INTERNATIONAL SOCIETY OF GEOGRAPHICAL & EPIDEMIOLOGICAL OPHTHALMOLOGY

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SOCIETE INTERNATIONALE D'OPHTALMOLOGIE GEOGRAPHIQUE ET EPIDEMIOLOGIQUE

Title : The occurrence and management of serious adverse events following ivermectin treatment 
in co-endemic onchocerciasis and loiasis areas of Center Province, Cameroon 

Authors & Affiliation:

Nancy J. Haselow, Helen Keller International (HKI), Cameroon and 
Julie Akame, formerly Ministry of Public Health, Cameroon and currently HKI/Cameroon

Final Abstract:

The issue of serious adverse events (SAE) due to ivermectin in areas co-endemic for loiasis and onchocerciasis 
has been known for some time. It was not until 1999, however, when Okola Health District of the Center 
Province of Cameroon experienced a large number of verified SAE cases (23) with coma (16) and 3 deaths 
after just 22,810 people had been treated, that a more intensive effort was made to develop a plan to detect, 
manage and monitor SAEs. Since then, the Center Province of Cameroon has documented the highest number
of L. loa encephalopathy SAE cases than any other place in the world. The rate of coma (excluding the less 
startling neurological cases) per number treated is 1 per 26,530 treated. 
 

Year	No. SAEs	No. coma	No. deaths	Treated	%/population
1999	31	21	3	109,359	43.8%
2000	8	3	1	187,252	41.7%
2001	26	5	1	190,210	44.8%
2002	14	2	1	335,605	65.2%
Total	79	31	6	822,426

 
In addition to these serious adverse events, thousands of minor side effects have also been recorded, all of which 
combined, cause rumors and fear and reticence to take ivermectin. Since at least 65% coverage over 15 to 20 
years is necessary to eliminate onchocerciasis as public health problem, the presence of SAEs has slowed progress 
of onchocerciasis control in affected areas. Consequently, a system has been developed in Center Province of 
Cameroon to aid in early detection, referral and effective management of SAEs to avoid the most serious 
consequences and allay fears. The presence of SAEs requires additional program activities and inputs, a reinforced 
communication and training  strategy and effective supervision in order to motivate active community participation 
and achieve adequate treatment coverage over many years. 

The occurrence and management of serious adverse events following ivermectin treatment in co-endemic onchocerciasis and loiasis areas of Center Province, Cameroon

Background

Onchocerciasis, also known as River Blindness, is a disease caused by a parasite, the filaria onchocerca volvulus, which is transmitted to humans through the bite of the black fly. People most affected by onchocerciasis live near fast flowing rivers, which are breeding sites for the black fly. Onchocerciasis is the second leading infectious cause of blindness in the world (after trachoma) and the leading cause in some Sahelian countries. There are 35 countries in total, 28 in tropical Africa, Yemen, and 6 in Latin America that are endemic for onchocerciasis. According to 1994 estimates 122.9 million people throughout the world are exposed to the disease, again the overwhelming majority of who are in Africa (99%). 17.7 million people are infected (with over 95% living in Africa), out of which 6 million suffer from severe itching, 500,000 have a badly impaired vision, and 270,000 are blind.[1]

Onchocerciasis is more than a blinding disease, it is a chronic systemic disease, capable of causing extensive and disfiguring skin changes, musculoskeletal complaints, weight loss, changes in the immune system, and perhaps epilepsy and growth arrest as well.[1]

Table 1. Key signs and symptoms of onchocerciasis

Skin signs/symptoms:	Eye signs/symptoms:
· Intense itching · Skin rash · Nodules · Leopard skin (skin depigmentation) · Very dry or wrinkled skin (lizard skin) · Stretched skin and swelling in the groin area	· Red eyes · Irritated eyes and / or tearing · Light sensitivity · Night blindness · Reduced field of vision · Blindness

There are two main strains of onchocerciasis: the savannah type, which has a high rate of blindness; and the forest type with a high prevalence of skin manifestations, but blindness is less common. It is in areas of the forest type, where Loa loa, another filarial parasite found primarily in the blood of the human host is also endemic.

Mectizan® or ivermectin is the most effective drug for treating onchocerciasis. It should be taken by all eligible members of an onchocerciasis meso- or hyper-endemic community once a year for a period of 15 to 20 years in order to reduce symptoms and possibly arrest transmission of the disease so that it is no longer a public health problem in the community. An impact study on the effectiveness of ivermectin at reducing the burden of disease is currently ongoing by APOC. Ivermectin is also very effective against Loa loa, killing the microfilaria rapidly and causing a high number of serious adverse events (SAE) in areas where people have high Loa loa loads (people with >30,000 mf/dl blood are at highest risk of loa-related SAEs, however, >9,000 mf/dl blood is also considered at risk particularly among an immuno-suppressed population).

Note that an SAE in this case is defined as an adverse experience following treatment temporally with ivermectin (within 7 days) that results in death, a life-threatening experience, in-patient hospitalization, and / or persistent or significant disability.

The issue of serious adverse events in loiasis-endemic areas

The issue of serious adverse events or side effects due to ivermectin in areas co-endemic for loiasis and onchocerciasis has been known for some time [2, 3]. It was not until 1999, however, when Okola Health District of the Center Province of Cameroon experienced a large number of verified SAE cases (23) with coma (16) and 3 deaths [4] after just 22,810 people had been treated (1 coma case for every 1,425 people treated), that a more intensive effort was made to develop a plan to detect, manage and monitor SAEs (i.e. Tours, France Meeting in October 1999 and 9^th Technical Consultative Committee (TCC9) meeting in March 2000) [5] Recently, new recommendations for the classification, detection, and management of SAEs in co-endemic areas based on the accumulation of data and experience have been developed by the Mectizan® Expert Committee (MEC) and the Technical Consultative Committee of the African Program for Onchocercerciasis Control (APOC).[6]

 
Since 1999, the Center Province of Cameroon has documented more verified probable L. loa encephalopathy SAE cases than any other place in the world. In Center Province from 1999 through 2002, the rate of coma alone (excluding the other less serious L. loa encephalopathy cases) per number treated was 1 coma case per 26,530 people treated. As treatment coverage increased and people were in their third and fourth annual treatment cycles the overall number of coma cases per number treated from 1999-2004 has gone down to 1 coma case per 47,970 people treated and if we consider the last two years only (2003-2004), there was about 1 coma case per each 160,000 treatments. 
Table 2.  SAEs per population treated in Center Province, Cameroon from 1999-2004 

Year	No. SAEs	No. coma	No. deaths	No. treated	Treatment coverage	Coma case / no. treated
1999	31	21	3	109,359	43.8%	1 coma/5,208
2000	8	3	1	187,252	41.7%	1/62,417
2001	26	5	1	190,210	44.8%	1/38,042
2002	14	2	1	335,605	65.2%	1/167,803
2003	14	3	0	451,283	70.3%	1/150,478
2004	7	3	1	501,176	73.6%	1/167,059
Total	100	37	7	1,774,885		1/47,970

 
In addition to these serious adverse events, thousands (over 5,000 reported cases per year) of minor and moderate side effects have also been recorded in Center Province each year, all of which combined, cause rumors and fear and reticence to take ivermectin. With better surveillance, other provinces of Cameroon and other countries (e.g Sudan, DRC) started reporting more SAE cases in areas co-endemic with loiasis and onchocerciasis. In 2003, however, DRC also experienced a large number of apparent SAE cases with 20 deaths (5 in Tshopo and 15 in Bas-Congo) after their first round of treatment with ivermectin. Due to the lack of adequate diagnostic and clinical information, a differential diagnose could not be made to verify the cause of all these deaths (as due to L. loa encephalopathy following treatment with ivermectin). [NDGO Oncho Group Meeting, Nairobi, 3/2004] A recent joint MEC/MDP/APOC mission to Bas-Congo found that there were a total of 40 SAE cases after just over 97,000 treatments.  Of the 28 neurological SAE cases, 18 were probably related to L. loa encephalopathy. Still the rate of L. loa encephalopathy following treatment with ivermectin per number treated was almost two times higher in Okola Health District during 1999. (Kuimba, DRC: 4.8 cases/10,000 treated; Boma, DRC: 2.5 cases/10,000 treated; Seke, DRC: 1.8 cases/10,000 treated; Okola, Cameroon: 9.2 cases/10,000 treated). [T. Ukety, NGDO Group Meeting Atlanta, 9/2004] 
 

Mild side effects of ivermectin can include: itching, swelling of legs or arms, swelling of face, muscle pain, fever, skin rash, swelling of glands in the groin area, tiredness, headache, digestive trouble (diarrhea, nausea, vomiting), sensation of grains of sand in the eyes, and temporary blurry vision.

Serious side effects are very rare. Usually, if they occur, it is among people who are taking ivermectin for the first time, or among people suffering from loiasis. Serious side effects of ivermectin can include: respiratory problem (cough, noisy breathing, etc.), acute dizziness that prevents one from walking or standing up, high and/or continued fever, painful and/or continued headache, urinary incontinence, disorientation and confusion, serious exhaustion so one can hardly move and coma.

These co-endemic areas operate their programs with a unique challenge to manage all adverse side effects adequately, to maintain the cost per treatment at an acceptable level and to achieve and maintain a treatment coverage rate of at least 65% of the total population in order to adequately diminish transmission among the population and possibly eliminate onchocerciasis as a problem of public health and socio-economic importance [7, 8, 9, 10, 11]. This is not an easy undertaking. A review of several of the independent APOC monitoring reports from 1999 –2001 documented that mild and serious side effects were neither recorded nor reported in many projects, and in Cameroon, health education was not adequate to allay fears and misconceptions of community members about side effects. In the report of one of the CDTI Projects in the South West of Cameroon [12], the high rate of refusals (27.7%) among those eligible for treatment was closely linked to a high level of skepticism, doubt and pessimism among community members and the absence of a strong sensitization and mobilization effort. Likewise, an evaluation of the implementation of TCC9/Mectizan® Expert Committee guidelines in areas of Cameroon co-endemic for onchocerciasis and loiasis undertaken by APOC and the TCC in 2000 [13] found that, in general, communities did not have enough information on side effects to allay their fears. In the presence of SAEs, rumors and incomplete information, some community members acknowledged fear associated with even minor side effects and were understandably reticence to take ivermectin.

Figure 1 - Vicious Circle of SAEs and low coverage caused by increased fear to take ivermectin

The presence of SAEs has slowed progress of onchocerciasis control in affected areas. Since high coverage is required for 15 to 20 years and funds are decreasing for program activities, it was critical to develop a system to aid in early detection, referral and effective management of SAEs to avoid the most serious consequences, allay fears and speed up progress. In Center Province, Cameroon and elsewhere, much progress has been made in the past few years not only on improved detection and management of SAE cases, but also on community sensitization. It is clear that the presence of SAEs requires additional program activities and inputs such as a reinforced, more intensive and targeted communication and training strategy and effective supervision in order to motivate active community participation and achieve adequate treatment coverage over many years. These inputs increase the cost of CDTI programs in loiasis-endemic areas and mean that the time to achieve sustainability will be longer, yet Center Province has shown that these obstacles are not surmountable. 
 

Special programmatic issues to consider in the presence of Serious Adverse Events [14]

As a result of the high number of SAE cases experienced in Cameroon during 1999, additional research was done to better understand the issues related to SAE management. The Centre Pasteur of Cameroon study [15] further defined the parameters of SAEs (prevalence, timing of onset, risk factors), which allowed program recommendations to be made. They concluded that more training, more sensitization and more supervision are necessary to better manage SAE cases so that the prognosis on cases is improved. Using this information, evaluation findings and lessons learned over 5 years of CDTI implementation in a loiasis (as determined by a RAPLOA assessment or more generally, environmental mapping) and onchocerciasis co-endemic area of Cameroon, some of the special programmatic issues to consider when developing the distribution and communication strategy are outlined below.

Identification of onchocerciasis-endemic communities in loiasis-endemic areas: In order to minimize risk of serious adverse events in loiasis-endemic areas, mass treatment with ivermectin is undertaken in only the onchocerciasis hyper-endemic and meso-endemic villages in accordance with the MEC and TCC guidelines. The villages are identified based on rapid assessment techniques (REMO and/or REA) at the outset of the CDTI project.

Without adequate resources, careful planning, effective training or close supervision the categorization of villages can be inaccurate. Inaccessible villages and all eligible people should have an equal chance of inclusion in the survey, however, since the survey may be conducted by health personnel who do not always ensure the randomness of the sampling, the representativeness of the results can be questionable. Adequate training for the REA therefore is important to ensure that only hyper- and meso-endemic villages are included in mass treatment in order to minimize unnecessary risk of SAEs to people living in onchocerciasis hypo-endemic areas.

Careful communication is needed to inform and convince those people with onchocerciasis symptoms living in hypo-endemic villages to seek and receive treatment at a referral hospital and not from a CDD of a close by village (as the CDD can not monitor the person for SAEs post-treatment). In addition, considering that the endemicity of onchocerciasis is not necessarily static due to environmental related issues, the REA results should be updated as the project evolves and adjustments made in order to truly eliminate onchocerciasis as a public health problem.

Planning: Planning and effective organization take on more importance when distribution needs to be more synchronized from village to village in order to better control the distribution of ivermectin to ensure proper surveillance of SAEs. So that all SAE cases receive adequate attention and care at each level, each district and each community must abide by their action plan once developed, which should include more frequent consultation meetings between communities and MOH personnel, supervised community selection of CDDs, updating of census figures, and a specific plan for SAE management, training, sensitization, distribution and supervision.

The decentralization of referral hospitals is important for the recovery of SAE cases, in part, because patients who are treated near their usual residence are more likely to be assisted by family members in their nursing care. Finding an adequate number of referral hospitals is not easy in remote areas as these hospitals should have a well-trained team of professionals as well as necessary medications and equipment to properly manage SAE cases. Communities need to be informed of the designated referral hospital and be advised to go there as trained staff, needed medications and equipment to properly manage SAE cases are not necessarily found at the nearest hospital, which may be in an adjacent area not involved in CDTI.

Although cities are generally near a referral hospital, distributing ivermectin in cities with their more transient population and lack of cohesive community leadership, poses other problems in terms of selection of CDDs, taking an accurate census, implementing a motivating communication strategy to encourage participation in CDTI and surveillance of the population post-treatment.

Training: Early recognition of SAEs is one of the key elements to properly manage SAE cases. SAE recognition, prevention, referral, counselling, management and reporting must be a primary focus of all training and retraining at all levels (CDDs, nurses, doctors). Ensuring a high level of CDD competence on recognition of early signs of SAEs is critical. Contradictions between information in manuals, health education messages and what the community believes to be true should be highlighted and clarified. IEC supports can be used as reminders on SAE information to help community distributors. In addition, because of a relatively high turn-over among government health staff, steps must be taken to ensure that any new staff who arrive during distribution receive adequate training.

In addition, a team of health personnel (at least 4 people) at each referral hospital must be well trained on diagnosis (a thick blood smear should be done) and management of cases so that all personnel who come in contact with an SAE case have the necessary background, understanding and motivation to manage the case properly. Since most patients will have multiple complaints, a differential diagnosis is important to determine if the SAE is due to ivermectin or not. Interpersonal communication and counselling skills should also be taught so that hospital staff can give appropriate and caring feedback to family members. The Ministry of Health and HKI in Cameroon have drafted a guidebook for the management of SAEs.