Patient with sleeping sickness
Human African trypanosomiasis, also known as sleeping sickness, is a vector-borne parasitic disease. It is caused by infection with protozoan parasites belonging to the genus Trypanosoma. They are transmitted to humans by tsetse fly ( Glossina genus) bites which have acquired their infection from human beings or from animals harboring human pathogenic parasites.
Tsetse flies are found just in sub-Saharan Africa though only certain species transmit the disease. For reasons that are so far unexplained, in many regions where tsetse flies are found, sleeping sickness is not. Rural populations living in regions where transmission occurs and which depend on agriculture, fishing, animal husbandry or hunting are the most exposed to the tsetse fly and therefore to the disease. The disease develops in areas ranging from a single village to an entire region. Within an infected area, the intensity of the disease can vary from one village to the next.
Infection and symptoms
The disease is mostly transmitted through the bite of an infected tsetse fly but there are other ways in which people are infected:
- Mother-to-child infection: the trypanosome can cross the placenta and infect the fetus.
- Mechanical transmission through other blood-sucking insects is possible, however, it is difficult to assess its epidemiological impact.
- Accidental infections have occurred in laboratories due to pricks with contaminated needles.
- Transmission of the parasite through sexual contact has been reported.
In the first stage, the trypanosomes multiply in subcutaneous tissues, blood and lymph. This is also called haemo-lymphatic stage, which entails bouts of fever, headaches, enlarged lymph nodes, joint pains and itching
In the second stage the parasites cross the blood-brain barrier to infect the central nervous system. This is known as the neurological or meningo-encephalic stage. In general this is when more obvious signs and symptoms of the disease appear: changes of behaviour, confusion, sensory disturbances and poor coordination. Disturbance of the sleep cycle, which gives the disease its name, is an important feature. Without treatment, sleeping sickness is considered fatal although cases of healthy carriers have been reported.
Disease management: diagnosis
Disease management is made in 3 steps:
- Screening for potential infection. This involves using serological tests (only available for T. b.gambiense) and checking for clinical signs – especially swollen cervical lymph nodes.
- Diagnosing by establishing whether the parasite is present in body fluids.
- Staging to determine the state of disease progression. This entails clinical examination and in some cases analysis of the cerebrospinal fluid obtained by lumbar puncture.
Diagnosis must be made as early as possible to avoid progressing to the neurological stage in order to elude complicated and risky treatment procedures
The long, relatively asymptomatic first stage of T. b. gambiense sleeping sickness is one of the reasons why an exhaustive, active screening of the population at risk is recommended, to identify patients at an early stage and reduce transmission by removing their status of reservoir. Exhaustive screening requires a major investment in human and material resources. In Africa such resources are often scarce, particularly in remote areas where the disease is mostly found. As a result, some infected individuals may die before they can ever be diagnosed and treated.
The type of treatment depends on the form of the disease and the disease stage. The earlier the disease is identified, the better the prospect of a cure. The assessment of treatment outcome requires follow up of the patient up to 24 months and entails clinical assessment and laboratory exams of body fluids including in some cases, cerebrospinal fluid obtained by lumbar puncture, as parasites may remain viable for long periods and reproduce the disease months after treatment.
Treatment success in the second stage depends on drugs that cross the blood-brain barrier to reach the parasite.
New treatment guidelines for gambiense human African trypanosmiasis were issued by WHO in 2019. In total six different drugs are used for the treatment of sleeping sickness. These drugs are donated to WHO by manufacturers and distributed free of charge to disease endemic countries.
Drugs used in the treatment of first stage:
- Pentamidine: discovered in 1940, used for the treatment of the first stage of T. b. gambiense sleeping sickness. Despite non-negligible undesirable effects, it is in general well tolerated by patients.
- Suramin: discovered in 1920, used for the treatment of the first stage of T. b. rhodesiense. It provokes certain undesirable effects, including nephrotoxicity and allergic reactions.
Drugs used in the treatment of second stage:
- Melarsoprol: discovered in 1949, it is used for the treatment of both gambiense and rhodesiense infections. It is derived from arsenic and has many undesirable side effects, the most dramatic of which is reactive encephalopathy (encephalopathic syndrome) which can be fatal (3% to 10%). It is currently recommended as first-line treatment for the rhodesiense form, but rarely used in the gambiense form.
- Eflornithine: much less toxic than melarsoprol, registered in 1990 is only effective against T.b. gambiense. It is generally used in combination with nifurtimox (as part of the Nifurtimox-eflornithine combination therapy, NECT) but can be used also as monotherapy. The regimen is complex and cumbersome to apply.
- Nifurtimox: The Nifurtimox-eflornithine combination therapy, NECT, was introduced in 2009. It simplifies the use of eflornithine by reducing the duration of treatment and the number of IV perfusions, but unfortunately it has not been studied for T.b. rhodesiense. Nifurtimox is registered for the treatment of American trypanosomiasis but not for human African trypanosomiasis. Both drugs are provided free of charge by WHO to endemic countries with a kit containing all the material needed for its administration.
Drugs used in the treatment of both stages:
Fexinidazole is an oral treatment for gambiense human African trypanosomiasis It was included in 2019 in the WHO Essential medicines list and WHO human African Trypanosomiasis treatment guidelines. This molecule is indicated as first line for first stage and non-severe second stage. It should be administered for 10 days within 30 minutes after a solid meal and under supervision of trained medical staff. Currently a clinical trial for its use in rhodesiense HAT is ongoing.