Clinical picture, epidemiology and outcome of Loa-associated serious adverse events related to mass ivermectin treatment of onchocerciasis in Cameroon

Michel Boussinesq, Jacques Gardon, Nathalie Gardon-Wendel, Jean-Philippe Chippaux, Michel Boussinesq, Jacques Gardon, Nathalie Gardon-Wendel, Jean-Philippe Chippaux

Abstract

In August 2002, 65 cases of Loa-associated neurological Serious Adverse Events were reported after ivermectin treatment. The first signs, occurring within the 12-24 hours following treatment, included fatigue, generalized arthralgia, and sometimes agitation, mutism, and incontinence. Disorders of consciousness, including coma, generally appeared between 24 and 72 hours, and showed a rapid variation with time. The most frequent objective neurological signs were extrapyramidal. The patients presented with haemorrhages of the conjunctiva and of the retina. Biological examinations showed a massive Loa microfilaruria, the passage of Loa microfilariae into the cerebrospinal fluid, haematuria, and an increase in the C-reactive protein, all of which have been correlated with the high intensity of the initial Loa microfilaraemia. Eosinophil counts decreased dramatically within the first 24 hours, and then rose again rapidly. Electroencephalograms suggested the existence of a diffuse pathological process within the first weeks; the abnormalities disappearing after 3-6 months. Death may occur when patients are not properly managed, i.e. in the absence of good nursing. However, some patients who recovered showed sequelae such as aphasia, episodic amnesia, or extrapyramidal signs. The main risk factor for these encephalopathies is the intensity of the initial Loa microfilaraemia. The disorders of consciousness may occur when there are >50,000 Loa microfilariae per ml. The possible roles of co-factors, such as Loa strains, genetic predisposition of individuals, co-infestations with other parasites, or alcohol consumption, seem to be minor but they should be considered. The mechanisms of the post-ivermectin Loa-related encephalopathies should be investigated to improve the management of patients developing the condition.

References

    1. Chung K, Yang CC, Wu ML, Deng JF, Tsai WJ. Agricultural avermectins: an uncommon but potentially fatal cause of pesticide poisoning. Ann Emerg Med. 1999;34:51–57.
    1. De Sole G, Remme J, Awadzi K, Accorsi S, Alley ES, Ba O, Dadzie KY, Giese J, Karam M, Keita FM. Adverse reactions after large-scale treatment of onchocerciasis with ivermectin: combined results from eight community trials. Bull World Health Organ. 1989;67:707–719.
    1. Chijioke CP, Okonkwo PO. Adverse events following mass ivermectin therapy for onchocerciasis. Trans R Soc Trop Med Hyg. 1992;86:284–286.
    1. Gardon J, Gardon-Wendel N, Demanga-Ngangue , Kamgno J, Chippaux JP, Boussinesq M. Serious reactions after mass treatment of onchocerciasis with ivermectin in an area endemic for Loa loa infection. Lancet. 1997;350:18–22. doi: 10.1016/S0140-6736(96)11094-1.
    1. Boussinesq M, Gardon J, Gardon-Wendel N, Kamgno J, Ngoumou P, Chippaux JP. Three probable cases of Loa loa encephalopathy following ivermectin treatment for onchocerciasis. Am J Trop Med Hyg. 1998;58:461–469.
    1. Anderson F, Downing GM, Hill J, Casorso L, Lerch N. Palliative Performance Scale (PPS): a new tool. J Palliat Care. 1996;12:5–11.
    1. Ducorps M, Gardon-Wendel N, Ranque S, Ndong W, Boussinesq M, Gardon J, Schneider D, Chippaux JP. Effets secondaires du traitement de la loase hypermicrofilarémique par l'ivermectine. Bull Soc Pathol Exot. 1995;88:105–112.
    1. Fobi G, Gardon J, Santiago M, Demanga Ngangue, Gardon-Wendel N, M Boussinesq. Ocular findings after ivermectin treatment of patients with high Loa loa microfilaremia. Ophthalmic Epidemiol. 2000;7:27–39. doi: 10.1076/0928-6586(200003)7:1;1-2;FT027.
    1. Gentilini M, Domart A, Brumpt L, Hazard J, Le Quintrec Y. Filariose à Loa loa et protéinurie. Bull Soc Pathol Exot. 1963;56:207–217.
    1. Bariéty J, Barbier M, Laigre MC, Tchernia G, Lagrue G, Samarcq P, Fritel D, Milliez P. Protéinurie et loase. Etude histologique, optique et électronique d'un cas. Bull Mem Soc Med Hop Paris. 1967;118:1015–1025.
    1. Zuidema PJ. Renal changes in loiasis. Folia Med Neerl. 1971;14:168–172.
    1. Pillay VKG, Kirch E, Kurtzman NA. Glomerulopathy associated with filarial loiasis. JAMA. 1973;225:179.
    1. Katner H, Beyt BE, Krotoski WA. Loiasis and renal failure. South Med J. 1984;77:907–908.
    1. Abel L, Joly V, Yeni P, Carbon C. Apheresis in the management of loiasis with high microfilariaemia and renal disease. BMJ. 1986;292:24.
    1. Hall CL, Stephens L, Peat D, Chiodini PL. Nephrotic syndrome due to loiasis following a tropical adventure holiday: a case report and review of the literature. Clin Nephrol. 2001;56:247–250.
    1. Cruel T, Arborio M, Schill H, Neveux Y, Nedelec G, Chevalier B, Teyssou R, Buisson Y. Néphropathie et filariose à Loa loa. A propos d'un cas de réaction adverse à la prise d'ivermectine. Bull Soc Pathol Exot. 1997;90:179–181.
    1. Burchard GD, Kubica T, Tischendorf FW, Kruppa T, Brattig NW. Analysis of renal function in onchocerciasis patients before and after therapy. Am J Trop Med Hyg. 1999;60:980–986.
    1. Simpson CF, Jackson RF. Lesions in the liver and kidney of Dirofilaria immitis-infected dogs following treatment with ivermectin. Z Parasitenkd. 1985;71:97–105.
    1. Kamgno J, Gardon J, Boussinesq M. Essai de prévention des encéphalopathies à Loa loa post-ivermectine par l'administration d'une faible dose initiale. Med Trop (Mars) 2000;60:275–277.
    1. Anderson RI, Fazen LE, Buck AA. Onchocerciasis in Guatemala. II. Microfilariae in urine, blood, and sputum after diethylcarbamazine. Am J Trop Med Hyg. 1975;24:58–61.
    1. Duke BOL, Vincelette J, Moore PJ. Microfilariae in the cerebrospinal fluid, and neurological complications, during treatment of onchocerciasis with diethylcarbamazine. Tropenmed Parasitol. 1976;27:123–132.
    1. Martin-Prével Y, Cosnefroy JY, Tshipamba P, Ngari P, Chodakewitz JA, Pinder M. Tolerance and efficacy of single high-dose ivermectin for the treatment of loiasis. Am J Trop Med Hyg. 1993;48:186–192.
    1. Ackerman SJ, Kephart GM, Francis H, Awadzi K, Gleich GJ, Ottesen EA. Eosinophil degranulation. An immunologic determinant in the pathogenesis of the Mazzotti reaction in human onchocerciasis. J Immunol. 1990;144:3961–3969.
    1. Cooper PJ, Awadzi K, Ottesen EA, Remick D, Nutman TB. Eosinophil sequestration and activation are associated with the onset and severity of systemic adverse reactions following the treatment of onchocerciasis with ivermectin. J Infect Dis. 1999;179:738–742. doi: 10.1086/314647.
    1. Gibson DW, Connor DH, Brown HL, Fuglsang H, Anderson J, Duke BOL, Buck AA. Onchocercal dermatitis: ultrastructural studies of microfilariae and host tissues, before and after treatment with diethylcarbamazine (Hetrazan) Am J Trop Med Hyg. 1976;25:74–87.
    1. Racz P, Tenner-Tacz K, Büttner DW, Albiez EJ. Ultrastructural evidence for eosinophil-parasite adherence (EPA) reaction in human onchocercal lymphadenitis in the early period following diethylcarbamazine treatment. Tropenmed Parasitol. 1982;33:213–218.
    1. Ottesen EA. Description, mechanisms and control of reactions to treatment in the human filariases. Ciba Found Symp. 1987;127:265–283.
    1. Anonymous Ivermectin: possible neurotoxicity. World Health Organ Drug Information. 1991;5:127–128.
    1. Chippaux JP, Boussinesq M, Gardon J, Gardon-Wendel N, Ernould JC. Severe adverse reaction risks during mass treatment with ivermectin in loiasis-endemic areas. Parasitol Today. 1996;12:448–450. doi: 10.1016/0169-4758(96)40006-0.
    1. Fain A. Les problèmes actuels de la loase. Bull World Health Organ. 1978;56:155–167.
    1. Boussinesq M, Gardon J. Challenges for the future: loiasis. Ann Trop Med Parasitol. 1998;92:S147–S151. doi: 10.1080/00034989859690.
    1. Chippaux JP, Ernould JC, Gardon J, Gardon-Wendel N, Chandre F, Barberi N. Ivermectin treatment of loiasis. Trans R Soc Trop Med Hyg. 1992;86:289.
    1. Duong TH, Kombila M, Ferrer A, Bureau P, Gaxotte P, Richard-Lenoble D. Reduced Loa loa microfilaria count ten to twelve months after a single dose of ivermectin. Trans R Soc Trop Med Hyg. 1997;91:592–593.
    1. Gardon J, Kamgno J, Folefack G, Gardon-Wendel N, Bouchité B, Boussinesq M. Marked decrease in Loa loa microfilaraemia six and twelve months after a single dose of ivermectin. Trans R Soc Trop Med Hyg. 1997;91:593–594.
    1. Nzenze JR, Kombila MY, Boguikouma JB, Belembaogo E, Moussavou-Kombila JB, Nguemby-Mbina C. Encéphalopathie mortelle au cours d'une loase hypermicrofilarémique traitée par ivermectine. Première description au Gabon. Med Afr Noire. 2001;48:375–377.
    1. André J. Ivermectine et loase: une expérience centrafricaine. Med Trop (Mars) 1996;56:206.
    1. Buck AA, Anderson RI, McRae AA. Epidemiology of polyparasitism. II. Types of combinations, relative frequency and associations of multiple infections. Tropenmed Parasitol. 1978;29:137–144.
    1. Noireau F, Carme B, Apembet JD, Gouteux JP. Loa loa and Mansonella perstans filariasis in the Chaillu mountains, Congo: parasitological prevalence. Trans R Soc Trop Med Hyg. 1989;83:529–534.
    1. Njoo FL, Belling GAC, Oosting J, Vetter JCM, Stilma JS, Kijlstra A. Concurrent parasitic infections in onchocerciasis and the occurrence of adverse reactions after ivermectin treatment. Am J Trop Med Hyg. 1993;48:652–657.
    1. Lewallen S, Harding SP, Ajewole J, Schulenburg WE, Molyneux ME, Marsh K, Usen S, White NJ, Taylor TE. A review of the spectrum of clinical ocular fundus findings in P. falciparum malaria in African children with a proposed classification and grading system. Trans R Soc Trop Med Hyg. 1999;93:619–622.
    1. Fink DW, Porras AG. Pharmacokinetics of ivermectin in animals and humans. In: Campbell W, editor. Ivermectin and abamectin. New York-Berlin-Heidelberg, Springer-Verlag; 1989. pp. 113–130.
    1. Edwards G, Dingsdale A, Helsby N, Orme ML, Breckenridge AM. The relative systemic availability of ivermectin after administration as capsule, tablet, and oral solution. Eur J Clin Pharmacol. 1988;35:681–684.
    1. Shu EN, Onwujekwe EO, Okonkwo PO. Do alcoholic beverages enhance availability of ivermectin? Eur J Clin Pharmacol. 2000;56:437–438. doi: 10.1007/s002280000120.
    1. Richard-Lenoble D, Kombila M, Rupp EA, Pappayliou ES, Gaxotte P, Nguiri C, Aziz MA. Ivermectin in loiasis and concomitant O. volvulus and M. perstans infections. Am J Trop Med Hyg. 1988;39:480–483.
    1. Njoo FL, Beek WM, Keukens HJ, van Wilgenburg H, Oosting J, Stilma JS, Kijlstra A. Ivermectin detection in serum of onchocerciasis patients: relationship to adverse reactions. Am J Trop Med Hyg. 1995;52:94–97.
    1. Awadzi K, Opoku NO, Addy ET, Quartey BT. The chemotherapy of onchocerciasis. XIX: the clinical and laboratory tolerance of high dose ivermectin. Trop Med Parasitol. 1995;46:131–137.
    1. Gardon J, Boussinesq M, Kamgno J, Gardon-Wendel N, Demanga-Ngangue , Duke BOL. Effects of standard and high doses of ivermectin, given annually and 3-monthly, on the adult worms of Onchocerca volvulus: a double-blind, controlled, randomised study. Lancet. 2002;360:203–210. doi: 10.1016/S0140-6736(02)09456-4.
    1. Kumaraswami V, Ottesen EA, Vijayasekaran V, Devi SU, Swaminathan M, Aziz MA, Sarma GR, Prabhakar R, Tripathy SP. Ivermectin for the treatment of Wuchereria bancrofti filariasis. Efficacy and adverse reactions. JAMA. 1988;259:3150–3153. doi: 10.1001/jama.259.21.3150.
    1. Ismail MM, Premaratne UN, Abeyewickreme W, Jayasnghe KSA, de Silva WAS, Atukorale S, de Abrew K, Senanayake S, Dissanaike AS. Treatment of bancroftian filariasis with ivermectin in Sri Lanka: evaluation of efficacy and adverse reactions. Trop Biomed. 1991;8:71–75.
    1. Shenoy RK, Kumaraswami V, Rajan K, Thankom S, Jalajakumari Ivermectin for the treatment of periodic malayan filariasis: a study of efficacy and side effects following a single oral dose and retreatment at six months. Ann Trop Med Parasitol. 1992;86:271–278.
    1. Coutinho AD, Dreyer G, Medeiros Z, Lopes E, Machado G, Galdino E, Rizzo JA, Andrade LD, Rocha A, Moura I, et al. Ivermectin treatment of bancroftian filariasis in Recife, Brazil. Am J Trop Med Hyg. 1994;50:339–348.
    1. Cao WC, van der Ploeg CPB, Plaisier AP, van der Sluijs IJS, Habbema JDF. Ivermectin for the chemotherapy of bancroftian filariasis: a meta-analysis of the effect of single treatment. Trop Med Int Health. 1997;2:393–403.
    1. Cartel JL, Mouliat-Pelat JP, Glaziou P, Nguyen LN, Chanteau S, Roux JF. Results of a safety trial on single-dose treatments with 400 mcg/kg of ivermectin in bancroftian filariasis. Trop Med Parasitol. 1992;43:263–266.
    1. Schinkel AH, Smit JJM, van Tellingen O, Beijnen JH, Wagenaar E, van DeemterL, Mol CAAM, van der Valk MA, Robanus-Maandag EC, te Riele HPJ, et al. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell. 1994;77:491–502.
    1. Kwei GY, Alvaro RF, Chen Q, Jenkins HJ, Hop CEAC, Keohane CA, Ly VT, Strauss JR, Wang RW, Wang Z, et al. Disposition of ivermectin and cyclosporin A in CF-1 mice deficient in mdr1a p-glycoprotein. Drug Metab Dispos. 1999;27:581–587.
    1. Schinkel AH. P-Glycoprotein, a gatekeeper in the blood-brain barrier. Adv Drug Deliv Rev. 1999;36:179–194. doi: 10.1016/S0169-409X(98)00085-4.
    1. Lankas GR, Cartwright ME, Umbenhauer D. P-glycoprotein deficiency in a subpopulation of CF-1 mice enhances avermectin-induced neurotoxicity. Toxicol Appl Pharmacol. 1997;143:357–365. doi: 10.1006/taap.1996.8086.
    1. Umbenhauer DR, Lankas GR, Pippert TR, Wise LD, Cartwright ME, Hall SJ, Beare CM. Identification of a P-glycoprotein-deficient subpopulation in the CF-1 mouse strain using a restriction fragment length polymorphism. Toxicol Appl Pharmacol. 1997;146:88–94. doi: 10.1006/taap.1997.8225.
    1. Mealey KL, Bentjen SA, Gay JM, Cantor GH. Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics. 2001;11:727–733. doi: 10.1097/00008571-200111000-00012.
    1. Mealey KL, Bentjen SA, Waiting DK. Frequency of the mutant MDR1 allele associated with ivermectin sensitivity in a sample population of collies from the northwestern United States. Am J Vet Res. 2002;63:479–481.
    1. Brinkmann U, Eichelbaum M. Polymorphism in the ABC drug transporter gene MDR1. Pharmacogenomics J. 2001;1:59–64.
    1. Brinkmann U, Roots I, Eichelbaum M. Pharmacogenetics of the human drug-transporter gene MDR1: impact of polymorphisms on pharmacolotherapy. Drug Discov Today. 2001;6:835–839. doi: 10.1016/S1359-6446(01)01892-X.
    1. Cascorbi I, Gerloff T, Johne A, Meisel C, Hoffmeyer S, Schwab M, Schaeffeler E, Eichelbaum M, Brinkmann U, Roots I. Frequency of single nucleotide polymorphisms in P-glycoprotein drug transporter MDR1 gene in white subjects. Clin Pharmacol Ther. 2001;69:169–174. doi: 10.1067/mcp.2001.114164.
    1. Schaeffeler E, Eichelbaum M, Brinkmann U, Penger A, S Asante-Poku, Zanger UM, Schwab M. Frequency of C3435T polymorphism of MRD1 gene in African people. Lancet. 2001;358:383–384. doi: 10.1016/S0140-6736(01)05579-9.
    1. Kivits M. Quatre cas d'encéphalite mortelle avec invasion du liquide céphalo-rachidien par Microfilaria loa. Ann Soc Belg Med Trop. 1952;32:235–242.
    1. Van Bogaert L, Dubois A, Janssens PG, Radermecker J, Tverdy G, Wanson M. Encephalitis in Loa-loa filariasis. J Neurol Neurosurg Psychiatry. 1955;18:103–119.
    1. Cauchie C, Rutsaert J, Thys O, Bonnyns M, Perier O. Encéphalite à Loa-loa, traitée par l'association de cortisone et de carbamazine. Rev Belg Pathol Med Exp. 1965;31:232–244.
    1. Negesse Y, Lanoie LO, Neafie RC, Connor DH. Loiasis: "Calabar" swellings and involvement of deep organs. Am J Trop Med Hyg. 1985;34:537–546.
    1. Cross HF, Haarbrink M, Egerton G, Yazdanbakhsh M, Taylor MJ. Severe reactions to filarial chemotherapy and release of Wolbachia endosymbionts into blood. Lancet. 2001;358:1873–1875. doi: 10.1016/S0140-6736(01)06899-4.
    1. Keiser PB, Reynolds SM, Awadzi K, Ottesen EA, Taylor MJ, Nutman TB. Bacterial endosymbionts of Onchocerca volvulus in the pathogenesis of posttreatment reactions. J Infect Dis. 2002;185:805–811. doi: 10.1086/339344.
    1. McGarry HF, Pfarr K, Egerton G, Hoerauf A, Akue J-P, Enyong P, Wanji S, Kläger SL, Bianco AE, Beeching NJ, Taylor MJ. Evidence against Wolbachia symbiosis in Loa loa. Filaria Journal. 2003;2:9. doi: 10.1186/1475-2883-2-9.
    1. Chippaux JP, Nkinin SW, Gardon-Wendel N, Ducorps M. Libération d'antigènes de Loa loa après traitement par l'ivermectine. Bull Soc Pathol Exot. 1998;91:297–299.
    1. Awadzi K, Orme ML, Breckenridge AM, Gilles HM. The chemotherapy of onchocerciasis. VI. The effect of indomethacin and cyproheptadine on the Mazzotti reaction. Ann Trop Med Parasitol. 1982;76:323–330.
    1. Stingl P, Pierce PF, Connor DH, Gibson DW, Straessle T, Ross MA, Ribas JL. Does dexamethasone suppress the Mazzotti reaction in patients with onchocerciasis? Acta Trop. 1988;45:77–85.
    1. Dreyer G, de Andrade L. Inappropriateness of the association of diphenhydramine with diethylcarbamazine for the treatment of lymphatic filariasis. J Trop Med Hyg. 1989;92:32–34.
    1. Carme B, Danis M, Gentilini M. Traitement de la filariose à Loa loa: complications, résultats. A propos de 100 observations. Med Mal Infect. 1982;13:184–188.
    1. Samé-Ekobo A, Abolo ML, Njikam KL. Efficacité et tolérance de la loratadine (Clarityne ®) sur les manifestations allergiques post-thérapeutiques de l'onchocercose. Med Mal Infect. 1992;22:1187–1190.
    1. Thompson JH. ACTH as an adjunct to the treatment of loaiasis. Am J Trop Med Hyg. 1956;5:1103–1105.
    1. Awadzi K, Orme ML, Breckenridge AM, Gilles HM. The chemotherapy of onchocerciasis. VII. The effect of prednisone on the Mazzotti reaction. Ann Trop Med Parasitol. 1982;76:331–338.
    1. Awadzi K, Orme ML, Breckenridge AM, Gilles HM. The chemotherapy of onchocerciasis. IX. The effect of prednisone plus cyproheptadine on the Mazzotti reaction. Ann Trop Med Parasitol. 1982;76:547–555.
    1. Duke BOL. Studies on loiasis in monkeys. II. – The population dynamics of the microfilariae of Loa in experimentally infected drills (Mandrillus leucophaeus) Ann Trop Med Parasitol. 1960;54:15–31.
    1. Eberhard ML, Orihel TC. Development and larval morphology of Loa loa in experimental primate hosts. J Parasitol. 1981;67:556–564.
    1. Orihel TC, Eberhard ML. Loa loa: development and course of patency in experimentally-infected primates. Trop Med Parasitol. 1985;36:215–224.
    1. Dennis VA, Lowrie RC, Jr, Osae-Addo G, Blanchard JL. Microfilarial densities, hematologic changes, and serum antibody levels in Loa loa-infected rhesus monkeys (Macaca mulatta) Am J Trop Med Hyg. 1993;49:763–771.
    1. Pinder M, Everaere S, Roelants GE. Loa loa: immunological responses during experimental infections in mandrills (Mandrillus sphinx) Exp Parasitol. 1994;79:126–136. doi: 10.1006/expr.1994.1072.

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