Letters Erythropoietin for treating post-ivermectin Loa-related serious adverse events? Michel Boussinesq 1 , Joseph Kamgno 2 , Se ´ bastien D. Pion 1 and Charles D. Mackenzie 3 1 Unite ´ Mixte de Recherche 145, Institut de Recherche pour le De ´ veloppement and Universite ´ Montpellier 1, 911 avenue Agropolis, BP 64501, 34394 Montpellier Cedex 5, France 2 Filariasis Research Centre, BP 5261, Yaounde ´ , Cameroon 3 Filarial Diseases Unit, Michigan State University, East Lansing, MI 48824, USA Recent papers by Casals-Pascual et al. [1] and Maude and Beare [2] discuss the role that erythropoietin (Epo) could play in preventing brain damage in cerebral malaria, through its newly emphasized anti-inflammatory and neuroprotective effects [3]. Casals-Pascual et al. conclude their review by suggesting clinical trials be conducted to evaluate the effects of Epo in various other ischemic and inflammatory brain injuries. Post-ivermectin Loa loa- related encephalopathy could be a candidate for similar trials. Ivermectin is currently the mainstay of onchocerciasis control, and mass distribution of ivermectin with albenda- zole is being implemented to eliminate lymphatic filariasis in Africa. Since 1991, several hundreds of serious adverse events (SAEs) have been reported after ivermectin treat- ment, and it has been shown that, in general, they occur in patients harbouring Loa microfilaraemias exceeding 30,000 microfilariae (Mf) per ml [4]. Although becoming rarer as more and more endemic areas come under treat- ment, tens of cases are still reported every year, and these negatively affect the therapeutic coverages in loiasis-ende- mic areas. In addition, the possible occurrence of SAEs prevents the launching of lymphatic filariasis control activities 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, to an obstruction of the retinal vessels [5]. Indeed, these lesions are strikingly similar to those observed in patients with cerebral malaria, in which an obstructive process due to the sequestration of infected erythrocytes is thought to play a major role [6]. It has been suggested that the disappearance of Onchocerca volvulus Mf from the skin after ivermectin treatment is due to a reduction in their motility, followed by their drainage in the lymphatic sys- tem [7]. If a similar immobilizing effect occurs with Loa loa, then affected Mf could not pass through the blood stream efficiently, and this could lead to parasite emboli in the cerebral microcirculation and elsewhere; this would be more likely when there is a high microfilaraemia. Results of the only autopsy performed on a human also show that the obstruction is associated with other inflammatory processes [8]. When properly managed, the majority of patients devel- oping a post-ivermectin SAE recover without sequelae. However, some patients do not fully recover, and the condition can be fatal [4]: out of 65 cases reported from Cameroon 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 adequate hydration and nutrition, and the prevention of decubitus complications by nursing care and antibiotics. Although no strictly controlled trial has been conducted, corticosteroids do not seem to improve the condition in the short term, and may even induce iatrogenic complications [4]. The lack of a beneficial effect of steroids, or of other anti-inflammatory agents, has also been reported for cerebral malaria [10,11]. Apart from steroids and antibiotics, no chemotherapeutic agent has been used regularly in the management of Loa- related SAEs, and no specific treatment is currently recom- mended. Epo’s neuroprotective activity probably results from several mechanisms, including an anti-inflammatory effect (probably due to an inhibition of proinflammatory cyto- kines), the promotion of neuroangiogenesis, and the expression of antiapoptotic proteins through the Epo Re- ceptor – Janus tyrosine kinase-2 – Nuclear Factor-kB signaling pathway [1]. Considering the results obtained in cerebral malaria, it is prudent to consider whether treatment with Epo or other neuroprotective agents can also play a role in the management of post-ivermectin neurological SAEs. One of the advantages this might have relates to the interval of time between SAE occurrence and the start of treatment. Epo has been shown to be beneficial in the murine model of cerebral malaria even when admi- nistered at relatively low doses from Day 6 to Day 8 after infection [12], that is, after the occurrence of severe symp- toms. Post-ivermectin SAEs are usually seen in remote geographic areas, and medical treatment is often not available for two to three days. Assuming it functions in humans as it does in mice, Epo may be an important new agent for treating patients with a post-ivermectin ence- phalopathy, even when they are admitted to hospital. However, before administering Epo in humans, it certainly would be wise to strengthen the concept by testing the drug in the most appropriate model, that is, in baboons exper- imentally infected with Loa loa [13]. Should the clinical and pathological results in this model demonstrate a beneficial effect, then Epo could be proposed to treat human cases, and the outcomes be compared with those from the historic cases. As Epo has to be stored between 2 8C and 8 8C, logistical issues should also be considered, Corresponding author: Boussinesq, M. (michel.boussinesq@ird.fr). Update Trends in Parasitology Vol.26 No.1 4