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Introduction 

Onchocerciasis, or colloquially referred to as river blindness, is a disease caused by Onchocerca volvulus, a nematode that harms an infected person’s skin and eyes. It is the second major infectious cause of blindness in the world after trachoma (Barro et al., 2012). In addition, it is a vector-borne disease because its route of transmission is through a bite of an infected Simulium blackfly.  

In 2019, onchocerciasis resulted in 20.9 million infections worldwide, out of which 14.6 million people developed skin disease and 1.15 million experienced vision loss (CDC, 2019). Over 99% of these cases occurred only on one continent; people living in Africa experienced the highest risk of infection. The disease predominantly affects populations in low-income developing countries, making river blindness a neglected tropical disease (NTD). Being considered a NTD leads to onchocerciasis receiving less funding for treatment and prevention in contrast to diseases more common in wealthier countries, such as HIV/AIDS or malaria (CDC, 2019). Consequently, it becomes much more challenging to take measurements to control or possibly eradicate the disease. 

Within the affected countries, there are certain populations which are at the highest risk of infection. Since larvae and pupae of the Simulium blackflies develop in fast-flowing and well-oxygenated streams and rivers, onchocerciasis occurs in locations which are in proximity to water (Kamga et al., 2016). Therefore, populations which are at the highest risk of infection are the ones that live or work near streams or rivers where blackflies breed. These are usually rural communities with many agricultural workers, fishermen, and sand diggers, whose jobs are largely affected by the insects (Cheke et al., 2015). Since many bites are usually necessary for infection, short time travelers or people who are not regularly exposed to the vector are not at immediate risk. However, long-term travelers, missionaries, and field researchers are highly susceptible to the disease as a result of a more intense exposure to blackfly bites (CDC, 2019).  

Since 1995, many African countries have developed Community Directed Treatment with Ivermectin (CDTI) as a strategy in decreasing the number of cases of onchocerciasis (Dissak-Delon et al., 2017). The most successful method has been yearly administration of ivermectin, which was possible due to the generous donation of Merck who provided ivermectin free of charge for the treatment of onchocerciasis (Loum et al., 2017). Although many efforts were taken to eliminate the disease, there are still people dying from onchocerciasis every year. This paper considers epidemiology, possible prevention and treatment, as well as factors affecting the emergence of the disease. Based on the variety of research, it aims to familiarize the reader with the different elements that affect the disease and offer possible future goals in the elimination of onchocerciasis.  

Historical background 

Despite the African population being exposed to onchocerciasis for centuries, the disease was only scientifically identified in 1874 by John O’Neill. O’Neill was a British naval surgeon who lived in Ghana and managed to observe the worms through microscopic examinations from the papules of patients he saw suffering from the disease (Crump et al., 2012). It is believed that the disease originated in Africa and was later introduced to other parts in the world, particularly Yemen and six Latin American countries: Brazil, Colombia, Ecuador, Guatemala, Mexico, and Venezuela. The spread of the disease out of the African continent most probably resulted from  slave trade (Crump et al., 2012).  

Once the disease had been identified, it was established that there were two main methods to control the prevalence of onchocerciasis: vector control and drug treatment. Since there were no drugs developed up until much later, the most feasible way to prevent the transmission of the pathogen was to control the blackfly population. This was managed by using insecticides which would kill the blackflies, such as dichlorodiphenyltrichloroethane (DDT) (Crump et al., 2012). The insecticides were sprayed nearby rivers, the usual breeding sites of blackflies. In 1975, however, ivermectin was developed and it was soon acknowledged as the most successful in the treatment of river blindness. The treatment with ivermectin was promoted in the countries affected by the disease as a part of the above mentioned CDTI programs. Around the same time ivermectin began to be advanced, researchers discovered that there is an intracellular bacterium called Wolbachia which acts as an endosymbiont with O. volvulus. The bacterium has a crucial role in worm growth, and it is present in the developmental stages of adult worms, as well as the reproductive systems of females (Tamarozzi et al., 2011). The acquired knowledge on the dependency between the worm and this type of bacteria enabled the development of new treatments for onchocerciasis. The drug that is recognized as most successful in depleting the bacteria is the antibiotic doxycycline (Tamarozzi et al., 2011). In the current time, the advancements and understanding that have been gained continue to be used for the treatment of onchocerciasis, including both vector control and the use of drugs such as ivermectin and doxycycline.

Successful pathogen, vector, and symptoms 

Pathogen 

O.volvulus requires around one year to grow and mature, and its average life cycle is around 15 years. Male and female worms can be found in nodules where they are intertwined and are able to reproduce. During reproduction, the females can produce around 1000 microfilariae daily (Crump et al., 2012). Living microfilariae interact with the immune system by invading the skin and eyes, but only the dying or dead microfilariae are the ones that induce an inflammatory response in the body (Kamga et al., 2016). 

Vector 

The Simulium blackfly ingests microfilariae of the worm from an infected person and carries it in its body where it continues developing. The bite acts as a point of entry for the pathogen (Crump et al., 2012). Upon its next bite, the blackfly drops larvae in the blood of another person who then becomes infected. For the infection to be successful, it requires repeated bites from a blackfly because only one is not effective (CDC, 2019).  

Symptoms 

Once infected, some patients may not show any symptoms because the larvae do not always provoke an immune system response in the body. This usually happens in the beginning of the infection because most symptoms are caused by an immediate immune response to the dead or almost dying microfilariae (CDC, 2019). In symptomatic patients, symptoms usually include a skin rash with itchiness, eye disease, and nodules under the skin. A concerning skin damage is thinning of the skin and a loss of elasticity. In addition, some infected people experience changes in the color of their skin which has come to be referred to as “leopard skin”. Blindness is a more serious manifestation of the disease and usually occurs with a longstanding and intense infection (CDC, 2019). 

Prevention and treatment  

Ivermectin

Although a vaccine for onchocerciasis has not been developed, treatment is possible with ivermectin. Ivermectin is a broad-spectrum drug that is used against parasites, such as O.volvulus. The drug kills the larvae in the infected person and consequently reduces the symptoms. When taken annually, ivermectin can reduce the number of morbidity cases, and it can bring a significant reduction in the microfilariae in the skin and eyes (Weldegebreal et al., 2014).  

Many studies have attempted to assess the progress of CDTI programs in affected countries in order to gain insight into potential paths for eliminatinge onchocerciasis in the future. One such study has been done in Sierra Leone, where CDTI was attained after a devastating civil war. Koroma et al. (2018) examined hyper- and meso-endemic villages for onchocerciasis by using skin snips and then compared the results with the baseline data of the study sites.  The aim of their study was to assess the effectiveness of CDTI programs after five annual rounds of treatment. The baseline results from the study showed that microfilarial prevalence was higher in the study sites in the north compared to the southern districts, with the highest percentage being 69.6 in Koinadugu (Figure 10). The average microfilarial prevalence ranged between 39.01% to 61.94%. However, the results from 2010 showed a general decline in prevalence, especially in the northern part where it had been most predominant before (Figure 10). The overall microfilarial prevalence dropped by 60.22% in comparison to the initial data. Furthermore, additional findings from the study were that microfilarial prevalence was higher in males compared to females and it was lower in younger participants in the study. It is thought that males and older people have a higher prevalence because they tend to experience greater exposure to blackflies (Koroma et al., 2018). The study suggests that CDTI programs in Sierra Leone have promising results and should be continued in efforts to eliminate onchocerciasis. 

Another study in Cameroon in which CDTI programs have been happening for over a decade, again shows that recent treatments have been effective although they have not been successful in entirely eradicating onchocerciasis. Kamga et al. (2016) conducted a cross-sectional survey in eight communities in two health districts, where the study participants had clinical and parasitological examinations. The results from the study suggested that when comparing the microfilarial load (mf/ss) in 1991, 2011, and 2015, there had been a large decrease over the years. This was especially observed in the Biatsota community where it decreased from 14.5 mf/ss in 1991, to 3.3 mf/ss in 2011 and 1.0 in 2015 (Figure 5). This finding  suggests that treatment with ivermectin is an effective method in reducing the microfilarial load in the bodies of infected patients, but that onchocerciasis was still present in the communities. The researchers were interested in observing how patient compliance affected the persistence of the microfilaria. The results indicated that there were less microfilaria per skin snip in patients who had continued their treatment in the last five years (Figure 6). These results suggest that there should be both optimal compliance from patients, as well as regular ivermectin treatment in order to completely eliminate onchocerciasis. 

Eliminating Wolbachia to treat onchocerciasis  

As mentioned in the historical background, O.volvulus is endosymbiotic with the Wolbachia bacteria. The elimination of Wolbachia prompts for an inhibition of worm development, and reduces fertility and viability (Tamarozzi et al., 2011). Since the bacteria is able to be treated with doxycycline, alternative methods should be considered for possible elimination of onchocerciasis. 

In their study, Walker et al. (2015) measured the Wolbachia status and the viability of individual female adult worms by using a meta-analytical modeling framework. The aim of the study was to determine the efficacy of different treatment regimens of doxycycline, including different doses (100 mg or 200 mg) and durations (4, 5 or 6 weeks) of dose delivery. The researchers defined efficacy as the maximum proportional reduction in the percentage of adult female O. volvulus with Wolbachia. After collecting the results, the researchers concluded that each regimen was successful in the treatment of Wolbachia because the efficacy ranged from 86 to 96%. The treatment consisting of 100 mg doses given daily for 6 weeks was the only one to have over 90% efficacy in the box-and-whisker plot (Figure 11). The researchers confirm that doxycycline is the leading option for treatment of onchocerciasis due to its safety and effectiveness. As a recommendation for future studies, the researchers point out that other anti-Wolbachia treatments should be explored because they could serve as complementary methods in eliminating onchocerciasis. These methods could be especially useful in locations where the CDTI treatment has not been as efficient and the disease is still endemic. 

Another study done by Tamarozzi et al. (2012), evaluated the long-term effectiveness of treatment with doxycycline. The study was conducted four years after the implementation of the treatment in Cameroon. Their methods included inviting participants who completed the mass drug administration (MDA) both with doxycycline and ivermectin in 2007 or 2008, and those who only received treatment only with ivermectin in the same time period. To assess infection, skin biopsy was performed. The results indicated that MDA with doxycycline lead to a further reduction in the microfilaridermia prevalence; the percentage of microfiladermia prevalence with only ivermectin treatment was around 27%, whereas treatment with  ivermectin and added doxycycline lowered the prevalence to around 17% (Figure 12A). Consequently, the researchers supported the idea of doxycycline being distributed with onchocerciasis control programs.  

A common concern mentioned in both of the studies was that doxycycline treatment could be problematic due to issues with compliance from patients and complications with pregnant and breastfeeding women, and children. Although the effectiveness of doxycycline is acknowledged, the studies urge for more work in the development of other anti-Wolbachia drugs that would be safer for treatment of the above mentioned groups. 

Vector control

Since onchocerciasis is a vector-borne disease, vector control is a necessary strategy in the efforts to eliminate the disease. Research including epidemiological data and mathematical modeling has suggested elimination is not feasible by only relying on drug treatment with ivermectin or doxycycline. There are two main objectives that vector control can achieve: reducing the number of blackfly bites responsible for O. volvulus transmission and collecting blackflies to test the presence of the worm in order to assess the progress of the elimination programs.  

One possible method of vector control that could be used to limit the number of bites is using insecticides on the blackflies. Routledge et al. (2018) wanted to examine the frequency and the length of vector control required to reduce the biting rates of S. damnosum in savannah sites in Ghana and forest sites in Cameroon. Based on the model calibration, it was observed that using insecticides in the savannah was more effective than in the forest. In the forest, it took around 40 days for a decrease in the number of flies per trap. In comparison, it took only around 5 days for a decrease in the bites per human per day in the savannah (Figure 15). Nonetheless, the study supports the idea that vector control in areas where larvicidal insecticides can be effective should be encouraged and maintained regularly. The researchers suggested that insecticides should favorably be used weekly for the best progress. This method could help accelerate the elimination of onchocerciasis in endemic communities which struggled to achieve their goal by only treating the disease with ivermectin. However, the study also suggests that before such programs are implemented in communities, there should be an understanding of vector ecology and population dynamics. For instance, since there are different species of the vector, it is necessary to learn about the vector capacities and susceptibilities to insecticides. 

Along the discussion of vector control, community involvement is another promising method in the attempt to eradicate onchocerciasis because it enables affected populations to contribute in the process and educate themselves on the epidemiology of the disease. An example of a traditional method of vector control is the use of  human landing collectors (HLC) in Northern Uganda. However, the procedure was not regarded as efficient, and it could be hazardous since it had a potential risk of exposing the collectors to the worm. As an alternative, Loum et al. (2017) evaluated community-directed capturing of blackflies using a new method called Esperanza Window Trap (EWT) in two communities, Laminatoo and Gonycogo, in Uganda. EWT is inexpensive and can be made from locally available materials. It contains carbon dioxide and it is baited with human sweat attractants such as sweat-impregnated socks, BG sweetscents human bait lure and aroma beads with a mixture of human sweat components (Loum et al., 2017). The aim of the study was to observe whether the alternative method with EWT could be more effective than the traditional one with HLC. The results showed that on days when collections of HLC were high EWT traps also collected the most blackflies. Similar findings were found in both of the study sites where the experiment was conducted (Figures 13 and 14). However, EWT managed to catch many more flies on average, specifically 4.2 times as many per day as the traditional method. This allowed the researchers to confirm that EWT can catch more blackflies compared to the traditional HLC teams and that HLC could be replaced with EWT as a means of vector control in Uganda. In addition, their results showed that all of the different baits from the study were effective in appealing to blackflies and could be used in the EWT. Alimitation of the study is that it only controlled for the species S. damnosum; there are more species of blackflies which can be vectors for onchocerciasis. Therefore, future studies could evaluate the effectiveness of EWT on other species in different endemic areas for the disease. 

Factors affecting onchocerciasis 

Environmental factors

Since onchocerciasis is a vector-borne disease, environmental factors have a significant contribution in its prominence. In an environment favorable for blackflies, it could be expected that the vector would have better conditions to reproduce and increase its population. Furthermore, in a scenario where the population of blackflies were increased, it could be expected that there would be a larger number of bites and subsequently, an increase in the number of people infected with onchocerciasis. Accordingly, the control of the vector population is necessary to prevent the re-emergence of cases of the disease. In order for elimination to be feasible, changes in climate should be monitored to see their effect on the blackfly. 

In a study done in Ghana and Burundi,  researchers analyzed biophysical factors due to the fear of recrudescence of the disease. The aim of the study was to examine which factors had a significant correlation with the prevalence of onchocerciasis. The results indicated that rainfall, humidity, and elevation correlated significantly in Burundi, whereas in Ghana the only highly significant factor was elevation (Barro et al., 2012). In addition, onchocerciasis was predominantly found in rural communities near rivers, which supported the hypothesis of the study. The highest risk correlating with the highest nodule prevalence was proximity to water in both of the countries (Figure 1). This information can be helpful for creating maps that show areas where contracting onchocerciasis is more likely; however, although risk maps can be a useful method to predict the location of blackflies, they do not account for fluctuations in climatic conditions, which is a limitation. For that reason, the study acknowledges environmental factors as significant for the transmission of onchocerciasis and the researchers suggest that there should be more consideration put towards these factors in the efforts to control the vector population.  

Another environmental factor that can influence change in the vector population is climate change. Climate change is a serious concern for many diseases because its possible effects are still unknown. Concern for the effects of climate change on NTDs such as onchocerciasis are especial great because there is a high possibility that NTD would not get the appropriate support in treatment and prevention since priority would be given to more prominent diseases. Cheke et al. (2015) did research in Liberia and Ghana on the effect of climate change in relation to onchocerciasis. Their findings report that climate change could contribute to the disappearance of breeding sites of blackflies as a result of river floods or it could have an effect on the development times of larvae with the change of temperature. With an increase in the temperature, the development time for eggs, larvae, and pupae would decrease. Based on their results, the development time for eggs would decrease from 3 days to 1 day with an increase in temperature from 20°C to around 33°C (Figure 2). The study acknowledges that future climatic regimes will have an effect on onchocerciasis since the vector is dependent on water and temperature. Future research could include the examination of seasonality and migration of the blackflies.  

Sociocultural factors

Human behavior plays a crucial role in the prominence of onchocerciasis because it can either contribute in the efforts to eliminate the disease or be responsible for stagnation in elimination efforts and an increase in cases. In this regard, basic knowledge on transmission, prevention, and treatment, as well as compliance to the necessary treatment, are elements expected to be followed by the affected populations to effectively minimize the risk of onchocerciasis.  

In a study done by Weldegebreal et al. (2014), researchers looked at the level of knowledge, attitude, and practice members of the population had towards onchocerciasis and the treatment with ivermectin in the Quara district in Ethiopia. They prepared questionnaires for the study participants where they assessed their understanding of the disease. Based on the results, 190 (47.4%), 182 (45.4%) and 62 (15.5%) had a good level of knowledge, attitude and 

practice towards onchocerciasis, respectively (Figure 4). The results suggest that although onchocerciasis is a common disease in the area, the communities affected by it still have misunderstandings. For that reason, there should be more campaigns on educating the local population about the transmission, prevention, and treatment of onchocerciasis. This would help more people to become aware of how to protect themselves and when to seek treatment if they become infected. 

Also important to consider is stigmatization directed towards people with onchocerciasis infection. Diseases that manifest in physical changes, such as in the case of onchocerciasis, often result in infected people becoming singled out in the population. Since skin color changes and blindness are symptoms that are easily visible to others in the community, people with onchocerciasis can experience social ostracism and rejection (Tchounkeu et al., 2012). Therefore, not only does the disease cause physical complications to the patients, it can also lead to mental health issues and difficulties in being accepted by others in the societies they live in.  

A study conducted by Tchounkeu et al. (2012) attempted to observe the changes in stigmatization before and after the start of CDTI in four African countries: Cameroon, Democratic Republic of Congo (DRC), Nigeria, and Uganda. This was done by conducting interviews with people from households in the study areas, community leaders, and health personnel. According to the results, 58.2% of people would not marry a person with onchocerciasis (Table 1). Stigmatization specifically targets women and they were found to have a lower chance of getting married; this is concerning because of the gender norms in many countries in Africa. Moreover, the results suggest that stigmatization is more prevalent among the youth compared to the older population in all of the countries studied. Uganda had the highest tendency for stigmatization, and the results were significantly higher in both the young and old population. The lowest tendency to stigmatize people with onchocerciasis could be observed in the older Cameroonian population (Figure 3). When asked on the reasons for the stigmatization, respondents mentioned the fear of transmission (Tchounkeu et al., 2012). From this study, it can be noted that human behavior requires more attention when dealing with disease because of ostracism towards infected patients, which is something that is often not included in the discourse. These findings can be used in acknowledging which groups are the most affected by stigmatization, as well as which groups discriminate them the most. Using this information could help reduce the stigmatization in communities affected by onchocerciasis. 

Onchocerciasis and epilepsy

Although there are 50 to 70 million people with epilepsy around the world, the majority live in low and middle-income countries. Usually epilepsy and onchocerciasis occur separately, but sometimes an association between them has been suggested. The first association  between epilepsy and onchocerciasis was reported in the 1930s in Mexico. Consequently, many studies attempted to answer the question of whether there is a correlation between the disorder and the disease. 

In one such study, Chesnais et al. (2018) measured the microfilarial load in patients in 25 villages in Cameroon in 1991 and then repeated the study in 7 of those villages in 2017. The aim of the study was to measure the microfilarial load of O. volvulus during childhood and determine if there was a relationship with the incidence of epilepsy in those participants. Although the likelihood of epilepsy occurring due to onchocerciasis was not proved, the study mentioned that there were hypotheses suggesting direct microfilarial penetration in the central nervous system. This was not assessed in their study, but it was of interest to the researchers. After completing the study, the results  suggested that the risk of getting epilepsy increased with a higher microfilarial density, especially as the microfilarial density got close to or above 100 mf per snip. When the microfilarial density was lower, there was a smaller prediction incidence and it appeared to be slower (Figure 7). In addition, there were two principal findings that supported the hypothesis of the researchers. First, the study observed that the majority of cases of epilepsy occurred in individuals who had a high microfilarial density during childhood. In addition, only one out of 165 participants who did not have any microfilarial density during childhood experienced epilepsy. To conclude, even though it is not certain that O.volvulus causes the development of epilepsy, evidence supports the idea that there might be a relationship between the two. This finding brings further incentive for more attention to be given in the prevention of onchocerciasis. 

Lenaerts et al. (2018) also conducted a study with the aim or determining whether there is a correlation between epilepsy and onchocerciasis. In their study, they mentioned an observation that nodding syndrome, characterized by atonic seizures, occurs only in the same locations where onchocerciasis is endemic. Although not their principal study, the researchers also examined if the nodding syndrome was present in the study sites in the Democratic Republic of Congo (DRC) since it had not yet been documented there. Furthermore, the researchers acknowledged that the CDTI treatment has not been spatially or yearly consistent. For instance, the Draju village which was a part of the study has not been included in the treatment because it was considered hypo-endemic even though when examined, O. volvulus was present in 17 out of 52 people. The methods of their study included three stages; in the first one, the participants were screened for epilepsy, in the second one the diagnosis was validated by practitioners and in the last stage the diagnosis was confirmed by a neurologist.  

According to the results, the highest proportion of positive test results was found in the village with the highest prevalence of epilepsy, which is Mbesi (Figure 8 and 9). Moreover, the data indicated that there was a significant association between epilepsy and O. volvulus. Concerning the nodding syndrome, it was thought to be present in 8 out of 54 people with epilepsy;  this was the first time the syndrome had been found in the DRC. Prior to this study, nodding syndrome had only been reported in Uganda, South Sudan, and Tanzania which are other onchocerciasis endemic countries. This was a promising result for future research and improved diagnosis. Based on these results, the researchers urged for an implementation of CDTI treatments and increasing the outreach to more onchocerciasis endemic villages. 

Future goals and conclusion

Onchocerciasis is a neglected tropical disease that acts as a large hurdle to the developing world, predominantly the African continent. O. volvulus is a successful pathogen because even though there is treatment provided with ivermectin, doxycycline, and vector control, it still remains endemic in many communities. CDTI programs have been immensely effective in reducing the number of cases of onchocerciasis, but research suggests that alternative methods are required in order to achieve elimination. Furthermore, although doxycycline is considered to be the most successful in treating the endo-symbiotic Wolbachia bacteria, it encounters problems with compliance and the treatment is not inclusive towards every group. Therefore, other anti-Wolbachia drugs should be considered for an improved treatment. Besides drug treatment, vector control is a significant method of prevention because it promotes community engagement, it reduces the number of blackflies, and it helps assess the elimination progress. Combining these three methods of prevention and treatment, along with future research based on current understanding of the disease, could be a promising path towards the complete eradication of onchocerciasis on the African continent.  

In addition, in the efforts to eliminate the pathogen, environmental and sociocultural factors should be observed more carefully because they can heighten the success of O. volvulus. In this regard, water and temperature should be of principal concern when considering conditions that may aid in the the spread of onchocerciasis because the reproduction rate of the vector is highly dependent on these two factors. Another problem with environmental factors is the unknown effect of climate change on the vector population. For instance, it is thought that the occurrence of more droughts as a result of global warming would decrease the population of blackflies; conversely, it is thought that an increase in temperature would decrease the time for development, hence increasing the population. Furthermore, sociocultural factors are significant because human behavior can accelerate or hinder the treatment and prevention efforts. In order to accelerate the process, there is an urgent need for education on onchocerciasis for people living in endemic regions. With this measure, it is hoped that there would be a reduction in social ostracism and stigmatization towards infected people. Consequently, people with onchocerciasis could hopefully experience less mental health issues due to sociocultural factors and be  more willing to seek treatment.  

To conclude, the elimination of onchocerciasis in more communities in Africa is possible, but it requires the combined efforts of every affected group in addition to future research towards how improvement of the current treatment and prevention methods could be achieved. Treatment is important and would significantly help these affected populations. Furthermore, it is likely that treatment of onchocerciasis would not only help low-income communities in African countries, but possibly also aid in the prevention of other diseases that might be caused by onchocerciasis, such as mental health problems and epilepsy. Since the association between epilepsy and onchocerciasis is not proven, future research should also consider answering this question.

Works Cited 

Source: CDC. Centers for Disease and Control Prevention. 6 September 2019. https://www.cdc.gov/parasites/onchocerciasis/

Barro, Alassane S, and Tonny J Oyana. “Predictive and epidemiologic modeling of the spatial risk of human onchocerciasis using biophysical factors: a case study of Ghana and Burundi.” Spatial and spatio-temporal epidemiology vol. 3,4 (2012): 273-85. Doi:10.1016/j.sste.2012.08.001 

Cheke, Robert A et al. “Potential effects of warmer worms and vectors on onchocerciasis transmission in West Africa.” Philosophical transactions of the Royal Society of London. Series B, Biological sciences vol. 370,1665 (2015): 20130559. Doi:10.1098/rstb.2013.0559 

Chesnais, Cédric B et al. “The temporal relationship between onchocerciasis and epilepsy: a population-based cohort study.” The Lancet. Infectious diseases vol. 18,11 (2018): 1278-1286. Doi:10.1016/S1473-3099(18)30425-0 

Crump, Andy et al. “The onchocerciasis chronicle: from the beginning to the end?.” Trends in parasitology vol. 28,7 (2012) : 280-8. Doi :10.1016/j.pt.2012.04.005  

Dissak-Delon, Fanny Nadia et al. “Adherence to ivermectin is more associated with perceptions of community directed treatment with ivermectin organization than with onchocerciasis beliefs.” PloS neglected tropical diseases vol. 11,8 e0005849. 14 Aug. 2017, doi:10.1371/journal.pntd.0005849 

Kamga, Guy-Roger et al. “Still mesoendemic onchocerciasis in two Cameroonian community-directed treatment with ivermectin projects despite more than 15 years of mass treatment.” Parasites & vectors vol. 9,1 581. 14 Nov. 2016, doi :10.1186/s13071-016-1868-8 

Koroma, Joseph B. et al. “Impact of five annual rounds of mass drug administration with ivermectin on onchocerciasis in Sierra Leone. Infect Dis Poverty 7, 30 (2018). https://doi.org/10.1186/s40249-018-0410-y 

Lenaerts, Evy et al. “High prevalence of epilepsy in onchocerciasis endemic health areas in Democratic Republic of the Congo.” Infectious diseases of poverty vol. 7,1 68. 1 Aug. 2018, doi:10.1186/s40249-018-0452-1 

Loum, Denis et al. “Evaluation of Community-Directed Operation of Black Fly Traps for Entomological Surveillance of Onchocerca volvulus Transmission in the Madi-Mid North Focus of Onchocerciasis in Northern Uganda.” The American journal of tropical medicine and hygiene vol. 97,4 (2017): 1235-1242. Doi:10.4269/ajtmh.17-0244  

Routledge, I., Walker, M., Cheke, R.A. et al. Modelling the impact of larviciding on the population dynamics and biting rates of Simulium damnosum (s.l.): implications for vector control as a complementary strategy for onchocerciasis elimination in Africa. Parasites Vectors 11, 316 (2018). https ://doi.org/10.1186/s13071-018-2864-y 

Tamarozzi, Francesca et al. “Long term impact of large scale community-directed delivery of doxycycline for the treatment of onchocerciasis.” Parasites & vectors vol. 5 53. 20 Mar. 2012, doi:10.1186/1756-3305-5-53 

Tamarozzi, Francesca et al. “Onchocerciasis: the role of Wolbachia bacterial endosymbionts in parasite biology, disease pathogenesis, and treatment.” Clinical microbiology reviews vol. 24,3 (2011): 459-68. Doi:10.1128/CMR.00057-10 

Tchounkeu, Yolande Flore Longang et al. “Changes in stigma and discrimination of onchocerciasis in Africa.” Transactions of the Royal Society of Tropical Medicine and Hygiene vol. 106,6 (2012): 340-7. Doi:10.1016/j.trstmh.2012.02.009 

Walker, Martin et al. “Therapeutic efficacy and macrofilaricidal activity of doxycycline for the treatment of river blindness.” Clinical infectious diseases : an official publication of the Infectious Diseases Society of America vol. 60,8 (2015): 1199-207. Doi:10.1093/cid/ciu1152 

Weldegebreal, Fitsum et al. “Assessment of community’s knowledge, attitude and practice about onchocerciasis and community directed treatment with Ivermectin in Quara District, north western Ethiopia.” Parasites & vectors vol. 7 98. 10 Mar. 2014, doi:10.1186/1756-3305-7-98

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