A neglected disease

Benjamin Jelle Visser

 

This Global Medicine’s Neglected Disease is human African trypanosomiasis (HAT), also known as sleeping sickness. HAT is a vectorborne parasitic disease that exists exclusively in Africa. 

Typology

There are two forms of HAT, one of which is endemic mainly in East Africa and is caused by Trypanosoma brucei rhodesiense. This form represents less than 10% of the reported cases of sleeping sickness. The other form is endemic mainly in West and Central Africa and is caused by Trypanosoma brucei gambiense. This form represents more than 90% of the reported cases in Africa. These protozoan parasites are both transmitted by the tsetse fly (Glossina Genus), which name refers to the sound it makes. The two trypanosome species have indistinguishable morphologic appearances. However, the infections differ in clinical presentation, prognosis and treatment.

Epidemiology

Sleeping sickness occurs in 36 sub-Saharan countries within the habitat of the tsetse fly. About 60 million people are at risk of acquiring the disease. Countries particularly affected include Sudan, the Democratic Republic of Congo (ex-Zaire), Angola, Uganda and Tanzania (figure 1). The resurgence of sleeping sickness in the past few years has been facilitated by civil war, emigration, economic crisis, reduced health financing and a lack of human resources in these areas.

According to WHO estimates, at least 300 000 to 500 000 people are presently infected and 100 000 deaths can be attributed to HAT each year. Sleeping sickness is also reported more frequently among tourists, especially among those traveling to wild park areas near Lake Victoria, to the Tarangire, Serengeti en Lake Manyara National Parks, all of which are located in east Africa.

 

 

Transmission

Transmission usually takes place through a bite of the tsetse fly. Tsetse flies are prevalent in warm, shaded places of vegetation alongside rivers and lakes, in forests and in vast stretches of wooded savannah. Therefore, rural African populations that depend on fishing, agriculture, cattle breeding or hunting and that live in regions where transmission occurs are at the highest risk of becoming infected. People are often bitten during activities such as bathing and washing.

In west African HAT humans are the main reservoir for T. b. gambiense, whereas in east African wild animals are the reservoir for T. b. rhodesiense. Hence, east African HAT is a zoonotic disease, a difference which has important consequences for for instance strategies to control the disease.

Besides transmission via the bite of the tsetse fly, mother-to-child transmission can also occur. The parasite can cross the placenta and infect the fetus, leading to death or congenital deformities. Also, accidental infections have been reported due to accidents with contaminated needles.

Clinical features

Any bite from a tsetse fly, whether the fly is infected or not, produces a local reaction. Since the bite can be painful, patients may have noticed the exposure. When the bite is infected, a small local wound typically appears approximately after 5-15 days. A well-circumscribed, rubbery, painful papule, with a central blister or ulcer develops, surrounded by red infiltrated skin. This typical skin lesion is called a trypanosomal chancre. The diameter can range from 2-5 centimeters and is described at a frequency of 40-50% of the patients. After healing, which usually takes about a month, a depigmented scar can remain.

Both T. b. gambiense and T. b. rhodesiense infections are characterized by an early stage, the preliminary haematolymphatic stage, during which trypanosomes are found circulating in the blood and in lymph nodes, and a second (late) stage, with symptoms of meningoencephalitis. The differentiation between these stages is made by finding the parasite in the cerebrospinal fluid. This distinction is important because of its consequences for treatment.

The first stage, the haematolymphatic stage, lasts 6 to 12 months or longer. It is characterized by irregular headaches, arthralgias, general malaise and intermittent peaks of pyrexia (fever), corresponding with successive waves of parasitaemia and antibody production. Trypanosomes travel from the skin to the regional lymphatics, where they cause lymph node swelling (lymphadenopathy).

In T.b. gambiense, lymphadenopathy is typically seen in the posterior cervical nodes. The nodes are soft, mobile and not painful, and are classically referred to as Winterbottom’s sign. The English doctor Thomas Masterman Winterbottom, who was working in Sierra Leone, first described the disease in 1803. He was struck by the abundant occurrence of swollen cervical lymph nodes in sick persons. Slave-traders at the time also knew about this sign and avoided buying people with cervical lymphadenopathy.

Besides lymphadenopathy there is organomegaly, in particular enlargement of the spleen. Other nonspecific symptoms may be present, including pruritus, anaemia, leukocytosis, weight loss, facial swelling and thrombocytopenia. Occasionally pancarditis develops, leading to arrhythmias and cardiac failure. There can also be endocrine involvement, leading to impotence in men and amenorrhea in women.

 

In the late stage of T.b. gambiense infection, which lasts three to six months, progressive diffuse meningoencephalitis and parenchymal edema of the brain develop, ultimately resulting in coma and death. Symptoms include headache, difficulty concentrating, personality changes, psychosis and sensory disorders. Basal ganglia involvement in the brain results in ataxia and tremors, which are similar to those seen in Parkinson’s disease. Damage to the hypothalamus leads to alteration of the circadian sleep/wake cycle. Consequently, patients develop daytime somnolence and nighttime insomnia. Hence the name Sleeping Sickness. The patient can still be woken up, but will quickly fall asleep again. Ultimately, the patient’s deterioration progresses to a stuporous state (coma).

In the T.b. rhodesiense infection, the same sequence of events is seen as in T.b. gambiense infection, but the presentation and progression are very fast, developing CNS signs within weeks. Both infections are fatal if untreated or when the trypanosomes are resistant to therapy.

Diagnosis

The diagnosis HAT is made on the basis of symptoms and laboratory test findings. A definite diagnosis is made by detection of the parasite. The parasite can be found in fluid from the inoculation chancre, blood (thin & thick smear), lymph node fluid (needle aspiration) or cerebrospinal fluid (lumbar puncture). Examination of the cerebrospinal fluid (CSF) is mandatory whenever the diagnosis of HAT is suspected, both to help to confirm the diagnosis and to stage the infection. Late stage HAT usually presents as CSF pleocytosis. A white blood cell count of ≥5 per mm or an abnormal protein concentration is considered evidence of central nervous system (CNS) involvement. An uncommon but for HAT characteristic finding in the CSF are Mott cells. These are thought to be large eosinophilic plasma cells containing IgM that have failed to secrete their antibodies. There are also diagnostic methods available for low-resource regions. A cheap and practical method is a direct agglutination reaction of trypanosomes on a plastic card, with macro-scopic read-off (CATT = Card Agglutination Test for Trypanosomiasis), which is based upon agglutination of freeze-dried trypanosomes in the presence of a variant-specific antibody. This is also a good screening method in population studies and an easy tool in control/prevention programs of the disease.

Treatment

Treatment differs for T.b. gambiense and T.b. rhodesiense infection, although there is some overlap. Treatment recommendations also vary according to the stage of the disease. During the first stage, treatment with suramin sodium or pentamidine is usually successful. In the second stage these drugs are considered ineffective, presumably because the blood-brain barrier prevents the drugs from reaching trypanocidal levels in the CSF. Melarsoprol is commonly used for treatment during this stage, but has severe side effects. It causes vomiting, abdominal pain, hepatotoxicity, peripheral neuropathy, paraplegia, cardiac arrhythmias and albuminuria. It is estimated that between 3-5% of those treated in the late stage of HAT die from side effects of the treatment itself. Eflornithine has been successfully used to treat patients in the second stage of T.b. gambiense disease, but does not seem to be effective against T.b. rhodesiense.

All drugs mentioned here are expensive. Therefore, many poor people are denied necessary treatment and die as a consequence.

Prevention

Chemoprophylaxis is not recommended, and no vaccine is available for HAT. Due to the recent resurgence of sleeping sickness, an effective control and surveillance program is a necessity. The two main tools available to prevent transmission are vector control and case finding and early treatment. Vector control makes use of impregnated traps and screens. Also, the release of sterile tsetse males has been attempted and has proven quite successful in several areas. Case detection and early treatment aims to reduce the human reservoir. Both measurements are incorporated in the WHO Control and Surveillance Program, which ultimately aims to eliminate sleeping sickness in Africa.

Through these control and surveillance programs, considerable progress has been made in some regions. Major epidemics however continue to occur. At present time, HAT is nowhere near elimination, let alone eradication, despite a number of WHO programs. Human African Trypanosomiasis remains a significant cause of burden of disease on the African continent. 

About the author

Benjamin Jelle Visser is a fourth year medical student from the University of Amsterdam.

Acknowledgement

I thank Mrs. A. Deems (University of Amsterdam) for her helpful comments on the manuscript. 

Further reading

• Kennedy PG.  The continuing problem of human African trypanosomiasis (sleeping sickness). Ann Neurol. 2008 Aug;64(2):116-26

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