African trypanosomiasis, also known as African sleeping sickness or simply sleeping sickness, is an insect-borne parasitic infection of humans and other animals. It is caused by the species '' Trypanosoma brucei''. Humans are infected by two types, ''

Trypanosoma brucei gambiense ''Trypanosoma brucei'' is a species of parasitic kinetoplastid belonging to the genus ''Trypanosoma'' that is present in sub-Saharan Africa. Unlike other protozoan parasites that normally infect blood and tissue cells, it is exclusively extracellu ...

'' (TbG) and ''

Trypanosoma brucei rhodesiense ''Trypanosoma brucei'' is a species of parasitic kinetoplastid belonging to the genus ''Trypanosoma'' that is present in sub-Saharan Africa. Unlike other protozoan parasites that normally infect blood and tissue cells, it is exclusively extracellu ...

'' (TbR). TbG causes over 98% of reported cases. Both are usually transmitted by the bite of an infected tsetse fly and are most common in rural areas. Initially, the first stage of the disease is characterized by fevers, headaches, itchiness, and joint pains, beginning one to three weeks after the bite. Weeks to months later, the second stage begins with confusion, poor coordination, numbness, and trouble sleeping. Diagnosis is by finding the parasite in a

blood smear A blood smear, peripheral blood smear or blood film is a thin layer of blood smeared on a glass microscope slide and then stained in such a way as to allow the various blood cells to be examined microscopically. Blood smears are examined in th ...

or in the fluid of a lymph node. A

lumbar puncture Lumbar puncture (LP), also known as a spinal tap, is a medical procedure in which a needle is inserted into the spinal canal, most commonly to collect cerebrospinal fluid (CSF) for diagnostic testing. The main reason for a lumbar puncture is ...

is often needed to tell the difference between first- and second-stage disease. If the disease is not treated quickly it can lead to death. Prevention of severe disease involves screening the at-risk population with blood tests for TbG. Treatment is easier when the disease is detected early and before neurological symptoms occur. Treatment of the first stage has been with the medications

pentamidine Pentamidine is an antimicrobial medication used to treat African trypanosomiasis, leishmaniasis, '' Balamuthia'' infections, babesiosis, and to prevent and treat pneumocystis pneumonia (PCP) in people with poor immune function. In African tryp ...

or suramin. Treatment of the second stage has involved eflornithine or a combination of

nifurtimox Nifurtimox, sold under the brand name Lampit, is a medication used to treat Chagas disease and sleeping sickness. For sleeping sickness it is used together with eflornithine in nifurtimox-eflornithine combination treatment. In Chagas disease ...

and eflornithine for TbG.

Fexinidazole Fexinidazole is a medication used to treat African trypanosomiasis (sleeping sickness) caused by '' Trypanosoma brucei gambiense''. It is effective against both first and second stage disease. Some evidence also supports its use in Chagas disea ...

is a more recent treatment that can be taken by mouth, for either stages of TbG. While melarsoprol works for both types, it is typically only used for TbR, due to serious side effects. Without treatment, sleeping sickness typically results in death. The disease occurs regularly in some regions of

sub-Saharan Africa Sub-Saharan Africa is, geographically, the area and regions of the continent of Africa that lies south of the Sahara. These include West Africa, East Africa, Central Africa, and Southern Africa. Geopolitically, in addition to the List of sov ...

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 2018 there were 977 new cases. 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 The Democratic Republic of the Congo (french: République démocratique du Congo (RDC), colloquially "La RDC" ), informally Congo-Kinshasa, DR Congo, the DRC, the DROC, or the Congo, and formerly and also colloquially Zaire, is a country in ...

. Three major outbreaks have occurred in recent history: one from 1896 to 1906 primarily in

Uganda }), is a landlocked country in East Africa. The country is bordered to the east by Kenya, to the north by South Sudan, to the west by the Democratic Republic of the Congo, to the south-west by Rwanda, and to the south by Tanzania. The ...

and the Congo Basin, and two in 1920 and 1970, in several African countries. It is classified as a

neglected tropical disease Neglected tropical diseases (NTDs) are a diverse group of tropical infections that are common in low-income populations in developing regions of Africa, Asia, and the Americas. They are caused by a variety of pathogens, such as viruses, bac ...

. Other animals, such as cows, may carry the disease and become infected in which case it is known as Nagana or

animal trypanosomiasis Animal trypanosomiasis, also known as nagana and nagana pest, or sleeping sickness, is a disease of vertebrates. The disease is caused by trypanosomes of several species in the genus ''Trypanosoma'' such as '' Trypanosoma brucei''. ''Trypanosom ...

Signs and symptoms

African trypanosomiasis symptoms occur in two stages: the hemolymphatic stage and the neurological stage (the latter being characterised by parasitic invasion of the central nervous system). Neurological symptoms occur in addition to the initial features, however, and the two stages may be difficult to distinguish 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). The reasons for this are unclear and may be genetic. The low number of such cases may also have skewed findings. In such persons, the infection is said to present mainly as fever with gastrointestinal symptoms (e.g. diarrhoea and jaundice) with lymphadenopathy developing only rarely. Trypanosomal chancre Systemic disease is sometimes presaged by a trypanosomal

chancre A chancre ( )chancres
thefreedictionary is a painless

developing at the site of the infectious fly bite within 2 days of infection. The chancre is most commonly observed in ''T. b. rhodesiense'' infection, and only rarely in ''T. b. gambiense'' (however, in ''T. b. gambiense'' infection, chancres are more common in persons from non-endemic areas).

Hemolymphatic phase

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 phase, 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 Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. ...

(which may in fact 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 over the course of 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, the tell-tale swollen lymph nodes along the back of the neck, may appear. Winterbottom's sign is common in ''T. b. gambiense'' infection. 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. File:PMC5373517 pntd.0005324.g001.png, Chancre of human African trypanosomiasis File:AcuteSleepingSickness.jpg, Typical fine-spotted pink rash of acute African trypanosomiasis on the skin of the abdomen ("trypanid rash") File:SSHemorragicRash.jpg, Numerous spots of bleeding into the skin of the leg in a person infected with ''T. b. rhodesiense''

Neurological phase

The second phase of the disease, the neurological phase (also called the ''meningoencephalic stage''), begins when the parasite invades the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

by passing through the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable border of endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of the central nervous system where ne ...

. Progression to the neurological phase occurs after an estimated 21–60 days in case of ''T. b. rhodesiens''e infection, and 300–500 days in case of ''T. b. gambiense'' infection. In actuality, the two phases overlap and are difficult to distinguish based on clinical features alone; determining the actual stage of the disease is achieved by examining the

cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the ...

for the presence of the parasite. Sleep disorders Sleep-wake disturbances are a leading feature of neurological stage and gave the disease its common name ''African sleeping sickness''. Infected individuals experience a disorganized and fragmented sleep-wake cycle. Those affected experience

sleep inversion Sleep inversion or sleep-wake inversion is a reversal of sleeping tendencies. Individuals experiencing sleep-wake inversion exchange diurnal habits for nocturnal habits, meaning they are active at night and sleep during the day. Sleep-wake inversi ...

resulting in daytime sleep and somnolence, and nighttime periods of wakefulness and insomnia. Additionally, those affected also experience episodes of sudden sleepiness. Neurological/neurocognitive symptoms Neurological symptoms include: tremor, general muscle weakness,

hemiparesis Hemiparesis, or unilateral paresis, is weakness of one entire side of the body ('' hemi-'' means "half"). Hemiplegia is, in its most severe form, complete paralysis of half of the body. Hemiparesis and hemiplegia can be caused by different med ...

, 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/behavioural symptoms Individuals may exhibit psychiatric symptoms which may sometimes dominate the clinical diagnosis and may include aggressiveness,

apathy Apathy is a lack of feeling, emotion, interest, or concern about something. It is a state of indifference, or the suppression of emotions such as concern, excitement, motivation, or passion. An apathetic individual has an absence of inter ...

, irritability, psychotic reactions and hallucinations,

anxiety Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...

, emotional lability, confusion,

mania Mania, also known as manic syndrome, is a mental and behavioral disorder defined as a state of abnormally elevated arousal, affect, and energy level, or "a state of heightened overall activation with enhanced affective expression together wi ...

, attention deficit, and

delirium Delirium (also known as acute confusional state) is an organically caused decline from a previous baseline of mental function that develops over a short period of time, typically hours to days. Delirium is a syndrome encompassing disturbances ...

Advanced/late 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 phase is irreversible.

Cause

''Trypanosoma brucei gambiense'' accounts for the majority of African trypanosomiasis cases, with humans as the main reservoir needed for the transmission, while ''Trypanosoma brucei rhodesiense'' is mainly zoonotic, with the occasional human infection. African trypanosomiasis is dependent on the interaction of the parasite (trypanosome) with the tsetse flies (vector), as well as the host (human for ''Trypanosoma brucei gambiense'', and animals for ''Trypanosoma brucei rhodesiense''). The risk of contracting African trypanosomiasis is dependent on coming in contact with an infected tsetse fly.

''Trypanosoma brucei''

There are two subspecies of the parasite that are responsible for starting the disease in humans. ''

'' causes the diseases in west and central

Africa Africa is the world's second-largest and second-most populous continent, after Asia in both cases. At about 30.3 million km2 (11.7 million square miles) including adjacent islands, it covers 6% of Earth's total surface area ...

, whereas ''

'' has a limited geographical range and is responsible for causing the disease in east and southern Africa. In addition, a third subspecies of the parasite known as ''

Trypanosoma brucei brucei ''Trypanosoma brucei'' is a species of parasitic kinetoplastid belonging to the genus ''Trypanosoma'' that is present in sub-Saharan Africa. Unlike other protozoan parasites that normally infect blood and tissue cells, it is exclusively extracellu ...

'' is responsible for affecting animals but not humans. Humans are the main reservoir for ''T. b. gambiense'' but this species can also be found in pigs and other animals. Wild game animals and cattle are the main reservoir of ''T. b. rhodesiense''. These parasites primarily infect individuals in sub-Saharan Africa because that is where the vector (tsetse fly) is located. The two human forms of the disease also vary greatly in intensity. ''T. b. gambiense'' causes a

chronic condition A chronic condition is a health condition or disease that is persistent or otherwise long-lasting in its effects or a disease that comes with time. The term ''chronic'' is often applied when the course of the disease lasts for more than three m ...

that can remain in a passive phase for months or years before symptoms emerge and the infection can last about three years before death occurs. ''T. b. rhodesiense'' is the

acute Acute may refer to: Science and technology * Acute angle ** Acute triangle ** Acute, a leaf shape in the glossary of leaf morphology * Acute (medicine), a disease that it is of short duration and of recent onset. ** Acute toxicity, the adverse ef ...

form of the disease, and death can occur within months since the symptoms emerge within weeks and it is more virulent and faster developing than ''T. b. gambiense''. Furthermore, trypanosomes are surrounded by a coat that is composed of

variant surface glycoprotein Variant surface glycoprotein (VSG) is a ~60kDa protein which densely packs the cell surface of protozoan parasites belonging to the genus ''Trypanosoma''. This genus is notable for their cell surface proteins. They were first isolated from '' Tryp ...

s (VSG). These proteins act to protect the parasite from any lytic factors that are present in human plasma. The host's immune system recognizes the glycoproteins present on the coat of the parasite leading to the production of different

antibodies An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of ...

(IgM and IgG). These antibodies will then act to destroy the parasites that circulate around the blood. However, from the several parasites present in the plasma, a small number of them will experience changes in their surface coats resulting in the formation of new VSGs. Thus, the antibodies produced by the immune system will no longer recognize the parasite leading to proliferation until new antibodies are created to combat the novel VSGs. Eventually, the immune system will no longer be able to fight off the parasite due to the constant changes in VSGs and infection will arise.

Vector

The tsetse fly (genus ''Glossina'') is a large, brown, biting fly that serves as both a host and vector for the trypanosome parasites. While taking blood from a mammalian host, an infected tsetse fly injects metacyclic trypomastigotes into skin tissue. From the bite, parasites first enter the lymphatic system and then pass into the bloodstream. Inside the mammalian host, they transform into bloodstream trypomastigotes, and are carried to other sites throughout the body, reach other body fluids (e.g., lymph, spinal fluid), and continue to replicate by binary fission. The entire life cycle of African trypanosomes is represented by extracellular stages. A tsetse fly becomes infected with bloodstream trypomastigotes when taking a blood meal on an infected mammalian host. In the fly's midgut, the parasites transform into procyclic trypomastigotes, multiply by binary fission, leave the midgut, and transform into epimastigotes. The epimastigotes reach the fly's salivary glands and continue multiplication by binary fission. The entire life cycle of the fly takes about three weeks. In addition to the bite of the tsetse fly, the disease can be transmitted by: * Mother-to-child infection: the trypanosome can sometimes cross the placenta and infect the fetus. * Laboratories: accidental infections, for example, through the handling of blood of an infected person and organ transplantation, although this is uncommon. * Blood transfusion *

Sexual contact Human sexual activity, human sexual practice or human sexual behaviour is the manner in which humans experience and express their sexuality. People engage in a variety of sexual acts, ranging from activities done alone (e.g., masturbation) t ...

Horse-flies ( Tabanidae) and

stable flies ''Stomoxys calcitrans'' is commonly called the stable fly, barn fly, biting house fly, dog fly, or power mower fly. Unlike most members of the family Muscidae, ''Stomoxys calcitrans'' ('sharp mouth' + 'kicking') and others of its genus suck bl ...

( Muscidae) possibly play a role in transmission of nagana (the animal form of sleeping sickness) and the human disease form.

Pathophysiology

Tryptophol is a chemical compound produced by the trypanosomal parasite in sleeping sickness which induces sleep in humans.

Diagnosis

The gold standard for diagnosis is identification of trypanosomes in a sample by microscopic examination. Samples that can be used for diagnosis include

chancre A chancre ( )chancres
thefreedictionary is a painless

fluid, lymph node aspirates, blood,

bone marrow Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...

, and, during the neurological stage,

. Detection of trypanosome-specific antibodies can be used for diagnosis, but the sensitivity and specificity of these methods are too variable to be used alone for clinical diagnosis. Further,

seroconversion In immunology, seroconversion is the development of specific antibodies in the blood serum as a result of infection or immunization, including vaccination. During infection or immunization, antigens enter the blood, and the immune system begins t ...

occurs after the onset of clinical symptoms during a ''T. b. rhodesiense'' infection, so is of limited diagnostic use. Trypanosomes can be detected from samples using two different preparations. A wet preparation can be used to look for the motile trypanosomes. Alternatively, a fixed (dried) smear can be stained using Giemsa's or Field's technique and examined under a microscope. Often, the parasite is in relatively low abundance in the sample, so techniques to concentrate the parasites can be used prior to microscopic examination. For blood samples, these include centrifugation followed by examination of the buffy coat; mini anion-exchange/centrifugation; and the quantitative buffy coat (QBC) technique. For other samples, such as spinal fluid, concentration techniques include centrifugation followed by examination of the sediment. Three serological tests are also available for detection of the parasite: the micro-CATT (card agglutination test for trypanosomiasis), wb-CATT, and wb-LATEX. The first uses dried blood, while the other two use whole blood samples. A 2002 study found the wb-CATT to be the most efficient for diagnosis, while the wb-LATEX is a better exam for situations where greater sensitivity is required.

Prevention

Currently there are few medically related prevention options for African trypanosomiasis (i.e. no vaccine exists for immunity). Although the risk of infection from a tsetse fly bite is minor (estimated at less than 0.1%), the use of insect repellants, wearing long-sleeved clothing, avoiding tsetse-dense areas, implementing bush clearance methods and wild game culling are the best options to avoid infection available for local residents of affected areas. In July 2000, a resolution was passed to form the Pan African Tsetse and Trypanosomiasis Eradication Campaign (PATTEC). The campaign works to eradicate the tsetse vector population levels and subsequently the protozoan disease, by use of insecticide-impregnated targets, fly traps, insecticide-treated cattle, ultra-low dose aerial/ground spraying (SAT) of tsetse resting sites and the sterile insect technique (SIT). The use of SIT in Zanzibar proved effective in eliminating the entire population of tsetse flies but was expensive and is relatively impractical to use in many of the endemic countries afflicted with African trypanosomiasis. A pilot program in

Senegal Senegal,; Wolof: ''Senegaal''; Pulaar: 𞤅𞤫𞤲𞤫𞤺𞤢𞥄𞤤𞤭 (Senegaali); Arabic: السنغال ''As-Sinighal'') officially the Republic of Senegal,; Wolof: ''Réewum Senegaal''; Pulaar : 𞤈𞤫𞤲𞤣𞤢𞥄𞤲𞤣𞤭 ...

has reduced the tsetse fly population by as much as 99% by introducing male flies which have been sterilized by exposure to

gamma ray A gamma ray, also known as gamma radiation (symbol γ or \gamma), is a penetrating form of electromagnetic radiation arising from the radioactive decay of atomic nuclei. It consists of the shortest wavelength electromagnetic waves, typically ...

s. Regular active surveillance, involving detection and prompt treatment of new infections, and tsetse fly control is the backbone of the strategy used to control sleeping sickness. Systematic

screening Screening may refer to: * Screening cultures, a type a medical test that is done to find an infection * Screening (economics), a strategy of combating adverse selection (includes sorting resumes to select employees) * Screening (environmental), ...

of at-risk communities is the best approach, because case-by-case screening is not practical in endemic regions. Systematic screening may be in the form of mobile clinics or fixed screening centres where teams travel daily to areas of high infection rates. Such screening efforts are important because early symptoms are not evident or serious enough to warrant people with gambiense disease to seek medical attention, particularly in very remote areas. Also, diagnosis of the disease is difficult and health workers may not associate such general symptoms with trypanosomiasis. Systematic screening allows early-stage disease to be detected and treated before the disease progresses, and removes the potential human reservoir. A single case of sexual transmission of West African sleeping sickness has been reported.

Treatment

First stage

The treatment for first-stage disease is

fexinidazole Fexinidazole is a medication used to treat African trypanosomiasis (sleeping sickness) caused by '' Trypanosoma brucei gambiense''. It is effective against both first and second stage disease. Some evidence also supports its use in Chagas disea ...

by mouth or

by injection for ''T. b. gambiense''. Suramin by injection is used for ''T. b. rhodesiense''.

Second stage

Fexinidazole may be used for the second stage of TbG, if the disease is not severe. Otherwise a regimen involving the combination of

and eflornithine, nifurtimox-eflornithine combination treatment (NECT), or eflornithine alone appear to be more effective and result in fewer side effects. These treatments may replace melarsoprol when available. NECT has the benefit of requiring less injections of eflornithine. Intravenous melarsoprol was previously the standard treatment for second-stage (neurological phase) disease and is effective for both types. Melarsoprol is the only treatment for second stage ''T. b. rhodesiense''; however, it causes death in 5% of people who take it. Resistance to melarsoprol can occur.

Prognosis

If untreated, ''T. b. gambiense'' almost always results in death, with only a few individuals shown in a long-term 15 year follow-up to have survived after refusing treatment. ''T. b. rhodesiense'', being a more acute and severe form of the disease, is consistently fatal if not treated. Disease progression greatly varies depending on disease form. For individuals which are infected by ''T. b. gambiense'', which accounts for 98% of all of the reported cases, a person can be infected for months or even years without signs or symptoms until the advanced disease stage, where it is too late to be treated successfully. For individuals affected by ''T. b. rhodesiense'', which accounts for 2% of all reported cases, symptoms appear within weeks or months of the infection. Disease progression is rapid and invades the central nervous system, causing death within a short amount of time.

Epidemiology

In 2010, it caused around 9,000 deaths, down from 34,000 in 1990. As of 2000, the disability-adjusted life-years (9 to 10 years) lost due to sleeping sickness are 2.0 million. From 2010 to 2014, there was an estimated 55 million people at risk for ''gambiense'' African Trypanosomiasis and over 6 million people at risk for ''rhodesiense'' African trypanosomiasis. In 2014, the World Health Organization reported 3,797 cases of Human African Trypanosomiasis when the predicted number of cases were to be 5,000. The number of total reported cases in 2014 is an 86% reduction to the total number of cases reported in 2000. The disease has been recorded as occurring in 37 countries, all in sub-Saharan Africa. It occurs regularly in southeast Uganda and western Kenya, and killed more than 48,000 Africans in 2008. The Democratic Republic of the Congo is the most affected country in the world, accounting for 75% of the ''Trypanosoma brucei gambiense'' cases. The population at risk being about 69 million with one third of this number being at a 'very high' to 'moderate' risk and the remaining two thirds at a 'low' to 'very low' risk. The number of people being affected by the disease has declined. At this rate, sleeping sickness elimination is a possibility. The World Health Organization plans to eradicate sleeping sickness by 2030.

History

The condition has been present in Africa for thousands of years. Because of a lack of travel between indigenous people, sleeping sickness in humans had been limited to isolated pockets. This changed after Arab slave traders entered central Africa from the east, following the

Congo River The Congo River ( kg, Nzâdi Kôngo, french: Fleuve Congo, pt, Rio Congo), formerly also known as the Zaire River, is the second longest river in Africa, shorter only than the Nile, as well as the second largest river in the world by discharg ...

, bringing parasites along. Gambian sleeping sickness travelled up the Congo River, and then further east. An Arab writer of the 14th century left the following description in the case of a sultan of the Mali Kingdom: "His end was to be overtaken by the sleeping sickness (''illat an-nawm'') which is a disease that frequently befalls the inhabitants of these countries especially their chieftains. Sleep overtakes one of them in such a manner that it is hardly possible to awake him." The British naval surgeon John Atkins described the disease on his return from West Africa in 1734: French naval surgeon Marie-Théophile Griffon du Bellay treated and described cases while stationed aboard the hospital ship ''Caravane'' in

Gabon Gabon (; ; snq, Ngabu), officially the Gabonese Republic (french: République gabonaise), is a country on the west coast of Central Africa. Located on the equator, it is bordered by Equatorial Guinea to the northwest, Cameroon to the nort ...

in the late 1860s. In 1901, a devastating epidemic erupted in

, killing more than 250,000 people, including about two-thirds of the population in the affected lakeshore areas. According to ''The Cambridge History of Africa'', "It has been estimated that up to half the people died of sleeping-sickness and

smallpox Smallpox was an infectious disease caused by variola virus (often called smallpox virus) which belongs to the genus Orthopoxvirus. The last naturally occurring case was diagnosed in October 1977, and the World Health Organization (WHO) c ...

in the lands on either bank of the lower river Congo." The causative agent and vector were identified in 1903 by David Bruce, and the

subspecies In biological classification, subspecies is a rank below species, used for populations that live in different areas and vary in size, shape, or other physical characteristics ( morphology), but that can successfully interbreed. Not all specie ...

of the protozoa were differentiated in 1910. Bruce had earlier shown that ''T. brucei'' was the cause of a similar disease in horses and cattle that was transmitted by the tsetse fly (''Glossina morsitans''). The first effective treatment,

atoxyl Arsanilic acid, also known as aminophenyl arsenic acid or aminophenyl arsonic acid, is an organoarsenic compound, an amino derivative of phenylarsonic acid whose amine group is in the 4-position. A crystalline powder introduced medically in the l ...

, an

arsenic Arsenic is a chemical element with the symbol As and atomic number 33. Arsenic occurs in many minerals, usually in combination with sulfur and metals, but also as a pure elemental crystal. Arsenic is a metalloid. It has various allotropes, b ...

-based drug developed by Paul Ehrlich and

Kiyoshi Shiga was a Japanese physician and bacteriologist. He had a well-rounded education and career that led to many scientific discoveries. In 1897, Shiga was credited with the discovery and identification of the ''Shigella'' ''dysenteriae'' microorganis ...

, was introduced in 1910, but blindness was a serious side effect. Suramin was first synthesized by Oskar Dressel and Richard Kothe in 1916 for

Bayer Bayer AG (, commonly pronounced ; ) is a German multinational pharmaceutical and biotechnology company and one of the largest pharmaceutical companies in the world. Headquartered in Leverkusen, Bayer's areas of business include pharmaceutic ...

. It was introduced in 1920 to treat the first stage of the disease. By 1922, Suramin was generally combined with tryparsamide (another pentavalent organoarsenic drug), the first drug to enter the nervous system and be useful in the treatment of the second stage of the gambiense form. Tryparsamide was announced in the ''Journal of Experimental Medicine'' in 1919 and tested in the

Belgian Congo The Belgian Congo (french: Congo belge, ; nl, Belgisch-Congo) was a Belgian colony in Central Africa from 1908 until independence in 1960. The former colony adopted its present name, the Democratic Republic of the Congo (DRC), in 1964. Colo ...

by Louise Pearce of the Rockefeller Institute in 1920. It was used during the grand epidemic in West and Central Africa on millions of people and was the mainstay of therapy until the 1960s. American medical missionary

Arthur Lewis Piper Arthur Lewis Piper (31 December 1883 – 1983) was a medical missionary in the Belgian Congo, supported by the Detroit Epworth League.Springer, John McKendree. Pioneering in the Congo. 2. Katanga Press, 1916. Print. He worked for the Mission Confer ...

was active in using tryparsamide to treat sleeping sickness in the Belgian Congo in 1925.

Pentamidine Pentamidine is an antimicrobial medication used to treat African trypanosomiasis, leishmaniasis, '' Balamuthia'' infections, babesiosis, and to prevent and treat pneumocystis pneumonia (PCP) in people with poor immune function. In African tryp ...

, a highly effective drug for the first stage of the disease, has been used since 1937. During the 1950s, it was widely used as a prophylactic agent in western Africa, leading to a sharp decline in infection rates. At the time, eradication of the disease was thought to be at hand. The organoarsenical melarsoprol (Arsobal) developed in the 1940s is effective for people with second-stage sleeping sickness. However, 3–10% of those injected have reactive encephalopathy (convulsions, progressive coma, or psychotic reactions), and 10–70% of such cases result in death; it can cause

brain damage Neurotrauma, brain damage or brain injury (BI) is the destruction or degeneration of brain cells. Brain injuries occur due to a wide range of internal and external factors. In general, brain damage refers to significant, undiscriminating t ...

in those who 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 Sjoerdsma and underwent clinical trials in the 1980s. The drug was approved by the United States

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

in 1990. Aventis, the company responsible for its manufacture, halted production in 1999. In 2001, Aventis, in association with Médecins Sans Frontières and the

World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level o ...

, signed a long-term agreement to manufacture and donate the drug. In addition to sleeping sickness, previous names have included negro lethargy, maladie du sommeil (Fr), Schlafkrankheit (Ger), African lethargy,, pp. 20–21. and Congo trypanosomiasis. Nyasaland, 1908-1913"> File:Sleeping Sickness Commission photos Wellcome L0049104.jpg, alt=Images from The British-led Sleeping Sickness Commission collecting tsetse flies, Uganda and Nyasaland, 1908-1913 File:Sleeping sickness commission photos Wellcome L0049109.jpg File:Sleeping sickness commission photos Wellcome L0049112.jpg File:Sleeping Sickness Commission photos Wellcome L0049121.jpg File:Sleeping sickness commission photos Wellcome L0049117.jpg File:Sleeping sickness commission photos Wellcome L0049108.jpg File:Sleeping sickness commission photos Wellcome L0049113.jpg File:Sleeping sickness commission photos Wellcome L0049115.jpg File:Sleeping Sickness Commission photos Wellcome L0049106.jpg File:Sleeping sickness commission photos Wellcome L0049111.jpg File:Sleeping sickness commission photos Wellcome L0049110.jpg File:Sleeping sickness commission photos Wellcome L0049114.jpg

Research

The genome of the parasite has been sequenced and several proteins have been identified as potential targets for drug treatment. Analysis of the genome also revealed the reason why generating a vaccine for this disease has been so difficult. ''T. brucei'' has over 800 genes that make proteins the parasite "mixes and matches" to evade immune system detection. Using a genetically modified form of a bacterium that occurs naturally in the gut of the vectors is being studied as a method of controlling the disease. Recent findings indicate that the parasite is unable to survive in the bloodstream without its

flagellum A flagellum (; ) is a hairlike appendage that protrudes from certain plant and animal sperm cells, and from a wide range of microorganisms to provide motility. Many protists with flagella are termed as flagellates. A microorganism may have f ...

. This insight gives researchers a new angle with which to attack the parasite. Trypanosomiasis vaccines are undergoing research. Additionally, the

Drugs for Neglected Diseases Initiative The Drugs for Neglected Diseases ''initiative'' (DND''i'') is a collaborative, patients' needs-driven, non-profit drug research and development (R&D) organization that is developing new treatments for neglected diseases, notably leishmaniasis, ...

has contributed to the African sleeping sickness research by developing a compound called

. This project was originally started in April 2007 and enrolled 749 people in the

DRC The Democratic Republic of the Congo (french: République démocratique du Congo (RDC), colloquially "La RDC" ), informally Congo-Kinshasa, DR Congo, the DRC, the DROC, or the Congo, and formerly and also colloquially Zaire, is a country in ...

and

Central African Republic The Central African Republic (CAR; ; , RCA; , or , ) is a landlocked country in Central Africa. It is bordered by Chad to the north, Sudan to the northeast, South Sudan to the southeast, the DR Congo to the south, the Republic of th ...

. The results showed efficacy and safety in both stages of the disease, both in adults and children ≥ 6 years old and weighing ≥ 20 kg. The

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Eur ...

approved it for first and second stage disease outside of Europe in November 2018. The treatment was approved in the DRC in December 2018.

Funding

For current funding statistics, human African trypanosomiasis is grouped with kinetoplastid infections. Kinetoplastids refer to a group of flagellate protozoa. Kinetoplastid infections include African sleeping sickness, Chagas' disease, and Leishmaniasis. All together, these three diseases accounted for 4.4 million

disability adjusted life year The disability-adjusted life year (DALY) is a measure of overall disease burden, expressed as the number of years lost due to ill-health, disability or early death. It was developed in the 1990s as a way of comparing the overall health and life ex ...

s (DALYs) and an additional 70,075 recorded deaths yearly. For kinetoplastid infections, the total global research and development funding was approximately $136.3 million in 2012. Each of the three diseases, African sleeping sickness, Chagas' disease, and Leishmaniasis each received approximately a third of the funding, which was about $36.8 million US dollars, $38.7 million US dollars, and $31.7 million US dollars, respectively. For sleeping sickness, funding was split into basic research, drug discovery, vaccines, and diagnostics. The greatest amount of funding was directed towards basic research of the disease; approximately $21.6 million US dollars was directed towards that effort. As for therapeutic development, approximately $10.9 million was invested. The top funder for kinetoplastid infection research and development are public sources. About 62% of the funding comes from high-income countries while 9% comes from low- and middle-income countries. High-income countries' public funding is the largest contributor to the neglected disease research effort. However, in recent years, funding from high-income countries has been steadily decreasing; in 2007, high-income countries provided 67.5% of the total funding whereas, in 2012, high-income countries public funds only provided 60% of the total funding for kinetoplastid infections. This downwards trend leaves a gap for other funders, such as philanthropic foundations and private pharmaceutical companies to fill. Much of the progress that has been made in African sleeping sickness and neglected disease research as a whole is a result of the other non-public funders. One of these major sources of funding has come from foundations, which have increasingly become more committed to neglected disease drug discovery in the 21st century. In 2012, philanthropic sources provided 15.9% of the total funding. The Bill and Melinda Gates Foundation has been a leader in providing funding for neglected disease drug development. They have provided $444.1 million US dollars towards neglected disease research in 2012. To date, they have donated over $1.02 billion US dollars towards the neglected disease discovery efforts. For kinetoplastid infections specifically, they have donated an average of $28.15 million US dollars annually between the years 2007 to 2011. They have labeled human African trypanosomiasis a high-opportunity target meaning it is a disease that presents the greatest opportunity for control, elimination, and eradication, through the development of new drugs, vaccines, public-health programs, and diagnostics. They are the second-highest funding source for neglected diseases, immediately behind the US National Institutes of Health. At a time where public funding is decreasing and government grants for scientific research are harder to obtain, the philanthropic world has stepped in to push the research forward. Another important component of increased interest and funding has come from industry. In 2012, they contributed 13.1% total to the kinetoplastid research and development effort, and have additionally played an important role by contributing to public-private partnerships (PPP) as well as product-development partnerships (PDP). A public-private partnership is an arrangement between one or more public entities and one or more private entities that exists to achieve a specific health outcome or to produce a health product. The partnership can exist in numerous ways; they may share and exchange funds, property, equipment, human resources, and intellectual property. These public-private partnerships and product-development partnerships have been established to address challenges in pharmaceutical industry, especially related to neglected disease research. These partnerships can help increase the scale of the effort towards therapeutic development by using different knowledge, skills, and expertise from different sources. These types of partnerships have been shown to be more effective than industry or public groups working independently.

Other animals and reservoir

''Trypanosoma'' of both the ''rhodesiense'' and ''gambiense'' types can affect other animals such as cattle and wild animals. African trypanosomiasis has generally been considered an anthroponotic disease and thus its control program was mainly focused on stopping the transmission by treating human cases and eliminating the vector. However, animal reservoirs were reported to possibly play an important role in the endemic nature of African trypanosomiasis, and for its resurgence in the historic foci of West and Central Africa.

References

External links

* *
Links to pictures of Sleeping Sickness
(Hardin MD/

University of Iowa The University of Iowa (UI, U of I, UIowa, or simply Iowa) is a public research university in Iowa City, Iowa, United States. Founded in 1847, it is the oldest and largest university in the state. The University of Iowa is organized into 12 co ...

) * {{DEFAULTSORT:African Trypanosomiasis Health in Africa Insect-borne diseases Parasitic diseases Protozoal diseases Wikipedia medicine articles ready to translate Wikipedia infectious disease articles ready to translate Sleep disorders Tropical diseases Zoonoses African trypanosomiasis