Sandbox 2

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: sleeping sickness, Human African trypanosomiasis

Overview

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 harbouring 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.

Overview

African trypanosomiasis has been present in Africa since at least the 14th century, and probably for thousands of years before that. The causative agent and vector were not identified until 1902–1903 by Sir David Bruce, and the differentiation between protozoa was not made until 1910. The first effective treatment, Atoxyl, an arsenic based drug developed by Paul Ehrlich and Kiyoshi Shiga was introduced in 1910 but blindness was a serious side effect. Numerous drugs designed to treat the disease have been introduced since then.

There have been three severe epidemics in Africa over the last century: one between 1896 and 1906, mostly in Uganda and the Congo Basin, one in 1920 in several African countries, and one that began in 1970 and is still in progress. The 1920 epidemic was arrested due to mobile teams systematically screening millions of people at risk. The disease had practically disappeared between 1960 and 1965. After that success, screening and effective surveillance were relaxed and the disease has reappeared in endemic form in several foci over the last thirty years.

Historical Perspective

Drug Developments

Suramin was introduced in 1920 to treat the first stage of the disease. By 1922, Suramin was generally combined with Tryparsamide (another pentavalent organo-arsenic drug) in the treatment of the second stage of the gambiense form. It was used during the grand epidemic in West and Central Africa in millions of people and was the mainstay of therapy until 1969.

Pentamidine, a highly effective drug for the first stage of the disease, has been used since 1939. During the fifties, it was widely used as a prophylactic agent in Western Africa, leading to a sharp decline in infection rates. At the time, it was thought that eradication of the disease was at hand.

The organo-arsenical melarsoprol (Arsobal) was developed in the 1940s, and is effective for patients with second stage sleeping sickness. However, 3 - 10% of those injected have reactive encephalopathy (convulsions, progressive coma, or psychotic reactions), and 10 - 70% die; it can cause brain damage in those that survive the encephalopathy. However, due to its effectiveness, melarsoprol is still used today. Resistance to melarsoprol is increasing, and combination therapy with nifurtimox is currently under research.

Eflornithine (difluoromethylornithine or DFMO), the most modern treatment, was developed in the 1970s by Albert Sjoerdsmanot and underwent clinical trials in the 1980s. The drug was approved by the United States Food and Drug Administration in 1990, but Aventis, the company responsible for its manufacture, halted production in 1999. In 2001, however, Aventis, in association with Médecins Sans Frontières and the World Health Organization, signed a long-term agreement to manufacture and donate the drug.

Biological Understanding of African Trypanosomiasis

The genome of the parasite has been decoded and several proteins have been identified as potential targets for drug treatment. The decoded DNA also revealed the reason why generating a vaccine for this disease has been so difficult. T. brucei has over 800 genes that manufacture proteins that the disease mixes and matches to evade immune system detection.

Recent findings indicate that the parasite is unable to survive in the bloodstream without its flagellum. This insight gives researchers a new angle with which to attack the parasite.

A new treatment based on a truncated version of the apolipoprotein L-1 of high density lipoprotein and a nanobody has recently been found to work in mice, but has not been tested in humans.

Research

An international research team working in the Democratic Republic of the Congo, Southern Sudan and Angola involving Immtech International and University of North Carolina at Chapel Hill have completed a Phase IIb clinical trial and commenced a Phase III trial in 2005 testing the efficacy of the first oral treatment for Sleeping Sickness, known at this point as "DB289".

Pathophysiology

Transmission

• 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 documented.

Human African trypanosomiasis takes 2 forms, depending on the parasite involved:

Trypanosoma brucei gambiense

• Trypanosoma brucei gambiense is found in 24 countries in west and central Africa.
• This form currently accounts for 97% of reported cases of sleeping sickness and causes a chronic infection.
• A person can be infected for months or even years without major signs or symptoms of the disease.
• When more evident symptoms emerge, the patient is often already in an advanced disease stage where the central nervous system is affected.

Trypanosoma brucei rhodesiense

• Trypanosoma brucei rhodesienseis found in 13 countries in eastern and southern Africa.
• Nowadays, this form represents under 3% of reported cases and causes an acute infection.
• First signs and symptoms are observed a few months or weeks after infection.
• The disease develops rapidly and invades the central nervous system. Only Uganda presents both forms of the disease, but in separate zones.

American trypanosomiasis or Chagas disease

• Another form of trypanosomiasis occurs mainly in Latin America.
• The causal organism belongs to a different Trypanosoma subgenus and is transmitted by a different vector.

Animal trypanosomiasis

• Other parasite species and sub-species of the Trypanosoma genus are pathogenic to animals and cause animal trypanosomiasis in wild and domestic animals.
• In cattle the disease is called Nagana.
• Trypanosomiasis in domestic animals, particularly in cattle, is a major obstacle to the economic development of affected rural areas.

Animals can host the human pathogen parasites, especially T.b. rhodesiense, of which domestic and wild animals are an important reservoir. Animals can also be infected with T.b. gambiense and act as a reservoir to a lesser extent. However the precise epidemiological role of the animal reservoir in the gambiense form of the disease is not yet well known.

Major human epidemics There have been several epidemics in Africa over the last century:

one between 1896 and 1906, mostly in Uganda and the Congo Basin; one in 1920 in a number of African countries; and the most recent epidemic started in 1970 and lasted until the late 1990s. The 1920 epidemic was controlled thanks to mobile teams which carried out the screening of millions of people at risk. By the mid-1960s, the disease was under control with less than 5000 cases reported in the whole continent. After this success, surveillance was relaxed, and the disease reappeared, reaching epidemic proportions in several regions by 1970. The efforts of WHO, national control programmes, bilateral cooperation and nongovernmental organizations (NGOs) during the 1990s and early 21st century reversed the curve.

Since the number of new human African trypanosomiasis cases reported between 2000 and 2012 dropped by 73%, the WHO neglected tropical diseases roadmap targeted its elimination as a public health problem by 2020.

Disease burden

Sleeping sickness threatens millions of people in 36 countries in sub-Saharan Africa. Many of the affected populations live in remote rural areas with limited access to adequate health services, which complicates the surveillance and therefore the diagnosis and treatment of cases. In addition, displacement of populations, war and poverty are important factors that facilitate transmission.

In 1998, almost 40 000 cases were reported, but estimates were that 300 000 cases were undiagnosed and therefore untreated. During the most recent epidemic the prevalence reached 50% in several villages in Angola, the Democratic Republic of the Congo, and South Sudan. Sleeping sickness was the first or second greatest cause of mortality in those communities, even ahead of HIV/AIDS. In 2009, after continued control efforts, the number of cases reported dropped below 10 000 (9878) for the first time in 50 years. This decline in number of cases has continued with 2804 new cases reported in 2015, the lowest level since the start of systematic global data-collection 76 years ago. The estimated number of actual cases is below 20 000 and the estimated population at risk is 65 million people. Current disease distribution The disease incidence differs from one country to another as well as in different parts of a single country.

In the last 10 years, over 70% of reported cases occurred in the Democratic Republic of the Congo (DRC). The DRC is the only country that currently reports more than 1000 new cases annually and accounts for 84% of the cases reported in 2015. Central African Republic is the only country that declared between 100 and 200 new cases in 2015. Countries such as Angola, Burkina Faso, Cameroon, Chad, Congo, Côte d'Ivoire, Equatorial Guinea, Gabon, Gjana, Guinea, Malawi, Nigeria, South Sudan, Uganda, United Republic of Tanzania, Zambia and Zimbabwe are reporting fewer than 100 new cases per year. Countries like Benin, Botswana, Burundi, Ethiopia, Gambia, Guinea Bissau, Kenya, Liberia, Mali, Mozambique, Namibia, Niger, Rwanda, Senegal, Sierra Leone, Swaziland and Togo have not reported any new cases for over a decade. Transmission of the disease seems to have stopped in some of these countries but there are still some areas where it is difficult to assess the exact situation because the unstable social circumstances and/or difficult accessibility hinder surveillance and diagnostic activities.

Epidemiology and demographics

There are two subspecies of the parasite Trypanosoma brucei that cause disease in humans. The clinical features of the infection depend on the subspecies involved. The two subspecies are found in different regions of Africa. At present, there is no overlap in their geographic distribution.

T. b. rhodesiense (East African sleeping sickness) is found in focal areas of eastern and southeastern Africa. Each year a few hundred cases are reported to the World Health Organization. Over 95% of the cases of human infection occur in Tanzania, Uganda, Malawi, and Zambia. Animals are the primary reservoir of infection. Cattle have been implicated in the spread of the disease to new areas and in local outbreaks. A wild animal reservoir is thought to be responsible for sporadic transmission to hunters and visitors to game parks. Infection of international travelers is rare, but it occasionally occurs. In the U.S., one case per year, on average, is diagnosed. Most cases of sleeping sickness imported into the U.S. have been in travelers who were on safari in East Africa.

T. b. gambiense (West African sleeping sickness) is found predominantly in central Africa and in limited areas of West Africa. Most of the sleeping sickness in Africa is caused by this form of the parasite. Epidemics of sleeping sickness have been a significant public health problem in the past, but the disease is reasonably well-controlled at present, with 7,000-10,000 cases reported annually in recent years. Over 95% of the cases of human infection are found in Democratic Republic of Congo, Angola, Sudan, Central African Republic, Chad, and northern Uganda. Humans are the important reservoir of infection, although the parasite can sometimes be found in domestic animals (e.g., pigs, dogs, goats). Imported infection in the U.S. is extremely rare, and most cases have occurred in African nationals who have immigrated rather than in returning U.S. travelers.

History and symptoms

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, 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.

	Symptoms
First stage (hemo-lyphatic stage)	Fever Headaches Joint pains and itching
Second stage (neurological or meningo-encephalic stage)	Changes of behaviour Confusion Sensory disturbances Poor coordination Disturbance of the sleep cycle,

Diagnosis

• Definitive diagnosis rests on the observation of trypanosomes by microscopy.
• In T. b. rhodesiense infection, the identification of suspected cases relies on the clinical presentation and a history of exposure. The level of parasitemia is relatively high, particularly in the first stage of disease, and trypanosomes can be found in blood.
• In centrifuged blood, the parasite sediments just above the white cells, and examination of buffy coat will increase sensitivity. Slides stained with Giemsa can be used, but it is easiest to find the parasite by microscopic examination of fresh wet preparations, because the trypanosomes are motile and attract the eye. Delay between sampling and microscopy should be minimized, because trypanosomes will lose motility within a few hours. Parasites can also be found in fluid expressed in trypanosomal chancres and in lymph node aspirates. Serologic testing is not used for the diagnosis of T. b. rhodesiense infection.

Detecting trypanosomes in T. b. gambiense infection is more difficult.

Serology

• The card agglutination test for trypanosomiasis/T. b. gambiense is a serologic screening test used for mass population screening in endemic areas of Africa. It is not available in the U.S.
• The test is not specific enough for confirmation of infection, but it is helpful in identifying suspect cases.
• For parasitologic confirmation, a posterior cervical lymph node (if present) is punctured and the fluid examined. The yield in lymph node examination varies from about 40% to 80%.
• Trypanosomes can also be found in blood, however, the yield is low, and concentration techniques (e.g. buffy coat examination, miniature anion-exchange centrifugation technique) are helpful. Serial examinations on consecutive days may be needed.
• Treatment decisions are based on the stage of the disease. Every patient diagnosed with African trypanosomiasis must undergo a lumbar puncture for the examination of CSF. *The most widely used criteria for defining second stage disease are the observation of trypanosomes in CSF or a white cell count of 6 or higher. Other indications of second stage disease include elevated protein and an increase in nonspecific IgM in CSF.

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 examining 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

Treatment

The type of treatment depends on the disease stage. The drugs used in the first stage are safer and easier to administer than those for second stage. Also, 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 laboratory exams of body fluids including 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. Such drugs are toxic and complicated to administer. In total five 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. Medical treatment of African trypanosomiasis should begin as soon as possible and is based on the infected person’s symptoms and laboratory results. Medication for the treatment of African trypanosomiasis is available through the CDC. Pentamidine isethionate and suramin (under an investigational New Drug Protocol from the CDC Drug Service) are the drugs of choice to treat the hemolymphatic stage of West and East African Trypanosomiasis, respectively. Melarsoprol is the drug of choice for late disease with central nervous system involvement (infections by T.b. gambiense or T. b. rhodiense).

Hospitalization for treatment is necessary. Periodic follow-up exams that include a spinal tap are required for 2 years. If a person fails to receive medical treatment for African trypanosomiasis, death will occur within several weeks to months.

Medical Therapy

Antimicrobial Regimen

• Sleeping sickness

• 1. East african trypanosomiasis

• 1.1 T. b. rhodesiense, hemolymphatic stage

• 1.1.1 Adult

• Preferred regimen: Suramin 1 gm IV on days 1,3,5,14, and 21

• 1.1.2 Pediatric

• Preferred regimen: Suramin 20 mg/kg IV on days 1, 3, 5, 14, and 21

• 1.2 T. b. rhodesiense, CNS involvement

• 1.2.1 Adult

• Preferred regimen: Melarsoprol 2-3.6 mg/kg/day IV for 3 days. After 7 days, 3.6 mg/kg/day for 3 days. Give a 3rd series of 3.6 mg/kg/d after 7 days.

• 1.2.2 Pediatric

• Preferred regimen: Melarsoprol 2-3.6 mg/kg/day IV for 3 days. After 7 days, 3.6 mg/kg/day for 3 days. Give a 3rd series of 3.6 mg/kg/d after 7 days

• 2. West african trypanosomiasis

• 2.1 T. b. gambiense, hemolymphatic stage

• 2.1.1 Adult

• Preferred regimen: Pentamidine 4 mg/kg/day IM/ IV for 7-10 days

• 2.1.2 Pediatric

• Preferred regimen: Pentamidine 4 mg/kg/day IM/IV for 7-10 days
• Note (1): Pentamidine should be used during pregnancy and lacation only if the potential benefit justifies the potential risk
• Note (2): IM/IV Pentamidine have a similar safety profile in children age 4 months and older as in adults. Pentamidine is listed as a medicine for the treatment of 1st stage African trypanosomiasis infection (Trypanosoma brucei gambiense) on the WHO Model List of Essential Medicines for Children, intended for the use of children up to 12 years of age.

• 2.2 T. b. gambiense, CNS involvement

• 2.2.1 Adult

• Preferred regimen: Eflornithine 400 mg/kg/day IV qid for 14 days

• 2.2.2 Pediatric

• Preferred regimen: Eflornithine 400 mg/kg/day IV qid for 14 days
• Note (1): Eflornithine should be used during pregnancy and lactation, only if the potential benefit justifies the potential risk
• Note (2): The safety of Eflornithine in children has not been established. Eflornithine is not approved by the Food and Drug Administration (FDA) for use in pediatric patients. Eflornithine is listed for the treatment of 1st stage African trypanosomiasis inTrypanosoma brucei gambiense infection on the WHO Model List of Essential Medicines for Children, intended for the use of children up to 12 years of age.

Prevention

Wear protective clothing, including long-sleeved shirts and pants. The tsetse fly can bite through thin fabrics, so clothing should be made of medium-weight material. Wear neutral-colored clothing. The tsetse fly is attracted to bright colors and very dark colors. Inspect vehicles for tsetse flies before entering. The flies are attracted to moving vehicles. Avoid bushes. The tsetse fly is less active during the hottest period of the day. It rests in bushes but will bite if disturbed. Use insect repellant. Though insect repellants have not proven effective in preventing tsetse fly bites, they are effective in preventing other insects from biting and causing illness.