O. vovulus microfilaria
Onchocerciasis, also known as "river blindness," "Roble’s disease," "craw-craw," or "sowda," is the world's second leading cause of blindness due to infection, with trachoma being number one. It is a chronic, non-fatal disease caused by a parasitic worm, Onchocerca volvulus, that enters the body through the bite of a blackfly.
It is estimated that 37 million people are infected at present with onchocerciasis and that among these more than 250,000 are blind and 500,000 have some degree of visual impairment (T.D.R. 2005).
The preferred treatment for onchocerciasis is the drug ivermectin (trade name Mectizan). Although ivermectin represents millions of dollars in research and development, and the work of countless numbers of researchers worldwide, since 1988 it has been provided free of charge by the company that developed this drug (Merck). This generosity is an example of how the world community, and those with means, can respond to a crisis that largely affects impoverished individuals in developing nations, giving freely of their resources to help those in need.
Distribution of vectors
The distribution and spread of onchocerciasis is a result of blackflies that carry the infectious nematode, Onchocerca volvulus. The primary agent for transmission (the vector) of this parasite is the fly genus Simulium. In Africa, where 99% of the cases occur, covering 30 countries in the sub-Saharan region, the most widespread vector is Simulium damnosum(sensu stricto). There are some regional species that are also important such as S. ethiopiense in Ethiopia , S. woodi in Malawi and Tanzania, and S. neavei in east Africa.
In Latin America, S. ochraceum, S. metallicum, and S. callidum are important vectors in Mexico, Guatemala, and Venezuela. In Colombia and Ecuador, S. exiguum is the primary vector with S. amazonicum being predominant in Brazil (W.H.O. 1987).
Blackfly life cycle
Blackflies, of the Simulium damnosum complex, lay their eggs in swiftly moving water where the eggs attach to submerged objects, such as rocks and plants. When the eggs hatch, within 36 to 48 hours, they become black larvae that remain attached. They feed and molt over a period of 8 to 10 days and then pupate for 2 to 5 days without losing their anchorage. After pupation, the adult fly emerges. The adults of S.damnosum may live up to one month, but other Simulium species may live up to three months.
The eggs of the female blackfly become fertilized when she mates with an adult male blackfly. After mating, she will seek a blood meal from a warm-blooded mammal. This blood nourishes the eggs and allows them to reach maturity. The female fly then seeks flowing water to lay her eggs and begin the cycle again.
Blackflies will feed on both livestock and people, and some species of Onchocerca, other than O. volvulus, will develop within cattle. Although there are a few reported cases of O. volvulus developing naturally in gorillas and spider monkeys, human beings are the most important natural host (Awadzi 1989).
The emergence of blackflies from rapidly moving rivers and streams makes any human beings living or working nearby a prime target for being bitten. Those who spend more time near the river are more likely to become bitten and infected by blackflies. The infection often develops into blindness and thus came to be known as "river blindness." People came to realize that they should move their villages away from the river and avoid working near it if they wanted to avoid the blindness. However, adult flies have been known to travel up to 150 kilometers. It was not until 1926 that Breadablane Blacklock, a Scottish parasitologist, discovered the connection between flies and the blindness of onchocerciasis while working in Sierra Leone (Blacklock 1926).
O. volvulus life cycle
The female fly bites the subject and causes a pool of blood to form on the skin surface. When she drinks this blood from an infected person, she will also receive the first stage microfilariae (L1) of the nemotode parasite, which will pass through the mouth (proboscis) and into the stomach. Most of the parasites will be digested by the stomach of the fly, but the few that survive will migrate into the cells of the flight muscles. They will molt twice, within seven days, to form stage three infective microfilariae (L3), which will then migrate back to the proboscis of the mouth.
When the fly has another blood meal, the third stage microfilariae (L3) will be carried into the human host when the fly injects its anticoagulant saliva. The microfilariae of the nemotode parasite enter the subcutaneous tissues of the host, where, within 3 months, they will mature into male and female adults. The adults will then mate and produce offspring that are stage one microfilaria. The formation of these microfilariae requires usually more than one year after the initial infection. It has been estimated that a single fertilized adult female can release up to 1,000 to 2,000 (L1) microfilariae per day into the skin, where they can live from 6 to 30 months. They stay near subepidermal capillaries, which makes them available to the invading proboscis of the next blackfly vector.
Adults worms become encased in fibrous connective tissue forming nodules. Within these subepidermal nodules, they continue to live and produce millions of (L1) microfilariae for up to 10 to 15 years.
O. volvulus morphology
The adult nematode worms are visible to the naked eye. They are white or cream colored with a threadlike appearance and tapered at both ends. The female worm is much larger than the male, measuring 230 millimeters to 500 millimeters (mm) long and 0.25 to 0.50 mm in width. The male is only 19 to 42 mm long with a width of about 0.14 mm.
The microfilariae require a microscope for examination. They have rounded heads, pointed tails, and measure 300 to 360 microns in length and 5 to 9 microns in width. They may be distinguished from other genera of microfilariae (Mansonella) by the absence of nuclei in the tip of the pointed tail (Awadzi 1989).
There may be no symptoms of the disease at first. The time from a bite by an infected blackfly to the first presence of microfilariae in the skin ranges from 7 to 34 months. The first skin symptom, excluding a reaction to the bite, is usually itching (pruritis) (Eezzuduemhoi et al. 2005).
Once the adult worms form a palpable skin nodule, then snips of skin (1-2 milligrams) above the nodule can be incubated in saline and examined under a microscope for microfilariae. At this stage, it is too late to kill the adult worms.
Blood smears are usually negative since the parasites remain in the subcutaneous tissues. Eosinophil counts may be elevated in only 30 percent of patients (Sinha et al. 2006). Microfilariae have been found in urine, cerebrospinal fluid, and sputum in people living in heavily infested areas.
If there are no palpable nodules, and skin snips above bony protuberances are negative, then a DEC patch test may be applied. A mixture of 10 percent diethylcarbamazine (DEC) suspended in Nivea cream is applied to the skin as a patch. The appearance of a localized inflammatory response is a positive indication of the presence of microfilariae. This test is reported to be able to detect only 30-80 percent of infections (Sinha et al. 2006).
Immunodiagnostic procedures to detect multiple antibodies of O. volvulus with only a single drop of blood have been developed. The sensitivity of the enzyme-linked immunosorbent assays (ELISA) is only 70-80 percent but the specificity is greater than 95 percent. This test requires expensive lab equipment to read the results and is not feasible in a field setting. An alternative procedure that uses rapid antibody cards to detect an immunoglobulin G4 response to the O.volvulus antibody (Ov-16) can be used and read in the field. This method is still being evaluated.
At present there is no early diagnosis for onchocerciasis that is 100 percent reliable. The goal is to detect the presence of microfilariae as soon as possible and begin ivermectin treatment before they have a chance to become adults.
Disease symptoms and pathology
In 1874, John O'Neill, an Irish surgeon,discovered the presence of O. volvulus microfilariae in skin snips taken from patients in Ghana. This was the first indication of a disease that would later be called onchocerciasis.
The areas most affected by O. volvulus are the skin, lymph nodes, and eyes. Onchocerciasis presents itself with varying degrees of involvement of each of these tissues depending on the geographic area and individual susceptibility. Some may show severe skin lesions without the blindness and others may show blindness with only minimal skin and lymph node involvement.
When the microfilariae migrate to the skin, they are a target for the immune system. White blood cells release various cytokines that have the effect of damaging the surrounding tissue and causing inflammation. This kills some microfilariae but is the cause of several symptoms associated with this disease.
In the skin, this can cause intense itching that can lead to persistent and continuous scratching that over time destroys the skin. It becomes swollen and chronically thickened, a condition often called lizard skin or elephant skin. The skin may also become lax as a result of the loss of elastic fibers. Over time, the skin may lose some of its melanin pigment in some areas and gain melanin in other areas this gives rise to a condition known as leopard skin.
The adult worms gradually become encased in a fibrous capsule that lies in the dermis and usually protrudes above bony bulges such as the head, shoulders, wrists, hips, knees, and ankles. These fibrous subepidermal protrusions are called skin nodules, onchocercal nodules, or onchocercomas. Skin nodules may contain two or three adult females plus an occasional adult male which may migrate between nodules to fertilize the females. The much smaller microfilariae may be present as they are being released by the fertilized females. As the adults age, they become calcified within the nodules (Kenney 1973).
The lymph nodes are visibly affected in this disease. There is scarring of the outer capsule. In some cases, the lymph nodes are swollen, especially in the groin area. The lymphphoid follicles show signs of atrophy. The germinal centers are fewer than normal. The central medulla is filled with eosinophils, mast cells, and plasma cells among others. Microfilariae are usually present in the fibrous capsule and may also be found in smaller numbers in the blood and lymph vessels of the nodes (Awadzi 1989)
The infection of the eyes tends to be progressive and happens very quickly in those with head nodules, which serve as a source of microfilariae. The microfilariae migrate to the surface of the cornea where they are attacked by the immune system. The cornea becomes opaque in small regions (punctate keratitis) as the microfilaria die. This condition can be reversed as the inflammation subsides. However, if the infection is chronic, the entire cornea can become irreversibly opaque, resulting in blindness.
With specialized microscopy, the microfilariae can be observed within the anterior chamber, the cornea, and the vitreous humor of the eye. The live microfilariae appear to cause minimal damage but upon their death, a severe inflammatory response ensues.
The iris and ciliary body of the eye can also be invaded by microfilariae producing anterior uveitis. This can cause a distortion of the pupil, atrophy of the iris, glaucoma, and cataracts.
The choroid and retina of the eye can also be affected in a condition called chorioretinitis. The choroid becomes inflamed and shows a loss of pigment from the vessels. The retinal pigment epithelium shows decreased pigmentation in some areas and increased pigmentation in others. The photoreceptors begin to disappear and then the inner layers of neuronal connections to the optic nerve begin to degenerate. Surprisingly, the macular region, responsible for visual acuity, is spared until the latter stages of onchocerciasis. The mechanism of how chorioretinitis is accomplished (pathogenesis) is not understood (Eezzuduemhoi et al. 2005).
Treatment and control
The preferred treatment for onchocerciasis is ivermectin, trade name mectizan. It is a semisynthetic lactone that was first produced in 1982 by Merck, Sharp, and Dohme. It is obtained as an isolate from the fermentation products of the bacterium Streptomyces avermitilis.
The recommended dosage is 150 micrograms per kilogram of body weight. A single dose will kill 90 percent of the microfilariae for up to one year. However, for people living in heavily infested areas, treatment is recommended every six months (Eezzuduemhoi 2005). While the drug does not kill the adult worms, it does prevent them from producing additional offspring, which alleviates some of the symptoms and decreases transmission to other people.
Since 1988, ivermectin has been provided free of charge by Merck & Co. through the Mectizan Donation Program. This program works together with ministries of health and non-governmental development organizations such as the World Health Organization to provide free mectizan to those who need it.
Precautions for ivermectin include pregnant women, children under age 5, and people who are infected by another filarial worm known as Loa loa. Carriers of loasis can have severe reactions to ivermectin.
The donation of ivermectin, representing millions of dollars in research and development, and the countless numbers of researchers all over the world working to find a solution to a disease that affects several nations of impoverished people, is an example of how the world community, and those with means, can respond to a crisis. When one part of the world becomes sick, then others can respond freely to offer their resources without exploiting the need to gain maximum profit.
There are various control programs that aim to stop the spread of onchocerciasis. The first was the Onchocerciasis Control Program (O.C.P.) which was launched in West Africa in 1975 by the United Nations and at its peak covered 30 million people in eleven countries. Through the use of larvicide spraying of rivers to control black fly populations and the use of ivermectin to treat infected people, the O.C.P. eliminated most of the onchocerciasis in its targeted areas and was discontinued in 2002.
In 1992, the Onchocerciasis Elimination Program for the Americas (O.E.P.A.) was launched. The OEPA also relies on ivermectin. In 1995, the African Program for Onchocerciasis Control (A.P.O.C.) began supplying another nineteen countries with the ivermectin from Merck and Co., but without the larviciding of rivers.
The research on developing macrofilaricides, drugs that can kill or sterilize the adult worms, continues. Moxidectin, a compound similar in structure to ivermectin, has shown some promise in killing adult Onchocerca in animals (T.D.R. 2005).
Another line of continuing research is to control the population of blackflies. One approach is through spraying chemical larvicides into the water to prevent fly development. At first DDT was used, which was replaced by the organophosphorus insecticide temephos or abate. An alternative to chemicals is the use of biological controls.
The bacterium known as Bacillus thuringiensis israelensis has been used to replace chemical insecticides for blackflies in most countries. It is more specific and less toxic to other organisms.
Antibiotics and Wohlbachia
New research suggests that the main inflammatory response thought to be caused by O. volvulus may actually be caused by a bacterium of the genus Wolbachia. These bacteria live within male and female nematodes and are transmitted to their offspring, the microfilariae. They appear to be important in producing the inflammatory response to microfilariae in the eye (Andre et al. 2002). When microfilariae die, the bacteria are released and induce a severe immune response. Treatment with the antibiotic doxycycline kills the bacteria and prevents this response. New evidence also indicates that doxycycline treatment for 6 weeks can make the female worms sterile for up to two years and thus unable to produce L1 microfilariae (Smith et al. 2006).
- Andre, A. S., N. M. Blackwell, L. R. Hall, A. Hoerauf, N. W. Brattig, L. Volkmann, M. J. Taylor, L. Ford, A. G. Hise, J. H. Lass, E. Diaconu, amd E. Pearlman. 2002. The role of endosymbiotic Wolbachia bacteria in the pathogenesis of river blindness. Science 295(5561):1892-1895.
- Awadzi, K. in R. Goldsmith and D. Heyneman,D. (eds.) 1989. Tropical Medicine and Parasitology. Norwalk, CT:Appleton & Lange.
- Blacklock, B. 1926. The development of Onchocerca volvulus in Simulium damnosum. Ann. Trop. Med. Parasitol. 20:1-48
- Eezzuduemhoi, D., and D. Wilson. 2005. Onchocerciasis. Retrieved May 23, 2007.
- Kenney, M. 1973. Scope Monograph on Pathoparasitology: A color Atlas of Parasites in Tissue Sections. Upjohn Co., Kalamazoo, Michigan.
- O'Neill, J. 1874. On the presence of a filaria in "Craw-Craw." The Lancet February 20, 1874: 265-266.
- Sinha,S., R. A. Schwartz, R. Kapila, and M. A. Forgione, Jr. 2006. Onchocerciasis. Retrieved May 23, 2007.
- Smith, D. S., D. Goverman, and J. Bass. 2006. Onchocerciasis course at Stanford.
- T. D. R. (Tropical Disease Research) 2005. Seventeenth Programme Report, Progress 2003-2004.
- W.H.O. (World Health Organization). 1987. WHO Expert Committee on Onchocerciasis, Third report. Geneva, Switzerland: World Health Organization.
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