Ebola Outbreak in West Africa, 2013-2014

Hilary D. Marston, Gregory K. Folkers, Anthony S. Fauci

Disclosures

AccessMedicine from McGraw-Hill 

The Ebola virus disease outbreak now ravaging parts of West Africa is the largest on record. In fact, West Africa has seen more cases of the disease in 2014 than have been seen in all other outbreaks combined. The appearance in West Africa of Zaire ebolavirus was initially reported in March 2014, in a rural area of Guinea close to its borders with Sierra Leone and Liberia. Subsequent sequencing analyses from cases in Guinea and Sierra Leone indicate that the virus emerged in December 2013, likely from a single zoonotic introduction in a young child in Guéckédou, Guinea. From that first case of Ebola virus disease, the virus has spread to five countries (Guinea, Sierra Leone, Liberia, Nigeria, and Senegal), causing 4293 suspected and confirmed cases and claiming 2296 lives (as of September 6, 2014). Prior to 2014, the largest outbreak of Ebola virus disease on record, caused by Sudan ebolavirus, resulted in 425 cases and 224 deaths in Uganda.

There are several reasons for the scope and severity of the current outbreak. Importantly, affected nations in West Africa lack experience in confronting this virus, as this is the first report of Ebola virus disease in the region. Traditional practices in the area, such as the ritual bathing, touching, and kissing of corpses, have facilitated transmission. Further, the outbreak epicenter is plagued by weak health infrastructure, a small health workforce that struggles to meet the needs of an impoverished population, and governments struggling to recover from recent regional conflicts. Moreover, the occurrence of the outbreak in proximity to porous borders allows individuals to travel easily; cross-border coordination of public health control measures has been more difficult than in past outbreaks. The spread of the virus into populous capital cities of affected countries has complicated contact tracing, isolation, and quarantine, and it has facilitated extension of the outbreak via travel to Nigeria and more recently Senegal.

The species of virus at the heart of the outbreak, Zaire ebolavirus has historically been thought to have the highest fatality rate of all Ebola species, up to 90%. Although it is difficult to accurately pinpoint a case fatality rate (CFR) in the middle of an outbreak, it appears that the CFR in the current outbreak is closer to 50%. While still alarmingly high, prompt reporting of cases and rapid administration of aggressive supportive care are likely helping to curb mortality in some areas. Moreover, outbreaks historically have been relatively short-lived with high mortality early on, before the etiologic agent was recognized and proper public health measures (isolation, contact tracing, careful use of personal protective equipment) initiated. In longer outbreaks, the CFR has been observed to fall over time, as has been seen in the current outbreak in West Africa.

Thus far, the clinical syndrome in the outbreak appears consistent with that reported previously. The incubation period typically lasts 8–10 days with a range of 2–21 days, and transmission appears to occur via contaminated body fluids (blood, stool, vomitus, saliva) from a symptomatic individual or corpse of a person who had Ebola virus disease. Symptoms begin with fever, nausea, vomiting, and diarrhea. A minority of cases have hemorrhagic complications. The most prominent symptom is profound weakness, and the most prominent sign is hypotension due to capillary leak and gastrointestinal fluid losses. Electrolyte measurement is often unavailable in the affected region, although in two carefully documented cases treated in U.S. hospitals, electrolyte loss, particularly of potassium, was profound. Thus hypotension and electrolyte depletion are often the apparent immediate cause of death. As such, aggressive and empiric fluid and electrolyte repletion appear to be necessary to improve survival. These tactics remain the cornerstone of treatment.

Significant attention has been paid to novel therapies to combat the disease, most notably a cocktail of three humanized mouse monoclonal antibodies called ZMapp. The drug was administered to a handful of patients; 2 died and 4 survived. However, with only a small number of cases, no conclusions about efficacy (or harm) can be drawn. Nonhuman primate studies, however, show promise. ZMapp administration was associated with 100% survival in 18 rhesus macaques, even when administered 5 days after exposure. Quantities of the drug are now exhausted and manufacturing is being expedited. Other compounds under investigation include small interfering RNA compounds and RNA-polymerase inhibitors. An advanced siRNA was shown to protect 66–100% of rhesus macaques, depending on the number of doses given. Prompt administration after exposure appears to be important to efficacy. Favipiravir, an RNA-polymerase inhibitor, is approved for use against pandemic influenza in Japan and is currently being investigated for use against Ebola virus disease, but the dosing regimen is uncertain.

Vaccine candidates also are being advanced through human trials. One candidate began phase 1 trials in September, 2014, and one is set to launch phase 1 trials in early fall. The first, developed by the National Institutes of Health and GlaxoSmithKline, is built on a replication-incompetent Chimpanzee Adenovirus Type 3 backbone, into which the Zaire ebolavirus and Sudan ebolavirus glycoprotein genes are inserted. The vaccine protected 100% of nonhuman primates challenged at 5 weeks, and 50% at 10 months. The second, developed by the Public Health Agency of Canada and NewLink Genetics, is built on a vesicular stomatitis virus backbone, from which the gene for the neurotropic G protein is deleted and replaced with the gene encoding the Zaire ebolavirus glycoprotein. The nonhuman primate results with this candidate have not yet been published, but the vaccine has attracted interest for pre- and postexposure prophylaxis applications. It was used in a single patient exposed to filovirus in the laboratory setting without adverse consequences except for fever. Phase 1 trial timelines for both vaccines have been accelerated, but initial safety data will be collected before introduction into outbreak areas. Other vaccine candidates are in various stages of preclinical testing.

Although vaccines and therapeutics are under investigation, core public health measures remain the cornerstone of control in Ebola virus disease outbreaks. Case identification, prompt isolation and contact tracing, strict adherence to use of personal protective equipment, and aggressive supportive care have successfully ended Ebola outbreaks in the past, and such efforts are being intensified today. Clinicians outside of the outbreak zone will need to pay careful attention to travel history and maintain a high index of suspicion, erring on the side of isolation given the nonspecific nature of early symptoms.

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