Tag: Immunoglobulin M

Other Names:- Human African trypanosomiasis, sleeping sickness, African lethargy, or Congo trypanosomiasis.

Defenition:–
African trypanosomiasis or Sleeping sickness is infection with organisms carried by certain flies. It results in swelling of the brain. It is a parasitic disease of people and animals, caused by protozoa of the species Trypanosoma brucei and transmitted by the tsetse fly.

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The disease is endemic in some regions of Sub-Saharan Africa, covering about 36 countries and 60 million people. It is estimated that 50,000 to 70,000 people are currently infected, the number having declined somewhat in recent years.  Four major epidemics have occurred in recent history, one lasting from 1896–1906 and the other two in 1920 and 1970. In 2008 there was an epidemic in Uganda.

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History
The condition 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 identified in 1902–1903 by Sir David Bruce, and the differentiation between the subspecies 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. Numerous drugs designed to treat the disease have been introduced since then.

Symptoms and clinical features:-
Gambienseinfections lead to drowsiness during the day, but insomnia at night. Sleep becomes uncontrollable as the disease gets worse, and eventually leads to coma.

General symptoms include:

*Anxiety
*Drowsiness
*Fever
*Headache
*Increased sleepiness
*Insomnia at night
*Mood changes
*Sweating
*Swollen lymph nodes all over the body
*Swollen, red, painful nodule at site of fly bite
*Uncontrollable urge to sleep

Symptoms begin with fever, headaches, and joint pains. As the parasites enter through both the blood and lymph systems, lymph nodes often swell up to tremendous sizes. Winterbottom’s sign, the tell-tale swollen lymph nodes along the back of the neck, may appear. If untreated, the disease slowly overcomes the defenses of the infected person, and symptoms spread to include anemia, endocrine, cardiac, and kidney diseases and disorders. The disease then enters a neurological phase when the parasite passes through the blood-brain barrier. The symptoms of the second phase give the disease its name; besides confusion and reduced coordination, the sleep cycle is disturbed with bouts of fatigue punctuated with manic periods progressing to daytime slumber and night-time insomnia. Without treatment, the disease is invariably fatal, with progressive mental deterioration leading to coma and death. Damage caused in the neurological phase can be irreversible.

In addition to the bite of the tsetse fly, the disease is contractible in the following ways:

*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 (might be possible, but happens rarely)

Causes:–
Sleeping sickness is caused by two organisms, Trypanosoma brucei rhodesiense and Trypanosomoa brucei gambiense. The more severe form of the illness is caused by rhodesiense.

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Trypanosoma forms in a blood smear.

Tsetse flies carry the infection. When an infected fly bites you, painful, red swelling occurs at the site of the bite. The infection then spreads through your blood, causing episodes of fever, headache, sweating, and swelling of the lymph nodes.

The flagellate reproduces in the bloodstream, and the symptoms develop gradually as the burden of parasites and their harmful effects increases. It also migrates into the central nervous system, producing the characteristic symptoms.

T. brucei gambiense is the cause of a persistent infection that lasts several years until it finally develops into a coma, from which the patient cannot be woken. Hence the name ‘sleeping sickness’.

If the central nervous system is sufficiently affected, the patient can no longer be cured, and eventually dies, possibly from other infections that may be superimposed on the primary disease.

When the infection spreads to the central nervous system, it causes the symptoms typical of sleeping sickness . When it reaches the brain, behavioral changes such as fear and mood swings occur, followed by headache, fever, and weakness. Inflammation of the heart ( myocarditis) may develop.

Life cycle:-
The tsetse fly is large, brown and stealthy. While taking blood from a mammalian host, an infected tsetse fly (genus Glossina) injects metacyclic trypomastigotes into skin tissue. The parasites enter the lymphatic system and pass into the bloodstream

1.Inside the host, they transform into bloodstream trypomastigotes

2.are carried to other sites throughout the body, reach other blood fluids (e.g., lymph, spinal fluid), and continue the replication by binary fission

3.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

4.In the fly’s midgut, the parasites transform into procyclic trypomastigotes,

5.multiply by binary fission,

6.leave the midgut, and

7.transform into epimastigotes

8.The epimastigotes reach the fly’s salivary glands and continue multiplication by binary fission.
The cycle in the fly takes approximately 3 weeks to progress.

Diagnosis:
A physical examination may show signs of meningoencephalitis (inflammation of the brain and its covering, the meninges).

Tests include the following:

*Albumin levels
*Blood smear
*Cerebrospinal fluid tests
*Complete blood count (CBC)
*Globulin levels
*Lymph node aspiration

Most antibody and antigen test are not very helpful because they can’t distinguish between current and previous infection. Specific IgM levels in the cerebrospinal fluid may be helpful, however.

The diagnosis rests upon demonstrating trypanosomes by microscopic examination of chancre fluid, lymph node aspirates, blood, bone marrow, or, in the late stages of infection, cerebrospinal fluid. A wet preparation should be examined for the motile trypanosomes, and in addition a smear should be fixed, stained with Giemsa (or Field), and examined. Concentration techniques 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. Isolation of the parasite by inoculation of rats or mice is a sensitive method, but its use is limited to T. b. rhodesiense. Antibody detection has sensitivity and specificity that are too variable for clinical decisions. In addition, in infections with T. b. rhodesiense, seroconversion occurs after the onset of clinical symptoms and thus is of limited use.

Three similar serological tests are 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.

Possible Complications:-
Complications include injury related to falling asleep while driving or performing other activities, and progressive damage to the nervous system.

Treatment:-
First line, first stage
The current standard treatment for first stage disease is:

*Intravenous or intramuscular pentamidine (for T.b. gambiense); or
*Intravenous suramin (for T.b. rhodesiense)

The drug Eflornithine — previously used only as an alternative treatment for sleeping sickness due to its labour-intensive administration — was found to be safe and effective as a first-line treatment for the disease in 2008, according to the Science and Development Network’s Sub-Saharan Africa news updates. Researchers tracked over 1,000 adults and children at a centre in Ibba, Southern Sudan—the first use of eflornithine on a large scale— and it was highly effective in treating the issue.

According to a treatment study of Trypanosoma gambiense caused human African trypanosomiasis, use of eflornithine (DMFO) resulted in fewer adverse events than treatment with melarsoprol.

All patients should be followed up for two years with lumbar punctures every six months to look for relapse.

First line, second stage:-
The current standard treatment for second stage (later stage) disease is:

Intravenous melarsoprol 2.2 mg/kg daily for 10 consecutive days.
Alternative first line therapies include:

Intravenous melarsoprol 0.6 mg/kg on day 1, 1.2 mg/kg IV melarsoprol on day 2, and 1.2 mg/kg/day IV melarsoprol combined with oral 7.5 mg/kg nifurtimox twice a day on days 3 to 10; or
Intravenous eflornithine 50 mg/kg every six hours for 14 days.
Combination therapy with eflornithine and nifurtimox is safer and easier than treatment with eflornithine alone, and appears to be equally or more effective. It has been recommended as first-line treatment for second stage T. b. gambiensis disease.

Resistant disease:-
In areas with melarsoprol resistance or in patients who have relapsed after melarsoprol monotherapy, the treatment should be:

*melarsoprol and nifurtimox, or
*eflornithine

Outdated protocols
The following traditional regimens should no longer be used:

*(old “standard” 26-day melarsoprol therapy) Intravenous melarsoprol therapy (3 series of 3.6 mg/kg/day intravenously for 3 days, with 7-day breaks between the series) (this regimen is less convenient and patients are less likely to complete therapy);

*(incremental melarsoprol therapy) 10-day incremental-dose melarsoprol therapy (0.6 mg/kg iv on day 1, 1.2 mg/kg iv on day 2, and 1.8 mg/kg iv on days 3–10) (previously thought to reduce the risk of treatment-induced encephalopathy, but now known to be associated with an increased risk of relapse and a higher incidence of encephalopathy)

History and research:-
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% 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, 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.

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”.

Trypanosomiasis vaccines are undergoing research.

Drug targets and drug discovery:-
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 organism 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 single domain antibody has recently been found to work in mice, but has not been tested in humans.

The cover story of the August 25, 2006 issue of Cell journal describes an advance; Dr. Lee Soo Hee and colleagues, working at Johns Hopkins, have investigated the pathway by which the organism makes myristate, a 14-carbon length fatty acid. Myristate is a component of the variant surface glycoprotein (VSG), the molecule that makes up the trypanosome’s outer layer. This outer surface coat of VSG is vital to the trypanosome’s avoidance of immunological capture. Dr. Lee and colleagues discovered trypanosomes use a novel fatty acid synthesis pathway involving fatty acid elongases to make myristate and other fatty acids.

Prognosis:–
Without treatment, death may occur within 6 months from cardiac failure or from rhodesiense infection itself. Gambiense infection causes the classic “sleeping sickness” disease and gets worse more quickly, often over a few weeks. Both diseases should be treated immediately.

Prevention and control:-
For in depth information on prevention of the disease via tsetse fly control see Tsetse fly control……...click & see

Prevention and control focus on, where it is possible, the eradication of the parasitic host, the tsetse fly. Two alternative strategies have been used in the attempts to reduce the African trypanosomiases. One tactic is primarily medical or veterinary and targets the disease directly using monitoring, prophylaxis, treatment, and surveillance to reduce the number of organisms which carry the disease. The second strategy is generally entomological and intends to disrupt the cycle of transmission by reducing the number of flies. Instances of sleeping sickness are being reduced by the use of the sterile insect technique.

Regular active surveillance, involving case detection and treatment, in addition to tsetse fly control, is the backbone of the strategy for control of sleeping sickness. Systematic screening of communities in identified foci is the best approach as case-by-case screening is not practically possible in highly endemic regions. Systematic screening may be in the form of mobile clinics or fixed screening centres where teams travel daily to the foci. The nature of gambiense disease is such that patients do not seek treatment early enough because the symptoms at that stage are not evident or serious enough to warrant seeking medical attention, considering the remoteness of some affected areas. Also, diagnosis of the disease is difficult and most health workers may not be able to detect it. Systematic screening allows early-stage disease to be detected and treated before the disease progresses, and removes the potential human reservoir. There is a single case report of sexual transmission of West African sleeping sickness, but this is not believed to be an important route of transmission.

Other animals:
Trypanosoma of both the rhodesiense and gambiense types can affect other animals such as cattle and wild animals. In animals it is known as nagana (animal African trypanosomiasis)

Disclaimer: This information is not meant to be a substitute for professional medical advise or help. It is always best to consult with a Physician about serious health concerns. This information is in no way intended to diagnose or prescribe remedies.This is purely for educational purpose.

Resources:
http://en.wikipedia.org/wiki/African_trypanosomiasis
http://www.netdoctor.co.uk/travel/diseases/sleeping_sickness.htm
http://www.nlm.nih.gov/medlineplus/ency/article/001362.htm

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