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My disease of study is Onchocerciasis. It is cause by the nematode Onchocerca volvulus and transmitted by Simulium  or their common name Blackflies.

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Onchocerciasis, or river blindness, is a neglected tropical disease (NTD) caused by the parasitic worm Onchocerca volvulus. It is transmitted through repeated bites by blackflies of the genus Simulium. The disease is called river blindness because the blackfly that transmits the infection lives and breeds near fast-flowing streams and rivers, mostly near remote rural villages. The infection can result in visual impairment and sometimes blindness. Additionally, onchocerciasis can cause skin disease, including intense itching, rashes, or nodules under the skin. Worldwide onchocerciasis is second only to trachoma as an infectious cause of blindness.

Images: Left/Right: Blackflies, the vector of onchocerciasis. Center: Microfilariae of O. volvulus from a skin nodule of a patient from Zambia, stained with H&E. Image taken at 1000x oil magnification. (Credit: WHOexternal icon , DPDx, CDC)

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Onchocerciasis, or river blindness, is a neglected tropical disease (NTD) caused by the parasitic worm Onchocerca volvulus. It is transmitted through repeated bites by blackflies of the genus Simulium. The disease is called river blindness because the blackfly that transmits the infection lives and breeds near fast-flowing streams and rivers, mostly near remote rural villages.

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Onchocerciasis was first detected in 1874 by John O' Neil while he was examining skin snips from patients in Ghana. The suspected infectious agent is a parasite. Onchocerciasis is a chronic disease. Chronic means it is ongoing or constantly returning.

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The year 2012 marks the 25th anniversary of the donation of ivermectin to fight onchocerciasis and the projected date for elimination of transmission of the disease in the Americas. This review looks at the history of onchocerciasis, from its discovery through to 2025, by which time it is projected that the disease will have been eliminated as a public health problem, except in a handful of sub-Saharan countries, where it should be well on the way towards elimination.

Can science, human ingenuity and teamwork conquer onchocerciasis?

In 1945, the renowned ophthalmologist Sir Harold Ridley wrote, "...it is inconceivable that, in the end, science will be defeated by a filaria". The words appeared at the end of a seminal article he published on onchocerciasis (river blindness), a parasitic disease prevalent throughout tropical Africa for centuries []. He may soon be proved correct, for the fight to control onchocerciasis, which has been progressing since 1946 and became truly international and gathered momentum since 1974, has been pioneering, innovative and highly successful, a model for others to follow. The long-term efforts at onchocerciasis control, together with sustained political commitment of national governments, bilateral donors, and non-governmental development organisations (NGDOs) and affected communities themselves, is a major, yet relatively unheralded public health and development success story. Investments in onchocerciasis control also provide one of the highest economic rates of return of all international development initiatives, some 15-20% []. The year 2012 marks the 25th anniversary of the global donation of a curative drug, ivermectin, for as long as it is needed, as well as being the target date for eliminating onchocerciasis from the Americas, and evidence has recently emerged that it may well be possible to eliminate the disease from its origins in Africa using mass administration of ivermectin. Unsurprisingly, onchocerciasis control has been labelled 'one of the most triumphant public health campaigns ever waged in the developing world' [

].

References

1. Gaillard, J. et al. (2005) Africa. In UNESCO, World Science Report, pp. 177-202, UNESCO

2. Davidson A. Hygiene and Diseases of Warm Climates. Young J. Pentland, 1893

3. The "blinding filarial" of Guatemala (Onchocerca caecutiens, Brumpt 1919).

in: Proceedings of the International Conference on Health Problems in Tropical Countries. United Fruit Company, 1924: 241-255

4. Wolbachia endosymbionts: an Achilles' heel of filarial nematodes.

in: Hoerauf A. Rao R.U. Wolbachia: A Bug's Life in Another Bug. Karger, 2007: 31-51

5. Doxycycline in the treatment of human Onchocerciasis: kinetics of Wolbachia endobacteria reduction and of inhibition of embryogenesis in female Onchocerca worms.

: 261-273

6. Habbema, J.D.F. et al. (2007) Health Impact Assessment, Erasmus University and African Programme for Onchocerciasis Control, WHO Department of Control of Neglected Tropical Diseases. ( http://www.who.int/apoc/publications/APOC%20rapid%20HIA_final%20report_def.pdf)

7. World Health Organization/African Programme for Onchocerciasis Control (2011) WHO African Programme for Onchocerciasis Control: Progress Report 2011, WHO

World Health Organization/African Programme for Onchocerciasis Control Final Communiqué

17th Session of the Joint Action Forum, Kuwait City, Kuwait, 12-14 December, 2011, WHO 2012

9. Mectizan Donation Programme (2012) Annual Highlights 2011: Celebrating 25 years of the Mectizan Donation Program in 2012. ( http://www.mectizan.org/sites/default/files/Annual%20Highlights%202011%20English.pdf)

10. Liese, B. et al. (1991) Organizing and Managing Tropical Disease Control Programmes: Lessons of Success, World Bank Technical Paper No. 159, World Bank

11. Longitudinal evaluation of repellent activity of Ocimium gratissimum (Labiatae) volatile oil against Simulium damnosum.

: 201-205

12. Handbook of Drugs for Tropical Parasitic Infections.

2nd edn. Taylor and Francis, 1995

13. Avermectins, new family of potent anthelmintic agents: efficacy of the B 1A component.

: 372-378

14. Mode of action of avermectin.

in: Ōmura S. Macrolide Antibiotics; Chemistry, Biology and Practice. 2nd edn. Academic Press, 2002: 571-575

15. Moxidectin.

in: Vercruysse J. Rew R.S. Macrocyclic Lactones in Antiparasitic Therapy. CABI Publishing, 2002

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DOI: https://doi.org/10.1016/j.pt.2012.04.005

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Disease origins and spread

Onchocerciasis is prevalent throughout many major river basins in Africa, the traditional homes of the rural, subsistence farming population of the continent. It is also called river blindness because the blood-feeding flies that transmit the ultimately blinding disease inhabit lush, fertile land alongside the rivers in which they breed. Onchocerciasis was first scientifically observed almost 140 years ago, despite it having been around for centuries. Subsequently, scientists recognised that humans develop the disease after being bitten by vector blackflies of the genus Simulium ( Box 1) that were carrying infective larvae of a filarial threadworm parasite, Onchocerca volvulus ( Box 2). Some 13 million km ² of the earth became covered by the disease, with infection rates varying considerably depending on altitude, rainfall levels, latitude and environmental factors affecting the breeding of the insect vector. More than 99% of people infected with O. volvulus live in sub-Saharan Africa. Following the independence of South Sudan, the disease ( Box 3) affects 31 African nations, with Nigeria accounting for 25% of the total global infection. It was also inadvertently introduced into other parts of the world through human activity, the locations being Yemen and six Latin American nations, Brazil, Colombia, Ecuador, Guatemala, Mexico and Venezuela []. Other forms of onchocerciasis affect various animals, including wild game, livestock, draught animals and dogs.

The vector

In tropical Africa, Onchocerca parasites are transmitted primarily by Dipteran blackflies of the Simulium damnosum complex, members of the Simulium neavei group also being vectors. Some game animals, notably elands and buffalo, are possible reservoir hosts, which, if true, will make disease eradication in places where these animals exist impractical [

]. In the Western hemisphere, varieties of Simulium species bite humans and may transmit parasites.

Female blackflies require a bloodmeal to develop their eggs. When the fly bites, microfilarial parasites move towards the bite site, are ingested, and undergo development in the insect vector. During a bloodfeed, the mandibles of the fly cut into the skin with rapid scissor-like movements causing blood to pool, the blood being sucked by cibarial and pharyngeal pumps, with blood-feeding usually taking 4-5 min ( http://www.blackfly.org.uk/simbiol2.html). The bites can be an entry point for any pathogens that the flies carry or which exist in the environment [

,

]. Infected female flies deposit infective Onchocerca larvae, which enter the human body.

Female blackflies lay their eggs (in batches of 200-300) on vegetation in rapid flowing, turbulent, well-oxygenated streams and rivers up to 1400 m in elevation. In 2-3 weeks the eggs develop into aquatic larvae, attaching themselves to plant stems or rocks just below the water surface, before developing into the adult form, the process occurring in as little as 6 weeks.

Adult blackflies usually remain close to the watercourse where they emerge, although they can travel vast distances borne on prevailing winds, with studies showing that S. damnosum can invade land up to 400 km from their origin. Prone to desiccation, the flies are photophobic, sheltering in grass and locating a human host when they walk past; flies usually feed during cooler hours of early morning or late afternoon (coinciding with active farming periods). Their riverine ecological and behavioural peculiarities mean they infest the most fertile land available.

Repeated infective bites, sometimes over many months, cause infection - in hyperendemic areas, one person may suffer several thousand bites a day. The consequence is an overall lowering of productivity, ill health, disfigurement and often abandonment of infested areas, devastating socioeconomic wellbeing in affected communities. Recent reports indicate that the cost to individual families in Africa can be catastrophic with poor subsistence farmers in Nigeria spending half of their annual income to treat ailments associated with blackfly bites [

Socioeconomic implications of Simulium damnosum complex infestation in some rural communities in Odeda local government area of Ogun State,Nigeria.

]. Blackfly bites have also accounted for reduced tourism and deaths in wild animals and livestock [

].

The parasite

O. volvulus has not been transmitted experimentally to humans by infected flies, but epidemiological evidence suggests that the prepatent period between inoculum and appearance of microfilariae is between 3 and 18 months, being most commonly around 15 months [

]. Once in the human body, infective larvae, which mature in around 12 months but can exist for 14 years, develop into adult worms which then mate. Adult male and female worms, usually paired, are predominantly found in fibrous subcutaneous nodules or cysts. The nodules, which feel like rubber, do not cause pain or tenderness. They are commonly found over a bony area, usually over the ribs and iliac crests in Africa and on the forehead in the Americas. Nodule size varies (generally being smaller in the Americas), as do the numbers on any individual, the highest recorded being 126. The nearer the nodule is to the eye, the greater the chance of ocular involvement. The nodules usually contain more than one pair of worms, commonly intertwined, as well as several single males, which are considerably smaller than the females (which can be up to 300 mm in length). Reproduction is ovoviviparous, with females producing embryonic microfilariae, often in excess of 1000 daily. The reproductive lifespan of a female is 14-15 years. Adult worms may live for 15 years and can produce microfilariae for up to 10 years [

], whereas microfilariae live for 6 months to 3 years [

The intake and transmissibility of Onchocerca volvulus microfilariae by Simulium damnosum fed on patients treated with Diethylcarbamazine, Suramin or Mel W.

]. Microfilariae of the African and American worms are indistinguishable. They migrate primarily to the skin, mammary glands, eye and lymph glands but are not usually found in the blood. Thousands of microfilariae eventually die, stimulating the immune system of the host and provoking the inflammatory tissue reactions responsible for symptoms of the disease.

The disease

In humans, infection can lead to severe visual impairment, including permanent blindness. Immature Onchocerca worms (microfilariae) enter virtually every part of the eye, except the lens, and cause inflammation, bleeding and other complications. The result is impaired vision and, eventually, blindness from corneal opacities, complicated cataract, choridoretinal degeneration and optic atrophy, with a tendency for bilateral symmetry leading to both eyes being damaged. Of perhaps greater significance, infection also results in the formation of skin nodules and onchocercal skin disease, which is manifest in skin lesions that cause severe itching, dermatitis and depigmentation, which can culminate in gross and stigmatising skin disfigurement. Skin lesions are widespread, numerous and readily visible, being named 'leopard skin' and 'elephant skin'. The skin becomes dry and wrinkled, losing its elasticity, causing those affected to look much older than their age. It is believed that skin lesions and ocular complications are caused by the immune response of the host to the dead parasites, live microfilariae inducing no such response. However, living adult worms do stimulate a reticuloendothelial response which helps form the fibrous nodules in which they dwell [

]. Unrelenting itching alone is estimated to account for 60% of the disease burden, and onchocerciasis has also been shown to curtail life expectancy by up to 15 years [

World Health Organization

First WHO Report on Neglected Tropical Diseases: Working to Overcome the Global Impact of Neglected Tropical Diseases.

]. The socioeconomic costs of the disease to a nation are known to be in the tens of millions annually.

Recently, there has been an increasing and, as yet unexplained, association between onchocerciasis and some mental conditions, especially in children. In Uganda, since the 1960s, onchocerciasis infection has been linked with Nakalanga syndrome, a hyposexual dwarfism usually associated with dental caries and mental disturbances. Elsewhere in parts of Africa where onchocerciasis and epilepsy occur together, and where belief in spirits is deep-rooted, there is an anecdotal link between the two [

,

].

Nodding syndrome, a mysterious permanent neurologic condition is increasingly being reported from Sudan, Uganda and Tanzania. Although its aetiology and pathophysiology remain unknown, infected children (mainly 5-15 years old) exhibit epileptic-like seizures, impaired cognition and nod their heads constantly when they are given food. Most afflicted with Nodding syndrome also have antibodies for Onchocerca and live near rivers or fast-moving streams but no association has yet been proven. The disease is also associated with malnourishment and vitamin B ₆ deficiency [

].

Although not proven, it is generally accepted that disease foci outside Africa are the consequence of accidental introduction of the parasite, almost certainly due to infected individuals being transported via the slave trade []. A recent United Nations Educational, Scientific and Cultural Organization (UNESCO) analysis concluded that 15-18 million captives were involved in the Trans-Atlantic trade alone (not including those who died en route). More than half toiled in sugarcane plantations in the Caribbean and Brazil [

]. An estimated 40% of the total went to Brazil, which, in 1888, was the last of the New World territories to abolish slavery. Most of the slaves transported in the Trans-Atlantic trade originated in areas of Africa where onchocerciasis was endemic ( Figure 1 a-d), with the current distribution of the disease reflecting the destination of slaves.

The 2007 bicentennial of the abolition of the slave trade drew attention to the legacy of slavery, especially its inhuman and socially devastating consequences, as well as its detrimental public health impact. Transportation of millions of slaves facilitated introduction of a range of parasitic diseases to the Americas which persist today, including onchocerciasis [, ]. The introduction of the causative parasites, coupled with the presence of competent vectors, allowed the imported diseases to be transmitted in the new environments, a view first espoused by parasitologists more than a century ago []. Compelling evidence supporting this hypothesis has only relatively recently appeared, for example, molecular studies of O. volvulus finding very limited heterogeneity in New World strains, but discovering that they share a strong affinity with West African strains [].

Onchocerciasis timeline: from discovery - through control - to elimination

1874. John O'Neill, a British naval surgeon based in the Gold Coast (now Ghana) was intrigued by an irritating and intractable skin disease afflicting many locals. Similar to scabies, it was known locally as 'kra kra' or 'craw-craw'. Microscopic examination of specimens taken from papules of patients showed easily visible, minute worms that contorted violently. O'Neill recorded "at the head, or blunted extremity, two small dots are noticed, but their nature could not be determined" []. This proved to be the first observation of the microfilaria of O. volvulus.

1890. An unknown German surgeon in the Gold Coast excised two lumps (nodules), each the size of the egg of a small bird, from the scalp and the chest of two locals. Discovering the nodules contained worms, he sent them to Rudolf Leuckart in Germany for identification. Leuckart found several female and male worms in each nodule, the females being 6-70 mm in length and the males approximately half that size, all coiled together in a compact ball. The worm mass was in a cavity containing fluid laden with embryos. Leuckart did not announce his discovery, but informed the renowned British parasitologist Sir Patrick Manson. Manson subsequently published a brief note, acknowledging Leuckart, labelling the parasite Filaria volvulus (from the Latin 'volvo, volvere' meaning to roll or turn round) [

].

1899. Labadie-Lagrave and Deguy removed a female worm from a nodule on a French soldier who had returned from West Africa and identified it as F. volvulus [].

1901. The first detailed descriptions of adult worms (male and female) and microfilariae were published [

].

1910. Raillet and Henry transferred the parasite from the genus Filaria to the genus Onchocerca, which had been erected by Diesing in 1841. The name Onchocerca was derived from a combination of the Greek word 'Onchos' meaning 'hook' and 'Kerkos' or 'Cercos' meaning 'tail' [

]. Humans are the only definitive host for O. volvulus.

1915. Ocular onchocerciasis was first identified by Robles and Pacheco-Luna in Guatemala. Robles encountered a patient with erysipelas of the face accompanied by fever, pruritus and poor vision but could not identify any cause. He subsequently examined a boy with identical symptoms who also had oedema of the eyelids, the forehead, and upper lip and who displayed a cherry-sized nodule on his forehead. Robles excised the nodule and discovered the first adult Onchocerca in the Americas, reporting, "I understood then that the erysipelas lesions surely were due to the presence of this parasite" []. He later postulated that Simulium flies might be the vector of the parasites and that there was a link between infection and eye disease [].

1919. The worm in the Americas was designated Onchocerca caecutiens (the blinding filaria) by Brumpt [

]. Calderon posited that eye lesions were caused by toxins released by the worms (V.M. Calderon, PhD thesis, Tipografia Sanchez et de Guise, 1920).

1920. Montpelier and Lacroix confirmed the presence of microfilariae in the skin of African patients and linked it to their dermatitis [].

1921. Ouzilleau and colleagues made the first mention of African patients with onchocercal elephantiasis and eye disease, but did not draw any specific connection, and the role of onchocerciasis as a significant cause of blindness in Africa was not recognised until the mid-1940s [

].

1923. Blacklock started investigating the mode of transmission of onchocerciasis in Sierra Leone. As microfilariae were found in the skin but not blood, he proposed that any arthropod transmitting the worms must damage the skin and dislodge the larvae in its efforts to reach blood. He eventually noticed that a common small blackfly, prophetically named Simulium damnosum, was biting humans. The fly does not actively seek a host, but waits in short grass for one to pass, biting low on the body, usually around the lower leg and ankle [

,

,

].

1924. Fülleborn argued that the two forms of Onchocerca found in Africa and the Americas were morphologically indistinct and that there was only one species, O. volvulus [

The "blinding filarial" of Guatemala (Onchocerca caecutiens, Brumpt 1919).

in: Proceedings of the International Conference on Health Problems in Tropical Countries. United Fruit Company, 1924: 241-255

]. It is the only Onchocerca species to affect humans, although many others are parasites of livestock and companion animals. In Africa, buffalo and elands may serve as reservoirs of O. volvulus, making it difficult to eradicate onchocerciasis in areas where herds of game abound. In Australia, Onchocerca gibsoni became a serious problem in cattle, making the animals unfit for human consumption and rendering the skin worthless []. This was exploited later for screening of potential anti-onchocerciasis drugs, as the human parasite cannot be cultured in the laboratory.

1925. In the middle of the 1920s, it became clear that the unsheathed microfilariae obtained from O. volvulus adults were the same microfilariae seen in the skin. It seemed certain that the filariae seen in the skin 50 years earlier by O'Neill were in fact O. volvulus microfilariae [].

1930. Ochoterena reported that Simulium ochraceum was the main vector in the Americas. This species bites higher up, some 1.5 m above ground, which is why nodules in America are usually located on the head []. Many species of Simulium transmit the parasite, and it was believed that Onchocerca can also be spread by other blood-feeding insect vectors.

1930. Hissette compiled the first comprehensive report of eye lesions, finding that 20% of onchocerciasis sufferers were blind in a focus on the Sankuru River in the Belgian Congo and that 50% of the villagers had impaired vision []. He later found a second focus with the same pathology on the Uéle River. He described the pathological mechanism of the blindness in 1932 []. Two years later, a Harvard African Expedition went to the Belgian Congo, headed by Richard Strong, to check Hissette's observations. Hissette travelled with the Americans, the expedition confirming that all of his findings were correct [].

1930. Hoffman confirmed that Simulium species were the vectors in Central America [

].

1946. With no suitable therapeutic drugs available ( Figure 2), vector control was the only feasible control intervention. Killing of blackfly larvae in waterways used for breeding was regarded as the most suitable method, with dichlorodiphenyltrichloroethane (DDT) successfully and widely used as an insecticide during World War II, as the apparently ideal tool for the task. DDT applied to watercourse blackfly breeding sites at a concentration as low as 0.1 ppm for 30 min eliminated Simulium larvae. In the Kodera region of Kenya, where a 70% prevalence of onchocerciasis caused it to be labelled the 'Valley of the Blind' [], Garnham and McMahon treated watercourses in a 170-km ² foci by applying 13 applications of DDT at 2.5 ppm for 30 min over a 6-7-month period, resulting in eradication of Simulium naevei vectors [].

1948. Vector control was initiated in the Congo Basin at Leopoldville, where all the African population was infected, with 5% blind, and 45% of resident Europeans also having the disease. The huge discharge of water in the River Congo negated application of DDT to the river as a whole, yet dusting of vegetation with DDT proved useless. Consequently, an aircraft was used to dispense an aerosol of pesticide over the river at around 8 mg DDT per km ² over a 3-month period, resulting in the complete removal of S. damnosum adults and larvae. This was proof that aerial spraying of insecticide over vast expanses of rivers was a viable way to eliminate blackflies [].

1954. The Victoria Nile was treated with DDT at 0.4 ppm/30 min in 12 weekly applications. Two years later, the river was retreated with DDT at 0.2 ppm/30 min in 10 weekly applications, resulting in eradication of Simulium. Eradication programmes are very economical, but only possible where fly populations are isolated []. Two important vectors, S. damnosum and Simulium sirbanum, are capable of travelling over 300 km [].

1954. Skin snip diagnosis, estimating the concentration of microfilariae in the skin via multiple weighted skin snips, was developed [].

1972. World Bank President, Robert McNamara, visited West Africa and was appalled to find that in some villages, half the population was blind, most of those infected showing signs of skin disease, having low self esteem or being socially isolated and that children could not perform well at school through the distraction of constant scratching. In addition, fertile river valleys, home to the vector blackflies, were being abandoned, exacerbating the existing poverty and famine, with the disease causing annual economic losses of some $30 million. He was convinced of the value of eliminating the vector flies and became determined to take steps to tackle onchocerciasis, proactively mobilizing international agencies, governments and donors to do so [].

1974. The Onchocerciasis Control Programme (OCP) in West Africa was launched to undertake vector control in seven countries, with the objective of eliminating onchocerciasis as a public health problem and to mitigate its negative impact on the social and economic development of affected regions []. At the time, 1.5 million people were affected, with 128 000 blind, in the River Volta basin target area []. Control was based on aerial application of insecticide (mainly Temephos, which replaced DDT), using helicopters or small fixed-wing aircraft, over rivers and waterways to kill blackfly larvae in their breeding sites. Vector elimination to interrupt transmission needed to continue for approximately 14 years, the estimated lifespan of the adult worm. OCP was expanded to include four additional countries in 1978. It aimed to protect 30 million people covering a land area of 1.2 million km ². By the mid-1970s, regular aerial spraying treatment of 14 000 km of watercourses, covered an area of 700 000 km ² of savannah [].

1981. Initial human clinical trials began to investigate the use of ivermectin against onchocerciasis ( Figure 2). The drug, discovered in 1975 and the world's first endectocide and an excellent anthelmintic, was found to be extremely safe and effective [, , ].

1988. Distribution of the free therapeutic drug ivermectin (donated in 1987 by the manufacturer, Merck & Co. Inc. under the brand name Mectizan ®) was incorporated into OCP activities. Mass treatment with ivermectin (via the use of mobile teams) was added as an adjunct to vector control and, increasingly, as the sole, cost-effective control measure [].

1991. With the donation of Mectizan ®, NGDOs were proactively involved in mass distribution of the drug to control onchocerciasis. Following their increasing contribution, an international NGDO group was formed to help promote worldwide interest in control measures and to support and promote the use of ivermectin in endemic countries [].

1994. The United Nations Development Programme (UNDP)/World Bank/World Health Organization (WHO) Special Programme for Research and Training in Tropical Diseases (TDR) began to develop the innovative Community Directed Treatment mechanism. Community-Directed Treatment with ivermectin (CDTI) became the core element in work to eliminate onchocerciasis. The strategy relies on active community participation, empowering communities to take responsibility for ivermectin delivery - deciding how, when and by whom the ivermectin should be administered. In at-risk, remote rural populations of sub-Saharan Africa where health systems are weak and under-resourced, the CDTI strategy has proven to be highly effective and one of the world's most successful mechanisms for reducing disease. In addition, an innovative, low-cost technique was devised to estimate the prevalence and distribution of the disease and allow a Rapid Epidemiological Mapping of Onchocerciasis (REMO) [].

1995. The African Programme for Onchocerciasis Control (APOC) was launched with the objective of controlling onchocerciasis in the 19 remaining endemic countries in Africa by establishing self-sustaining CDTI systems. The initial goal was to establish sustainable CDTI mechanisms, within 12-15 years, to deliver ivermectin to over 90 million people once annually, thereby protecting 120 million people at risk of infection and preventing over 40 000 cases of blindness annually. The donation and distribution of ivermectin involves a large, comprehensive global Public-Private partnership maximizing the use of essential contributions from United Nations (UN) agencies, bilateral donors, multilateral development agencies, governments, non-governmental organisations, the private sector and all local communities who are affected by onchocerciasis. APOC is also charged, where possible, with eliminating the vector - and hence the disease - from carefully selected isolated foci using environmentally safe insecticides.

1999/2000. CDTI is expanded to incorporate delivery of integrated disease interventions, including vitamin A supplements, drugs to combat schistosomiasis and lymphatic filariasis, antimalaria bednets, etc.

2002. The significance of the endosymbiotic bacteria Wolbachia, found in Onchocerca, became apparent []. Living microfilariae cause little or no inflammation, even in the anterior chamber of the eye. However, when they die the host response to degenerating worms can result in ocular inflammation causing progressive loss of vision, blindness tending to occur in adulthood after many years of infection. Treatment with DEC can cause the 'Mazzotti reaction', the severity of which is dependent on the number of microfilariae containing Wolbachia in the skin and eyes [

]. This was also the case when Hissette induced erysipelas in a 12-year-old boy in 1933 by killing worms in his head nodules []. Acute and severe inflammatory responses in people infected with O. volvulus are associated with the release of Wolbachia into the blood following death or damage to worms, suggesting that Wolbachia may be a cause of acute inflammatory disease [

]. Post-treatment reactions might also be related to Wolbachia products that mediate inflammatory responses []. Anti- Wolbachia products could minimise inflammatory responses seen following treatment, a view supported by treatment of O. volvulus-infected individuals with doxycycline, resulting in elimination of skin microfilaria, presumably through direct effects on the endosymbiont [

].

2008. Following control measures in Africa, it was estimated that 25.7 million people were infected: 265 000 were blind, 746 000 had impaired vision and 4.2 million suffered severe itching. This compared with 1995, when nearly 42 million people were estimated to be infected, with 385 000 people blind, 944 000 with impaired vision, and some 29.7 million cases of severe pruritus []. An in-depth Health Impact Assessment of APOC predicted that only 7% of the at-risk population would be infected by 2015, compared with 49% in 1995. Moreover, whereas 15% of the population was suffering from troublesome itching in 1995, it will be nearly eliminated by 2015 [

]. In Latin America, all target countries had established at least 85% coverage, and there were no new cases of onchocercal blindness; eye lesions attributable to onchocerciasis had been eliminated in 9 of 13 target foci [].

2009. Over 11 600 African villages in 19 nations had been mapped to determine endemicity levels using REMO. In Mali and Senegal, sustained high coverage with ivermectin had actually eliminated transmission of O. volvulus in several foci [].

2010. An estimated 123.3 million people globally required ivermectin chemotherapy, whereas only 81.02 million were treated during the first 11 months of the year []. In Africa, APOC treated 75.9 million people, reporting a 20% reduction in nodules, 86% reduction in severe itching, >500 000 cases of blindness prevented since 1974, a 33% reduction in prevalence of blindness and a cumulative total of 7.5 million Disability Adjusted Life Years (DALYs) saved. Approximately 96% of the APOC target geographic area was being covered, with an average of 79% therapeutic coverage in stable countries and 71% in post-conflict nations. Around 145 000 rural communities were actively engaged in ivermectin distribution, with a cumulative 500 million ivermectin treatments having been dispensed by around 1 million community-based drug distributors trained by APOC since its inception. An evaluation in seven APOC countries confirmed the feasibility of eliminating onchocerciasis using annual ivermectin treatment [, ,

World Health Organization/African Programme for Onchocerciasis Control (2011) WHO African Programme for Onchocerciasis Control: Progress Report 2011, WHO

, ].

2011. Additional to the 7.5 million onchocerciasis DALYs saved by APOC, a further 1 million DALYs were thought saved due to the 'off-target' beneficial impact of ivermectin on other diseases (such as lymphatic filariasis and ascariasis). The cost of mass treatment with ivermectin, estimated to be $257 million, equated to $41 per DALY averted. The Nigerian government pledges $5 million to APOC, the first such contribution from an African country and a reflection of the continuing and increasing contribution and commitment of APOC member governments in the fight to conquer the disease []. In the Americas, only Brazil and Venezuela are still distributing ivermectin [

].

2020. 'Vision 2020: The Right to Sight' target date was set for elimination of all forms of avoidable blindness ( http://www.vision2020.org/main.cfm). Current projections indicate that elimination of onchocerciasis from the Americas and Yemen is feasible by 2015 and by 2020, 23 of the 31 endemic African countries will have eliminated onchocerciasis, protecting another 60 million Africans [].

2025. Proposed date for cessation of APOC. Continuing surveillance and some ivermectin distribution in a handful of countries will need to be undertaken to move toward continent-wide disease elimination. The Mectizan Donation Program is envisaged to be devolved [

] and global elimination is deemed possible [].

Concluding remarks

Successful programmes to control NTDs operate best if they maintain a flexible, dynamic technological and end-user driven approach [

Liese, B. et al. (1991) Organizing and Managing Tropical Disease Control Programmes: Lessons of Success, World Bank Technical Paper No. 159, World Bank

]. International onchocerciasis control efforts confirm the huge benefits that result from multinational, multidisciplinary groups and individuals working cohesively, the immeasurable beneficial impact of empowering affected communities to be part of the solution, and the substantial health, social and economic improvements that can result from investment in such activities.

Eliminating onchocerciasis as a public health threat will depend on (i) maintaining high treatment coverage with ivermectin for the lifespan of adult worms; (ii) supporting governments to sustain high treatment coverage; (iii) establishing sustainable CDTI activities in post-conflict countries; (iv) establishing integrated delivery systems allowing other proven health interventions to be delivered safely and cost-effectively via APOC's community-directed delivery mechanisms; and (v) continuing research to discover better diagnostic tools, a macrofilaricidal agent and other drugs or drug combinations, especially so if ivermectin resistance begins to appear. All of these will help strengthen existing fragile, under-resourced and understaffed health infrastructure and help rid the world of one of its most devastating, debilitating, disfiguring and stigmatising diseases - and thereby make Sir Harold Ridley's prediction come true.

Acknowledgements

The authors would like to express their sincere appreciation to Dr Uche Amazigo, recently retired Director of APOC, for her valuable support and for her constructive comments on this manuscript.

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The onchocerciasis chronicle: from the beginning to the end?

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The year 2012 marks the 25th anniversary of the donation of ivermectin to fight onchocerciasis and the projected date for elimination of transmission of the disease in the Americas.

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Onchocerciasis originated in Africa and spread Latin America and Middle East.  In the 16th century it was introduced to the Americas through the slave trade. It infected the native population and through migration, continued to spread to places like Columbia and Northern Venezuela. The disease has infected roughly 18 million people.

Sources:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3214172/

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Virulence is how much harm a pathogen can do to its host.  The virulence for Onchocerciasis is a 5.9% mortality rate. Onchocerciasis has gone down over the last decades due to better vector control methods.

Sources
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3313942/#:~:text=The%20attributable%20mortality%20risk%20due,was%20estimated%20to%20be%205.9%25.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3214172/

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The medical treatment for Onchocerciasis is drug treatment and vector control. DEC was used as drug treatment at first however it had very serious adverse reactions to patients when used for long term treatment. Now Ivermectin is the drug used. It only targets the microfilaria and has to be taken for the entire lifespan of the adult worms (macrofilaria), 10-12 years. Vector control methods used are DDT and BTI insecticides. There is no new medical advances to treating Onchocerciasis yet, but because Ivermectin only targets the microfilaria and they are showing resistance, research is being done for a new drug that will also target the macrofilaria.

Sources
https://www.sciencedirect.com/science/article/pii/S0065308X05610093

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The leadership to control this disease has been passed on to many different organizations. The main focus for all of them was the distribution of ivermectin treatment and vector control methods in endemic areas. The most innovated imitative used to combat the disease was created by the African Programme for Onchocerciasis Control (APOC). They created a mapping system of endemic areas to better distribute ivermectin. They were many programs made to combat this disease. A better ideas that could have helped elimination would be more collaboration between the programs.

Sources:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548320/
https://www.who.int/news-room/fact-sheets/detail/onchocerciasis

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Onchocerciasis - or "river blindness" - is a parasitic disease caused by the filarial worm Onchocerca volvulus transmitted by repeated bites of infected blackflies ( Simulium spp.). These blackflies breed along fast-flowing rivers and streams, close to remote villages located near fertile land where people rely on agriculture.

In the human body, the adult worms produce embryonic larvae (microfilariae) that migrate to the skin, eyes and other organs. When a female blackfly bites an infected person during a blood meal, it also ingests microfilariae which develop further in the blackfly and are then transmitted to the next human host during subsequent bites.

Clinical signs and symptoms

Onchocerciasis is an eye and skin disease. Symptoms are caused by the microfilariae, which move around the human body in the subcutaneous tissue and induce intense inflammatory responses when they die. Infected people may show symptoms such as severe itching and various skin changes. Infected people may also develop eye lesions which can lead to visual impairment and permanent blindness. In most cases, nodules under the skin form around the adult worms.

Geographical distribution

Onchocerciasis occurs mainly in tropical areas. More than 99% of infected people live in 31 countries in sub-Saharan Africa: Angola, Benin, Burkina Faso, Burundi, Cameroon, Central African Republic, Chad, Republic of Congo, Côte d'Ivoire, Democratic Republic of the Congo, Equatorial Guinea, Ethiopia, Gabon, Ghana, Guinea, Guinea-Bissau, Kenya, Liberia, Malawi, Mali, Mozambique, Niger, Nigeria, Rwanda, Senegal, Sierra Leone, South Sudan, Sudan, Togo, Uganda, United Republic of Tanzania.

Onchocerciasis is also transmitted in the Yanomami area of Brazil and Venezuela (Bolivarian Republic of) as well as in Yemen.

Prevention, control and elimination programmes

Between 1974 and 2002, disease caused by onchocerciasis was brought under control in West Africa through the work of the Onchocerciasis Control Programme (OCP), using mainly the spraying of insecticides against blackfly larvae (vector control) by helicopters and airplanes. This was later supplemented by large-scale distribution of ivermectin since 1989.

The OCP relieved 40 million people from infection, prevented blindness in 600 000 people, and ensured that 18 million children were born free from the threat of the disease and blindness. In addition, 25 million hectares of abandoned arable land were reclaimed for settlement and agricultural production, capable of feeding 17 million people annually.

The African Programme for Onchocerciasis Control (APOC) was launched in 1995 with the objective of controlling onchocerciasis in the remaining endemic countries in Africa and closed at the end of 2015 after beginning the transition to onchocerciasis elimination. Its main strategy was the establishment of sustainable community-directed treatment with ivermectin (CDTI) and vector control with environmentally-safe methods where appropriate. In APOC's final year, more than 119 million people were treated with ivermectin, and many countries had greatly decreased the morbidity associated with onchocerciasis. More than 800,000 people in Uganda and 120,000 people in Sudan no longer required ivermectin by the time that APOC closed.

In 2016, the Expanded Special Project for the Elimination of Neglected Tropical Diseases in Africa (ESPEN), was set up to cover the five preventive chemotherapy NTDs with 4 core objectives:

1. Scale up treatments towards the achievement of 100% geographic coverage, 2. Scale down: stopping treatments once transmission has been interrupted or control achieved, 3. Strengthen information systems for evidence-based action, and 4. Improve the effective use of donated medicines through enhance supply chain management. ESPEN is housed in the WHO Regional Office for Africa.

With support from ESPEN, ivermectin treatments continued to scale up, reaching 152.9 million people in 2019, but due to COVID-19 disruptions, the number of people treated declined by 26.9% in 2020.

The Onchocerciasis Elimination Program of the Americas (OEPA) began in 1992 with the objective of eliminating ocular morbidity and interruption of transmission throughout the Americas by 2015 through biannual large-scale treatment with ivermectin. All 13 foci in this region achieved coverage of more than 85% in 2006, and transmission was interrupted in 11 of the 13 foci. Elimination efforts are now focused on the Yanomami people living in Brazil and Venezuela (Bolivarian Republic of), representing a total population at risk of only 35,228 people.

On 5 April 2013, the Director-General of WHO issued an official letter confirming that Colombia has achieved elimination of onchocerciasis. Colombia was the first country in the world to be verified and declared free of onchocerciasis by WHO. This has been followed by Ecuador in September 2014, Mexico in July 2015, and Guatemala in July 2016. More than 500 000 people no longer need ivermectin in the Americas.

Treatment

WHO recommends treating onchocerciasis with ivermectin at least once yearly for 10 to 15 years. Where Treatment of individuals with high levels of O. volvulus co-exists with L. loa in the blood can sometimes result in severe adverse events. Affected countries, should follow the Mectizan Expert Committee (MEC)/APOC recommendations for the prevention and management of severe adverse events. Loa loa, treatment strategies may need to be adjusted. Loa loa is a parasitic filarial worm that is endemic in Angola, Equatorial Guinea, Gabon, Cameroon, the Central African Republic, the Republic of Congo, the Democratic Republic of the Congo, Nigeria , Tchad and South Sudan.

WHO response

WHO provides administrative, technical and operational research support to three regions where onchocerciasis is transmitted.

The Onchocerciasis Technical Advisory Subgroup (OTS) setup by WHO in 2017 is providing guidance and oversight for operational research to identify endemic areas that require MDA. In areas co-endemic for lymphatic filariasis, research efforts are focused on developing strategies for co-evaluation of onchocerciasis and lymphatic filariasis, in order to support proper decision making regarding the stopping of MDA.

Diagnosis of onchocerciasis remains a challenge for programmes. The NTD Diagnostics Technical Advisory Group identified development of new diagnostic tools for onchocerciasis as a specific priority. A subgroup was convened to prepare 2 target product profiles (TPPs) for new diagnostics for mapping onchocerciasis and for a confirmatory test for deciding to stop MDA. The TPPs have now been posted on the WHO website.

The WHO Regional Office for Africa, which had an overall supervisory role for OCP from 1975 to 2002 and APOC from 1995 to 2015, currently supervises ESPEN which coordinates control and elimination strategies in that region.

Through the OEPA partnership, WHO collaborates with endemic countries and international partners in the WHO Region of the Americas. Although there is no official programme to coordinate activities in the WHO Eastern Mediterranean Region, the two countries in the region collaborate on elimination activities and receive the support of ESPEN to achieve elimination of river blindness.

With the shift from control to elimination, large areas in Africa require mapping to assess whether transmission is active and treatment required. A sampling strategy name Onchocerciasis elimination mapping has been developed to help countries conduct those assessments and start treatment where needed.

Research priorities

Optimizing strategies to reach marginalized and migratory populations.

Validating mapping and safe intervention strategies in settings where onchocerciasis and loiasis are con-endemic.

Defining starting and stopping thresholds for MDA.

Development of robust diagnostics tools to support programme decision-making.

Demonstrating the programmatic utility of vector control measures.

Testing new therapeutic regimens.

Optimizing survey design through the use of new geostatistical tools.

Developing post-verification strategies.

Exploring opportunities to integrate surveillance.

To achieve elimination goals for onchocerciasis, an ambitious research agenda will be needed to support programme progress. Specific research needs include:

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Onchocerciasis - or "river blindness" - is a parasitic disease caused by the filarial worm Onchocerca volvulus. It is transmitted through the bites of infected blackflies (Simulium spp.) that breed in fast-flowing rivers and streams, mostly in remote villages located near fertile land where people rely on agriculture.

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Beyond the physical effect, what was the societal and sociological impact of this disease?

Beyond the physical effect, there has been social isolation and economic issues for the community and those who are infected. The behavior of society changed because of the programs created to eradicate this disease. Community education programs about control of these diseases, so there was better understanding of its effects. Because of the debilitating disabilities people have due to the disease, I believe society has started to learn to not stigmatize those who suffer from it. It is shown in the study as well that people who have been infected have had isolation from their community no matter the economic status or education level. However it is also shown that this effect lesson after the person is treated.

Sources:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7249366/

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1. The most revealing aspect to me as I researched onchocerciasis more was about the leadership around eradicating this disease. There were many organizations on the federal, state, international level, however this disease has not been completely eradicated even with this large amount of research and funding efforts. It is now a major neglected tropical disease even though it effects so many people for so long.

2. One thing that I learned about my disease that surprised me was specifically how macro filaria cause blindness. They travel through the lymph system of the host. However they do not distinguish the eye separately from the lymph system and will travel across it. This causes irritation and the body's immune response is to attack the eye, eventually causing blindness.

3. One thing that I came across that I think I should've put more detail about the age range that is most effected by this disease because it heavily correlates to the social aspect of it.