Adverse reactions from community directed treatment with ivermectin (CDTI) for onchocerciasis and loiasis in Ondo State, Nigeria.
Meanwhile, a single annual dose treatment with ivermectin by community directed distributors forms the principal intervention in the control of the disease, Mild adverse reactions, including pruritus (itching), fever and rashes within the first 2-3 days of ivermectin administration have been variously documented (Gardon et al. 1997, Kipp 2003, WHO 2003). However, the diversity of adverse symptoms is complicated in regions of co-endemicity of onchocerciasis with loiasis. Serious complications, such as severe and sometimes fatal encephalopathic adverse reactions and coma in patients with onchocerciasis combined with high intensity of Loa loa have been reported (Chippaux et al. 1996, Gardon et al. 1997, Boussinesq et al. 1998). Also, ivermectin is contra-indicated in patients with trypanosomiasis and central nervous disorders, especially meningitis. In the absence of a clinical macrofilaricide, the risk of severe reactions threatens the success of the control programme in certain African communities with endemic loiasis.
Using rapid epidemiological mapping of onchocerciasis, the pattern of onchocerciasis endemicity in Ondo State, South western Nigeria was undertaken in 1994 by the State task force. Ondo State is in a bioclimatic zone, ranging from rainforest to savannah mosaic. It is highly endemic for onchocerciasis. Ivermectin administration started in 1994 under the auspices of the United Nations Children Education Fund in five local government areas. In June 2000, the African Programme for Onchocerciasis Control and communities directed treatment with ivermectin commenced in sixteen onchocerciasis endemic local government areas in the State.
MATERIALS AND METHODS
Study site: The study involved 60 communities in six selected local government areas in Ondo State, South Western Nigeria. The studied local government areas were Owo, Akure North, Ifedore, Akure South, Ondo East and Ondo West. The projected population of the state is about 2.9 million. Ondo state covers an area of 15 600 square kilometers, lying in the bioclimatic zone, ranging from rainforest to forest, savanna mosaic to guinea savannah and mountainous areas. The study areas were randomly selected within the onchocerciasis endemic areas under mass ivermectin treatment. The main occupations in the State are farming and trading. Advocacy was established at all levels of government, prior to the commencement of the study.
A total of 4 800 individuals (2 331 males and 2 469 females), 18 years old and above were randomly selected and interviewed during the survey. A modified rapid assessment procedure for loiasis (TDR 2000) was administered by house to house visits in the study areas. The rapid assessment procedure for loiasis was used in establishing the local name, the history and occurrence of loiasis in the studied communities. The year/years of treatment and impacts of ivermectin administration were recorded for individuals interviewed.
Statistical analysis: The data obtained were statistically analyzed using the Chi-square test.
Of the 4 800 individuals, 2 398 were reported to have participated in the community directed treatment with ivermectin between the periods 1996 to 2004(Table 1). Amongst these participants, ivermectin had been administered only once in 1 771 (73.84 %) of the treated respondents. The overall coverage of 49.96%, ranging from 0-52% was reported in the different communities (Table 2). Participation and coverage in the community directed treatment with ivermectin was highest in Ifedore Local Government Area and least in Owo Local Government Area (Table 3). Both genders participated in a 1: 1 ratio in the community directed treatment with ivermectin within the various local government areas (Table 3). This study revealed that the age groups 21-30 and 31-40 were actively involved in community directed treatment with ivermectin programme in the State (Table 2). It was noted that participation in the community directed treatment with ivermectin was significantly age-related in some local government areas.
Adverse reactions to ivermectin experienced within the communities ranged from pruritus (itching); swelling or oedema of the body, particularly the face, stooling, general body pain, muscular or joint pain, rashes, body stiffness and general malaise occurring within the first week of drug administration. These reactions were indicated to extend in some respondents for a period of 7-14 days. Adverse reactions occurred in various combinations. In most cases, 914 (38.15%) respondents' experienced adverse reactions on ivermectin administration (Table 4).
The predominant overall adverse reaction in each community was itching (18.5%). Itching occurring for 1-5 days was usually accompanied by other symptoms and may extend for two weeks in some areas. Swelling or oedema of the body, particularly the face (8.1%), rashes (3.4%), boils (3.4%), headache and fever (0.72%) were experienced by respondents in the various communities (Table 5). Generally, adverse reactions were experienced within 1-7 days. Stooling was experienced by 0.40% of individuals after ivermectin administration. The degree of adverse reactions varied in the different local government areas (Table 6), with Ifedore Local Government Area recording the highest level of occurrence of adverse reactions. Ondo East Local Government Area had the lowest record of adverse reactions.
Adverse reactions were high in the 21-30 years age group with 154 (22.4%) individuals. This was statistically significant (P>0.05). The age groups 50- 70 years and above recorded significant adverse reactions. However, adverse reactions were not significant in relation to the gender of the respondents. Within the gender, adverse reactions occurred in 51.10% and 48.80% males and females respectively. The ratio of male to female with adverse reactions was 1:1.06. Consequent to ivermectin treatment some respondents (0.96%) experienced intestinal worm expulsion.
Loiasis endemicity in the communities ranged from low to moderate. The common name for loiasis in all the communities is "aran oju" (meaning eye worm).
Community directed treatment with ivermectin (CDTI) is the principal drug delivery strategy for onchocerciasis control. In Ondo State, ivermectin treatment control programme commenced in 1994, under the auspices of United Nations in five local government areas. In June 2000, the African Programme for Onchocerciasis Control and ivermectin strategy became operational. The treatment coverage is still low. This report affirms a 49.95% community directed treatment with ivermectin in the study areas. African Programme for Onchocerciasis Control recommends at least a target of 65% therapeutic coverage annually. This study reveals that 2 402 (50.04%) of the respondents have not received ivermectin in the study area. A small percentage of the communities had achieved the target therapeutic coverage. A major reason for this is that community directed treatment with ivermectin is irregular and haphazard.
Several problems currently associated with drug distribution coverage in the state includes, instability and disruption of the programme by state bureaucratic processes, fuel scarcity, fund disbursement and general lack of adequate commitment to the programme by local government coordinators. The lack of incentives for the community directed distributors and inaccessibility of some target communities are additional obstacles to drug distribution.
The success of African Programme for Onchocerciasis Control will depend on the sustenance of community directed treatment with ivermectin (Amazigo et al. 2002)
Adverse reactions to ivermectin occurred in 53.79% of respondents that participated in the drug treatment. There is no gender difference in their participation in the community directed treatment with ivermectin. Gender issues relating to community directed treatment with ivermectin constitute a challenge to African Programme for Onchocerciasis Control (Clemmons et al. 2002, Seketeli 2002). Within the study period, 1 221(50.92%), females participated in the programme. Many respondents, 1 771 (73.85%) had only been administered the drug once, since the inception of the programme. This report establishes the low level and haphazard distribution of ivermectin in the study areas. However, the African Programme for Onchocerciasis Control recommends several years of annual ivermectin administration to effectively establish reduced transmission of onchocerciasis and thereby intercept the disease endemicity in the African region.
Adverse reactions experienced are varied and similar to those that has been documented in previous studies (Zea-Flores et al 1992, Burnham 1993, Baraka et al. 1995, Kipp et al. 2003). Significantly itching, oedema, boils and rashes were the reported adverse reactions. Host inflammatory responses had been indicated due to dying microfilariae and not by direct drug toxicity (Turner et al. 1994). No fatal, severe adverse reaction was reported in all the communities. The attitudes of individuals to adverse reactions and further treatment were non-conflicting. Similar reports have been documented (Baraka et al. 1995). Rapid procedure for loiasis is a useful tool in the continued rapid assessment of community prevalence of loiasis infection especially in areas of co-infection of loiasis with onchocerciasis.
According to the data, the prevalence of loiasis in all the communities was much below 40%. The low endemicity of loiasis is considered to have low risk of adverse reactions during mass drug therapy with ivermectin (Tropical Disease Research 2002). The level of loiasis endemicity varied considerably between the local government areas and communities. The bioclimatic conditions of the different local government areas will affect the vector habitat, thereby impacting on the occurrence of the disease. While every community had a local name for the eye worm, Calabar swelling "awoka" (meaning moving about) was not common and tended to be less specific in the study areas.
Ondo State is hypoendemic for loiasis (Ibidapo et al. pers comm) and thereby ivermectin administration is considered relatively safe, despite some degree of reported adverse reactions. Severe or fatal adverse reactions were non existent.
The need to monitor adverse reactions following repeated ivermectin treatment is important to achieve the goals and objectives of African Programme on Onchocerciasis Control. Reduced adverse reactions from first to sixth rounds of treatments (40.6% to 15.6%) in 890 individuals in Kwara State, in Nigeria have been recorded (Oyibo and Fagbenro-Beyioku 2003). They concluded that adverse reaction rates did not affect future participation in community directed treatment with ivermectin, as adequate community mobilization with health education messages were in place. Similar reports were documented by Kipp et al.2003 and Baraka et al. 1995. The pretreatment density of microfilariae in the skin influences the occurrence and intensity of adverse reactions. Continued drug delivery has been indicated to result in diminishing adverse reactions over time (Zea-Flores et al. 1992, Burham 1993). Despite some degree of adverse reactions experienced by respondents in this study, participation, acceptability and compliance to ivermectin administration was reasonable in consonance with the programmes' objectives.
The efficacy and action of ivermectin against filarial infections especially lymphatic filiariasis, many intestinal parasites, lice and scabies have been documented. Zea-Flores et al. 1992 reported 38% worm expulsion on ivermectin administration in Guatamela. While this is considered to be an added advantage in ivermectin administration; affected individuals in many of the communities considered worm expulsion to be an adverse reaction. It is believed amongst the rural communities that a 'healthy' individual requires some degree of intestinal worm infection. Socio-culturally, worm expulsion was considered to be an adverse reaction by some rural respondents.
The occurrence of adverse reactions was predominant in the age group 21-30. This may probably be due to the degree of exposure of ivermectin to this age bracket or may be influenced by the level of parasitism, since the intensity of microfilariae in the skin influence the nature and severity of adverse reactions.
This study revealed the need to increase ivermectin distribution to effectively achieve the targeted goals of the programme. The low endemicity of Loa loa in the study area permits the administration of ivermectin. A biannual mass drug administration in Ondo state has been recommended by Idowu 2004 as a consequence of the high endemicity of the disease in the region.
This investigation was financially supported by Sight Savers International, Nigeria. We are grateful to the Onchocerciasis State coordinator, for his personal commitment to the success of this project.
Received 07-VI-2007. Corrected 30-VI-2008. Accepted 31-VII-2008.
Amazigo, U.V., O.M. Obono, K.Y.Dadzie, J.Remme, J.Jiya, R.Ndyomugyenyi, I.B.Rongon, M.Noma & A.Seketeli. 2002. Monitoring community directed treatment programmes for sustainability: lessons from the African Programme for Onchocerciasis Control (APOC). Ann Trop Med Parasit. 96: 575-592
Awadzi K., N.O.Opokn, E.T.Addy & B.T.Quartey. 1995. The chemotherapy of onchocerciasis XIX: The chemical and laboratory tolerance of high dose ivermectin. Trop Med Parasitol. 46: 31-7
Burnham, G.M. 1993. Adverse reactions to ivermectin treatment for onchorcerciasis: results of a placebo -controlled, double-blind trial in Malawi. Trans R Soc Trop Med Hyg. 87: 313-7
Baraka O.Z., A.K.Khier, K.M. Ahmend, M.M. Ali., A.E. el Mardi, B.M. Mahmoud, M.H.Ali., M.M. Homeida & J.F.Williams.1995. Community based distribution of ivermectin in eastern Sudan: acceptability and early post-treatment reactions. Trans R Soc Trop Med Hyg. 9: 316-8.
Boussinesq M., I. Gardon , N.Gardon-Wendel, I.Kamgno, P.Ngoumou & I.P.Chippaux 1998. Three probable cases of Loa loa encephalopathy following ivermectin treatment for onchocerciasis. Am J Trop Med Hyg. 58: 461-469.
Boussinesq M., I.Gardon., I.Kamgno & S.D.S. Pion. 2001. Relationship between the prevalence and intensity of Loa loa infection in the Central Province of Cameroon. Ann Trop Med Parasit. 95: 495-507.
Clemmons L., U.V.Amazigo, A.C.Bissek, M.Noma, U.Oyene, U.Ekpo, J.Msuya-Mpanju,, S.Katenga & A. Seketeli. 2002. Gender issues CDTI of the African Programme for Onchocerciasis Control (APOC). Ann Trop Med Parasit. 96: S59-S74.
Chippaux J.P., M.Boussinesq, J. Gardon, N.Gardon-Wendel & J.C.Ernould .1996. Severe adverse reaction risk during mass treatment with ivermectin in loiasisendemic areas. Parasitol. Today.12: 448-450.
Clemmons L, U.V.Amazigo, A.C. Bissek, M.Noma, U. Oyene, J. Msuya-Mpanju, S. Katenga & A. Seketeli. 2002. Gender issues in community -directed treatment with ivermectin CDTI of the African Programme for Onchocerciasis Control (APOC). Ann Trop Med Parasit. 96: S59-S74.
Ety'ale D. 2001. Vision 2020: update on onchocerciasis community. Eye Health. 14: 19-20.
Etay'ale D. 2002. Eliminating onchocerciasis as a public health problem: the beginning of the end. Brit J Opthamol. 86: 844-846
Gardon J., N. Gardon-Wendel, Demangangangue, J. Kamgno, J.P. Chippaux & M. Boussinesq. 1997. Serious reactions after mass treatment of onchocerciasis with ivermectin in an endemic area for Loa loa infection. Lancet. 350: 18-22.
Idowu E.T. 2004. Epidemiological, clinco-parasitological and control studies of onchocerciasis in selected communities of Ondo state, Nigeria. Ph.D. Thesis, University of Lagos, Nigeria.
Kipp W., J. Bamhuhiiga, T. Rubaale & D.W. Buttner. 2003. Adverse reaction to ivermectin treatment in Simulium neavei-transmitted onchocerciasis Am J Trop Med Hyg.69: 621-3.
Oyibo W.A. & A.F. Fagbenro-Beyioku. 2003. Adverse reaction following annual ivermectin treatment of onchcerciasis in Nigeria. Int J Infect Dis. 7: 156-9
Seketeli A., G. Adeoye, A.Eyamba, E.Noruka , P.Drameh, U.V. Amazigo, M.Noma, F.Agboton, Y.Ahoton , O.Kale & K.Y. Dadziek. 2002 The achievement and challenges of the African programme for onchocerciasis control (APOC). Ann Trop Med Parasit. 96: S15-S28.
Turner, P.F., K.A. Rocket, E.A. Otlesan., H. Francis, K. Awadzi & I.Clark. 1994. Inter leukin-6 and tumor necrosis factor in the pathogenesis of adverse reactions after treatment of lymphatic filariasis and onchocerciasis. J Infect Dis 69: 1071-5.
Tropical Disease Research 2000.World Health Organization (WHO) Implementation and sustainability of community directed treatment with ivermectin. Geneva. UNDP/ World Bank / WHO Special Programme for Research and Training in Tropical Disease. TDR / AFR / RP/96.1.
Tropical Disease Research (TDR). 2002. Guidelines for rapid assessment of Loa loa. UNDP/World Bank/ WHO.TDR/IDE/RAPLOA/02. 138 p.
World Health Organization 2003. Report of a multicountry study: The involvement of community-directed distributors of ivermectin in other health and development activities. UNDP/World Bank/WHO TDR/IDE/ CDD1/03.1.
Zea-Flores R, Richards FO Jr. Gonzalez-Peralta C, Castro Ramirez J, Zea-Flores G., Collins RC, Cupp E.1992. Adverse reactions after community treatment onchorcerciasis with ivermectin in Guatamela. Trans R Soc Trop Med Hyg. 86: 663-6.
O.A. Otubanjo (1), G.O. Adeoye (1), C.A. Ibidapo (2), B. Akinsanya (1), P. Okeke (1), T. Atalabi (1), E.T. Adejai (3) & E. Braide (4)
(1.) Department of Zoology, University of Lagos, Akoka, Yaba, Lagos, Nigeria; email@example.com, firstname.lastname@example.org, email@example.com
(2.) Department of Zoology, Faculty of Science, Lagos State University, Ojo, Lagos, Nigeria; firstname.lastname@example.org
(3.) Onchocerciasis Section, Ministry of Health, Ondo State, Nigeria.
(4.) Department of Biological Sciences, University of Calabar, Calabar, Cross River State, Nigeria; email@example.com
TABLE 1 Summary of CDTI coverage from 1989-2004 in the studied population Female (%) Male (%) Total 1989 -- 1 (100.00) 1 1996 -- 1 (100.00) 1 1997 2 (33.33) 4 (66.67) 6 1998 10 (35.71) 18(64.29) 28 1999 21 (39.62) 32 (60.38) 53 2000 43 (42.57) 58 (57.43) 101 2001 130 (49.81) 131 (50.19) 261 2002 302 (47.86) 329 (52.14) 631 2003 702 (54.00) 598 (46.00) 1300 2004 11 (68.75) 5 (31.25) 16 Total 1221 (50.92) 1177 (49.08) 2398 WithoutCDTI 1248 (51.96) 1154 (48.04) 2402 Overall Total 2469 (51.44) 2331 (48.56) 4800 TABLE 2 CDTI coverage by age group in the six LGAs in Ondo state AGE 15-20 21 -30 GROUP (Yrs) Owo Examined 151 223 (1) No (%) 46 57 Positive Examined (30.46%) (25.56%) Akure North Examined 112 234 (2) No (%) 21 43 Positive Examined (18.75%) (18.38%) Ifedore Examined 177 239 (3) No (%) 75 105 Positive Examined (42.37%) (43.93%) Akure South Examined 132 212 (4) No (%) 40 73 Positive Examined (30.30%) (34.43%) Ondo East Examined 204 246 (5) No (%) 49 49 Positive Examined (24.02%) (19.92%) Ondo West Examined 156 252 (6) No (%) 37 83 Positive Examined (23.72%) (32.94%) Total Examined 932 1406 No. Positive 268 410 (%) (28.76%) (29.16%) AGE 31-40 41- 51 GROUP (Yrs) Owo Examined 138 109 (1) No (%) 51 42 Positive Examined (36.96%) (38.53%) Akure North Examined 164 99 (2) No (%) 40 33 Positive Examined (24.39%) (35.35%) Ifedore Examined 112 112 (3) No (%) 74 89 Positive Examined (66.07%) (79.46%) Akure South Examined 175 102 (4) No (%) 74 55 Positive Examined (42.29%) (53.92%) Ondo East Examined 142 87 (5) No (%) 33 23 Positive Examined (23.24%) (26.44%) Ondo West Examined 144 89 (6) No (%) 65 48 Positive Examined (45.14%) (53.93%) Total Examined 875 598 No. Positive 337 292 (%) (38.51%) (48.83%) AGE 51 -60 61-70 GROUP (Yrs) Owo Examined 74 59 (1) No (%) 33 25 Positive Examined (44.59%) (42.37%) Akure North Examined 89 59 (2) No (%) 37 27 Positive Examined (41.57%) (45.76%) Ifedore Examined 87 41 (3) No (%) 67 25 Positive Examined (77.01%) (60.98%) Akure South Examined 71 44 (4) No (%) 47 23 Positive Examined (66.20%) (52.27%) Ondo East Examined 61 48 (5) No (%) 12 18 Positive Examined (19.67%) (37.50%) Ondo West Examined 73 60 (6) No (%) 36 35 Positive Examined (49.32%) (58.33%) Total Examined 455 311 No. Positive 232 153 (%) (50.99%) (49.20%) AGE >71 TOTAL GROUP (Yrs) Owo Examined 25 800 (1) No (%) 15 269 Positive Examined (60.00%) (33.63%) Akure North Examined 23 800 (2) No (%) 8 211 Positive Examined (34.78%) (26.38%) Ifedore Examined 24 800 (3) No (%) 14 449 Positive Examined (58.33%) (56.13%) Akure South Examined 26 800 (4) No (%) 15 327 Positive Examined (57.69%) (40.88%) Ondo East Examined 24 800 (5) No (%) 8 192 Positive Examined (33.33%) (24%) Ondo West Examined 25 800 (6) No (%) 13 317 Positive Examined (52.00%) (39.63%) Total Examined 147 4800 No. Positive 73 1765 (%) (49.66%) (36.77%) TABLE 3 CDTI coverage by sex in the six local government areas in Ondo State CDTI COVERAGE RATES Male Female Owo ( 01) Examined 345 455 No. (%) Positive 161 (45.87) 190 (54.13) Akure North (02) Examined 443 357 No. (%) Positive 271 (61.04) 173 (38.96) Ifedore (03) Examined 343 457 No. (%) Positive 93 (27.10) 120 (26.30) Akure South (04) Examined 409 391 No. (%) Positive 219 (53.50) 187 (47.80) Ondo East (05) Examined 395 405 No. (%) Positive 128 (32.40) 143 (35.31) Ondo West (06) Examined 396 404 No. (%) Positive 177 (44.70) 174 (43.10) TOTAL Examined 2469 2331 No. (%) Positive 1177 (47.80) 1221 (52.40) TOTAL Owo ( 01) Examined 800 No. (%) Positive 351 (43.88) Akure North (02) Examined 800 No. (%) Positive 444 (55.50) Ifedore (03) Examined 800 No. (%) Positive 213 (26.63) Akure South (04) Examined 800 No. (%) Positive 406 (50.75) Ondo East (05) Examined 800 No. (%) Positive 271 (33.87) Ondo West (06) Examined 800 No. (%) Positive 351 (43.88) TOTAL Examined 4800 No. (%) Positive 2398 (49.95) TABLE 4 Percentage adverse reactions in the six Local Government Areas in Ondo State Adverse % Adverse Local government CDTI Count reactions reactions area Count Count Owo LGA. 351 128 36.47 Akure North LGA 444 257 57.88 Ifedore LGA 587 224 38.16 Akure South LGA 394 106 26.90 Ondo East LGA 271 79 29.15 Ondo West LGA 351 120 34.19 TOTAL 2398 914 38.12 TABLE 5 Adverse reactions experienced within the studied population Local Government Areas in % Adverse Reaction 1 2 3 4 Itching 16.43 3.83 21.8 13.71 Swelling 6.52 2.92 3.92 6.60 Stooling 0.57 -- 0.34 0.51 Body Pain 1.70 0.23 0.85 1.02 Headache and Fever -- 0.23 0.85 0.51 Weakness 1.42 0.90 -- 3.05 Boils/Rashes 3.97 0.90 3.07 2.03 Body Stiffness 0.85 -- 0.17 -- Adverse Reaction Local Government Areas in % 5 6 Itching 10.7 17.38 17.91 Swelling 9.59 10.54 7.93 Stooling 0.74 -- 0.40 Body Pain -- 1.14 0.85 Headache and Fever 0.74 -- 0.72 Weakness 2.95 1.99 2.29 Boils/Rashes 2.95 5.41 3.30 Body Stiffness -- -- 0.28 TABLE 6 Adverse reactions in the different Local Government Areas Adverse % WITHIN Reactions % WITHIN LG Adverse LOCAL GOVERNMENT COUNT YES CODE Reactions OWO 800 100 12.50% 7.75% AKURE NORTH LGA 800 393 49.13% 30.47% IFEDORE LGA 800 529 66.13% 41.00% AKURE SOUTH 800 90 11.25% 6.98% ONDO EAST 800 60 7.50% 4.65% ONDO WEST 800 118 14.75% 9.15% TOTAL 4800 1290(53.79%) N.B 2,398 respondents participated in CDTI.