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Trypanosoma forms in a blood smear
African trypanosomiasis or sleeping sickness is a parasitic disease of humans and other animals. It is caused by protozoa of the species Trypanosoma brucei. There are two type that infect humans, Trypanosoma brucei gambiense (T.b.g) and Trypanosoma brucei rhodesiense (T.b.r.). T.b.g 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, in the first stage of the disease, there are fevers, headaches, itchiness, and joint pains. This begins 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 via finding the parasite in a blood smear or in the fluid of a lymph node. A lumbar puncture is often needed to tell the difference between first and second stage disease.
Prevention of severe disease involves screening the population at risk with blood tests for T.b.g. Treatment is easier when the disease is detected early and before neurological symptoms occur. Treatment of the first stage is with the medications pentamidine or suramin. Treatment of the second stage involves: eflornithine or a combination of nifurtimox and eflornithine for T.b.g. While melarsoprol works for both it is typically only used for T.b.r. due to 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. As of 2010 it caused around 9,000 deaths, down from 34,000 in 1990. An estimated 30,000 people are currently infected with 7000 new infections in 2012. 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. Other animals like cows may carry the disease and become infected.
Signs and symptoms
African trypanosomiasis symptoms occur in two stages. The first stage, known as the haemolymphatic phase, is characterized by fever, headaches, joint pains, and itching. Fever is intermittent, with attacks lasting from a day to a week, separated by intervals of a few days to a month or longer. Invasion of the circulatory and lymphatic systems by the parasites is associated with severe swelling of lymph nodes, often to tremendous sizes. Winterbottom's sign, the tell-tale swollen lymph nodes along the back of the neck, may appear. Occasionally, a red sore called a chancre will develop at the location of the tsetse fly bite. If left untreated, the disease overcomes the host's defenses and can cause more extensive damage, broadening symptoms to include anemia, endocrine, cardiac, and kidney dysfunctions. The second, neurological phase, begins when the parasite invades the central nervous system by passing through the blood–brain barrier. Disruption of the sleep cycle is a leading symptom of this stage and is the one that gave the disease the name 'sleeping sickness.' Infected individuals experience a disorganized and fragmented 24-hour rhythm of the sleep-wake cycle, resulting in daytime sleep episodes and nighttime periods of wakefulness. Other neurological symptoms include confusion, tremor, general muscle weakness,hemiparesis and paralysis of a limb. Parkinson-like movements might arise due to non-specific movement disorders and speech disorders. Individuals may also exhibit psychiatric symptoms such as irritability, psychotic reactions, aggressive behaviour, or apathy which can sometimes dominate the clinical diagnosis. 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 monthswhereas an untreated infection with T.b. gambiense will cause death after several years. Damage caused in the neurological phase is irreversible.
There are two subspecies of the parasite that are responsible for initiating the disease in humans. Trypanosoma brucei gambiense causes the diseases in west and centralAfrica whereas, Trypanosoma brucei rhodesiense 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 bruceiis responsible for affecting animals but not humans. Humans are the main reservoir forT. 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 that can remain in a passive phase for months or years before symptoms emerge and the infection can last about 3 years before death occurs. T. b. rhodesiense is the acute 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 glycoproteins (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 differentantibodies (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.
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 (This may be possible)
The gold standard for diagnosis is identification of trypanosomes in a patient sample by microscopic examination. Patient samples that can be used for diagnosis includechancre fluid, lymph node aspirates, blood, bone marrow, and, during the neurological stage, cerebrospinal fluid. 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 occurs after the onset of clinical symptoms during a T. b. rhodesiense infection, so is of limited diagnostic use.
Trypanosomes can be detected from patient 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, 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.
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. At the 25th ISCTRC (International Scientific Council for Trypanosomiasis Research and Control) in Mombasa, Kenya, in October, 1999, the idea of an African-wide initiative to control tsetse and trypanosomiasis populations was discussed. During the 36th summit of the African Union in Lome, Togo, 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.
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 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 patients 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.
For T.b.g. intravenous eflornithine or the combination of nifurtimox and eflornithine appear to be more effective and easier to give. This treatments may replace melarsoprol when available with the combination being first line. Intravenous melarsoprol was previously the standard treatment for second-stage (neurological phase) disease and is effective for both types. It is the only treatment for second stage T.b.r. however can cause death in 5% of people who take it. Resistance to melarsoprol can occur.
If untreated, African trypanosomiasis usually but not always results in death.
As of 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.Over 60 million people living in some 250 locations are at risk of contracting the disease, and under 10,000 new cases were reported in 2009.
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 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 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 once Arab slave traders entered central Africa from the east, following the Congo River, bringing parasites along. Gambian sleeping sickness travelled up the Congo River, then further eastwards. In 1901, a devastating epidemic erupted in Uganda, 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 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 differentiation between thesubspecies of the protozoa made in 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.
Suramin was introduced in 1920 to treat the first stage of the disease. By 1922, Suramin was generally combined with tryparsamide (another pentavalent organoarsenic 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. The American medical missionary Arthur Lewis Piper was the first person to use and bring back tryparsamide to the Belgian Congo in 1925.
Pentamidine, a highly effective drug for the first stage of the disease, has been used since 1939. 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 patients 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 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 Sjoerdsmanot and underwent clinical trials in the 1980s. The drug was approved by the United States Food and Drug Administration in 1990, butAventis, 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.
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 bacteria that occurs naturally in the gut of the vectors is being studied as a method of controlling the disease.
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