Erythropoietin for treating post-ivermectin Loa-related serious adverse events?

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    Updateoping a post-ivermectin SAE recover without sequelae.play a major role [6]. It has been suggested that thedisappearance of Onchocerca volvulus Mf from the skinafter ivermectin treatment is due to a reduction in theirmotility, followed by their drainage in the lymphatic sys-tem [7]. If a similar immobilizing effect occurs withLoa loa,then affected Mf could not pass through the blood streamefficiently, and this could lead to parasite emboli in thecerebral microcirculation and elsewhere; this would bemore likely when there is a high microfilaraemia. Resultsof the only autopsy performed on a human also show thatthe obstruction is associated with other inflammatoryprocesses [8].

    When properly managed, the majority of patients devel-

    infection [12], that is, after the occurrence of severe symp-toms. Post-ivermectin SAEs are usually seen in remotegeographic areas, and medical treatment is often notavailable for two to three days. Assuming it functions inhumans as it does in mice, Epo may be an important newagent for treating patients with a post-ivermectin ence-phalopathy, even when they are admitted to hospital.However, before administering Epo in humans, it certainlywould be wise to strengthen the concept by testing the drugin the most appropriate model, that is, in baboons exper-imentally infected with Loa loa [13]. Should the clinicaland pathological results in this model demonstrate abeneficial effect, then Epo could be proposed to treathuman cases, and the outcomes be compared with thosefrom the historic cases. As Epo has to be stored betweenLetters

    Erythropoietin for treatingserious adverse events?

    Michel Boussinesq1, Joseph Kamgno2, Se1Unite Mixte de Recherche 145, Institut de Recherche pour le DeBP 64501, 34394 Montpellier Cedex 5, France2 Filariasis Research Centre, BP 5261, Yaounde, Cameroon3 Filarial Diseases Unit, Michigan State University, East Lansing

    Recent papers by Casals-Pascual et al. [1] and Maude andBeare [2] discuss the role that erythropoietin (Epo) couldplay in preventing brain damage in cerebral malaria,through its newly emphasized anti-inflammatory andneuroprotective effects [3]. Casals-Pascual et al. concludetheir review by suggesting clinical trials be conducted toevaluate the effects of Epo in various other ischemic andinflammatory brain injuries. Post-ivermectin Loa loa-related encephalopathy could be a candidate for similartrials.

    Ivermectin is currently the mainstay of onchocerciasiscontrol, and mass distribution of ivermectin with albenda-zole is being implemented to eliminate lymphatic filariasisin Africa. Since 1991, several hundreds of serious adverseevents (SAEs) have been reported after ivermectin treat-ment, and it has been shown that, in general, they occur inpatients harbouring Loa microfilaraemias exceeding30,000 microfilariae (Mf) per ml [4]. Although becomingrarer as more and more endemic areas come under treat-ment, tens of cases are still reported every year, and thesenegatively affect the therapeutic coverages in loiasis-ende-mic areas. In addition, the possible occurrence of SAEsprevents the launching of lymphatic filariasis controlactivities in those areas where loiasis is co-endemic.

    These SAEs are often accompanied by retinal lesions(white-centered haemorrhages, exudates) whose appear-ance strongly suggests that they are due, at least in part, toan obstruction of the retinal vessels [5]. Indeed, theselesions are strikingly similar to those observed in patientswith cerebral malaria, in which an obstructive process dueto the sequestration of infected erythrocytes is thought toCorresponding author: Boussinesq, M. (michel.boussinesq@ird.fr).

    4ost-ivermectin Loa-related

    stien D. Pion1 and Charles D. Mackenzie3

    oppement and Universite Montpellier 1, 911 avenue Agropolis,

    I 48824, USA

    However, some patients do not fully recover, and thecondition can be fatal [4]: out of 65 cases reported fromCameroon between 1989 and 2001, 23.5% died and 11.8%had partial neurologic deficits [9]. At present, the treat-ment of these SAE cases relies on the provision of adequatehydration and nutrition, and the prevention of decubituscomplications by nursing care and antibiotics. Although nostrictly controlled trial has been conducted, corticosteroidsdo not seem to improve the condition in the short term, andmay even induce iatrogenic complications [4]. The lack of abeneficial effect of steroids, or of other anti-inflammatoryagents, has also been reported for cerebral malaria [10,11].Apart from steroids and antibiotics, no chemotherapeuticagent has been used regularly in the management of Loa-related SAEs, and no specific treatment is currently recom-mended.

    Epos neuroprotective activity probably results fromseveralmechanisms, including an anti-inflammatory effect(probably due to an inhibition of proinflammatory cyto-kines), the promotion of neuroangiogenesis, and theexpression of antiapoptotic proteins through the Epo Re-ceptor Janus tyrosine kinase-2 Nuclear Factor-kBsignaling pathway [1]. Considering the results obtainedin cerebral malaria, it is prudent to consider whethertreatment with Epo or other neuroprotective agents canalso play a role in the management of post-ivermectinneurological SAEs. One of the advantages this might haverelates to the interval of time between SAE occurrence andthe start of treatment. Epo has been shown to be beneficialin the murine model of cerebral malaria even when admi-nistered at relatively low doses from Day 6 to Day 8 after

    Trends in Parasitology Vol.26 No.12 8C and 8 8C, logistical issues should also be considered,

  • and the best strategy to ensure rapid treatment wouldprobably be to keep the compound in the reference healthstructures of loiasis-endemic areas.

    Should Epo prove to prevent death or sequelae in post-ivermectin SAE cases, this would have a positive impact onthe ivermectin treatment programs directed against onch-ocerciasis. In addition, it might open new perspectives forcombating lymphatic filariasis in loiasis-endemic areas.

    References1 Casals-Pascual, C. et al. (2009) Can erythropoietin be used to preventbrain damage in cerebral malaria? Trends Parasitol. 25, 3036

    2 Maude, R.J. and Beare, N.A.V. (2009) Fluorescein angiography findingsstrengthen the theoretical basis for trialling neuroprotective agents incerebral malaria. Trends Parasitol. 25, 350351

    3 Feng, Q. (2006) Beyond erythropoiesis: the anti-inflammatory effects oferythropoietin. Cardiovasc. Res. 71, 615617

    4 Boussinesq,M. et al. (2003) Clinical picture, epidemiology and outcomeof Loa-associated serious adverse events related to mass ivermectintreatment of onchocerciasis in Cameroon. Filaria J. 2 (Suppl 1), S4

    5 Fobi, G. et al. (2000) Ocular findings after ivermectin treatment ofpatients with high Loa loa microfilaremia. Ophthalmic Epidemiol. 7,2739

    6 White, V.A. et al. (2009) Retinal pathology of pediatric cerebral malariain Malawi. PLoS ONE 4, e4317

    7 Jurgens, S. and Schulz-Key, H. (1990) Effect of ivermectin on the verticaldistribution ofOnchocerca volvulusmicrofilariae in the skin. Trop. Med.Parasitol. 41, 165168

    8 Kamgno, J. et al. (2008) Encephalopathy after ivermectin treatment in apatient infected with Loa loa and Plasmodium spp. Am. J. Trop. Med.Hyg. 78, 546551

    9 Twum-Danso, N.A.Y. (2003) Loa loa encephalopathy temporally relatedto ivermectin administration reported from onchocerciasis masstreatment programs from 1989 to 2001: implications for the future.Filaria J. 2 (Suppl 1), S7

    10 Prasad, K. andGarner, P. (1999) Steroids for treating cerebral malaria.Cochrane Database Syst. Rev. 3, CD000972

    11 Van der Heyde, H.C. et al. (2006) A unified hypothesis for the genesis ofcerebral malaria: sequestration, inflammation and hemostasis leadingto microcirculatory dysfunction. Trends Parasitol. 22, 503508

    12 Bienvenu, A.L. et al. (2008) Artesunate-erythropoietin combination formurine cerebral malaria treatment. Acta Trop. 106, 104108

    13 Wanji, S. et al. (2008) A Loa/baboon model for investigating themechanisms of encephalopathy following ivermectin administration.Am. J. Trop. Med. Hyg. 79 (Suppl.), 113

    1471-4922/$ see front matter 2009 Elsevier Ltd. All rights reserved.doi:10.1016/j.pt.2009.10.002 Available online 29 October 2009

    Update Trends in Parasitology Vol.26 No.15

    Erythropoietin for treating post-ivermectin Loa-related serious adverse events?References

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