Sleeping sickness

MedlinePlus = 001362
eMedicineSubj = med
eMedicineTopic = 2140
MeshID = D014353

Sleeping sickness or human African trypanosomiasis is a parasitic disease of people and animals, caused by protozoa of species "Trypanosoma brucei" and transmitted by the tsetse fly. [ [http://www.nlm.nih.gov/medlineplus/ency/article/001362.htm "Sleeping sickness,"] "Medline Plus," retrieved May 28, 2008.] The disease is endemic in certain 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. [cite paper
author=WHO Media centre
title=Fact sheet N°259: African trypanosomiasis or sleeping sickness
date=2006
url=http://www.who.int/mediacentre/factsheets/fs259/en/] Three 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. [ [http://allafrica.com/stories/200805120552.html "Uganda: Sleeping Sickness Reaching Alarming Levels,"] "New Vision," May 11, 2008.]

Clinical features

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 telltale 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 nighttime 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. [ [http://allafrica.com/stories/200805120552.html "Uganda: Sleeping Sickness Reaching Alarming Levels,"] "New Vision," May 11, 2008.]

In addition to the bite of the tsetse fly, the disease is contractible in the following ways:
*Mother to child infection: the trypanosome can cross the placenta and infect the fetus, causing perinatal death.
*Laboratories: accidental infections, for example, through the handling of blood of an infected person and organ transplantation, although this is uncommon.
*Blood transfusion

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 not identified until 1902–1903 by Sir David Bruce, and the differentiation between protozoa was not made until 1910. The first effective treatment, Atoxyl, an arsenic based drug developed by Paul Ehrlich and Kiyoshi Shiga was introduced in 1910 but blindness was a serious side effect. Numerous drugs designed to treat the disease have been introduced since then.

There have been three severe epidemics in Africa in recent history: one between 1896 and 1906, mostly in Uganda and the Congo Basin, one in 1920 in several African countries, and one that began in 1970 and is still in progress. The 1920 epidemic was arrested due to mobile teams systematically screening millions of people at risk. The disease had practically disappeared between 1960 and 1965. After that success, screening and effective surveillance were relaxed and the disease has reappeared in endemic form in several foci over the last thirty years. [cite paper
author=WHO Media centre
title=Fact sheet N°259: African trypanosomiasis or sleeping sickness
date=2001
url=http://www.who.int/mediacentre/factsheets/fs259/en/index.html]

Geographic distribution and epidemiology

The disease is found in two forms, depending on the parasite, either "Trypanosoma brucei gambiense" or "Trypanosoma brucei rhodesiense". "T. b. gambiense" is found in central and western Africa; it causes a chronic condition that can extend in a passive phase for months or years before symptoms emerge. "T. b. rhodesiense", is the acute form of the disease but has a much more limited range. It is found in southern and eastern Africa; its infection emerges in a few weeks and is more virulent and faster developing. According to recent estimates, the disability adjusted life years (9 to 10 years) (DALYs) lost due to sleeping sickness are 2.0 million. [cite paper
author=World Health Organization (Geneva)
title=World Health Report 2000: Health Systems Improving Performance
date=2000
url=http://www.who.int/tdr/diseases/tryp/direction.htm#Refs] Recent estimates indicate that over 60 million people living in some 250 foci are at risk of contracting the disease, and there are about 300,000 new cases each year. [cite paper
author=WHO Expert Committee on Control and Surveillance of African trypanosomiasis (Geneva)
title=WHO Technical Report Series,No.881
date=1998
url=http://www.who.int/tdr/diseases/tryp/direction.htm#Refs] The disease has been recorded as occurring in 36 countries, all in sub-Saharan Africa. It is endemic in southeast Uganda and western Kenya and kills more than 40,000 Africans a year. [ [http://allafrica.com/stories/200805120552.html "Uganda: Sleeping Sickness Reaching Alarming Levels,"] "New Vision," May 11, 2008.]

Humans are the main reservoir for "Trypanosoma brucei 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".

Horse-flies (Tabanidae) and Stomoxydinae possibly could play a role by mechanical transmission (in special situations) not only of Nagana (the animal form of sleeping sickness) but also of the human disease form. [cite journal
author=Cherenet T, Sani RA, Panandam JM, Nadzr S, Speybroeck N, van den Bossche P
title=Seasonal prevalence of bovine trypanosomosis in a tsetse-infested zone and a tsetse-free zone of the Amhara Region, north-west Ethiopia
journal=The Onderstepoort journal of veterinary research
year=2004 |volume=71 | issue=4 | pages= 307–312
url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15732457&query_hl=1]

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 (4,5). In the fly's midgut, the parasites transform into procyclic trypomastigotes, multiply by binary fission (6), leave the midgut, and transform into epimastigotes (7). The epimastigotes reach the fly's salivary glands and continue multiplication by binary fission (8). The cycle in the fly takes approximately 3 weeks to progress.

Laboratory diagnosis

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. PMID 12481210

Treatment

The current standard treatment for first stage disease is:
* Intravenous pentamidine (for "T.b. gambiense"); or
* Intravenous suramin (for "T.b. rhodesiense")

However, the drug Eflornithine was found safe as first-line sleeping sickness treatment in 2008, according to the Science and Development Network's Sub-Saharan Africa news updates. [http://www.scidev.net/en/sub-suharan-africa/news/sub-saharan-africa-news-in-brief-13-25-march.html] 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. Researchers tracked over 1,000 adults and children at a centre in Ibba, Southern Sudan — the first use of eflornithine on a large scale. It is highly effective in treating this issue

The current standard treatment for second stage (later stage) disease is:
* Intravenous melarsoprol 2.2 / daily for 10 consecutive days. [cite journal | title=Efficacy of new, concise schedule for melarsoprol in treatment of sleeping sickness caused by Trypanosoma brucei gambiense: a randomised trial | journal=Lancet | year=2000 | volume=355 | issue=9213 | pages=1419–25 | pmid=10791526 | doi=10.1016/S0140-6736(00)02141-3 | author=Burri, C | unused_data=Burri C, Nkunku S, Merolle A, "et al." ] 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;cite journal |author=Bisser S, N'Siesi FX, Lejon V, "et al" |title=Equivalence trial of melarsoprol and nifurtimox monotherapy and combination therapy for the treatment of second-stage Trypanosoma brucei gambiense sleeping sickness |journal=J. Infect. Dis. |volume=195 |issue=3 |pages=322–9 |year=2007 |pmid=17205469 |doi=10.1086/510534] or
* Intravenous eflornithine 50 mg/kg every six hours for 14 days. [cite journal | author=van Nieuwenhove S, Schechter PJ, Declercq J, "et al." | title=Treatment of gambiense sleeping sickness in the Sudan with oral DFMO (DL-alfa-difluoromethyl ornithine) an inhibitor of ornithine decarboxylase: first field trial | journal=Trans R Soc Trop Med Hyg | year=1985 | volume=79 | issue=5 | pages=692–8 | doi=10.1016/0035-9203(85)90195-6 ]

In areas with melarsoprol resistance or in patients who have relapsed after melarsoprol monotherapy, the treatment should be:
* melarsoprol and nifurtimox, or
* eflornithine

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);cite journal | author=Pepin J, Mpia B | title=Randomized controlled trial of three regimens of melarsoprol in the treatment of "Trypanosoma brucei gambiense" trypanosomiasis | journal=Trans R Soc Trop Med Hyg | year=2006 | volume=100 | pages=437–41 | pmid=16483622 | doi=10.1016/j.trstmh.2005.03.017]
* (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);

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. [cite journal |author=Chappuis F, Udayraj N, Stietenroth K, Meussen A, Bovier PA |title=Eflornithine is safer than melarsoprol for the treatment of second-stage Trypanosoma brucei gambiense human African trypanosomiasis |journal=Clin. Infect. Dis. |volume=41 |issue=5 |pages=748–51 |year=2005 |pmid=16080099 |doi=10.1086/432576]

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

History of treatment for sleeping sickness

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, New 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". [cite news
first=David
last=Williamson
title=Compound might defeat African sleeping sickness, clinical trial beginning this month
date=August 25, 2005
publisher=University of North Carolina
url=http://usinfo.state.gov/xarchives/display.html?p=washfile-english&y=2005&m=August&x=20050826160501cmretrop0.7327387&t=livefeeds/wf-latest.html] [cite news
author=Staff
page=5
title=Clinical Trials Update
date=September 15, 2005
publisher=Genetic Engineering News]

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 disease mixes and matches to evade immune system detection. [cite journal |author=Berriman M, Ghedin E, Hertz-Fowler C, "et al" |title=The genome of the African trypanosome Trypanosoma brucei |journal=Science |volume=309 |issue=5733 |pages=416–22 |year=2005 |pmid=16020726 |doi=10.1126/science.1112642 |url=http://www.sciencemag.org/cgi/content/full/309/5733/416]

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. [cite web | title=African Sleeping Sickness Breakthrough | url=http://domino.lancs.ac.uk/info/LUNews.nsf/I/448E635736B6B25A8025714700317FD1 | accessdate=April 7 | accessyear=2006 ]

A new treatment based on a truncated version of the apolipoprotein L-1 of high density lipoprotein and a nanobody has recently been found to work in mice, but has not been tested in humans. [
New Scientist, [http://www.newscientist.com/channel/health/mg19526181.400-cholesterol-secret-of-our-killer-blood.html 25 Aug. 2007, pp. 35-7] ]

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.

Prevention and control

"For in depth information on prevention of the disease via tsetse fly control see Tsetse fly control. "

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. [cite web
title=Strategic Direction for African Trypanosomiasis Research
work=Special Programme for Research and Training in Tropical Diseases
url=http://www.who.int/tdr/diseases/tryp/direction.htm
accessdate=2006-03-01]

There is a single case report of sexual transmission of West African sleeping sickness. cite journal
author=Rocha G, Martins A, Gama G, Brandão F, Atouguia J
title=Possible cases of sexual and congenital transmission of sleeping sickness
journal=Lancet
volume=363
pages=247
pmid=14738812
doi=10.1016/S0140-6736(03)15345-7
year=2004 ] This is not believed to be an important route of transmission. A case of sexually transmitted sleeping sickness was the focus of an episode of the television program House.

ee also

*Drugs for Neglected Diseases Initiative
*David Bruce (microbiologist)
*Sleep disorder
*The other important human tropical disease caused by Trypanosomes is Chagas-disease, occurring in America.

References

External links

* [http://www.doctorswithoutborders.org/news/sleepingsickness/index.cfm Sleeping sickness information page] at Médecins Sans Frontières
* [http://www.dndi.org Drugs for Neglected Diseases Initiative]
* [http://www.msf.org/msfinternational/invoke.cfm?component=pressrelease&objectid=50A057B8-7B34-41EA-95D003BD9DDE0B79&method=full_html Medecins Sans Frontieres' Eflornithine press release, 2001]
* [http://www.lib.uiowa.edu/hardin/md/trypanosomiasisAfr.html Links to pictures of Sleeping Sickness (Hardin MD/ University of Iowa)]
* [http://www.ucsf.edu/mckerrow/slide.html The Sandler Center for Basic Research in Parasitic Diseases, University of California, San Francisco] .
* [http://kfwh.org Kids For World Health]
* [http://www.scidev.net/en/sub-suharan-africa/news/sub-saharan-africa-news-in-brief-13-25-march.html Eflornithine 'safe as first-line sleeping sickness treatment']