African Trypanosomiasis Sleeping Sickness Biology Essay

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African trypanosomiasis also known as "sleeping sickness" is a wide spread parasitic disease (disease caused by organism that lives in or on another from which it obtains nourishment) that can be fatal if not treated. It is estimated by the World Health Organisation (WHO) that it has 450 000 cases each year, however in the past there have epidemics (a rapid spread or increase) such as between 1896 and 1906 where it is believed that 300 000 to 500 000 died from the disease. [1] African trypanosomiasis is common in the sub-Saharan region near rivers, lakes, in gallery forests and in Savannahs where the large brown tsetse flies are present. It occurs in these remote rural areas because the health systems are weak and because most of these areas depend on agriculture, fishing, animal husbandry or hunting so they are exposed to the tsetse flies. [2]The disease has been present in Africa for a minimum of 14 centuries with millions of people being affected by it.

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As you can see below (in figure 1) the distribution of trypanosomiasis in Africa comprises currently an area of 8 million km2 between 14 degrees North and 20 degrees South latitude.

tryp_map.gif [Fig. 1]

Distribution of human African trypanosomiasis.

http://www.who.int/tdrold/dw/images/legend5.gifEpidemic

http://www.who.int/tdrold/dw/images/legend6.gifHigh endemicity

http://www.who.int/tdrold/dw/images/legend4.gifLow endemicity

http://www.who.int/tdrold/dw/images/legend7.gifAt risk

http://www.who.int/tdrold/dw/images/legend3.gifAbsence of the disease 

As well as African trypanosomiasis also occurs in South America it is called the American trypanosomiasis or the Chagas disease however the organism causing that disease is different to the Tsetse flies. African trypanosomiasis is however more common than the South American version and it is estimated that around 50,000 to 70,000 people are currently infected with it and around 48,000 people died from it in 2008. [3] If, like most diseases, African Trypanosomiasis is diagnosed early there is a high chance of survival. There are no effective vaccines, and the drugs used to treat this disease are often toxic and usually have many side effects. Untreated cases have a 100 percent mortality rate. [4]

The extent of African Trypanosomiasis is shown more clearly when compared to other diseases and during epidemic periods prevalence reached 50% in several villages in the Democratic Republic of Congo, Angola and Southern Sudan. Sleeping sickness was the first or second greatest cause of mortality in those communities, ahead of even HIV/AIDS. [5]

There are two types of African trypanosomiasis which are common in humans. The first of the two sub species is trypanosomiasis brucei gambiense which causes a slow chronic trypanosomiasis in humans. This mostly occurs in central and western Africa, where humans are thought to be the primary target. The second is T. brucei rhodesiense and this causes a rapid onset of trypanosomiasis in humans and this is most common in southern and eastern Africa, where animals are the primary target.

Tsetse flies are large flies which can be easily misinterpreted for a housefly but can be distinguished by various characteristics. These flies cause human sleeping sickness and animal trypanosomiasis (or nagana) as well as other diseases and its estimated it kills around 250,000 to 300,000 people a year. Tsetse flies are multivoltine (they have more than 2 generations per year) and there are 23 species of this fly existent today. Tsetse flies include all the species in the genus Glossina, which are generally placed in their own family, the Glossinidae. [6]

AfrTryp_LifeCycle.gif[Fig. 2]

[1] When a tsetse fly bites it takes blood from a human or animal host.

[2] If the tsetse fly is infected it injects metacyclic trypomastigotes into skin tissue and the parasites enter the lymphatic system (part of the immune system) and pass into the bloodstream. Inside the host, they transform into bloodstream trypomastigotes and are carried to other parts of the body.

[3] After this bloodstream trypomastigotes reach other blood fluids such as lymph, spinal fluid and continue the replication by binary fission (Asexual reproduction where parent cells divide into two equal parts.).

[4/5] The entire life cycle of African Trypanosomes is in extracellular (outside the cells) stages. A tsetse fly becomes infected with bloodstream trypomastigotes when taking a blood meal on an infected host .

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[6] In the tsetse flies midgut (the mid section of the digestive tract), the parasites generate a cycle of trypomastigotes, they then multiply by binary fission and leave the midgut.

[7] Thereafter the parasites transform into epimastigotes (a developmental stage in trypanosomes)

[8] The epimastigotes reach the fly's salivary glands and continue multiplication by binary fission . This cycle in the fly takes approximately 3 weeks to occur.

http://www.icp.ucl.ac.be/~opperd/parasites/images/dia3.jpg[Fig.3]

This picture shows an African male in the late stage of African trypanosomiasis

Describe the biological processes involved in producing solutions to the problem

You can spot African trypanosomiasis early if the following symptoms occur, and treating the disease early increases the chances of survival. Symptoms of sleeping sickness begin with fever, headaches, and joint pains. If untreated, the disease slowly overcomes the immune defences of the infected person, and symptoms spread to anaemia, cardiovascular and kidney disorders. The disease then enters a neurological phase when the parasite passes through the blood-brain barrier (BBB). The symptoms of the second phase is what gives the disease its name, sleeping sickness, besides confusion and reduced coordination, the sleep cycle is disturbed with a period of lower level consciousness and periods of inability to sleep progressing to daytime drowsiness and night-time insomnia. Without treatment, the disease is fatal, with progressive mental deterioration leading to coma and death. Damage caused in the neurological phase can be irreversible. [7]

Stage 1 illness:

2 to 3 weeks later, Stage 1 disease develops as a result of the protozoa being carried through the blood and lymph circulation of the host. This phase of the illness is represented by a high fever that falls and rises again, also irritating rashes, and headaches may occur. The Gambiense form, in particular, includes extreme swelling of lymph tissue, with enlargement of both the spleen and liver, and greatly swollen lymph nodes. During this stage, the heart may be affected by a severe inflammatory reaction, particularly when the infection is caused by the Rhodesiense variety of trypanosomiasis.

These symptoms usually occur because of our immune system trying to defeat the invading organism; this is because of the increasing activity of our cells damaging organs and tissues. This may cause some blood vessels to leak and as a result of this the protozoa may spread further around the body.

The immune system responds so violently because the trypanosomes survive so well by quickly changing specific markers, which are the outer coats of unique proteins. These proteins stimulate the host's immune system to produce immune cells which will specifically target the marker, allowing quick destruction of those cells bearing the markers. Trypanosomes, however, are able to express new markers at such a high rate of change that the host's immune system is constantly trying to catch up.

Stage 2 illness

This involves the nervous system, especially Gambiense sleeping sickness, which has a phase in which the symptoms involve the brain. These symptoms are that the patient's speech becomes slurred, mental processes slow, and the patient sits and stares for long periods of time, or sleeps. Other symptoms resemble Parkinson's disease, including imbalance when walking, slow and shuffling gait, trembling of the limbs, involuntary movements, muscle tightness, and increasing mental confusion. Untreated, these symptoms could eventually lead to coma and then to death. [8]

There are various treatments for the disease but it depends on the how bad the disease has got and what stage it is at. Suramin, eflornithine, pentamidine, and several drugs which contain arsenic (a chemical which in higher doses is highly poisonous to humans), are all effective anti-trypanosomal agents.

When the disease is in its early stages it is easier to control and its treatments are the most effective, the least toxic, so the earlier the identification of the disease, the better the prospect of a cure.

At the second stage the treatments depend on drugs that can cross the blood and the brain, to reach the parasite, however these drugs are more toxic and therefore carry a risk with them. There are four drugs that have been registered for the treatment of sleeping sickness which are; pentamidine, melarsoprol, eflornithine and suramin.

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If the disease is diagnosed early, the chances of cure are high. The type of treatment depends on the phase of the disease: initial or neurological. During which the second stage of the trypanosome parasites reside in the cerebrospinal fluid (CSF) so success in the latter phase depends on having a drug that can cross the blood-brain barrier (BBB) to reach the parasite. Four drugs have been used until now. Without treatment, sleeping sickness will lead to death. Unfortunately, however, those medications effective against the Trypanosoma brucei complex protozoa all have significant potential side effects for the patient.

An external file that holds a picture, illustration, etc. Object name is AFHS0604-0223Fig1.jpg Object name is AFHS0604-0223Fig1.jpg

[Fig 4]

Sleeping sickness in South-Eastern Uganda from 1905- 2001

As you can see in figure 5 there were a high number of deaths of people from Trypanosomiasis from 1905-1915 but even thought the number decreases there have still been a lot of cases in this small region in the past 30 years and the number has been predicted to increase from

The First Stage Treatment

Suramin:

Suramin is a colourless derivative. The development of suramin followed observations that a number substances. Suramin has six negative charges at physiological pH, thereby preventing its diffusion across cell membranes and it could possibly be used against late stage trypanosomiasis because it does not cross the BBB.

Suramin is generally considered the drug of choice for the early stages of human African trypanosomiasis, especially T. b. rhodesiense infections.

Because of the size and charge of suramin it makes it unsuitable to have a specific transporter. Suramin easily binds to many proteins. At attainable levels, more than 75% of suramin is bound to proteins, which include low-density lipoproteins (LDL). LDL and transferin are taken up through a receptor-mediated endocytosis and suramin enters the parasite specifically found to LDL. Accumulation of the drug in trypanosomes is relatively slow.

In some studies, suramin has interfered with the metabolism of trypanosomes in different ways:

It hampers the receptor mediated uptake of LDL, the carrier of cholesterol which is required for parasite growth

Suramin, which enters via receptor mediated endocytosis in association with LDL, is most likely to accumulate inside the lysosome. Several of the enzymes encountered by suramin on its way from the extracellular fluid to the secondary lysosomes become inhibited by suramin.

Many glycolytic enzymes located inside the glycosome on the African trypanosome carry a high positive charge, and therefore are all inhibited by micro molar levels of suramin.

Second Stage Treatment

Eflornithine:

Eflornithine is an off-white, odourless, powder; the compound is freely soluble in water and sparingly soluble in ethanol. It is used mainly as a backup drug for melarsoprol but now in places such as Uganda it has become the first line treatment for sleeping sickness. Adverse drug reactions during eflornithine therapy are frequent. Their occurrence and intensity increase with the duration of treatment and the severity of the general condition of the patient. Generally, adverse reactions to eflornithine are reversible after the end of treatment.

Trypanosomes are more susceptible to the drug than human cells, possibly due to the slow turnover of the ODC enzyme (which is key in the biosynthesis of polyamines) in T. b. gambiense. Eflornithine can effectively inhibit ODC activity and use the supply of polyamines in trypanosomes, which bring them into a motionless state that makes them vulnerable to the host's immune attack. Therefore, a sufficiently active immune system is required to achieve a cure. Additionally, eflornithine induces the differentiation of thin forms to larger forms which do not divide anymore and therefore become accessible to the immune system. [9]

It was found in a study that the effectiveness of eflornithine was 98.7% on its patients which is a high cure rate.

Explain how the processes used are appropriate in terms of producing effective solutions to address the problem

As you can see a total of 6 patients died, 5 of them on the 14 day course therefore the 7 day course seems to be much more effective. The 7 day course seems to be cause less adverse events in general then the 14 day course. [Fig. 5]

However concluding figure 6 we can see that the probability of cure is higher in the 14 day regime then the 7 day regime. So even though there are some side effects of the 14 day regime still has a greater chance of curing the disease.[Fig. 6]

F1_medium.gif [Fig. 7]

A total of 103 patients with second-stage disease were enrolled. Cure rates were 94.1% for the eflornithine group and 96.2% for the nifurtimox-eflornithine group. Drug reactions were frequent in both arms, and severe reactions affected 25.5% of patients in the eflornithine group and 9.6% of those in the nifurtimox-eflornithine group, resulting in 2 and 1 treatment suspensions, respectively. There was 1 death in the eflornithine arm and no deaths in the nifurtimox-eflornithine arm. [10]

The nifurtimox-eflornithine combination appears to be a promising first-line therapy for second-stage sleeping sickness. [10]

F1_medium.gif [Fig 8] shows the probability of an event free survival among 1055 patients; they were treated with eflornithine for newly diagnosed second stage human African trypanosomiasis in Ibba, Southern Sudan.

1756-3305-1-3-3.jpg[Fig. 9]

The combined efforts of chemotherapy, systematic case detection and vector control led to a dramatic reduction in the incidence of sleeping sickness at the beginning of the 1960s as shown in figure 2. The grey bars represent the number of cases whilst the line graph shows the population screened.

Identify 2 implications of the solution encountered

Suramin

As suramin can only be injected it causes problems as African Trypanosomiasis can be spread easily from the needles not bring cleaned properly. If the patients who don't have the disease are injecting with the same unclean needle as people who are diagnosed this would result in the non-infected patients being infected.

Further problems of suramin are that it has many side effects which include abdominal pain, diarrhoea, metallic taste and joint pain. Less common side effects are loss of vision and swelling around eyes. It can even rarely cause fainting and death.

The advantages are that many of these side effects can be stopped by using a small sample dose, 100 mg IV, to test any toxic reactions of the patients.

Eflornithine

The route of application makes financial difficulties due to the workload and the additional material needed. A recently investigated abbreviated course of 7 days was found to cause a high relapse rate for the treatment of new cases. The superior outcome reported for the treatment of relapses still has to be confirmed, since there were a very small number of participants in the study. If there was an oral form for the treatment of sleeping sickness it would be more appropriate as it would be cheaper and less time consuming.

In a study the average cost of eflornithine per patient being 552.3 USD and the cost per patient's life saved averaging 559.8 USD. [10]

Eflornithine also has side effects which include acne stinging skin; headache; dry skin; itching; erythema (redness); dyspepsia(upset stomach or indigestion); alopecia

Fortunately there are advantages of this drug as efforts for the developments of an oral form of eflornithine are currently being made under the World Health Organisation/World Bank special programme for research and training in tropical diseases. This drug is generally better tolerated than the first line drug melarsoprol.

It was found in a study that the effectiveness of eflornithine was 98.7% on its patients which is very high and therefore if the illness is treated within its late stages, stage 2, the chances of survival are still high.

Evaluate the benefits and risks to humans, organisms and the environment

Benefits:

The side effects of Suramin can be stopped by using a small sample dose, 100 mg IV, to test any toxic reactions of the patients, so this means it could

An oral form of eflornithine is currently being made under the World Health Organisation/World Bank special programme for research and training in tropical diseases. This would lead to cheaper costs of to treat a patient; therefore more people can be treated and cured.

Effectiveness of eflornithine is 98.7% on its patients which is very high and therefore if the illness is treated within its late stages, stage 2, the chances of survival are still high, so a lot less people die when using the treatment.

Disadvantges:

The average cost of eflornithine per patient being 552.3 USD is far too high to cure most of the people especially because the treatment mainly depends on donated money as the government of the Third World countries are too poor to afford the treatment, so by using this lots of people may never be treated and therefore there may be a rise in the death rate.

As the treatment of patients decreases, if people donate less, the number of deaths from the disease will increase.

Further disadvantages of the treatments are that they both carry many side effects, even though some of these side effects aren't major, the lack of treatments in these poor countries could result in a gradual decrease in health over time.

Also some of the side effects and over doses could lead to death or serious illnesses so it is important to administer the drugs carefully and correctly as the end result could be fatal.

Discuss alternative views or solutions for the problem encountered

Pentamidine:

Pentamidine can be used instead of suramin for a first stage treatment of trypanosomiasis. It is medication with a very slow rate of diffusion across biological membranes and it only treats the T.B.G. form of African sleeping sickness in the first stage. It could be injected or inhaled by the patient.

Because of poor GI absorption, the drug is administered IV/IM and is strongly bound to tissues, including spleen, liver, and kidney. Clinical improvement usually noted within 24 h of injection. Reported to have a >90% cure rate. Pentamidine does not penetrate the blood-brain barrier effectively and, therefore, does not treat CNS infection. [9]

Fifty-eight patients in the early-late stage (early central nervous system involvement) of Trypanosoma brucei gambiense trypanosomiasis were treated with pentamidine and divided into four groups according to cerebrospinal fluid (CSF) indicators: white blood cell (WBC) count, protein level (CSF protein), and the presence or absence of trypanosomes.

Group 1 consisted of eight patients with normal CSF WBC counts and CSF protein levels and trypanosomes in the CSF.

Group 2 consisted of nine patients with elevated CSF WBC counts, normal level of CSF protein, and trypanosomes in the CSF.

Group 3 consisted of 31 patients with high CSF WBC counts, normal CSF protein levels, but no trypanosomes in the CSF.

Group 4 consisted of 10 patients with normal CSF WBC counts and CSF protein levels and trypanosomes demonstrated by CSF culture.

Post-treatment follow-up of all patients for at least one year revealed three relapses. There were two deaths from diseases unrelated to trypanosomiasis or to the treatment protocol. Of these patients, 52 were followed for more than two years, the time necessary to confirm a complete cure, indicating a cure rate of 94%. Pentamidine is therefore effective in treating the early-late stage of T. b. gambiense trypanosomiasis, and is comparable with melarsoprol or eflornithine in terms of its tolerance and availability. [11]

Side effects:

Shortness of breath; closing of the throat; hives; swelling of the lips, face, or tongue; rash; or faintin;, bleeding or bruising; blurred vision; chest pain or irregular heart beat; chills; difficulty breathing dizziness, fainting spells or excessive tiredness; drastic appetite changes; mouth ulcers severe stomach pain; severe headache; seizureshttp://bryanking.net/wp-content/uploads/2009/01/hives.jpg

[Fig 10]

This picture shows hives

which is a common side

effect of pentamidine

Melarsoprol:

Melarsoprol contains an arsenic element with a reactive arsenoxide group. The presence of the arsenoxide enables the ability of lipid solubility and this allows passage across the BBB. Apart from its transport function, the arsenoxide group mediates in the killing of the parasites in the bodily fluid; CSF (Cerebrospinal fluid). Modification of the melarsoprol parent ring to generate other analogous compounds can have a significant impact on its trypanocidal efficacy. The trivalent arsenicals; melarsoprol, melarsen oxide and phenylarsen are highly active with a minimum inhibitory concentration.

Usually the transport of melarsoprol into the trypanosome parasite is accomplished by purine tranporters. Purine transport is highly developed in trypanosomes as they do not synthesize nucleic acids and must directly acquire them from their hosts.

Resistance

The failure of melarsoprol to cure 10% of the late stage sleeping sickness patients possibly relates to the fact that these individuals accumulate levels of the drug in the brain. However, one study has indicated that the levels of drug are similar in the CSF of relapsing and non-relapsing patients, so parasites at other extravascular sites may be key to the treatment failure. In some regions, treatment failures have reached high levels up to 30%. Parasites retrieved from the patients with these treatment failures were less responsive to melarsoprol than parasites isolated from other foci. This clearly points to some form of mutation towards resistance. Indeed arsenic refractory parasites do possess an unusual amino purine transporter which accumulates melarsoprol and the loss of this transporter in the parasite leads to drug resistance. T. brucei contains several of the purine nucleoside transporter activities. [9]

Melarsoprol is a good alternative and is used as the first line drug against Human African Trypanosomiasis (HAT) in many countries. This is because the drug has longer intervals between when the dosages should be taken so it requires fewer resources and is therefore cheaper.

However melarsoprol is a highly dangerous treatment, only administered by injection under the supervision of a physician. It causes a range of side effects, among them convulsions, fever, unconsciousness etc. It is fatal in and of itself in approx. 10% of the cases. Meanwhile eflornithine is a modern and far less dangerous treatment for HAT but it is expensive not widely available in the market and the money for supplies are usually dependable on donations.

Melarsoprol is a good alternative and is used as the first line drug against Human African Trypanosomiasis (HAT) in many countries. This is because the drug has longer intervals between when the dosages should be taken so it requires fewer resources and is therefore cheaper.

However melarsoprol is a highly dangerous treatment, only administered by injection under the supervision of a physician. It causes a range of side effects, among them convulsions, fever, unconsciousness etc. It is fatal in and of itself in approx. 10% of the cases. Meanwhile eflornithine is a modern and far less dangerous treatment for HAT but it is expensive not widely available in the market and the money for supplies are usually dependable on donations.