Katie King

Sarah Loaiza

Taylor Grimes

 

Ivermectin Protocol: Guidelines for the Treatment of Onchocerciasis in Areas Co-endemic for Onchocerciasis and Loiasis in Cameroon

 

 

I. Introduction

 

            Onchocerciasis, more commonly known as River Blindness, has been a scourge to humanity for thousands of years and is the second leading cause of blindness today. The gravity of its impact has prompted much attention. In 1987, Merck & Co., Inc., one of the largest pharmaceutical companies in the world, discovered and developed an efficacious broad-spectrum anti-parasitic medication, ivermectin. Merck’s decision to donate ivermectin, titled Mectizan®, to those suffering from onchocerciasis for as long as needed, has freed millions of people from the shackles of this parasitic disease. According to the UNESCO World Science Report of 2005, “the progress that has been made in combating River Blindness with ivermectin represents one of the most triumphant public health campaigns ever waged in the developing world”[1].  However, the seemingly miraculous, infallible drug has one large drawback: those suffering from onchocerciasis who simultaneously possess a high intensity load of Loa loa infection could potentially suffer from severe adverse effects (SAEs) including neurological reactions such as encephalopathy.[2]

The most important risk encountered in distributing Mectizan® for the control of onchocerciasis in areas where Loa loa is co-endemic is the development of an encephalopathic syndrome in people with very high levels of L. loa [> 30,000 microfilaria/milliliter blood (mf/ml)] following treatment with ivermectin. [3]  This syndrome, which occurs rarely, is characterized by symptoms ranging from low-grade fever to confusion to even death.[4]  In an attempt to combat these events, much effort was placed into identifying areas of high co-endemicity. The World Health Organization’s Rapid Assessment Procedure for Loiasis (RAPLOA), both a community-wide and individual questionnaire, relates the prevalence of key clinical manifestations of loiasis, such as a history of eye worm, to the level endemicity of the infection and serves as a useful tool to identify areas at high potential risk of Loa loa post ivermectin treatment encephalopathy.[5] With the current advanced satellite mapping of areas in Cameroon with high endemicity of loiasis, consequent of RAPLOA’s, careful attention can now be paid to ivermectin distribution in these areas in order to avoid encephalopathy.

II. Specific Aims

            As a result of RAPLOA’s success, the issue at hand now moves from identification of high risk areas to the designing of ivermectin protocol for these now identified co-endemic areas. Once an area has been designated as meso-endemic or hyper-endemic for onchocerciasis and loiasis, then careful distribution and monitoring of ivermectin must be established. The problem in Cameroon lies in the lack of action and change post the recognition of these highly co-endemic areas. Some groups such as The Mectizan® Donation Program have offered and published literature regarding recommendations for a safer distribution of ivermectin, but these particular 2004 recommendations have failed to achieve full implementation.[6] Dr. Yao Sodahlon, the Associate Director of The Mectizan® Donation Program reiterates, “The recommendations are intended to facilitate effective, safe distribution of Mectizan® in known and suspected L. loa endemic places but because the ultimate decision on how to proceed with community-based mass treatment is up to the National Onchocerciasis Task Force (NOTF) and the Ministry of Health of the given country,  attention should be given to community awareness and teaching people on how to detect the adverse affects.”[7]

Therefore, the focus of our proposed design is twofold: it will first center on perfecting the logistical and operational aspects of ivermectin distribution in these designated areas and will simultaneously take on a public health education angle intending to enhance community awareness and educate community distributors. Increasing community awareness and education of the SAEs following treatment with ivermectin will help communal members to recognize such symptoms and react appropriately by taking the patient to a designated health facility for clinical management of such cases.

In order to best understand the steps that led to the proposed programmatic design, a background of both loiasis and onchocerciasis is necessary. Following the general disease information including epidemiology, geography, and modes of transmission, emphasis will be placed on the diagnostic and treatment portion of onchocerciasis as it proves the underlying problem of the situation at hand. Current treatment and its adverse effects in areas of co-endemicity will be examined while potential areas of intervention highlighted. The progression of understanding the biology behind the diseases, then the geography of each including overlapping areas, then over viewing the treatment of choice, and finally understanding the potentially adverse side effects will naturally lead us to areas in need of change and gaps open for intervention.

III. Background

Loiasis is found predominantly in the jungles of the Congo, Sudan and West Africa, most commonly in Cameroon and near the Ogowe River as it provides a perfect environment for the vector.  Like most vector dependent diseases, the areas in which Loa loa are found are the rain forest climates where the vector, Chrysops (Mango fly) thrives.  Endemic areas in this region are estimated to have an adult prevalence rate range between 9% and 70% of the population.  Loa loa affects humans of all ages; however, it is generally more prevalent in adult men.[8]  Fortunately, there are no serious long-term damages to humans as a result of infection. 

Onchocerciasis is caused by the nematode, Onchocerca volvulus that is present across Central Africa, Yemen, Saudi Arabia, as well as some countries in Central and South America.[9]   Approximately 18 million people suffer from onchocerciasis worldwide and causing the loss of thousands of DALYs with the associated morbidity.[10]

Figure 1. Onchocerciasis lifecycle (BasáĖez)http://medicine.plosjournals.org/archive/1549-1676/3/9/figure/10.1371_journal.pmed.0030371.g001-M.jpg

Both L. loa and O. volvulus are tissue dwelling nematodes with similar life cycles.  Loa loa is transmitted to humans when the mango fly bites the host and the infective larvae which have matured in the fly then migrate out of the fly, onto the surface of human skin and ultimately into the open bite wound.  The flies are infected by ingesting microfilariae from a human host during a blood meal.  Similarly, Similium flies breed near fast moving water, and serve as the vector for O. volvulus by depositing infective larvae on the skin when the fly takes a blood meal. The larvae develop subcutaneously and eventually form nodules within a year of infection. When another black fly takes a blood meal and ingests the O. volvulus they may then transmit the infection to other humans.[11] [See figure 1]

The most obvious symptom of L. loa is the passage of worms across the bridge of the nose and the eye.  Adult worms travel throughout the body’s subcutaneous tissue but usually go unnoticed, but may cause eyelid swelling or localized edema, known as Calabar swellings in the subcutaneous tissue.  These swellings can be up many inches in diameter and often are accompanied with pain and pruritus.  Calabar swellings and the appearance of a worm in the eye are the most commonly used signs for diagnosis because microfilariae do not become apparent in the blood until years after infection and maturation of the worms.  The presence of Calabar swellings does not definitively indicate the presence of a live worm, but actually indicates an allergic reaction to either dead worms or the metabolic by products of the worms.[12] 

            Nodules are usually present in individuals with onchocerciasis.  The microfilariae that the adult worms produce may also cause inflammatory reactions in the skin. Onchodermatitis results from the skin reactions where the skin becomes wrinkled, discolored, and thickened.  Complications and swelling may occur, resulting in “hanging groin”.  The most famous symptom of onchocerciasis is blindness.  The presence of O. volvulus may be confirmed with skin snips, nodulectomy, or a recently developed specific antibody based rapid diagnostic test.[13] 

There are a number of ways that loa infection may be treated, but ivermectin remains the prominent microfilaricidal as it is both safe and efficacious.  Although ivermectin is not as fast acting as DEC, it does not cross the blood-brain barrier like DEC making it a safer drug.  Ivermectin has little effect on the adult worms, and thus individuals must be retreated annually.[14]   The Mectizan Donation Program (MDP) is committed to distributing ivermectin throughout onchocerciasis endemic areas in Africa.  Thus far the program has been quite successful; however an obstacle has arisen in co-endemic areas, especially in Cameroon, with onchocerciasis and loiasis where some individuals with a high parasitic load have SAEs.     

Severe neurologic problems such as encephalopathy and coma have occurred after treatment with ivermectin in cases of co-infection with high microfilaraemia of L. loa (>30,000mf/ml) with O. volvulus.[15]  Recovery from neurological side effects associated with onchoceriasis and loa loa co-infection is possible with correct and rapid diagnosis and treatment. David Addis of the Center for Disease Control explains,

 

During the mid-1990s, reviews of the clinical features of Mectizan®-associated L. loa encephalopathy revealed that basic supportive care (i.e., hydration, feeding, and nursing care) was critical for patient recovery; indeed, prompt and sustained supportive care is the most important therapeutic measure... Thus, mass distribution of Mectizan® in L. loa-endemic areas should be preceded by community education to increase awareness of possible SAEs following treatment. During and after mass drug distribution, intensified surveillance for SAEs is required, as is a referral system to appropriate health facilities for any SAEs that may occur. [16]

 

Development and distribution of a more appropriate treatment seems an unlikely solution as it will take considerable time and funding and SAEs are not very common.  Until an effective and safe drug treatment is found, the most effective strategy is to quickly diagnose and treat the reactions to the ivermectin treatment. A dose-reduction strategy of ivermectin and albendazole has been tested as a possible solution to avoid SAEs by lowering the initial parasitic load below the risk threshold level, but at this point it appears it will not prove to be any safer or effective at different dosages.[17] 

            As numerous filarial infections may be treated with ivermectin, the mass distribution programs are critical in highly endemic areas of Africa.  While the SAEs are rare, they pose a problem for the mass distribution of ivermectin, thus making SAEs a pertinent issue to avoid unnecessary mortality.  Currently the African Programme for Onchocerciasis Control (APOC) uses statistical modeling to decide which areas are highly co-endemic where patients have a risk of SAEs and uses precautionary measures where the prevalence of L. loa is more than 20% or where the history of eye worm passage is more than 40%.[18]  In order to determine the co-endemic populations that are at risk from mass distribution of ivermectin a rapid diagnostic test has been developed for loiasis (RAPLOA) that may be easily completed as it only involves a questionnaire to determine the history of loiasis.  The Mectizan Expert Committee established the recommendations that are currently being implemented in 2004. 

 

IV. Programmatic Design

 

            The underlying intention of the following programmatic design is to set in place a standard protocol for ivermectin distribution and to enhance the knowledge of the community caretakers, the patients’ specific caretakers, and the community as a whole of the signs and symptoms of an adverse reaction to ivermectin. The goal, in a few words, is to facilitate effective detection. With knowledgeable caretakers at hand, patients who have received ivermectin and who happen to have high loads of Loa loa will be brought into health care facilities much faster and will avoid extreme negative outcomes such as full scale encephalopathy or even death.[19] A protocol must be established for areas designated as highly endemic for loiasis and a plan must be implemented for ways to educate the caretakers in recognizing the adverse symptoms.

Previous studies show that there is a close relationship between the intensity of Loa loa microfilariae infection and prevalence of loiasis suggesting that a distribution map based upon the prevalence of infection would alone provide sufficient information to delineate areas of high risk of adverse reactions.[20] From these studies, we have chosen the target villages to implement our programmatic design. The villages chosen contain a prevalence threshold of over 20% Loa loa prevalence. Such villages chosen for the purposes of our plan include: Ntem, Ngun, Nwanti, Ngu, Sabongari, Nking, Mniripkwa, and Nwat. [See Figure 2].  For the purposes of our design, the villages containing prevalence rates between 20% and 30% will be labeled as meso-endemic and the villages containing prevalence rates over 30% will be labeled as hyper-endemic.

Figure 2. Prevalence Map of Loa Loa in Cameroon[21]       

 

            In order to achieve the goal of eliminating the severe adverse effects associated with ivermectin treatment, we propose to draft, print, and distribute information manuals containing a new standard protocol for ivermectin treatment to these villages in Cameroon. The first aspect of our proposed protocol, and first section of the manual, will begin with the patient who is suffering from onchocerciasis and ivermectin is about to be administered for treatment. Before such treatment begins, we propose that the health care physician first administer an individualized RAPLOA test in order to predict any prevalence of Loa loa infection in the patient. The individual RAPLOA test includes the following questions:

Individual questionnaire:

• “Have you ever experienced or noticed worms move along the white part of your eye?”

After writing down the response, the interviewer then showed a photograph, guided the

respondent to recognize the worm in the eye, and asked the second question:

• “Have you ever had the condition in this picture?”

The respondent was then asked a third question:

• “How long (in days) did the worm stay before disappearing?”

For the Calabar Swelling, the questions were related to the transient nature of swellings

and the tendency to itch. The three questions were the following:

• “Have you ever experienced swellings under the skin that change position or disappear

(local name for Calabar Swelling)?”

• “How long (in days) did the swelling last before disappearing?” and:

• “Did the swelling itch?”[22]

After the RAPLOA test, evaluation of the patient’s prevalence of history of eye worm should be converted to a percent. Similar to the criteria used for the villages, patients with prevalence rates between 20% and 30% will be labeled as meso-endemic and patients with prevalence rates between 30% and 40% will be labeled as hyper-endemic. From these recognized Loa loa infected patients, careful administration of ivermectin will take place along with a specific protocol of information for the health personnel to relay to both the patient and any caretaker that may be present. In reference to a previous public health strategy, the DOTS (Directly Observed Treatment, Short Course) program for the elimination of tuberculosis, proved a highly effective strategy as it focused on the surveillance and monitoring of the patient post-treatment.[23] Inspired by the DOTS program, we have designed a standard protocol for ivermectin administration which places heavy focus on both relaying to the patient and caretaker the specific adverse side effects accompanying ivermectin and careful monitoring of the patient particularly within 2-3 days post-treatment.

The most important channel for intervention begins with the health personnel and community distributors of ivermectin. When handing out ivermectin in the designated meso- or hyper-endemic areas, it is crucial to take maximal caution both pre-treatment and post-treatment. A manual type book will be printed and given to each health care facility in the aforementioned villages. The handbook will contain a copy of the individualized RAPLOA test to be administed prior to treatment, ways to calculate the percentage score of the patient after the test, instructions as to what to tell the patient if they are labeled as meso- or hyper-endemic, a chart explaining the severe adverse side effects of ivermectin treatment on patients with high loads of Loa loa [Figure 2], and instructions as to the appropriate steps following detection of such symptoms. Beginning intervention at the health personnel level with standard ivermectin protocol is the first step towards eliminating the problem at hand.

Figure 2: Clinical Signs and Symptoms to Monitor Post-ivermectin Treatment[24]

§  Severe Fatigue, Myalgia, Arthalgia

§  Low-grade Fever

§  Low Back Pain, Difficulty Standing Up or Walking

§  Confusion, Agitation, Lethargy, Dysarthia, Mutism

§  Urinary Incontinence

§  Sub-Conjucntival Hemorrhages

During surveillance within the first 2-3 days of treatment, if such symptoms should appear, the manual will inform caretakers to immediately evacuate the patient to the nearest designated health care facility where proper clinical care can take place to prevent or treat encephalopathy.

            The distribution of the manuals throughout all health care facilities in the aforementioned villages will significantly aid in the decrease of encephalopathy experienced by patients with the Loa loa infection. With emphasis placed on the monitoring of patients during the crucial time period of 2-3 days post treatment, early detection of the onset will occur and therefore prevention of the adverse outcomes as well. Simultaneously, community awareness of the issue, resulting from the public distribution of manuals to medical facilities, will aid in the decrease of the negative outcomes as more community members will be educated as to not only the fact that the problem exists but also to ways to prevent greater adverse outcomes from occurring.

 



[1]References

 

[1] “A New Drug for River Blindness?”  World Health Organization. 2007. www.who.int/tdr/ir/moxidectin.pdf.

 

[2] “Recommendations for the treatment of onchocerciasis with Mectizan ®in areas co-endemic for onchocerciasis and loiasis”. The Mectizan® Expert Committee/ The Mectizan® Donation Program. June 2004.

 

[3] Kamagno, Joseph, et al. “Encephalopathy after Ivermectin Treatment in a Patient Infected with Loa Loa and Plasmodium”. The American Journal of Tropical Medicine and Hygiene. 4(2008): 546-551.

 

[4] Wanji, Samuel, et al. “Combined Utilization of Rapid Assessment Procedures for Loiasis (RAPLOA) and Onchocerciasis (REA) in Rain Forest Villages in Cameroon”. Filarial Journal. 4(2005): 65-78.

 

[5] “Rapid Assessment Procedures for Loiasis”. World Health Organization. 2001. www.who.int/tdr/cd_publications/pdf/raploa.pdf.

 

[6] “Recommendations for the treatment of onchocerciasis with Mectizan ®in areas co-endemic for onchocerciasis and loiasis”. The Mectizan® Expert Committee/ The Mectizan® Donation Program. June 2004.

 

[7] Sodahlon, Yao. Personal Email Interview. 20 May, 2008.

 

[8] "Parasites and Health: Filariasis."  <http://www.dpd.cdc.gov/DPDx/HTML/Filariasis.asp?body=Frames/A-F/Filariasis/body_Filariasis_l_loa.htm.>.

 

[9]  John, David T. and William A. Petri, Jr. Markell and Voge’s Medical Parasitology. St. Louis: Saunders El Sevier, 2006.

 

[10] World Health Organization. Onchocerciasis (river blindness). Report from the Tenth Inter American Conference on Onchocerciasis, Guayaquil, Ecuador. Wkly Epidemiological Record 2001; 76:205–212.

 

[11] BasáĖez MG, Pion SDS, Churcher TS, Breitling LP, Little MP, et al. (2006) River Blindness: A Success Story under Threat? PLoS Med 3(9): e371

 

[12] John, David T. and William A. Petri, Jr. Markell and Voge’s Medical Parasitology. St. Louis: Saunders El Sevier, 2006.

 

[13] Udall, Don. “Recent Updates on Onchocerciasis: Diagnosis and Treatment” CID (2007): 53-60.

 

[14] Hodgkin, Catherine, et al. "The Future of Onchocerciasis Control in Africa." PLOS Neglected Tropical Diseases (2007 ): 1-4.

 

[15] “Recommendations for the treatment of onchocerciasis with Mectizan ®in areas co-endemic for onchocerciasis and loiasis”. The Mectizan® Expert Committee/ The Mectizan® Donation Program. June 2004.

 

[16] Addis, David G., et al. “A Framework for Decision-Making for Mass Distribution of Mectizan® in Areas Endemic for Loa loa”. U.S. Centers for Disease Control and Prevention, Atlanta, GA, USA

[17] Kamgno, Jay, et. al. “Randomized, controlled, double-blind trial with ivermectin on Loa loa microfilaraemia: efficacy of a low dose (approximately 25 microg/kg) versus current standard dose (150 microg/kg).” Transactions of the Royal Society of Tropical Medicine and Hygiene (2007): 777-785

 

[18] Diggle, P.J., et al. "Spatial Modeling and the Prediction of Loa Loa Risk: decision making under uncertainty ." Annals of Tropical Medicine and Parasitology (2007): 499-509.

 

[19] Boussinesq M amd Chippaux JP. “Relationships between the prevalence and intensity of Loa loa infection in the Central province of Cameroon.” Annals of Tropical Medicine & Parasitology. 2001, 95:495-507.

 

[20] Thomson C., Madeleine, et al. ”Mapping the Distribution of Loa loa in Cameroon in Support of the African Program for Onchocerciasis Control.”  Filaria Journal. 3(2004): 128-140.

 

[21] Thomson C., Madeleine, et al. ”Mapping the Distribution of Loa loa in Cameroon in Support of the African Program for Onchocerciasis Control.”  Filaria Journal. 3(2004): 128-140.

 

[22] “Rapid Assessment Procedures for Loiasis”. World Health Organization. 2001. www.who.int/tdr/cd_publications/pdf/raploa.pdf.

 

[23] “The Stop TB Strategy” World Health Organization. 2006. http://www.who.int/tb/strategy/en/.

 

[24] Kamgno, Jay, et al. “Encephalopathy after ivermectin treatment in a patient infected with Loa loa”. The American Journal of Tropical Medicine and Hygiene. 4(2008): 546-551.