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This week at Infection Landscapes I will cover onchocerciasis, which is more commonly known as "river blindness" for reasons that will shortly become clear. The helminth causing this infection is vector-borne, adding further complexity to its transmission dynamics. As the second leading infectious cause of blindness in the world, onchocerciasis is also associated with a large burden of disease, particularly in sub-Saharan Africa.
The Worm. Onchocerciasis is caused by Onchocerca volvulus, which is a nematode, and transmitted to humans by Simulium black flies. The microfilarial larvae of this helminth are the source of the pathology in humans:
The life cycle of O. volvulus requires both a definitive host, i.e. humans, and an intermediate host, i.e. black flies. Fully formed microfilariae are released from gravid adult females in an infected human host. When a susceptible Simulium black fly takes a blood meal from this infected human host, the fly ingests the microfilariae with the blood. Upon reaching the gut of the fly, the microfilariae pass out of the gut and migrate to the thoracic flight muscles, where they proceed with their first (J1) and second (J2) larval stages of development. J2 larvae migrate to the saliva of the fly where they further develop into the infectious third stage larvae (J3). When the black fly with infectious J3 larvae takes a blood meal from a susceptible human host, these larvae enter the bite wound and migrate to subcutaneous tissues, where they form nodules and undergo their final developmental stage into adult worms. This last developmental stage requires between 6 and 12 months. The adult worms will mate when they reach maturity. The adult males leave their nodules and seek out females in the subcutaneous tissue. After mating, females produce an average of 700 eggs per day over the course of their adult lives, which average 8 to 10 years. Each microfilaria produced can live for an average of 1 to 2 years before it dies, giving these organisms ample time to encounter another black fly and carry on through the life cycle. The graphic below, produced by the Centers for Disease Control and Prevention (CDC) is a nice depiction of the life cycle of O. volvulus.
The symbiotic relationship between this helminth and a bacterium constitutes another critical, and fascinating, component to the worm's life cycle. Wolbachia is a genus of bacteria that commonly infects many species of insects, and a few species of nematodes. These ubiquitous bacteria can engage either parasitic or symbiotic relationships with their hosts. In the case of the Wolbachia-Onchocerca-Simulium triad, an extraordinarily complex symbiosis has evolved wherein O. volvulus requires infection with Wolbachia bacteria in order to complete its larval development in the black fly. Without this bacterial infection, the helminth larvae cannot develop and their life cycle is arrested.
The Vector. Human infection with O. volvulus is vectored by the black fly, i.e. a member of the Simuliidae family. Black flies that transmit Onchocerca infections are members of the genus Simulium, which is comprised of hundreds of different species, many of which are capable of serving as vectors for this helminth:
Black flies occupy a fascinating ecology, which conforms to specific features of the landscape even though they are widely distributed throughout the world. Black flies oviposit in flowing water systems. When the larvae emerge from the eggs they remain submerged and anchor themselves to fixed objects, typically rocks, in the bed of the lotic environment. The larvae employ a system of passive "fishing" to feed, whereby extendable-retractable mouth fans are used to catch food items, such as bacteria and algae, as they are carried past by the water current:
The larvae further develop into pupae under the water and finally emerge from the water as adults in a bubble of air.
The adult flies' diets differ by sex. Much like most adult mosquitoes, the males subsist on plant juices alone while females also seek out the blood of vertebrate hosts. Thus, blood proteins are also likely important for egg production in females. The females are day biters and host preferences differ by Simulium species, as does their geographic range.
The Disease. Onchocerciasis pathogenesis is due to the microfilariae and the Wolbachia that infect them. The adult worms are effectively sealed off from the host's immune system in their subcutaneous nodules. The microfilariae, on the other hand, are in direct contact with blood and tissue and, thus, with the host's immune system. As such, the microfilariae are capable of stimulating a potent inflammatory response in the host, which leads to disease.
There are typically three main organ systems that are involved in O. volvulus infection: the skin, the lymphatics, and the eye.
Onchocerciasis involving the skin is known as onchodermatitis. In minor, low volume infections, the infection may be entirely subclinical, but can also present with mild itching or discoloring of the skin. As the number of nodules increases, however, symptoms become more pronounced. Intense pruritus is a defining clinical characteristic of moderate to severe infections. The intense itching and associated scratching usually also present with a papular rash. In high volume infections, the itching can be so severe that it renders those affected physically disabled and can sometimes even result in suicide. With chronic infection, onchodermatitis can be quite taxing on the skin, with a general thickening and hardening and subsequent development of a "lizard skin" appearance. Depigmentation is also common in chronic infections wherein the skin can take on a leopard-like appearance. As the skin continues to degrade, it will wrinkle and age prematurely:
Lymphadenopathy presents as the microfilariae locate in lymph nodes, with pronounced nodules commonly developing at these sites. Interestingly, there are geographic differences in the lymphatic sites that are most often involved. For example, in the Americas the lymph nodes of the head and neck are more frequently affected, whereas in sub-Saharan Africa the femoral and inguinal lymph nodes are more commonly affected.
Ocular onchocerciasis is the second leading infectious cause of blindness in the world. All parts of the eye can be affected. Ocular infection begins with microfilariae migration to the cornea. Early infection usually presents with a tearing, irritated conjunctivitis, often with a hypersensitivity to light. Keratitis lesions are also typically apparent on the cornea at this time. This stage of infection is probably an inflammatory response similar to that induced in the skin. At this stage, the infection can clear, inflammation subside, and full recovery ensue. However, a sclerosing keratitis develops among those with chronic infection, which is common in areas of high endemicity. Over time, as the the cornea continues to sclerose it becomes increasingly opaque until light is effectively blocked altogether:
This pathology is the primary cause of blindness in onchocerciasis. However, because the microfilariae can invade any structure in the eye, pathology can also derive from damage to the posterior eye, including the retina and optic nerve.
There is increasing evidence that the potent inflammatory response stimulated by the microfilariae is due to O. volvulus' symbiont, Wolbachia. As mentioned above, these bacteria are necessary catalysts to the larval development of this helminth in the black fly. However, these bacteria produce potent molecules that are proinflammatory to the human host. As the microfilariae die, these bacteria are released and subsequently interact with the human immune system, thus leading to the inflammatory responses associated with onchocerciasis. In fact, antibiotic treatment to eliminate the Wolbachia from the microfilariae has been associated with a drastic reduction in blindness among the chronically infected even without clearance of the helminths.
The Epidemiology and the Landscape. Worldwide, there are approximately 37 million people infected with O. volvulus. The vast majority of these occur in sub-Saharan Africa, however, there are small localized areas of endemicity in Central America and in the warm, moist, yet mountainous altitudes of northern South America. Of those who are infected, between 300,000 and 500,000 are visually impaired, and the disability-adjusted life years associated with general infection are substantive, with approximately 60% attributable to non-ocular skin-involved pruritis:
Because of the reproductive ecology of Simulium flies, fast moving water is the central feature of the landscape required for transmission of O. volvulus to humans:
Accordingly, in endemic areas, infection transmission is associated with residential or occupational distance to flowing rivers and streams in mountainous terrain. As such, communities in close proximity to moving water are at high risk in topographically varied areas of endemicity. However, transmission is not exclusive to these sites because some Simulium species have broad flight ranges that extend well beyond (up to 40 miles for some species) their reproductive sites. Therefore, while risk of infection is certainly concentrated at the reproductive sites of fast moving water, the overall endemicity is typically more diffuse, and geographic risk more extensive, than the narrow corridor delineated by the waterway.
These features of black fly ecology and subsequent landscape of transmission make vector control an extraordinarily difficult, and largely unfeasible, approach to the prevention of onchocerciasis.
Prevention and Control. As described above, vector control of onchocerciasis is too difficult to achieve success at the population level. Currently, prevention and control strategies, primarily led by the African Programme for Onchocerciasis Control (APOC) and Onchocerciasis Elimination Program for the Americas (OEPA), employ therapeutic and prophylactic administration of ivermectin, which is very effective against filarial helminths, but cannot be administered to individuals who are infected with Loa loa nematodes as it causes severe reactions in the host that can lead to extensive secondary disease.
More generally, de-worming campaigns do offer some hope, even for regional elimination of onchocerciasis. However, as one might expect, there are obstacles to overcome in de-worming. First, ivermectin is not free, so without adequate funding poor communities will not be able to prioritize the cost. Second, effective ways to deliver ivermectin to communities need to be implemented, which can be logistically challenging particularly in remote communities or during times of the year when travel may be restricted (i.e. during the rainy season). Third, the extensive use, or misuse, of ivermectin will likely lead to resistance in O. volvulus, thus making the drug ineffective. Nevertheless, if adequate resources can be put behind de-worming campaigns, and if delivery systems can be adapted to actively engage community members in the delivery and monitoring of ivermectin to simultaneously circumvent logistical obstacles and reduce the development of resistance, then substantial reductions in onchocerciasis may still be possible.
This week at Infection Landscapes I will cover onchocerciasis, which is more commonly known as "river blindness" for reasons that will shortly become clear. The helminth causing this infection is vector-borne, adding further complexity to its transmission dynamics. As the second leading infectious cause of blindness in the world, onchocerciasis is also associated with a large burden of disease, particularly in sub-Saharan Africa.
The Worm. Onchocerciasis is caused by Onchocerca volvulus, which is a nematode, and transmitted to humans by Simulium black flies. The microfilarial larvae of this helminth are the source of the pathology in humans:
Microfilariae of Onchocerca volvulus
The symbiotic relationship between this helminth and a bacterium constitutes another critical, and fascinating, component to the worm's life cycle. Wolbachia is a genus of bacteria that commonly infects many species of insects, and a few species of nematodes. These ubiquitous bacteria can engage either parasitic or symbiotic relationships with their hosts. In the case of the Wolbachia-Onchocerca-Simulium triad, an extraordinarily complex symbiosis has evolved wherein O. volvulus requires infection with Wolbachia bacteria in order to complete its larval development in the black fly. Without this bacterial infection, the helminth larvae cannot develop and their life cycle is arrested.
The Vector. Human infection with O. volvulus is vectored by the black fly, i.e. a member of the Simuliidae family. Black flies that transmit Onchocerca infections are members of the genus Simulium, which is comprised of hundreds of different species, many of which are capable of serving as vectors for this helminth:
Black flies occupy a fascinating ecology, which conforms to specific features of the landscape even though they are widely distributed throughout the world. Black flies oviposit in flowing water systems. When the larvae emerge from the eggs they remain submerged and anchor themselves to fixed objects, typically rocks, in the bed of the lotic environment. The larvae employ a system of passive "fishing" to feed, whereby extendable-retractable mouth fans are used to catch food items, such as bacteria and algae, as they are carried past by the water current:
1. Pupa 2. Larva
Notice the mouth fans on the larva that are used for catching food in moving water
The larvae further develop into pupae under the water and finally emerge from the water as adults in a bubble of air.
The adult flies' diets differ by sex. Much like most adult mosquitoes, the males subsist on plant juices alone while females also seek out the blood of vertebrate hosts. Thus, blood proteins are also likely important for egg production in females. The females are day biters and host preferences differ by Simulium species, as does their geographic range.
The Disease. Onchocerciasis pathogenesis is due to the microfilariae and the Wolbachia that infect them. The adult worms are effectively sealed off from the host's immune system in their subcutaneous nodules. The microfilariae, on the other hand, are in direct contact with blood and tissue and, thus, with the host's immune system. As such, the microfilariae are capable of stimulating a potent inflammatory response in the host, which leads to disease.
There are typically three main organ systems that are involved in O. volvulus infection: the skin, the lymphatics, and the eye.
Onchocerciasis involving the skin is known as onchodermatitis. In minor, low volume infections, the infection may be entirely subclinical, but can also present with mild itching or discoloring of the skin. As the number of nodules increases, however, symptoms become more pronounced. Intense pruritus is a defining clinical characteristic of moderate to severe infections. The intense itching and associated scratching usually also present with a papular rash. In high volume infections, the itching can be so severe that it renders those affected physically disabled and can sometimes even result in suicide. With chronic infection, onchodermatitis can be quite taxing on the skin, with a general thickening and hardening and subsequent development of a "lizard skin" appearance. Depigmentation is also common in chronic infections wherein the skin can take on a leopard-like appearance. As the skin continues to degrade, it will wrinkle and age prematurely:
Lymphadenopathy presents as the microfilariae locate in lymph nodes, with pronounced nodules commonly developing at these sites. Interestingly, there are geographic differences in the lymphatic sites that are most often involved. For example, in the Americas the lymph nodes of the head and neck are more frequently affected, whereas in sub-Saharan Africa the femoral and inguinal lymph nodes are more commonly affected.
Ocular onchocerciasis is the second leading infectious cause of blindness in the world. All parts of the eye can be affected. Ocular infection begins with microfilariae migration to the cornea. Early infection usually presents with a tearing, irritated conjunctivitis, often with a hypersensitivity to light. Keratitis lesions are also typically apparent on the cornea at this time. This stage of infection is probably an inflammatory response similar to that induced in the skin. At this stage, the infection can clear, inflammation subside, and full recovery ensue. However, a sclerosing keratitis develops among those with chronic infection, which is common in areas of high endemicity. Over time, as the the cornea continues to sclerose it becomes increasingly opaque until light is effectively blocked altogether:
This pathology is the primary cause of blindness in onchocerciasis. However, because the microfilariae can invade any structure in the eye, pathology can also derive from damage to the posterior eye, including the retina and optic nerve.
There is increasing evidence that the potent inflammatory response stimulated by the microfilariae is due to O. volvulus' symbiont, Wolbachia. As mentioned above, these bacteria are necessary catalysts to the larval development of this helminth in the black fly. However, these bacteria produce potent molecules that are proinflammatory to the human host. As the microfilariae die, these bacteria are released and subsequently interact with the human immune system, thus leading to the inflammatory responses associated with onchocerciasis. In fact, antibiotic treatment to eliminate the Wolbachia from the microfilariae has been associated with a drastic reduction in blindness among the chronically infected even without clearance of the helminths.
The Epidemiology and the Landscape. Worldwide, there are approximately 37 million people infected with O. volvulus. The vast majority of these occur in sub-Saharan Africa, however, there are small localized areas of endemicity in Central America and in the warm, moist, yet mountainous altitudes of northern South America. Of those who are infected, between 300,000 and 500,000 are visually impaired, and the disability-adjusted life years associated with general infection are substantive, with approximately 60% attributable to non-ocular skin-involved pruritis:
World Health Organization estiated: Age-standardised disability-adjusted life year (DALY) rates from Onchocerciasis by country (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
Because of the reproductive ecology of Simulium flies, fast moving water is the central feature of the landscape required for transmission of O. volvulus to humans:
Accordingly, in endemic areas, infection transmission is associated with residential or occupational distance to flowing rivers and streams in mountainous terrain. As such, communities in close proximity to moving water are at high risk in topographically varied areas of endemicity. However, transmission is not exclusive to these sites because some Simulium species have broad flight ranges that extend well beyond (up to 40 miles for some species) their reproductive sites. Therefore, while risk of infection is certainly concentrated at the reproductive sites of fast moving water, the overall endemicity is typically more diffuse, and geographic risk more extensive, than the narrow corridor delineated by the waterway.
These features of black fly ecology and subsequent landscape of transmission make vector control an extraordinarily difficult, and largely unfeasible, approach to the prevention of onchocerciasis.
Prevention and Control. As described above, vector control of onchocerciasis is too difficult to achieve success at the population level. Currently, prevention and control strategies, primarily led by the African Programme for Onchocerciasis Control (APOC) and Onchocerciasis Elimination Program for the Americas (OEPA), employ therapeutic and prophylactic administration of ivermectin, which is very effective against filarial helminths, but cannot be administered to individuals who are infected with Loa loa nematodes as it causes severe reactions in the host that can lead to extensive secondary disease.
More generally, de-worming campaigns do offer some hope, even for regional elimination of onchocerciasis. However, as one might expect, there are obstacles to overcome in de-worming. First, ivermectin is not free, so without adequate funding poor communities will not be able to prioritize the cost. Second, effective ways to deliver ivermectin to communities need to be implemented, which can be logistically challenging particularly in remote communities or during times of the year when travel may be restricted (i.e. during the rainy season). Third, the extensive use, or misuse, of ivermectin will likely lead to resistance in O. volvulus, thus making the drug ineffective. Nevertheless, if adequate resources can be put behind de-worming campaigns, and if delivery systems can be adapted to actively engage community members in the delivery and monitoring of ivermectin to simultaneously circumvent logistical obstacles and reduce the development of resistance, then substantial reductions in onchocerciasis may still be possible.