage.