R.D.L. Akkerman, J. Van Paassen, C. Nederstigt , W.M.J. Pelt, D.J. van Westerloo
Department of Intensive Care, Leiden University Medical Centre, Leiden, the Netherlands
Potential pandemic pathogens series: Ebola virus
History of Ebola virus
Ebolavirus (EBOV) is a member of the family of the Filoviridae together with five other genera: Marburgvirus, Cuevavirus, Dianlovirus, Striavirus and Thamnovirus. Importantly, novel filoviruses of unknown pathogenic potential continue to be discovered by global surveillance programs. Filoviridae are filamentous virions containing a negative sense RNA genome that may attach and infect human cells (figure 1). Four variants of EBOV have caused disease in humans and are known as the Zaire, Sudan, Bundibugyo and Tai Forest strains. EBOV was first discovered in 1976 when the Zaire variant of Ebola caused outbreaks in the Democratic Republic of Congo (DRC) and neighbouring countries in Central Africa. The infection was unknown at the time, spread quickly and was associated with a dramatic case-fatality rate of approximately 90%. Scientists who arrived in Zaire were baffled to see how quickly the virus spread and how deadly it was. A sample from a patient with this mysterious illness in the village of Yambuku in northern Zaire was flown to Antwerp for further investigation. It was shown to contain a ‘novel spaghetti-formed Marburg-like virus’. Due to the fact that the sample was collected in Yambuku it was first considered to name the virus after this village. However, scientists did not want to stigmatise the village forever with the name of a horrible disease. They decided to call it Ebola which is the name of a nearby river and means ‘black river’ in the local language. At the same time of the Zaire outbreak, the Sudan species appeared in another location in Africa, which means that in 1976 two dissimilar variants of Ebola had arisen at the same time. The Sudan strain has since been found in four outbreaks which have occurred in Uganda and Sudan with related case-fatality rates of approximately 50%. The Bundibugyo species was seen in an outbreak in Uganda in 2007 with a lower case-fatality rate of approximately 30%. The recent 2014-2016 West African monster epidemic of the Zaire variant started out in a rural area in Guinea but spread quickly to urban areas and crossed borders to cause the first global epidemic of Ebola. This outbreak infected 15,000 people in Liberia, Guinea and Sierra Leone and stimulated a frantic worldwide effort to research possible therapies and vaccines. Due to early and fast progress in these areas, as well as international help in providing prompt medical care, the case-fatality rate in this last epidemic dropped to approximately 40%. In addition, a fourth variant called Tai Forest is also able to cause disease in humans. It has been identified as the cause of non-fatal illness in only one individual in the Ivory Coast exposed to a dead chimpanzee during a necropsy.
Transmission and pathogenesis
Filoviridae are zoonoses which are maintained in natural reservoirs. Current data suggest that bats are at least one of the reservoir hosts in Africa. Other mammals (e.g. gorilla, chimpanzee and small antelopes called duikers) may be implicated as intermediate or amplifying hosts. Human-to-human transmission is mediated by direct unprotected contact with body fluids of alive or deceased individuals with Ebola. The various transmission routes are depicted in figure 2. The risk of infection depends on the type of body fluid exposure and the infectious inoculum. Infection risk is highest after direct contact of damaged skin or unprotected mucous membranes with blood, faeces or vomitus. However, Ebola has also been detected in a variety of other bodily fluids such as urine, semen, saliva, aqueous humour, vaginal fluid and breast milk. Interestingly, the ritual washing during funerals of deceased individuals played a significant role in the spread of infection during the 2014-2016 West African epidemic. After entry in the body through mucous membranes or damaged skin, Ebola infects many different cell types. Figure 1 shows an electron microscopy image of Ebola sticking to kidney cells. Macrophages and dendritic cells are probably the first cell types to be infected resulting in cell death and release of new viral particles into the extracellular fluid. Progression of the infection is facilitated by virus-induced suppression of type I interferon. Lymphogenous spread of Ebola is then followed by blood stream infection and dissemination of the infection throughout the whole body, resulting in direct tissue damage, organ dysfunction, profuse gastrointestinal dysfunction and diarrhoea, a systemic inflammatory response syndrome, disseminated intravascular coagulation and bleeding as well as impairment of adaptive immunity.
Clinical picture and diagnosis
The incubation period of Ebola disease is 2 to 21 days (typically: 6 to 10 days).
The first phase of the disease (1-3 days) is characterised by non-specific symptoms such as fever, malaise, fatigue and myalgia. Laboratory results may show leukopenia, thrombocytopenia and elevated liver enzymes. During the second phase (day 3-10), gastrointestinal symptoms will develop such as anorexia, sore throat, dysphagia, nausea, vomiting and diarrhoea. Fluid losses may be significant. Other symptoms include a fairly typical conjunctival injection, headache, abdominal pain, arthralgias and chest pain. Approximately 20% of patients will now develop a maculopapular rash involving mainly the face and torso. Haemorrhagic symptoms occur in less than half of affected patients. Usually bleeding starts from the gums followed by the formation of petechiae. Severe gastrointestinal blood loss may also be present. Laboratory results may show persistently elevated liver enzymes, elevated creatinine as well as electrolyte disorders. Furthermore, thrombocytopenia and an elevated PT/PTT/D-dimer may be seen consistent with disseminated intravascular coagulation. Secondary complications include bacterial superinfections, kidney injury and respiratory failure which may in part be caused by aggressive fluid resuscitation. This phase may result in death during the second week of illness as a consequence of multiorgan failure caused by hypovolaemic and/or distributive shock. Survivors typically begin to improve during the second week of illness. The convalescent period can persist for more than two years and includes a ‘post-Ebola syndrome’ which involves musculoskeletal symptoms, fatigue, headache, neurocognitive abnormalities, uveitis, tinnitus and hearing loss. Interestingly, Ebola has been shown to persist in some body fluids even after clearance of the virus from the blood. A cohort study of male survivors during the West African epidemic showed that Ebola virus can persist in semen for up to 19 months following acute infection.
Diagnostic tests for Ebola include detection of specific RNA sequences by RT-PCR in the blood or detection of viral antigens by immunoassays. RT-PCR results may be available in approximately 2 to 6 hours but are not commonly available in most settings where epidemics have occurred. Diagnostic testing should be carried out in a biosafety level 4 laboratory when available. A false-negative result may occur early in the disease course (<72 hours) and this may warrant repeat testing in symptomatic patients who initially test negative depending of pretest likelihood of infection. Rapid immunoassays detecting Ebola antigens were developed during the West African epidemic and are useful when RT-PCR is not available. These tests are not recommended for the testing of asymptomatic patients.
Treatment and prevention
Treatment and prevention of Ebola has made great strides forward since the last major epidemic (2014-2016) although mortality remains high, especially when treatment is started relatively late as is usually the case in Africa. An overview of the current treatment and prevention options of Ebola disease can be found in table 1. Treatment of Ebola disease can be divided in supportive care and antiviral therapies. Supportive care primarily aims to maintain or restore normal physiology and includes fluid and electrolyte replacement, mechanical ventilation or oxygen therapy, blood products, analgesics, antiemetic drugs, renal replacement therapy and antimicrobial therapy in case of a bacterial superinfection. Antiviral therapies include the use of antibodies (Inmazeb, ZMapp and Ansuvimab) against the Zaire species of Ebola and other investigational therapies. Importantly, the recent PALM trial conducted during the Ebola epidemic in North Kivu (DRC, 2018 to 2019) investigated the efficacy of Inmazeb, Ansuvimab, remdesivir and ZMapp. ZMapp, a combination of monoclonal antibodies directed against viral surface glycoproteins, was considered the control group as an earlier randomised controlled trial found a reduction of mortality in the ZMapp group compared with the placebo group (PREVAIL II trial). The PALM trial was stopped early because an interim analysis of a subgroup of 499 patients with a low initial viral load showed a significantly greater survival among patients who received Inmazeb or Ansuvimab compared with ZMapp or remdesivir. Overall mortality at 28 days in the Ansuvimab group was 35.1% versus 49.7% in the ZMapp group (p=0.007). Mortality in the Inmazeb group was 33.5% compared with 51.3% in a ZMapp subgroup enrolled during the same study period (p=0.002). Importantly, earlier treatment was associated with improved survival which had not been shown previously. Unfortunately, other investigational therapies such as convalescent plasma did not show a survival benefit.. Favipiravir, a prodrug which after metabolisation inhibits viral RNA-dependent RNA polymerase, may improve survival. The efficacy, however, should be further investigated.
Prevention consists of infection control measures, outbreak management and vaccines. It is recommended to follow the infection prevention and control recommendations from the World Health Organisation. This includes hand hygiene, contact/droplet precautions, environmental cleaning/disinfection and personal protective equipment. Personal protective equipment should include double gloves, boot covers, a liquid impermeable gown, a hood that covers the head and neck, full face shield and FFP2 mask.
Outbreak management is complex as initial symptoms are nonspecific and involves identifying and isolating suspected patients. Contacts of a proven case should be monitored and quarantined during the incubation period. Community participation, communication and trust in authorities are crucial for implementation of preventive measures. Ritual washing during funerals and contact with bushmeat should be avoided or modified to include wearing protective clothing and cooking, respectively. Currently, two vaccination strategies have been found to be effective and safe. A single-dose recombinant vesicular stomatitis virus-Zaire Ebola vaccine (rVSV-ZEbola; Ervebo) that carries the Ebola glycoprotein gene was shown to offer substantial protection against Ebola disease in Liberia and Guinea during the West African epidemic with antibody titres persisting for at least two years.[20,21] Importantly, the rVSV-ZEbola vaccine is not administered routinely but used in the context of a ring vaccination strategy and pre-exposure prophylaxis of healthcare workers. One of the reasons why a ring vaccination strategy is chosen is the logistical problems that are associated with administering a vaccine that has to be kept at -80°C in warm and resource-poor Africa. The second vaccination option incorporates a prime-boost strategy with the Ad26.ZEbola/MVA-BN-Filo vaccine. The first vaccination is a recombinant human adenovirus 26 virus encoding the Zaire ebolavirus glycoprotein. The booster is administered after an interval of eight weeks and consists of a modified vaccinia Ankara virus carrying the genes of Zaire and Sudan Ebola glycoproteins as well as the nucleoprotein of the Tai Forest species. Several studies have shown that this vaccine is safe and immunogenic with antibodies present for at least one year.
Pandemic potential of Ebola virus
The pandemic threat of a pathogen is determined by several factors including human-to-human transmissibility, the absence of effective and available therapies or vaccines, virulence factors, case-fatality rate and the ability for transmission during the incubation period. The acceleration of vaccine and antiviral drug development during and after the 2014-2016 West African epidemic fortunately mitigates the risk of a future pandemic caused by Ebola, especially through (ring) vaccination strategies. However, the logistical problems of vaccination are very high and the level of protection in potentially only partially vaccinated areas is still uncertain. The case-fatality rate remains very high though when infection becomes apparent. Another pandemic risk is emergence of a new type of Ebola disease caused by zoonotic spillover of a previously unknown or a mutated virus.[23,24]
Therefore, prevention of the next pandemic should primarily focus on vaccination strategies in vulnerable areas but as well on reduction of zoonotic spillover. This may include changes in bushmeat consumption practices, livestock production, livestock trade and the development of worldwide surveillance programs. Interestingly, a 5th species of Ebola of concern called Reston virus has been identified which is fortunately nonpathogenic in humans. Reston virus was first described in 1989 as it resulted in an outbreak in imported macaques in Virginia. In 2008, the Reston virus was discovered in pigs in the Philippines and some asymptomatic pig farmers were shown to have IgG antibodies against the virus. Reston virus was subsequently identified in pigs in China resulting in food safety concerns. Moreover, new filoviruses were detected in bats and two new genera of filoviruses have been described in fish with one of them being discovered in Europe.[26,27] The pathogenic potential of these new filoviruses is as yet unknown.
Ebolavirus is a genus of the Filoviridae family. It is a zoonosis and four species are known to cause disease with a high case-fatality rate. Human transmission is mediated by direct contact with body fluids of alive or deceased patients The 2014-2016 West African epidemic accelerated the development of antiviral therapies and vaccines potentially mitigating the future pandemic risk through vaccination strategies. However, the case-fatality rate of established infection is still very high despite new therapies. The emergence of a new comparable filovirus disease caused by zoonotic spillover of a previously unknown or mutated virus is a realistic scenario. Prevention of future pandemics should focus on reduction of zoonotic spillover, worldwide surveillance programs and vaccination in vulnerable areas.
All authors declare no conflict of interest. No funding or financial support was received.
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