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Onchocerciasis
Classification and external resources

Adult Black Fly (Simulium yahense) with parasite (Onchocerca volvulus) emerging from the insect's antenna. Magnified 100x.
ICD-10 B73.
ICD-9 125.3
DiseasesDB 9218
eMedicine med/1667 oph/709
MeSH D009855

Onchocerciasis (pronounced /ˈɒŋkɵsɜrˈsaɪ.əsɨs/ or /ˈɒŋkɵsɜrˈkaɪ.əsɨs/), also known as river blindness and Robles' Disease, is a parasitic disease caused by infection by Onchocerca volvulus, a nematode (roundworm).[1] Onchocerciasis is the world's second-leading infectious cause of blindness.[1] It is not the nematode but its endosymbiont, Wolbachia pipientis, that causes the severe inflammatory response that leaves many blind.[2] The parasite is transmitted to humans through the bite of a blackfly of the genus Simulium. The larval nematodes spread throughout the body. When the worms die their Wolbachia symbionts are released, triggering a host immune system response that causes intense itching and can destroy nearby tissue, such as the eye.[3]

The vast majority of infections occur in sub-Saharan Africa, although cases have also been reported in Yemen and isolated areas of Central and South America.[4] An estimated 18 million people suffer from onchocerciasis, with approximately 270,000 cases of blindness related to the infection.[1]

In 1915, Dr. Rodolfo Robles Valverde's study on patients with river blindness in Guatemala led to the discovery that the disease is caused by filaria volvulus and sheds light on the life cycle and transmission of the parasite. Using case studies of coffee plantation workers in Guatemala, Robles hypothesized that the vector of the disease is a day-biting insect, and more specifically two anthrophilic species of Simulium flies found in the endemic areas. He published his findings on a “new disease” from Guatemala associated with subcutaneous nodules, anterior ocular lesions, dermatitis, and microfilariae in 1917.[5]

Treatment may involve the use of the drug ivermectin. For best effect, entire communities are treated at the same time. A single dose may kill first-stage larvae (microfilariae) in infected people and prevents transmission for many months in the remaining population.[6] Other drugs are also available including the tetracycline-class antibiotic doxycycline, which kills the Wolbachia and renders the female nematodes sterile. The removal of the palpable nodules is common in Guatemala, Ecuador, and Mexico.[7]

Contents

[edit] Classification

Onchocerciasis may be divided into the following phases or types:[8]:440-441[verification needed]

Erisipela de la costa
An acute phase characterized by swelling of the face with erythema and itching.[8]:440 Onchocerciasis causes different kinds of skin changes and these changes vary in different geographic regions. This skin change, erisípela de la costa, of acute onchocerciasis is most commonly seen among victims in Central and South America.[7]
Mal morando
A cutaneous condition characterized by inflammation that is accompanied by hyperpigmentation.[8]:440
Sowda
A cutaneous condition, a localized type of onchocerciasis.[8]:440

Additionally, the various skin changes associated with onchocerciasis may be described as follows:[8]:440

Leopard skin
A term referring to the spotted depigmentation of the skin that may occur with onchocerciasis.[8]:440
Elephant skin
A term used to describe the thickening of human skin that may be associated with onchocerciasis.[8]:440
Lizard skin
A term used to describe the thickened, wrinkled skin changes that may result with onchocerciasis.[8]:441

[edit] Life cycle of Onchocerca volvulus

The life of the O. Volvulus parasite can be traced through the black fly and the human hosts in the following steps:[9]

  1. A Simulium female black fly takes a blood meal on an infected human host ingesting microfilaria.
  2. The microfilaria enter the gut and thoracic flight muscles of the black fly progressing into the first larval stage (J1.).
  3. The larvae mature into the second larval stage (J2.) and moves to the proboscis and into the saliva in its third larval stage (J3.). Mature in about 7 days.
  4. The black fly takes another blood meal passing the larvae into the next human host’s blood.
  5. The larvae migrate to the subcutaneous tissue and undergo two more molts. They form nodules as they mature into adult worms over six to twelve months.
  6. After maturing, adult male worms mate with female worms in the subcutaneous tissue to produce between 700 and 1,500 microfilaria per day.
  7. The microfilaria migrate to the skin during the day and the black flies only feed in the day, so the parasite is in a prime position for the female fly to ingest it. Black flies take blood meals to ingest these microfilaria to restart the cycle.

[edit] Signs and symptoms

Adult worms remain in subcutaneous nodules, limiting access to the host's immune system.[citation needed] Microfilariae, in contrast, are able to induce intense inflammatory responses, especially upon their death. Dying microfilariae have been recently discovered to release Wolbachia Surface Protein that activates TLR2 and TLR4, triggering innate immune responses and producing the inflammation and its associated morbidity.[10] Wolbachia species have been found to be endosymbionts of O. volvulus adults and microfilariae, and are thought to be the driving force behind most of O. volvulus morbidity. The severity of illness is directly proportional to the number of infected microfilariae and the power of the resultant inflammatory response.[citation needed]

Skin involvement typically consists of intense itching, swelling, and inflammation.[11] A grading system has developed to categorize the degree of skin involvement:[12][13][verification needed]

  • Acute papular onchodermatitis - scattered pruritic papules;
  • Chronic papular onchodermatitis - larger papule, resulting in hyperpigmentation;
  • Lichenified onchodermatitis - hyperpigmented papules and plaques, with edema, lymphadenopathy, pruritus and common secondary bacterial infections;
  • Skin atrophy - loss of elasticity, skin resembles tissue paper, 'lizard skin' appearance;
  • Depigmentation - 'leopard skin' appearance, usually on anterior lower leg.

Ocular involvement provides the common name associated with onchocerciasis, river blindness and may involve any part of the eye from conjunctiva and cornea to uvea and posterior segment including retina and optic nerve.[11] The microfilariae migrate to the surface of the cornea. Punctate keratitis occurs in the infected area. This clears up as the inflammation subsides. However, if the infection is chronic, sclerosing keratitis can occur, making the affected area become opaque. Over time the entire cornea may become opaque, thus leading to blindness. There is some evidence to suggest that the effect on the cornea is caused by an immune response to bacteria present in the worms.[citation needed]

The Mazzotti reaction, first described in 1948, is a symptom complex seen in patients after undergoing treatment of onchocerciasis with the medication diethylcarbamazine (DEC). Mazzotti reactions can be life-threatening and are characterized by fever, urticaria, swollen and tender lymph nodes, tachycardia, hypotension, arthralgias, oedema, and abdominal pain that occur within seven days of treatment of microfilariasis. The phenomenon is so common when DEC is used for the treatment of onchocerciasis that this drug is the basis of a skin patch test used to confirm that diagnosis. The drug patch is placed on the skin, and if the patient is infected with the microfilaria of Onchocerca volvulus, localized pruritus and urticaria are seen at the application site.[14]

[edit] Prevention

There are various control programs that aim to stop onchocerciasis from being a public health problem. The first was the Onchocerciasis Control Programme (OCP), which was launched in 1974 and at its peak covered 30 million people in eleven countries. Through the use of larvicide spraying of fast flowing rivers to control black fly populations and, from 1988 onwards, the use of ivermectin to treat infected people, the OCP eliminated onchocerciasis as a public health problem. The OCP, a joint effort of the World Health Organisation, the World Bank, the United Nations Development Programme and the UN Food and Agriculture Organization, was considered to be a success and came to an end in 2002. Continued monitoring ensures that onchocerciasis cannot reinvade the area of the OCP.[15]

In 1992 the Onchocerciasis Elimination Programme for the Americas (OEPA) was launched. The OEPA also relies on ivermectin.[16]

In 1995 the African Programme for Onchocerciasis Control (APOC) began covering another nineteen countries and mainly relying upon the use of ivermectin. Its goal is to set up a community-directed supply of ivermectin for those who are infected. In these ways, transmission has declined.[17]

[edit] Treatment

The burden of onchocerciasis: children leading blind adults in Africa.

In mass drug administration (MDA) programmes, the treatment for onchocerciasis is ivermectin (trade name: Mectizan); infected people can be treated with two doses of ivermectin, six months apart, repeated every three years. The drug paralyses and kills the microfilariae, causing fever, itching, and possibly oedema, arthritis and lymphadenopathy. Intense skin itching is eventually relieved and progression towards blindness halted. In addition, while the drug does not kill the adult worm, it does prevent them from producing additional offspring. The drug therefore prevents both morbidity and transmission.

Ivermectin treatment is particularly effective because it only needs to be taken once or twice a year, needs no refrigeration, and has a wide margin of safety, with the result that it has been widely given by minimally trained community health workers.[18]

[edit] Antibiotics

For the treatment of individuals, doxycycline is used to kill the Wolbachia bacteria that live in adult worms. This adjunct therapy has been shown to significantly lower microfilarial loads in the host, and may have activity against the adult worms, due to the symbiotic relationship between Wolbachia and the worm.[19][20] In four separate trials over ten years with various dosing regimes of doxycycline for individualized treatment, doxycycline was found to be effective in sterilizing the female worms and reducing their numbers over a period of four to six weeks. Research on other antibiotics such as rifampicin has shown it to been effective in animal models at reducing Wolbachia both as an alternative and as an adjunct to doxycycline.[21] However, doxycycline treatment requires daily dosing for at least four to six weeks, making it more difficult to administer in the affected areas.[18]

[edit] Ivermectin

Ivermectin kills the parasite by interfering with the nervous system and muscle function, in particular, by enhancing inhibitory neurotransmission. The drug binds to and activates glutamate-gated chloride channels (GluCls).[18] These channels, present in neurons and myocytes, are not invertebrate-specific, but are protected in vertebrates from the action of ivermectin by the blood-brain barrier.[18] Ivermectin is thought to irreversibly activate these channel receptors in the worm, eventually causing an inhibitory postsynaptic potential (IPSP). The chance of a future action potential occurring in synapses between neurons decreases and the nematodes experience flaccid paralysis followed by death.[22][23][24]

Ivermectin is directly effective against the larval stage microfilariae Onchocerca volvulus, which it paralyzes so that they can be killed by eosinophils and macrophages. Ivermectin does not kill adult females (macrofilariae) but causes them to cease releasing microfilariae, perhaps by paralyzing the reproductive tract.[18]

Since 1988, ivermectin has been provided free of charge for use in humans by Merck through the Mectizan donation program (MDP). The MDP works together with ministries of health and non-governmental development organisations such as the World Health Organization to provide free ivermectin to those who need it in endemic areas.[25]

A study of 2501 people in Ghana showed that the prevalence rate doubled between 2000 and 2005 despite treatment, suggesting that the parasite is developing resistance to the drug.[21][26][27] A clinical trial of another antiparasitic agent, moxidectin (manufactured by Wyeth), began on July 1, 2009 (NCT00790998).[28]

[edit] Epidemiology

Disability-adjusted life year for onchocerciasis per 100,000 inhabitants.
  no data
  less than 10
  10-50
  50-60
  60-70
  70-80
  80-90
  90-100
  100-150
  150-200
  200-300
  300-400
  more than 400

99% of onchocerciasis cases occur in Africa.[4] As of 2008 about 18 million people were infected with this parasite; approximately 300,000 had been permanently blinded.[29] Onchocerciasis is currently endemic in 30 African countries, Yemen, and isolated regions of South America. Travelers who do not stay long in those areas have little risk of developing the disease as it requires prolonged exposure to the fly bites and parasite introduction.

Onchocerciasis is endemic in 36 countries across Africa, Latin America and Yemen.[30] Over 85 million people live in endemic areas and half of these reside in Nigeria. Another 120 million people are at risk for contracting the disease. Due to the vector’s breeding habitat, the disease is more severe along the major rivers in the northern and central areas of the continent, and severity declines in villages farther from rivers.[citation needed]

According to a 2002 WHO report, Onchocerciasis has not caused a single death, but its global burden is 987,000 disability adjusted life years (DALYs). The severe pruritis alone accounts for 60% of the DALYs. Infection reduces the host’s immunity and resistance to other diseases. This results in an estimated reduction in life expectancy of 13 years.[30]

[edit] Research

Animal models for the disease are somewhat limited, as the parasite only lives in primates, but there are close parallels. Litomosoides sigmodontis , which will naturally infect cotton rats, has been found to fully develop in BALB/c mice. Onchocerca ochengi, the closest relative of O. volvulus, lives in intradermal cavities in cattle and is also spread by blackflies. Both systems are useful but not exact animal models.[31]

[edit] See also

Rod of asclepius.png Medicine portal

[edit] References

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  3. ^ "Causes of river blindness". Sightsavers International. Archived from the original on 2007-10-15. http://web.archive.org/web/20071015154331/http://sightsavers.org/What+We+Do/Eye+Conditions/River+Blindness/World1629.html. Retrieved 2008-01-28.  (archived 2007-10-15)
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  14. ^ http://microblog.me.uk/420
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  16. ^ "Onchocerciasis Elimination Program for the Americas (OEPA)". Programmes and Projects. World Health Organization. http://www.who.int/blindness/partnerships/onchocerciasis_oepa/en/index.html. Retrieved 2010-06-15. 
  17. ^ "African Programme for Onchocerciasis Control (APOC)". Programmes and Projects. World Health Organization. http://www.who.int/blindness/partnerships/APOC/en/index.html. Retrieved 2010-06-15. 
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  19. ^ Trattler, Bill; Gladwin, Mark (2007). Clinical Microbiology Made Ridiculously Simple. Miami: MedMaster. ISBN 0-940780-81-X. OCLC 156907378. 
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  22. ^ Yates DM, Wolstenholme AJ (August 2004). "An ivermectin-sensitive glutamate-gated chloride channel subunit from Dirofilaria immitis". International Journal for Parasitology 34 (9): 1075–81. doi:10.1016/j.ijpara.2004.04.010. PMID 15313134. 
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  25. ^ Thylefors B, Alleman MM, Twum-Danso NA (2008 May). "Operational lessons from 20 years of the Mectizan Donation Program for the control of onchocerciasis". Trop Med Int Health 13 (5): 689–96. doi:10.1111/j.1365-3156.2008.02049.x. PMID 18419585. 
  26. ^ "River blindness resistance fears". BBC News. 2007-06-14. http://news.bbc.co.uk/2/hi/health/6753003.stm. Retrieved 2007-06-15. 
  27. ^ Osei-Atweneboana MY, Eng JK, Boakye DA, Gyapong JO, Prichard RK (June 2007). "Prevalence and intensity of Onchocerca volvulus infection and efficacy of ivermectin in endemic communities in Ghana: a two-phase epidemiological study". Lancet 369 (9578): 2021–9. doi:10.1016/S0140-6736(07)60942-8. PMID 17574093. http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(07)60942-8. 
  28. ^ [No author listed] (11 July 2009). "Fighting river blindness and other ills". Lancet 374 (9684): 91. doi:10.1016/S0140-6736(09)61262-9. PMID 19595328.  (editorial)
  29. ^ "What is river blindness?". Sightsavers International. Archived from the original on 2007-12-15. http://web.archive.org/web/20071215140210/http://www.sightsavers.org/What+We+Do/Eye+Conditions/River+Blindness/World1622.html. Retrieved 2008-01-28. 
  30. ^ a b "Epidemiology". Stanford University. 2006. http://www.stanford.edu/class/humbio103/ParaSites2006/Onchocerciasis/Epidemiology.html. 
  31. ^ Allen JE, Adjei O, Bain O, Hoerauf A, Hoffmann WH, Makepeace BL, Schulz-Key H, Tanya VN, Trees AJ, Wanji S, Taylor DW (April 2008). "Of mice, cattle, and humans: the immunology and treatment of river blindness". PLoS Negl Trop Dis 2 (4): e217. doi:10.1371/journal.pntd.0000217. PMC 2323618. PMID 18446236. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2323618. 

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