Wednesday, April 25, 2012

Onchocerciasis


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 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:

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. 

11 comments:

  1. It is interesting that such a leading cause of disability (second leading infectious cause of blindness in the world) is not publicized/targeted more in terms of health intervention. This is the first time I've ever heard of onchocerciasis. The difficulty in addressing this issue seems immense given the improbability of effective vector control. However, it seems as if, as with most interventions, money is the key issue. It seems as if many of these infections share the same conditions in terms of occurring in resource poor, hard to reach areas, and whose treatments could result in resistance if not done properly. I wonder if with some more publicity/information dissemination (and the funding that might come with it) would allow an intervention to be formed following the structure of a de-worming campaign for another organism. Have there been other successful de-worming campaigns with similar conditions? It might provide a good framework to form an intervention reducing this significant disease burden.

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  2. This is an interesting article on de-worming programs in general.

    www.dcp2.org/file/162/dcpp-helminths-web.pdf

    The attitude in this article seems very strongly in favor of widespread use of anti-helminth pharmaceutical intervention.


    But this is in the scientific context of findings such as those by Coles and Rhodes in 2005 that showed rapid selection of helminth anti-ivermectin factors.

    Overall, I think that the literature I saw supports the conclusion of Crump and Omura in 2011 that ivermectin is probably the best path to helminth control on a large scale at the current time.

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  3. This is super interesting! I definitely want to read up more on the pathophysiology of onchocerciasis. I think it's especially interesting that there is this required symbiotic relationship between the O volvulus and Wolbachia bacteria for the larval development. It makes me wonder if there are ways of prevention that could target the bacteria. I read a little bit about the Onchocerciasis Control Programme on the WHO website and was wondering is there research on whether identification and treatment of cases a sufficient prevention method or have they also tried a chemoprophylaxis? If so, was it found to be more effective?

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  4. Onchocerciasis truly is fascinating. First I’m curious as to why lymphadenopathy develops in different parts of the body in different regions of the world. Are our head and neck more exposed here in the Americas vs legs in sub-Saharan Africa? Also along the lines of Chrissy’s comment above, it’s not a de-worming campaign per se but are there efforts to distribute prophylaxis against the Wolbachia bacteria? It would at least help with the morbidity that comes with Onchocerciasis. Perhaps a combined campaign where ivermectin is given with an antibiotic so that resistance wont arise as much?

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    1. I also found how it manifests in different parts of the body very interesting! I don't think our heads and necks would be anymore exposed than regions in Africa because of it's warm climate.

      It seems like the WHO has a campaign against this illness for thirty years (booklet published in 2007) and claims to have treated 55 million Africans: http://www.who.int/tdr/publications/documents/elimin_riverblind.pdf

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  7. An insight read indeed! I first heard of this disease upon stumbling across a article announcing the winners of the Nobel Prize for anti-parasitic properties (http://www.bbc.com/news/health-34442097). I wonder what the statistics are now on the DALY rates from Onchocerciasis by country and whether the prevention and control strategies have been effective in high endemic countries such as Nigeria, Chad and Cameroon. I strongly agree that community engagement and health education is highly pivotal in strengthening the delivery and monitoring of ivermectin in under-resourced communities.

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    1. Perhaps ivermectin along with an antiobiotic to attack Wolbachia could be administered together to simultaneously clear the worms and prevent morbidity associated with the bacteria. The medication schedules could be packaged together to make it easier for local health providers to have access to both and encourage delivery of the entire regimen, in the hope of preventing development of resistance in either the bacteria or O. volvulus.
      Chrissy's comment above is also interesting, as it would appear that at least the adult nematodes would stay localized near where the fly bites, but if the microfilariae can travel through lymph and blood, it would seem they can attack any body region.

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  8. This was very informative. I picked this disease because river blindness was used a lot as an example in a lot of my undergrad bio classes. I didn't realize how long these flies live! 8-10 years are like some dogs.

    It was very interesting to find out about lymphadenopathy is different in the Americas and in Africa. I wonder why there are difference in the region of the body that is affected depending on geographic region... if it has to do with climate/environment/culture.

    I was curious of treatment so I looked up ivermectin. And the treatment schedule is one every 12 months (http://www.drugs.com/dosage/ivermectin.html), so it actually sounds feasible for areas where people do not move a lot.

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