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Onchocerciasis is the world’s second leading cause of blindness due to an infectious disease. In some West African communities, 50% of men over 40 years old are blind due to onchocerciasis (WHO, 2019). In addition to blindness, onchocerciasis also commonly causes extreme itching and subcutaneous nodules (Murdoch, 2018). Onchocerciasis is largely prevalent in Africa, with 99% of all infected people living in 31 African countries (WHO, 2019). This neglected tropical disease is caused by the parasitic worm Onchocerca volvulus which is transmitted through Simulium black flies (CDC, 2019). People who live or farm close to fast flowing streams and rivers are at a high risk of developing onchocerciasis because Simulium blackflies live and breed in these areas (WHO, 2019).  

Although it is commonly associated with blindness, onchocerciasis was first described by John O’Neill as a skin disease that the Ghanaian locals called craw-craw. In 1874, O’Neill first observed the worm causing this disease. A few years later, Rudolf Leuckart identified worms found in nodules, and Sir Patrick Manson published Leuckart’s findings, calling the worm Filaria volvulus. It was transferred to the Onchocera genus in 1910. In 1945, over 70 years after the first observation of O. volvulus, onchocerciasis was recognized to cause blindness by Sir Harold Ridley (Crump, Morel, and Omura, 2012). With no effective treatments, vector control was used as a preventative measure throughout the 1940s until the late 1980s (WHO, 2019). A drug for treatment was not discovered until the early 1980s when the use of Ivermectin was shown to be safe and effective. Ivermectin was donated in 1987 by Merck & Co. Inc and was distributed through mass drug administrations (J. Turner et al., 2010; Crump et al., 2012). Soon after, community directed treatment with Ivermectin (CDTI) was developed to distribute Ivermectin and has been very successful by involving communities and allowing them to take responsibility and initiative in control efforts (WHO, 2019).  

Onchocerciasis presents with varying symptoms, most commonly including skin disease. Onchocerciasis causes extreme itching and skin lesions, occurring in a large number of people from ages five and older (WHO, 2019; Murdoch, 2018). Repeated exposure to the O. volvulus worm eventually leads to onchocercal skin disease (OSD), also known as onchodermatitis (WHO, 2019). Itchy skin is usually one of the first symptoms to appear and is often severely debilitating. Young children often present with severe itching. Depigmentation, nodules, and atrophy are signs of onchodermatitis and occur progressively (Mundoch, 2018). Of the 20.9 million total onchocerciasis infections in 2017, 14.6 million people had skin disease (WHO, 2019). More rarely, onchocerciasis can cause irreversible vision impairment. Eye lesions cause vision impairment and as more lesions occur, impairment progressively gets worse (Hotterbeekx et al., 2019). This eventually leads to onchocerciasis related blindness which often occurs after the age of 20 because of this progression (Colebunders et al., 2019). Blindness affects 1.15 million people with onchocerciasis as of 2017 (WHO, 2019).  

Recent findings also suggest that there may be a link between onchocerciasis and epilepsy. The World Health Organization notes that onchocerciasis puts people at an increased risk of developing a form of the disorder called onchocerciasis-associated epilepsy (OAE), but little research has been done in this area (WHO, 2019; Colebunders et al., 2019). There is a spectrum of OAE, including the presentation of nodding syndrome (Colebunders et al., 2019). In those with nodding syndrome, the muscles of the head and neck are affected (Hotterbeekx, Ssonko, Oyet, Lakwo, and Idro, 2019). OAE often occurs around the ages 8-11, much sooner than blindness; it is associated with high mortality rates because of an inability to treat epilepsy in many regions where OAE is common (Murdoch, 2018). Although much more research must be done on OAE, many scientists believe that there is an association (Colebunders et al., 2019; Hotterbookx et al., 2019). Overall, onchocerciasis increases the risk of premature death and has a mortality risk of 5.9% (Walker et al., 2012).  

Diagnosis is done through a skin snip, which is a biopsy of the skin. This biopsy must be examined under a microscope and infection is determined by whether any O. volvulus larvae can be seen. There are also antibody tests which are often used in younger individuals (Murdoch, 2018; CDC, 2019). Ivermectin is the only drug used to treat onchocerciasis and to prevent the progression of symptoms. The only measure used to prevent infection from occurring is vector control as there is no vaccine (WHO, 2010).  

O. volvulus: A Successful Pathogen 

Simulium blackflies allow O. volvulus to survive and transmit from one host to the next. To begin infection, the blackfly bites a person, introducing the larvae, or microfilariae, to the host. Microfilariae then develop in the host’s subcutaneous tissue and migrate through the body, notably through the skin and to the eyes, and through the blood and lymphatic system (Murdoch, 2018). The adult female worm can produce as many as 1,000 microfilariae in a day (WHO, 2019). Adult filariae, or macrofilariae, live in nodules that are formed in subcutaneous tissue. Macrofilariae have an average lifespan of 15 years (CDC, 2019). Other blackflies then ingest microfilariae by biting an infected person. The microfilariae travel from the blackfly’s midgut to the thoracic muscles and develop into first stage larvae, and then third stage larvae. After the third-stage infective larvae are developed, they can travel to the head and mouth (Hotterbeekx, 2019). Then, the black fly will proceed to infect another person by biting them and infecting them with the filariae (CDC, 2019).  

O. volvulusdecreases the ability of regulatory T cellsto function properly, effectively hindering their host’s immune system. T cells help control immune responses to antigens, so when their ability to do this is diminished, the body is unable to respond to antigens as usual (Murdoch, 2018). Wolbachia bacteria have an endosymbiotic relationship with the O. volvulus worm and are thought to play a large role in the host’s immune response to infection. Both macrofilariae and microfilariae require the presence of Wolbachia for survival, and the fertility of the adult female worm depends on the presence of Wolbachia (Hotterbeekx et al., 2019; Klarmannschultz et al., 2017). When microfilariae die, Wolbachia are released, triggering inflammation and an immune response in the host. Cytotoxins are released by the host’s immune system to combat the bacteria, but theses cytotoxins are damaging to the host’s cells. The immune system ultimately ends up inflicting damage to the host itself. Onchodermatitis, a skin rash suffered by those with onchocerciasis, is caused by this immune response and gets progressively worse with repeated inflammation and immune response. An abnormal and severe form of onchodermatitis is swoda, or lichenified dermatitis; it is also known to be caused by immune responses. Presenting as itchy hyperpigmented plaque on one leg, lichenified dermatitis is thought to be the result of a low microfilarial load and a high immune response (Murdoch, 2018; Hotterbeekx et al., 2019). 

Similarly, death of the microfilariae that have migrated to the cornea or posterior regions of the eye also triggers an immune response and damages these cells, causing vision impairment. Repeated inflammation and immune response cause increasing levels of vision impairment (Hotterbeekx et al., 2019). It is also hypothesized that due to inflammatory responses in the eye, microfilariae can enter the central nervous system through optical nerves. It is thought that access to the central nervous system could be what causes OAE. Microfilariae are also found in the blood of individuals with high microfilarial loads; if microfilariae can cross the blood brain barrier through the bloodstream, it also could be what is responsible for causing OAE (Murdoch, 2018; Hotterbeekx, 2019).

Environmental Factors 

People at the highest risk of developing onchocerciasis live and farm near fast flowing streams and rivers where the Simulium black fly lives and breeds. The land nearby rivers and streams is often fertile and used for farming. People who spend large amounts of time in these areas have high exposure to the black fly. In a study done to identify factors driving onchocerciasis transmission in Cameroon, the two communities with the highest proportion of serological positive children were within 12 km of locations that infected and infective flies were found (Figure 1). The largest proportion of seropositive children recorded was 59% with 39% being the second largest (Table 1). This high proportion of seropositive children indicates high levels of transmission because CDTI has been in use for 20 years, long before they were born. Other communities outside of this 12 km range had lower proportions of seropositive children, indicating lower levels of transmission (Bakajika et al., 2018). These findings suggest that the environment people live in is an important aspect of transmission as the population of infected and infective flies differs in different locations. Since rivers where these flies are located often serve as natural borders between countries, and the black fly vector can cross these borders, it is important that neighboring countries work together to address transmission in these areas. The same study done by Bakajika et al. (2018) also found that transmission levels may fluctuate with season changes. Some species of black flies migrate seasonally to different areas, suggesting that there would be higher levels of transmission where the black fly is at a given time. In addition to migration, rainy season, which is August to November and April to June, was also found to significantly influence transmission levels. Of the infective flies caught by Bakajika et al. (2018), the flies caught during rainy season were more effective at transmitting infection. In the rainy season, around 2.5 third stage infective larvae were found in the head per infective fly (14 total infective flies), while in the dry season, only 2 infective larvae were found in the head in each of the 2 infective flies found (Table 2; Bakajika et al., 2018). The differing amounts of infective larvae in the head shows that in rainy season, when there were more infective larvae, the blackflies are more productive. Therefore, where one lives in relation to the vector and the season both play influential roles in the transmission of onchocerciasis in a particular location. 

Although onchocerciasis has successfully been controlled through vector control and Ivermectin, onchocerciasis is still problematic in rainforest regions of West and Central Africa. This is a result of Loa loa co-infections with O. volvulus (Kamgno et al., 2010; CDC, 2015). The parasitical nematode L. loa infects the host’s blood and causes the disease loiasis. Symptoms of loiasis can include itchy skin, swelling, an eye worm, and a visible worm underneath the skin; however, symptoms are not always present, complicating diagnosis (CDC, 2015). When Ivermectin is used in patients with L. loa and O. volvulus co-infections, severe adverse effects like encephalopathy, coma, or death can occur upon administration. These reactions are thought to be the result of an extreme immune response due to a high number of microfilariae dying. Their severity has caused the use of Ivermectin in these areas to be ceased (J. Turner et al., 2010). Because there are currently no alternative treatments, Kamgno et al. (2017) investigated an alternative method to treatment with Ivermectin. Persons with a L. loa microfilarial load greater than 20,000 microfilariae per milliliter of blood were identified as they are at risk to develop severe adverse reactions to Ivermectin. The population of at-risk individuals consisted of 2.1% of the total participants. Excluding these people who were at risk, Ivermectin was then distributed to the study participants. No adverse reactions that resulted in hospitalization or death occurred. Overall, 6.0% of total participants reported Ivermectin-associated adverse reactions (Kamgno et al., 2017). These findings suggest that it is a possibility to treat onchocerciasis with Ivermectin in L. loa co-endemic regions when at-risk individuals are not treated with ivermectin.  

A Neglected Tropical Disease 

As a neglected tropical disease, onchocerciasis affects the poorest people in the world and is often overlooked by pharmaceuticals and even by countries with onchocerciasis endemic regions. Research about onchocerciasis as a whole has largely been limited despite the condition having been described for many years. Treatments and vaccines for any disease are expensive to develop and for the individual using them. Because onchocerciasis affects some of the poorest people in the world, even if drugs and vaccines are available, many would be unable or struggle to pay for these drugs or vaccines. Knowing this, pharmaceuticals are unable to invest in developing a drug or vaccine that will not reap any economic benefit. Interest and support from governments of endemic countries is threatened because onchocerciasis has largely been eliminated as a public health problem. Budget cuts lead to less vector control and diminished ability to distribute and administer Ivermectin. Furthermore, successful control programs that have largely been able to eliminate onchocerciasis as a public health problem have recently ended and details of future programs, like funding, are unclear (Tekle et al., 2016).  

Overlooked by many, onchocerciasis remains a threat to numerous individuals in developing countries. Even in endemic areas, this debilitating disease is surrounded by stigma and discrimination. Visible skin disease causes extreme embarrassment to those infected and severe presentations, like hanging groin, which is atrophy caused by the progression of onchodermatitis, are often viewed negatively (Murdoch, 2018). Symptoms of onchocerciasis also contribute to economic difficulties in endemic regions. Severe itching and vision loss cause disability in some afflicted with onchocerciasis, leaving them less independent and making it difficult to do work. Many people are also forced to move away from homes and fertile farming land located near fast flowing streams and rivers. Overall, there is a decrease in productivity, only compounding to the existing poverty and underdevelopment (Murdoch, 2018).   

Furthermore, certain aspects about how the parasite interacts with the host, like how it inflicts damage and triggers the host’s immune response, are unknown. A very significant example of this is OAE. With no experimental evidence that onchocerciasis is associated with epilepsy, there is still compelling evidence relating the two (Colebunders et al., 2019).  A study by Levick et al. (2017) found that the prevalence of epilepsy in onchocerciasis endemic areas was 2-10 times higher than the prevalence in non-endemic areas. 3.3% of total participants in the study had a history of epilepsy. Of the participants with epilepsy, 30% lived in a household where there was another person with epilepsy. Levick et al. (2017) also determined case control pairs and found that people with epilepsy had taken Ivermectin less frequently that the control (Table 3). These findings about Ivermectin and epilepsy are important because OAE increases the risk of mortality (Colebunders et al., 2019; Murdoch, 2018). Limited access to healthcare and false beliefs, including that epilepsy is contagious, partially contribute to the increased risk of mortality. Limited access to healthcare is typical in onchocerciasis endemic areas because they are often more remote and outside of large cities. Treatments for epilepsy are often only available in the larger cities (Colebunders et al., 2019). Additionally, individuals with OAE are less likely to receive help from local health officials because they believe that epilepsy is contagious. Some do not even seek help for themselves due to this false belief (Colebunders et al., 2019). More research on OAE is critical so that the high risk of mortality can be addressed, but this too relies on increased overall funding and interest.  

Elimination of Onchocerciasis: The Need for Additional Treatments 

  Ivermectin has been used to prevent and to treat onchocerciasis since 1987. Given annually or biannually, Ivermectin targets the microfilariae, preventing the production of microfilariae, and consequently interrupting transmission (Tekle et al., 2016). Ivermectin also provides relief from symptoms like itching. The vast success of Ivermectin, which was not expected by the World Health Organization (WHO), has been largely due to CDTI (J. Turner et al., 2010). This success has given scientists the basis to believe that the elimination of onchocerciasis is possible (Tekle et al., 2016).  

The time needed for Ivermectin to effectively interrupt transmission, the risk of drug resistance, and its inability to be used in certain regions are problematic aspects of Ivermectin when considering elimination efforts. Because of the drug’s target on microfilariae, Ivermectin only prevents the production of microfilariae for a few months after taking the drug (WHO, 2010). The microfilariae continue to reproduce, black flies can still spread this worm from a host to another individual, and the chain of infection remains unbroken. It is only when the adult worms die, reproduction halts, and Ivermectin has been effective in targeting the microfilariae is the chain of infection broken and transmission interrupted. However, adult worms can live anywhere from 15-20 years, making Ivermectin effective only after taking it for many years (J. Turner et al., 2010). Although the drug itself has been donated for as long as it is needed, 15-20 years is a long time to rely on a single drug when it has already been in use for over 30 years. If Ivermectin is the only treatment being used to eliminate onchocerciasis, any interruption to its use will be detrimental to any progress made towards elimination. As the only safe and effective method of prevention and treatment, there is selective pressure, causing a high risk of drug resistance (J. Turner et al., 2010; H. Turner, Walker, Lustigman, Taylor, and Basanez, 2012). It is therefore unlikely that Ivermectin will be an effective treatment for the entire time frame that must be used for the elimination of onchocerciasis (H. Turner et al., 2012). Further increasing the risk of resistance, drug availability has proven difficult in areas of conflict and political unrest, and poor healthcare infrastructure, which are hard to reach due to geography. Even if resistance does not occur, drug availability problems will set back any progress and increase the time needed to interrupt transmission. Furthermore, Ivermectin is also problematic when used in areas that are co-endemic with L. loa infections. Although the possibility of treating onchocerciasis in these areas by testing for L. loa infections was demonstrated by Kamgno et al. (2017), there are additional costs to this method, and it may not be sufficient for elimination. The additional cost of performing a L. loa diagnostic blood test is a large disadvantage to Ivermectin distribution programs like CDTI. Additionally, logistics of L. loa testing like training, operating, and even participation, could prove to be challenging. Finally, this method of testing and not treating may not be effective enough to reach elimination goals. There is an evident need for additional treatments and/or a vaccine for onchocerciasis in order for elimination to occur.  

One drug that has had some research done on its ability to treat onchocerciasis is moxidectin. Awadazi, Opoku, Attah, Lazdins-Helds, and Kuesel (2014) conducted a study to observe the safety of using moxidectin in humans as it has only previously been used in animals.  The researchers found that 94.8% of all participants in Ivermectin and moxidectin groups had adverse reactions. These reactions included mild to moderate rash, mild to moderate increase in standing pulse rate, and a fall in mean arterial pressure (Table 4). Although significantly higher amounts of participants receiving moxidectin experienced adverse reactions than those receiving Ivermectin, all reactions resolved on their own. After day 8, the decrease in microfilarial density was significantly higher in all moxidectin treatment groups than the Ivermectin treatment group (Figure 2). Overall, moxidectin was found to be safe and efficacious in this study (Awadazi et al., 2014). More studies will be needed to confirm this, but this study shows the importance of safety when studying new drugs. Adverse reactions to drugs, like diethylcarbamazine, which was used in onchocerciasis patients, can cause severe reactions called Mazzotti reactions. As mentioned at the beginning of this paper, when drugs cause the death of microfilariae, the host immune response is triggered and this response has the potential to cause harm to the host (Awadazi et al., 2014). Because reactions can be severe, it is important that prospective drugs do not cause Mazzotti reactions.  

Another alternative drug being researched for the treatment of onchocerciasis is doxycycline. This antibiotic targets the Wolbachia bacteria and has been shown to be effective. A study done by Turner et al. (2010) looked at the effectiveness of doxycycline in areas that are co-endemic with L. loa infections. After 21 months, J. Turner et al. (2010) found significantly less microfilaridermia in participants who received doxycycline and Ivermectin together and doxycycline alone than those who received only Ivermectin. 89% of participants receiving doxycycline and Ivermectin and 67% of participants receiving only doxycycline were amicrofilaridermic after 21 months. These percentages are significantly greater than the 21% of participants who were amicrofiladermic in the Ivermectin only group (Figure 3). In addition to looking at the effectiveness of doxycycline, the researchers had participants keep close track of any new symptoms. Turner et al. (2010) found that doxycycline was tolerated well in these areas of co-endemicity with L. loa infections and that there were no significant differences in adverse events between the experimental groups. Additional studies should still be completed to confirm these findings. Communities like the ones studied by Bakajika et al. (2018) should be the main focus of doxycycline distribution as an alternative to Ivermectin because these communities still have high levels of transmission despite having used Ivermectin long enough to interrupt transmission without any notable noncompliance or drug availability problems. Additionally, these communities are not on track to meet 2025 elimination goals (Bakajika et al., 2018).  

Although the results give hope to the possibility of alternative treatment options, two major considerations for this treatment option are drug administration and availability. As an antibiotic, there is always the risk that Wolbachia will become resistant to doxycycline. Furthermore, doxycycline must be taken every day for a certain period of time and compliance is important for effectiveness. To address this issue, Klarmann-Schultz et al. (2017) conducted a study with the goal of identifying possible treatments that are shorter than the standard 4-week doxycycline treatment. Instead of observing the effects on microfiladermia, researchers primarily looked at how doxycycline affects Wolbachia and the adult O. volvulus worms in comparison to other treatments including albendazole, doxycycline and albendazole, minocycline, and 3-weeks of doxycycline. Albendazole is a drug used with Ivermectin to treat lymphatic filariasis and minocycline is a tetracycline derivative. Overall, the researchers found that the standard 4-week doxycycline treatment was the most effective, killing 98.8% of Wolbachia. The standard treatment was followed by a 3-week doxycycline regimen with albendazole treatment killing 81.4% of Wolbachia, a 3-week minocycline treatment, killing 72.7%, a 3-week doxycycline treatment, killing 64.1% of Wolbachia, and last, a 3-day albendazole treatment, killing 35.2% of Wolbachia (Table 5; Klarmann-Schultz et al., 2017). Although no shorter alternative to the 4-week doxycycline standard treatment was identified, the improved efficacy of albendazole in combination with doxycycline is important. Alone, albendazole was the least efficacious, but when paired with doxycycline, it was significantly more efficacious. This suggests an additive effect of the drugs, an enhanced ability to target and kill Wolbachia, and increased macrofilaricidal abilities. Further studies would be required to confirm the efficacy and safety of these treatment options, but Klarmann-Schultz et al. show possible alternatives to doxycycline alone.  

These alternative options can address problems that may arise in the future, such as drug resistance. It is also important to note that shortening the treatment of doxycycline reduces the amount of Wolbachia killed. A 4-week treatment can be problematic because with longer treatments there is more opportunity for drug incompliance. The use of moxidectin requires a much shorter dosage than a 4-week regimen of doxycycline and may be able to be used as an alternative drug (Awadzi et al., 2014). 

In addition to other drug treatments, some scientists have been researching possible vaccines to prevent onchocerciasis. A vaccine would be ideal because it would eliminate drug availability problems, decrease disease burden, and would likely be able to be used in populations that are not able to take certain drugs, like pregnant women and young children. There is currently no vaccine because of both biological and economic reasons. Humans are the only known hosts of O. volvulus and without an animal host, creating and testing possible vaccines is complicated. Additionally, there is not much interest from pharmaceutical companies as there is not a great economic incentive. Despite difficulties, the benefits of a vaccine have been recognized and have been the basis for starting The Onchocerciasis Vaccine for Africa (TOVA) Initiative. Three possible vaccines have been identified by TOVA, each showing to provide immunity in mice by using recombinant O. volvulus antigens (Hotez et al., 2015). Although these vaccines have not yet entered phase two trials, an effective vaccine would likely have a substantial impact on the communities and individuals directly impacted by onchocerciasis and on the global elimination efforts. H. Turner et al. (2015) modeled the effects that a vaccine would have specifically in L. loa co-endemic regions. The model demonstrated that after 15 years of 80% vaccine coverage, a vaccine would have the greatest reduction in microfilarial load in individuals under the age of 20 (Figure 4). This would be especially valuable because a previous study found that there is a nonlinear relationship between microfilarial load and mortality risk in which an increased microfilarial load in younger populations had a significantly greater risk of mortality compared to populations over the age of 20 (Figure 5; Walker et al., 2012). A vaccine would reduce the annual transmission potential for individuals under the age of 20 (Figure 6; H. Turner et al., 2015). As these individuals make up a large proportion of the total population, a vaccine would prevent them from being the biggest contributors to transmission (H. Turner et al., 2015). While these findings show a large benefit from an effective onchocerciasis vaccine, it must be noted that predicted annual transmission potential will not be reduced enough to interrupt transmission (H. Turner et al., 2015). This is especially important for L. loa co-endemic regions because it means that additional treatment drugs will still be required to achieve elimination. If L. loa co-endemic areas have access to both an effective vaccine and doxycycline, which has been shown to be successful in reducing microfiladermia in these areas (J. Turner et al., 2010), it seems possible that elimination will be able to be achieved.    

The Future of Onchocerciasis

Onchocerciasis has successfully been controlled since the use of Ivermectin as prevention and treatment began. Although it is no longer a public health problem, onchocerciasis impacts the lives of many by causing disability and creating an economic burden. To better understand onchocerciasis, disease presentation, and host immune response to infection, more research must be done. Specifically, OAE should be researched because of its increased risk of mortality. Increased efforts to prevent and treat onchocerciasis are necessary in order to reach elimination goals. This would include the development of additional treatments and possibly a vaccine. Although it will take more research to identify and prove their safety and efficacy, alternatives to Ivermectin are needed especially in communities in with L. loa co-infections. Alternatives to Ivermectin also address the drug’s many problems, like the large amount of time needed to interrupt transmission and the risk of drug resistant O. volvulus due to noncompliance during the long treatment. The elimination of onchocerciasis would eliminate a large economic burden plaguing development in affected regions, and it would greatly improve the lives of the millions of people at risk for this debilitating disease.

Appendix

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