Académie royale de Médecine de Belgique

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Emmanuel Bottieau (Institut de Médecine tropicale - Anvers) - Vidéo + Résumé

Clinical and therapeutic aspects of Ebola virus disease

Pr. Dr. Emmanuel Bottieau
Head of Unit of Tropical Diseases
Department of Clinical Sciences
Institute of Tropical Medicine, Antwerp, Belgium

Despite its devastating impact, the unprecedented outbreak of Ebolavirus disease (EVD), species Zaire, affecting West Africa (in particular Guinea, Liberia and Sierra Leone) since more than 1 year has paradoxically allowed improving our knowledge about this infection. It has also boosted the research on specific preventive and therapeutic interventions beyond the usual infection control measures. Although isolation of suspected and confirmed cases of Ebolavirus (EBOV) infection, contact tracing and protective personal equipment for caregivers remains the only strategies having demonstrated some efficacy in controlling previous outbreaks, it did not appear sufficient in a new “non-immune” environment with faster mobility and urban involvement.
As observed previously, the clinical presentation during the current epidemic is characterized in a vast majority of patients by early symptoms such as fever, severe asthenia and digestive manifestations that are non-specific in tropical settings. In an important proportion of patients, more severe symptoms develop within one week, including vomiting, cholera-like diarrhea, difficulty of swallowing, respiratory failure, circulatory collapse, bleeding manifestations  and neurological complications. Death occurs in an average of 7 days after symptom onset and fatality rate reached 70% in patients longitudinally followed, at least in the first months of the epidemic. Mortality is reported now at about 55% in dedicated Ebola treatment centers  but is still above 70% in children < 5 years, patients > 45 years and pregnant women. Beside the abovementioned clinical signs of severity and extremes of age, the Ebolavirus load has been consistently found as a predictor of death in the subset of patients in whom it has been tested and in ongoing trials. This findings fit with the physiopathology of EVD where the virus is able to first inhibit both innate and acquired (humoral and cellular) immunity allowing huge viral replication with subsequent endothelial and organ damages. More laboratory data originating from the trials are expected soon to help identifying patients at highest risk of adverse outcome and understanding the etiologies of death.  
Specific treatments are still experimental and rely on immunotherapy or antiviral therapy. Immunotherapy by administration to EVD patients of blood or plasma of survivors is a promising and  immediately available treatment (now that the pool of survivors increases) which is being explored in a trial in Guinea; many logistical, clinical and anthropological challenges exist however. Another option is the use of a cocktail of chimeric monoclonal antibodies, with Zmapp as a leading agent, for which safety and efficacy studies are being launched. The main challenge is its short supply for the moment. Antiviral treatments are also being explored and include mostly nucleos(t)ide analogues (favipiravir, brincidofovir, BMX4430), small interfering (or silencing) RNA agents (TKM-Ebola) and antisense phosphorodiamidate morpholino oligomers (PMOs) such as AVI-7537. So far only favipiravir (oral formulation available in Japan for the treatment of influenza) is being clinically evaluated in the field (JIKI trial in Guinea) with preliminary results available soon.
Vaccines have also rapidly progressed with 2 candidates entering large phase 3 clinical trials in affected fields: the recombinant vesicular stomatitis virus- vectored glycoprotein Zaire EBOV vaccine (rVSV-ZEBOV) and the chimpanzee adenovirus 3-vectored glycoprotein Zaire EBOV vaccine (cAd3-ZEBOV). A third heterologous vaccine based on prime-boost vaccination of adenovirus 26-vectored glycoprotein EBOV and modified vaccinia Ankara (MVA)-vectored filovirus is being evaluated in phase 1 studies. The rVSV-ZEBOV has been sporadically used in early post-exposure prophylaxis.
The current decline in EVD incidence is an excellent news for the region but will probably affect the capacity to rapidly obtain robust clinical data in terms of drug safety and efficacy. Because no major breakthrough is to be expected in the next future, efforts should be pursued in endemic countries to obtain the best level of supportive care, as reflected by the better prognosis of EVD cases treated in specialized high resource hospitals.