INTERNATIONAL SOCIETY OF GEOGRAPHICAL & EPIDEMIOLOGICAL OPHTHALMOLOGY 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

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).  

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] 

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.

Selection of Community Distributors:  Because of the increased knowledge and skills necessary to pass on the additional information to community members and to supervise post-treatment, the selection of the CDD is very critical and should be supervised by health personnel after discussion with the community as to the type of person needed to carry out the duties.  The CDD selected by the community must possess a minimal educational level, be stable, and be accepted by all the community.  This process is even more difficult in cities because of the lack of community cohesiveness and support.

Sensitization and Advocacy:  Because SAE cases, and particularly poor management of these cases, cause fear and breed rumors, during the sensitization of communities an emphasis must be placed on ensuring that sensitization activities focus on identification and prompt referral of SAEs at the community level.  Providing information on the reasons why side effects happen, their frequency and prognosis is also important to stopping rumors and allaying fears.  Counseling post-SAE may also serve to allay fears, but will require additional training of key community members.

Distribution:  The need to minimize problems associated with poor recognition and management of SAEs necessitates that individual communities have somewhat less control in the organization of mass treatment campaigns.  A joint distribution strategy needs to be elaborated to better ensure that treatment and post-treatment are adequately supervised by health personnel in each village.  Activities must be synchronized in a health area so that health personnel are available and so that the ivermectin supply is controlled.  Elements of the strategy might be:

o       Villages are grouped for scheduled treatment in a logical order so that the nurse is available to supervise post-treatment in each village as per TCC guidelines. 

o       The CDDs, with community leaders, organizes and promotes the distribution time before hand and gives the ivermectin at a central site in the village to reach the greatest number of residents.  Soon afterward, a mop-up can be done by the CDD either house-to-house or central site. 

o       The CDD watches each person swallow the ivermectin and refuses to give any ivermectin to anyone for later consumption by other family members not physically present. 

o       The nurse collects all of the unused ivermectin within a day after the distribution is completed in the village.  The control of ivermectin is critical to ensuring proper supervision of SAE cases.  Training and monitoring and tracking tools have been developed. 

Identification, referral and care of SAE cases:  Family members are usually the first to identify potential SAE cases based on the information that they are provided about potential adverse side effects due to ivermectin.  They must be adequately informed to contact the CDD in their community, who in turn, must understand the importance of timely referral of mild cases to the nurses for treatment and immediate referral of serious cases to the closest designated referral hospital. 

The cost to treat adverse effects is an issue with community members and a potential factor in low coverage as it can discourage participation.  In Cameroon, mild adverse reactions to ivermectin are generally supported by the patient and family, whereas the referral hospital takes complete charge of all serious cases, paying directly for diagnostic tests, medication and hospitalization.  Potential problems exist as those people with minor side effects often feel that they should be taken care of also.  Additionally, since only confirmed cases are free, some patients delay going to the hospital because they are not sure if their adverse health is due to ivermectin or not and they can not afford to pay.  For patients from hypo-endemic areas, although the test for loa loa is required at the hospital, neither the test, the consultation nor the treatment is free.  The cost information needs to be part of the IEC message to avoid false rumors or confusion that can discourage participation in CDTI.

Supervision and reporting:  There is a need for increased and improved supervision by health personnel and CDDs in accordance with the MEC and TCC guidelines.  In addition, follow-up by health personnel of recovering patients after hospitalization should be undertaken in communities.  Timely reporting and documentation must be strict. Unfortunately, the ability of many personnel to supervise and report accurately is often less than optimal due to the lack of skill, insufficient logistics and poor motivation.  Additional training and support on how to effectively supervise is needed.  Reporting procedures of potential and actual SAE cases must be discussed during training sessions as a critical element of proper SAE management so that each SAE case can be verified by project staff and follow-up undertaken to make sure interned patients receive adequate care.

Conclusion

It is clear that the presence of SAEs, even when they are well managed, requires a reinforced approach to convince people that the benefits of taking ivermectin outweighs the risk. Increased and improved supervision, training, and communication activities and skills are all needed to allay the fears caused by actual side effects and by rumors.  Reducing fears will help to increase treatment coverage, which will in turn reduce the number of SAEs over time, which will increase participation in CDTI so that onchocerciasis can be eliminated as a public health problem. 

Figure 2   - Ending the vicious circle of SAEs and low coverage caused by increased fear to take ivermectin     

                                                                                                                                Increased and improved communication

Improved and additional training

                                                                                                                Increased and improved supervision

Reduced number of SAEs

References: