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Understanding Ebola: the 2014 epidemic

Understanding Ebola: the 2014 epidemic Near the end of 2013, an outbreak of Zaire ebolavirus (EBOV) began in Guinea, subsequently spreading to neighboring Liberia and Sierra Leone. As this epidemic grew, important public health questions emerged about how and why this outbreak was so different from previous episodes. This review provides a synthetic synopsis of the 2014–15 outbreak, with the aim of understanding its unprecedented spread. We present a summary of the history of previous epidemics, describe the structure and genetics of the ebolavirus, and review our current understanding of viral vectors and the latest treatment practices. We conclude with an analysis of the public health challenges epidemic responders faced and some of the lessons that could be applied to future outbreaks of Ebola or other viruses. Keywords: Ebola, Ebolavirus, 2014 outbreak, Epidemic, Review Abbreviations: BEBOV, Bundibugyo ebolavirus;CIEBOV, Côte d’Ivoire ebolavirus;EBOV, Ebolavirus; EVD, Ebola virus disease or Ebola; Kb, Kilobase; MSF, Médecins Sans Frontières; REBOV, Reston ebolavirus; SEBOV, Sudan ebolavirus;WHO, World Health Organization; ZEBOV, Zaire ebolavirus Background NP (nucleoprotein), VP35 (polymerase cofactor), VP40 As of April 13th, 2016 there have been 28,652 total cases (matrix protein), GP (glycoprotein), VP30 (transcrip- of Ebola virus disease (EVD; or more generally Ebola) in tion activator), VP24 (secondary matrix protein), and the 2014–2015 West African epidemic [1]. Of these, RNA-dependent RNA polymerase [6]. There are currently 11,325 cases (40 %) were fatal [1]. During this epidemic, five recognized species of ebolavirus: Zaire ebolavirus the vast majority of cases were concentrated in Guinea, (ZEBOV), Sudan ebolavirus (SEBOV), Reston ebolavirus Liberia, and Sierra Leone, with a handful of cases (REBOV) (non-pathogenic to humans), Côte d’Ivoire ebo- imported to countries around the world [1]. This was lavirus (CIEBOV) also known as Tai Forest ebolavirus and the first outbreak of Ebola in West Africa, and the most Bundibugyo ebolavirus (BEBOV) [5, 7]. significant Ebola epidemic that has occurred worldwide Estimates of the rate of nucleotide substitution for since the virus was first described [2]. Here, we review filoviruses suggest that these viruses have substitution the current understanding of biology and genetics of rates approximately 100× times lower than other RNA the virus, the past and current epidemiology, and the viruses (e. g. retroviruses and influenza A) [8]. Based on public health response to the 2014–15 Ebola outbreak. these substitution rates, studies have concluded that ebolavirus and marburgvirus, a closely related filovirus that is also pathogenic in humans, likely diverged from Ebolavirus genetics each other several thousand years ago and that the The ebolavirus is a member of the family filoviridae, different species of ebolavirus diverged from each other which is composed of single-stranded negative-sense within the last ~1000 years ago [8, 9]. Genetic analysis enveloped RNA viruses [3]. These filamentous viruses of strains from the 2014–2015 West African Ebola are ~19 kilobases (kb) in length (800–1100 nanometers epidemic have been hindered, in part, due to the limited [nm] long and 80 nm in diameter) [4]. The ebolavirus understanding of the biology of this virus and further genome contains seven genes (3′ NP VP35 VP40 GP exacerbated by delays in sample export, bad record VP30 VP24 L 5′ [5]) encoding a number of proteins: keeping, and a small number of trained specialists [10, 11]. Gire et al. [12] analyzed 81 EBOV sequences, * Correspondence: schaackmobile@gmail.com 78 newly derived from patients in Sierra Leone and 3 Department of Biology, Reed College, 3203 SE Woodstock Blvd, Portland, OR 97202, USA previously published Guinean sequences, and found Full list of author information is available at the end of the article © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kaner and Schaack Globalization and Health (2016) 12:53 Page 2 of 7 341 fixed substitutions and 55 single-nucleotide poly- many locations, suggesting that infection (and survival) morphisms. They concluded that the substitution rate is frequent [4]. Retrospective analysis shows that wildlife during this outbreak is roughly twice as high as those deaths (non-human primates and antelope) tend to pre- previously reported. Other studies show contrasting cede human infections, which this could have important results, however; e.g. Spielman et al. [13] and Hoenen surveillance implications in terms of preventing future et al. [14] analyzed sequences from the recent epidemic outbreaks [20]. In addition, population declines in −4 −3 and reported a mutation rates of 9.6 × 10 and 1.3 × 10 apes have also been chronologically linked to human substitutions per site per year, respectively, which are Ebola outbreaks and a number of molecular studies similar to those reported during past outbreaks. have linked primate ebolavirus cases to human Ebola A more recent study by Carroll et al. [15] used 197 outbreaks [4]. new viral sequences in addition to publicly-available Although two types of transmission (animal-to-human sequences to trace the evolution of the viral genome and human-to-human) have been observed, nosocomial throughout the epidemic. They estimated the date of the transmission has played a key role in the spread of most recent common ancestor of the sampled viruses to Ebola. Transmission from animals has taken place via th th be between December 12 , 2013 and February 18 , the handling and butchering of infected animals, inc- 2014, which is supported by epidemiological evidence luding bats, non-human primates and duikers (a small that places the index case in late December 2013 [15]. forest antelope) [21]. Healthcare workers are especially Another recent study by Simon-Loriere et al. [16] ana- at risk for exposure to Ebola because they are more lyzed 85 new sequences from Guinean patients along likely to come into contact with contaminated bodily with 110 publicly-available EBOV sequences from this fluids [22]. The traditional funeral and burial practices in −3 outbreak and reported a mutation rate of 0.87 × 10 to West Africa involve washing the body by hand before −3 0.91 × 10 substitutions per site per year. They point burial and paying respect to the dead through physical out that evolutionary rates in RNA viruses can be strongly contact which are both exceptionally high-risk activities time-dependent, with higher rates observed over short with regard to the spread of Ebola [23]. The incubation time spans than long ones [16]. This may explain why period for Ebola can range from two to 21 days, but is certain estimates of mutation rates during this recent usually one to two weeks [24]. There is no evidence that epidemic have been higher than expected. Ebola is contagious during the incubation period, while infected individuals are still asymptomatic [25]. The Past Ebola outbreaks World Health Organization (WHO) will only declare an Since the first outbreak 40 years ago, EVD outbreaks Ebola outbreak over once 42 days (two incubation pe- have been rare, small and localized. The first recorded riods) have passed with no new infections reported [26]. outbreak of EVD took place in Zaire (now the De- Interrupting Ebola transmission requires rapid identifi- mocratic Republic of the Congo) in 1976, close to the cation of cases, contact tracing, and monitoring of Yambuku Catholic Mission Hospital located near the people identified as high risk [22, 27]. Based on a retro- Ebola River Valley [7]. At the same time, a separate out- spective study of the 1995 outbreak in Kikwit DRC, the break of EVD occurred near Maridi in West Equatoria greatest risk factor for secondary household transmission Region in Sudan [7]. Prior to 2014, the largest recorded of Ebola is direct contact with someone who has clinic- outbreak of Ebola (SEBOV in this case) took place in ally apparent illness [28]. This risk increases if there is Uganda from October 2000 to January 2001, with 425 contact with bodily fluids or the infected person is in the cases and 225 deaths [17, 18]. late stages of the disease. Direct contact was determined After the discovery of the virus, a large variety of to be necessary, but not sufficient, for transmission [28]. organisms were screened as possible Ebola reservoirs. To date, the only comprehensive analysis of viral excre- Bats both efficiently replicate the virus and survive infec- tion and environmental contamination from Ebola found tion, which made them standout as candidate reservoirs viral particles are present in blood, breast milk, saliva, [4]. Despite this initial evidence, the first direct evidence semen, feces, and tears [29]. A review of relevant lite- that bats are reservoir hosts of ebolavirus was reported rature by Thorsen et al. [30] found that the longest re- in a field study in 2005, almost 30 years after the discov- corded persistence of EBOV in semen is 284 days. While ery of the virus [19]. Immunoglobulin G (IgG) specific viral RNA was isolated from this sample, it is not known for ebolavirus was found in serum from bats of three if the viral particles were still infectious. Viable Ebola different species of fruit bat (Hypsignathus monstrosus, virus has been found in semen 82 days post-infection Epomps franqueti, and Myonycteris torquata) and phylo- and may be present much longer than this [30]. Further genetic analysis showed that they were most likely close complicating efforts to understand transmission was the relatives of ZEBOV strains [19]. Ebolavirus antibodies recent report of sexual transmission confirmed by both have since been reported in numerous bat species from contact tracing and genetic sequencing [31]. This case Kaner and Schaack Globalization and Health (2016) 12:53 Page 3 of 7 involved viral transmission from a male to a female 179 days after the onset of disease in the male patient [31]. 20 The standard treatment for Ebola patients has not changed in the last 50 years and consists of symptomatic 15 and supportive care [24]. Supportive care involves either oral or intravenous rehydration and electrolyte manage- ment; while symptomatic care involves the use of drugs 6 6 to reduce vomiting and diarrhea, along with medication to treat fever and pain [32–34]. Patients with high malaria 1.4 1.4 1.25 risk are also given anti-malarial medication and antibiotics to preemptively treat common infections that may hamper their ability to fight Ebola. Currently, drugs being de- veloped to treat Ebola work by inhibiting viral replication either by targeting viral transcripts for degradation, blo- cking translation, or acutely neutralizing the virus [35]. Other treatments that are being studied include passive Fig. 1 Average R s for common epidemic diseases, including Ebola, immunotherapy (blood transfusion from survivors) and at the height of the 2014 epidemic [43, 64–67] mechanical filtering of patient blood [36, 37]. Epidemiological dynamics of the 2014–2015 Ebola region), a conclusion later supported by bacteria found st epidemic in patient samples [23]. On February 1 , 2014 Ebola Understanding epidemiological dynamics can be challen- reached Conakry, the Guinean capital, through an in- ging during an outbreak when mortality rates are high fected member of the index case’s extended family, who and practical concerns, such as healthcare worker safety, died 4 days later, but by that time had initiated multiple need to be prioritized [38]. The main metric used to chains of transmission [23]. The Guinea Ministry of understand how fast a virus spread is R , the basic Health issued its first alert about the then unidentified th reproduction number [39, 40]. For Liberia, estimates disease on March 13 , 2014 and the regional office of place R at 1.59, 1.36 and 1.83 according to three differ- the WHO opened an investigation the same day, sus- ent studies [41] Pandey et al. 2014, [2]. In Guinea, R pecting Lassa fever (a hemorrhagic fever endemic to the has been estimated at 1.5 and 1.71 [2, 41]. Three separ- region). The next day, the Pasteur Institute in France ate studies posit very different R values for Ebola in confirmed that the pathogen infecting patients was rd Sierra Leone. One estimates an R of 2.53, another esti- ZEBOV and on March 23 , 2014 the WHO publicly mates 2.02, and a third estimates 1.4 [2, 41, 42]. The announced the outbreak with 49 confirmed cases and 29 third estimate was generated using a model based on deaths [23]. clustered social interactions rather than assuming ran- From early June to mid-September, the epidemic grew dom mixing between individuals, and may therefore be exponentially in Guinea, Liberia, and Sierra Leone, with more accurate [42]. According to the United Nations national case number doubling times of between 16 and (UN) the overall R for the whole epidemic was ap- 30 days [2]. Against this backdrop, the scaling up of the th proximately 1.4 in September (Fig. 1) and had fallen to international response began on July 9 , 2014, when the below 1.0 in December 2014 [43]. United Nations Security Council issued a statement expressing its deep concern about the Ebola epidemic The 2014–2015 Ebola epidemic and implored the international community to provide All infections in the 2014–2015 West African ZEBOV prompt assistance to prevent the further spread of the th epidemic can be traced back to an index case that was virus [43]. On August 8 , 2014, the WHO declared the reported from an 18-month-old boy from the village of outbreak an international public health emergency [2]. th Meliandou, Guinea in December 2013 [43–45]. A retro- Over a month later on September 18 , 2014, with 5,000 spective investigation by Saéz et al. [46] posits that the reported cases and almost 2,500 deaths, the UN Security index case was infected by contact with insectivorous Council held its first ever emergency meeting on a bats. The first official medical alert was issued on public health crisis [43]. th January 24 , 2014 when the head of the Meliandou The first recorded human-human transmission of health post informed district health officials of five cases EBOV outside of Africa occurred in Madrid, Spain. On th of severe and rapidly fatal diarrhea. A subsequent inves- September 30 , 2014, a nurse became sick after treating tigation by local health officials indicated that the symp- an Ebola patient who had been transferred to Spain from toms appeared to match cholera (also endemic to this West Africa [47, 48]. She eventually made a full recovery Seasonal Influenza Meningococcal Meningitis Pertussis (Whooping Cough) Measles Smallpox HIV/AIDS Ebola Basic Reproductive Rate (R ) 0 Kaner and Schaack Globalization and Health (2016) 12:53 Page 4 of 7 and none of her contacts became infected. The next Organization to provide essential health services [53]. cases occurred in the United States and further ignited Including international aid, the total cost of the epidemic fears internationally of Ebola risk. Thomas Eric Duncan, response is estimated at $4.3 billion USD so far [53]. a native of Liberia, flew from Liberia to Dallas, TX on Maternal health in West Africa has been dramatically th September 19 , 2014 [49]. He became ill several days affected by the Ebola epidemic. Pregnancy appears to later and went to the emergency room of Texas Health make people more vulnerable to the effects of Ebola in- th Presbyterian Hospital on September 25 where he was fection, particularly increasing their risk of hemorrhage diagnosed with sinusitis and discharged with antibiotics [55]. All pregnancies of women infected with Ebola end [49]. He returned to the emergency room three days in spontaneous miscarriage, stillbirth, or neonatal death later in much worse condition and was admitted to the within a few days [56]. There is evidence that the Ebola hospital [49]. Tests for EBOV came back positive on virus is able to cross from the placenta into both the th th September 30 and Duncan passed away on October 8 amniotic fluid and fetus [56]. Besides the risks to the [49, 50]. Subsequently, two nurses who had been in- mother, the large amount of blood and bodily fluids volved in Duncan’s treatment became ill and tested present at deliveries present a huge risk of infection for th positive for Ebola on October 12 and 15 , respectively healthcare workers [55]. A lot of the symptoms of preg- [47, 50]. Both nurses made a full recovery and were re- nancy related complications overlap with EVD and this leased from the hospital [47]. is further complicated by the poor condition of maternal th On March 29 2016 the WHO declared the end of health care in West Africa [56]. Many healthcare workers the Public Health Emergency of International Concern have refused to treat pregnant patients in countries with regarding Ebola in West Africa [51]. Liberia was initially widespread Ebola infection until they have tested negative th declared Ebola-free on May 9 , 2015, however several for EVD due to the risk of exposure, which poses a serious more clusters of Ebola cases have occurred over the past problem for women in need of invasive emergency proce- year. A cluster of six cases was reported in June 2015, dures [56]. Refusal of treatment combined with fears Liberia was eventually declared Ebola-free on September about Ebola has meant that many people have stopped rd 3 2015. Another cluster of three cases was reported in showing up for prenatal visits or assistance with delivery November 2015. Liberia was declared Ebola-free for the [55]. The United Nations Population Fund estimates that th third time January 14 2015 and has not reported any the Ebola epidemic will, either directly or indirectly, result new Ebola cases since that time [1]. Sierra Leone was in as many as 120,000 maternal deaths by the end of th first declared Ebola-free on November 7 , 2015. Two October 2015 [55]. new cases were reported in January 2016; following Another area of concern is psychological care for these cases Seirra Leone was declared Ebola-free on Ebola survivors and family members of Ebola patients th March 7 2016 [1]. Guinea was declared Ebola-free on [57]. The epidemic has created many psychological th December 29 , 2015, but reported five new cases in stresses beyond fear of the disease itself, including late March 2016 [1]. declining economies, closed borders and markets, and widespread hunger [58]. Discrimination against families West Africa after Ebola affected by Ebola and international stigma against coun- According to Médecins Sans Frontières (MSF; also known tries with widespread Ebola infections also contribute to as Doctors Without Borders), no one knows the true the development of mental health problems in affected number of deaths caused by the 2014–2015 Ebola epi- communities [58]. There is a severe scarcity of mental demic [52]. The lack of basic healthcare means that over- health workers in West Africa making delivery of effect- all morality rates have dramatically increased, in addition ive care even more difficult [58]. Currently, a shift in the to deaths resulting from direct viral infections [52, 53]. global health community’s attitude toward mental health For example, vaccination rates for common illnesses have is resulting in more funding for mental health programs, also dropped—it is estimated as of March 2015 over a and the WHO has started to address psychological care million more children will have not been vaccinated in its reports [57]. While these are encouraging signs, against measles than there were before the epidemic there is still a long way to go before Ebola survivors and began [54]. The number of people who lack food security families of Ebola victims receive adequate support. as a result of the 2014 Ebola epidemic is estimated to be in the hundreds of thousands and is expected to continue International engagement in public health to rise [53]. Prior to the epidemic, healthcare in these According to the WHO, Ebola in West Africa is an countries was severely underfunded– in 2012 the Liberian example of “an old virus in a new context”, which sums government spent $20 per person per year on healthcare, up some of the unique challenges faced during the Ebola Sierra Leone $16 and Guinea $9. This is far below the response in West Africa [23]. From early June to mid- minimum of $86 recommended by the World Health September 2015 the epidemic grew exponentially in Kaner and Schaack Globalization and Health (2016) 12:53 Page 5 of 7 Guinea, Liberia, and Sierra Leone, with national case warning and response system for outbreaks, increasing number doubling times between 16 and 30 days [23]. disease surveillance, and funding additional research into Against this backdrop, the scaling up of the international drugs, vaccines, and diagnostic tests, as well as creating a response to the West African Ebola epidemic began on system for accelerating the approval of these interventions th July 9 , 2014, when the United Nations Security Council during a crisis [60]. Jeremy Farrar of the Wellcome Trust, issued a statement expressing its deep concern about the and Seth Berkley of GAVI The Vaccine Alliance, argued Ebola epidemic and implored the international commu- that much more should have been done before this nity to provide prompt assistance to prevent the further outbreak, in terms of vaccine studies and vaccine approval spread of the virus [43]. protocols [61]. Funding for research and development of As of April 2015, there were 176 organizations operat- drugs and vaccines for diseases likely to cause future ing emergency programs in Guinea, Liberia, and Sierra epidemics, even though these are not the diseases that are Leone [59]. At this point, the total number of Ebola the most lucrative for drug companies, may be a key treatment unit beds exceeded the number of reported component of preventing future outbreaks [61]. Ebola patients and there were enough burial teams in place to ensure safe and dignified burials for all deaths Conclusions: what we have learned due to Ebola [59]. However, due to uneven distribution The 2014 Ebola epidemic in West Africa highlighted of these resources and the continued fear and suspicion major deficiencies in the ability of the international of Ebola treatment hospitals and burial teams in local public health and scientific communities to respond to communities, many patients were still going without infectious disease emergencies. It also provided a stark treatment or safe burials, resulting in new infections. reminder of the consequences of not investing in the According to the UN task force, the epidemic response development of healthcare infrastructure in developing needs to be tailored to adapt to the wide geographic countries. The current system of drug and vaccine devel- spread of Ebola even as the outbreak diminishes [59]. opment favors the development of drugs and vaccines According to the WHO, this outbreak demonstrated for chronic diseases that primarily affect people in the the severe lack of international capacity to respond to developed world, rather than diseases likely to cause public health crises [23]. It has been estimated that more epidemics. According to Currie et al. [62], the develop- than 30,000 children were orphaned by this epidemic ment of a mechanism for international cooperation in [23]. Access to routine healthcare has also been severely vaccine development and licensing is an urgent priority. effected by the outbreak, resulting in increased mortality The first step in preventing or minimizing future epi- from common and chronic illnesses [59]. One year after demics is to create an effective global monitoring system the official declaration of the 2014 Ebola epidemic, MSF for newly emerging pathogens. This relies on improving released a report critiquing the lack of international healthcare infrastructure around the world, resulting in a engagement with the epidemic response [52], specific- network of healthcare professionals who could serve as an ally, MSF president Dr. Joanne Liu who pointed out that early warning system for disease outbreaks. It is important the lack of international political motivation to intervene that knowledge from a variety of disciplines is employed in West Africa ended in July 2014 when the first case of to create a multifaceted approach to future outbreaks [62]. Ebola was diagnosed outside of Africa [52]. It was only Another important facet of the global response to disease at this time that the outbreak could no longer be seen as outbreaks is the rapid mobilization of personnel and a humanitarian crisis affecting a few poor countries in resources. Thirdly, the Ebola outbreak has demonstrated Africa, but instead began to be viewed as an inter- the risk that international mobility and air travel poses to national security threat to developed countries. This infection control, including the panic that can ensue when report by MSF also concluded that the interconnected- infected people move across international borders. The ness of the modern world means that world leaders can role of mobility and the importance of allocating resources no longer ignore health crises in distant countries [52]. to understand transmission and epidemiological risk has As a result of this epidemic, several influential edito- been underscored during the recent Zika virus outbreak, rials have called for renewed attention to international in part because of its previously unknown symptoms and public health issues. Bill Gates commented that the transmission dynamics (reviewed in [63]) problem was less that the current system did not work Ultimately the 2014 Ebola epidemic has shown that infec- well enough, but more that a system barely existed at all tion control measures can fail and that there is a significant [60]. In his editorial published in the New York Times, risk from infectious disease worldwide. The risks posed by Gates asserted that we must create a global warning and disease outbreaks are complicated by the lack of under- response system for outbreaks with a focus on building standing of the basic biology, limited access to healthcare, health systems within countries that can also be used poor infrastructure, and increased mobilization. Adequate for disease surveillance. He suggested creating a global scientific research and preparation, backed by careful policy Kaner and Schaack Globalization and Health (2016) 12:53 Page 6 of 7 implementation, are likely the key to limiting and respond- 12. Gire SK, Goba A, Andersen KG, Sealfon RS, Park DJ, Kanneh L, Jalloh S, et al. Genomic surveillance elucidates Ebola virus origin and transmission during ing effectively to future epidemics. Lessons learned from the 2014 outbreak. Science. 2014;345(6202):1369–72. past outbreaks can be applied to prevent or minimize the 13. Spielman SJ, Austin GM, and Claus OW. 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Understanding Ebola: the 2014 epidemic

Globalization and Health , Volume 12 (1): 7 – Dec 1, 2016

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2016 The Author(s).
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1744-8603
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10.1186/s12992-016-0194-4
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Abstract

Near the end of 2013, an outbreak of Zaire ebolavirus (EBOV) began in Guinea, subsequently spreading to neighboring Liberia and Sierra Leone. As this epidemic grew, important public health questions emerged about how and why this outbreak was so different from previous episodes. This review provides a synthetic synopsis of the 2014–15 outbreak, with the aim of understanding its unprecedented spread. We present a summary of the history of previous epidemics, describe the structure and genetics of the ebolavirus, and review our current understanding of viral vectors and the latest treatment practices. We conclude with an analysis of the public health challenges epidemic responders faced and some of the lessons that could be applied to future outbreaks of Ebola or other viruses. Keywords: Ebola, Ebolavirus, 2014 outbreak, Epidemic, Review Abbreviations: BEBOV, Bundibugyo ebolavirus;CIEBOV, Côte d’Ivoire ebolavirus;EBOV, Ebolavirus; EVD, Ebola virus disease or Ebola; Kb, Kilobase; MSF, Médecins Sans Frontières; REBOV, Reston ebolavirus; SEBOV, Sudan ebolavirus;WHO, World Health Organization; ZEBOV, Zaire ebolavirus Background NP (nucleoprotein), VP35 (polymerase cofactor), VP40 As of April 13th, 2016 there have been 28,652 total cases (matrix protein), GP (glycoprotein), VP30 (transcrip- of Ebola virus disease (EVD; or more generally Ebola) in tion activator), VP24 (secondary matrix protein), and the 2014–2015 West African epidemic [1]. Of these, RNA-dependent RNA polymerase [6]. There are currently 11,325 cases (40 %) were fatal [1]. During this epidemic, five recognized species of ebolavirus: Zaire ebolavirus the vast majority of cases were concentrated in Guinea, (ZEBOV), Sudan ebolavirus (SEBOV), Reston ebolavirus Liberia, and Sierra Leone, with a handful of cases (REBOV) (non-pathogenic to humans), Côte d’Ivoire ebo- imported to countries around the world [1]. This was lavirus (CIEBOV) also known as Tai Forest ebolavirus and the first outbreak of Ebola in West Africa, and the most Bundibugyo ebolavirus (BEBOV) [5, 7]. significant Ebola epidemic that has occurred worldwide Estimates of the rate of nucleotide substitution for since the virus was first described [2]. Here, we review filoviruses suggest that these viruses have substitution the current understanding of biology and genetics of rates approximately 100× times lower than other RNA the virus, the past and current epidemiology, and the viruses (e. g. retroviruses and influenza A) [8]. Based on public health response to the 2014–15 Ebola outbreak. these substitution rates, studies have concluded that ebolavirus and marburgvirus, a closely related filovirus that is also pathogenic in humans, likely diverged from Ebolavirus genetics each other several thousand years ago and that the The ebolavirus is a member of the family filoviridae, different species of ebolavirus diverged from each other which is composed of single-stranded negative-sense within the last ~1000 years ago [8, 9]. Genetic analysis enveloped RNA viruses [3]. These filamentous viruses of strains from the 2014–2015 West African Ebola are ~19 kilobases (kb) in length (800–1100 nanometers epidemic have been hindered, in part, due to the limited [nm] long and 80 nm in diameter) [4]. The ebolavirus understanding of the biology of this virus and further genome contains seven genes (3′ NP VP35 VP40 GP exacerbated by delays in sample export, bad record VP30 VP24 L 5′ [5]) encoding a number of proteins: keeping, and a small number of trained specialists [10, 11]. Gire et al. [12] analyzed 81 EBOV sequences, * Correspondence: schaackmobile@gmail.com 78 newly derived from patients in Sierra Leone and 3 Department of Biology, Reed College, 3203 SE Woodstock Blvd, Portland, OR 97202, USA previously published Guinean sequences, and found Full list of author information is available at the end of the article © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kaner and Schaack Globalization and Health (2016) 12:53 Page 2 of 7 341 fixed substitutions and 55 single-nucleotide poly- many locations, suggesting that infection (and survival) morphisms. They concluded that the substitution rate is frequent [4]. Retrospective analysis shows that wildlife during this outbreak is roughly twice as high as those deaths (non-human primates and antelope) tend to pre- previously reported. Other studies show contrasting cede human infections, which this could have important results, however; e.g. Spielman et al. [13] and Hoenen surveillance implications in terms of preventing future et al. [14] analyzed sequences from the recent epidemic outbreaks [20]. In addition, population declines in −4 −3 and reported a mutation rates of 9.6 × 10 and 1.3 × 10 apes have also been chronologically linked to human substitutions per site per year, respectively, which are Ebola outbreaks and a number of molecular studies similar to those reported during past outbreaks. have linked primate ebolavirus cases to human Ebola A more recent study by Carroll et al. [15] used 197 outbreaks [4]. new viral sequences in addition to publicly-available Although two types of transmission (animal-to-human sequences to trace the evolution of the viral genome and human-to-human) have been observed, nosocomial throughout the epidemic. They estimated the date of the transmission has played a key role in the spread of most recent common ancestor of the sampled viruses to Ebola. Transmission from animals has taken place via th th be between December 12 , 2013 and February 18 , the handling and butchering of infected animals, inc- 2014, which is supported by epidemiological evidence luding bats, non-human primates and duikers (a small that places the index case in late December 2013 [15]. forest antelope) [21]. Healthcare workers are especially Another recent study by Simon-Loriere et al. [16] ana- at risk for exposure to Ebola because they are more lyzed 85 new sequences from Guinean patients along likely to come into contact with contaminated bodily with 110 publicly-available EBOV sequences from this fluids [22]. The traditional funeral and burial practices in −3 outbreak and reported a mutation rate of 0.87 × 10 to West Africa involve washing the body by hand before −3 0.91 × 10 substitutions per site per year. They point burial and paying respect to the dead through physical out that evolutionary rates in RNA viruses can be strongly contact which are both exceptionally high-risk activities time-dependent, with higher rates observed over short with regard to the spread of Ebola [23]. The incubation time spans than long ones [16]. This may explain why period for Ebola can range from two to 21 days, but is certain estimates of mutation rates during this recent usually one to two weeks [24]. There is no evidence that epidemic have been higher than expected. Ebola is contagious during the incubation period, while infected individuals are still asymptomatic [25]. The Past Ebola outbreaks World Health Organization (WHO) will only declare an Since the first outbreak 40 years ago, EVD outbreaks Ebola outbreak over once 42 days (two incubation pe- have been rare, small and localized. The first recorded riods) have passed with no new infections reported [26]. outbreak of EVD took place in Zaire (now the De- Interrupting Ebola transmission requires rapid identifi- mocratic Republic of the Congo) in 1976, close to the cation of cases, contact tracing, and monitoring of Yambuku Catholic Mission Hospital located near the people identified as high risk [22, 27]. Based on a retro- Ebola River Valley [7]. At the same time, a separate out- spective study of the 1995 outbreak in Kikwit DRC, the break of EVD occurred near Maridi in West Equatoria greatest risk factor for secondary household transmission Region in Sudan [7]. Prior to 2014, the largest recorded of Ebola is direct contact with someone who has clinic- outbreak of Ebola (SEBOV in this case) took place in ally apparent illness [28]. This risk increases if there is Uganda from October 2000 to January 2001, with 425 contact with bodily fluids or the infected person is in the cases and 225 deaths [17, 18]. late stages of the disease. Direct contact was determined After the discovery of the virus, a large variety of to be necessary, but not sufficient, for transmission [28]. organisms were screened as possible Ebola reservoirs. To date, the only comprehensive analysis of viral excre- Bats both efficiently replicate the virus and survive infec- tion and environmental contamination from Ebola found tion, which made them standout as candidate reservoirs viral particles are present in blood, breast milk, saliva, [4]. Despite this initial evidence, the first direct evidence semen, feces, and tears [29]. A review of relevant lite- that bats are reservoir hosts of ebolavirus was reported rature by Thorsen et al. [30] found that the longest re- in a field study in 2005, almost 30 years after the discov- corded persistence of EBOV in semen is 284 days. While ery of the virus [19]. Immunoglobulin G (IgG) specific viral RNA was isolated from this sample, it is not known for ebolavirus was found in serum from bats of three if the viral particles were still infectious. Viable Ebola different species of fruit bat (Hypsignathus monstrosus, virus has been found in semen 82 days post-infection Epomps franqueti, and Myonycteris torquata) and phylo- and may be present much longer than this [30]. Further genetic analysis showed that they were most likely close complicating efforts to understand transmission was the relatives of ZEBOV strains [19]. Ebolavirus antibodies recent report of sexual transmission confirmed by both have since been reported in numerous bat species from contact tracing and genetic sequencing [31]. This case Kaner and Schaack Globalization and Health (2016) 12:53 Page 3 of 7 involved viral transmission from a male to a female 179 days after the onset of disease in the male patient [31]. 20 The standard treatment for Ebola patients has not changed in the last 50 years and consists of symptomatic 15 and supportive care [24]. Supportive care involves either oral or intravenous rehydration and electrolyte manage- ment; while symptomatic care involves the use of drugs 6 6 to reduce vomiting and diarrhea, along with medication to treat fever and pain [32–34]. Patients with high malaria 1.4 1.4 1.25 risk are also given anti-malarial medication and antibiotics to preemptively treat common infections that may hamper their ability to fight Ebola. Currently, drugs being de- veloped to treat Ebola work by inhibiting viral replication either by targeting viral transcripts for degradation, blo- cking translation, or acutely neutralizing the virus [35]. Other treatments that are being studied include passive Fig. 1 Average R s for common epidemic diseases, including Ebola, immunotherapy (blood transfusion from survivors) and at the height of the 2014 epidemic [43, 64–67] mechanical filtering of patient blood [36, 37]. Epidemiological dynamics of the 2014–2015 Ebola region), a conclusion later supported by bacteria found st epidemic in patient samples [23]. On February 1 , 2014 Ebola Understanding epidemiological dynamics can be challen- reached Conakry, the Guinean capital, through an in- ging during an outbreak when mortality rates are high fected member of the index case’s extended family, who and practical concerns, such as healthcare worker safety, died 4 days later, but by that time had initiated multiple need to be prioritized [38]. The main metric used to chains of transmission [23]. The Guinea Ministry of understand how fast a virus spread is R , the basic Health issued its first alert about the then unidentified th reproduction number [39, 40]. For Liberia, estimates disease on March 13 , 2014 and the regional office of place R at 1.59, 1.36 and 1.83 according to three differ- the WHO opened an investigation the same day, sus- ent studies [41] Pandey et al. 2014, [2]. In Guinea, R pecting Lassa fever (a hemorrhagic fever endemic to the has been estimated at 1.5 and 1.71 [2, 41]. Three separ- region). The next day, the Pasteur Institute in France ate studies posit very different R values for Ebola in confirmed that the pathogen infecting patients was rd Sierra Leone. One estimates an R of 2.53, another esti- ZEBOV and on March 23 , 2014 the WHO publicly mates 2.02, and a third estimates 1.4 [2, 41, 42]. The announced the outbreak with 49 confirmed cases and 29 third estimate was generated using a model based on deaths [23]. clustered social interactions rather than assuming ran- From early June to mid-September, the epidemic grew dom mixing between individuals, and may therefore be exponentially in Guinea, Liberia, and Sierra Leone, with more accurate [42]. According to the United Nations national case number doubling times of between 16 and (UN) the overall R for the whole epidemic was ap- 30 days [2]. Against this backdrop, the scaling up of the th proximately 1.4 in September (Fig. 1) and had fallen to international response began on July 9 , 2014, when the below 1.0 in December 2014 [43]. United Nations Security Council issued a statement expressing its deep concern about the Ebola epidemic The 2014–2015 Ebola epidemic and implored the international community to provide All infections in the 2014–2015 West African ZEBOV prompt assistance to prevent the further spread of the th epidemic can be traced back to an index case that was virus [43]. On August 8 , 2014, the WHO declared the reported from an 18-month-old boy from the village of outbreak an international public health emergency [2]. th Meliandou, Guinea in December 2013 [43–45]. A retro- Over a month later on September 18 , 2014, with 5,000 spective investigation by Saéz et al. [46] posits that the reported cases and almost 2,500 deaths, the UN Security index case was infected by contact with insectivorous Council held its first ever emergency meeting on a bats. The first official medical alert was issued on public health crisis [43]. th January 24 , 2014 when the head of the Meliandou The first recorded human-human transmission of health post informed district health officials of five cases EBOV outside of Africa occurred in Madrid, Spain. On th of severe and rapidly fatal diarrhea. A subsequent inves- September 30 , 2014, a nurse became sick after treating tigation by local health officials indicated that the symp- an Ebola patient who had been transferred to Spain from toms appeared to match cholera (also endemic to this West Africa [47, 48]. She eventually made a full recovery Seasonal Influenza Meningococcal Meningitis Pertussis (Whooping Cough) Measles Smallpox HIV/AIDS Ebola Basic Reproductive Rate (R ) 0 Kaner and Schaack Globalization and Health (2016) 12:53 Page 4 of 7 and none of her contacts became infected. The next Organization to provide essential health services [53]. cases occurred in the United States and further ignited Including international aid, the total cost of the epidemic fears internationally of Ebola risk. Thomas Eric Duncan, response is estimated at $4.3 billion USD so far [53]. a native of Liberia, flew from Liberia to Dallas, TX on Maternal health in West Africa has been dramatically th September 19 , 2014 [49]. He became ill several days affected by the Ebola epidemic. Pregnancy appears to later and went to the emergency room of Texas Health make people more vulnerable to the effects of Ebola in- th Presbyterian Hospital on September 25 where he was fection, particularly increasing their risk of hemorrhage diagnosed with sinusitis and discharged with antibiotics [55]. All pregnancies of women infected with Ebola end [49]. He returned to the emergency room three days in spontaneous miscarriage, stillbirth, or neonatal death later in much worse condition and was admitted to the within a few days [56]. There is evidence that the Ebola hospital [49]. Tests for EBOV came back positive on virus is able to cross from the placenta into both the th th September 30 and Duncan passed away on October 8 amniotic fluid and fetus [56]. Besides the risks to the [49, 50]. Subsequently, two nurses who had been in- mother, the large amount of blood and bodily fluids volved in Duncan’s treatment became ill and tested present at deliveries present a huge risk of infection for th positive for Ebola on October 12 and 15 , respectively healthcare workers [55]. A lot of the symptoms of preg- [47, 50]. Both nurses made a full recovery and were re- nancy related complications overlap with EVD and this leased from the hospital [47]. is further complicated by the poor condition of maternal th On March 29 2016 the WHO declared the end of health care in West Africa [56]. Many healthcare workers the Public Health Emergency of International Concern have refused to treat pregnant patients in countries with regarding Ebola in West Africa [51]. Liberia was initially widespread Ebola infection until they have tested negative th declared Ebola-free on May 9 , 2015, however several for EVD due to the risk of exposure, which poses a serious more clusters of Ebola cases have occurred over the past problem for women in need of invasive emergency proce- year. A cluster of six cases was reported in June 2015, dures [56]. Refusal of treatment combined with fears Liberia was eventually declared Ebola-free on September about Ebola has meant that many people have stopped rd 3 2015. Another cluster of three cases was reported in showing up for prenatal visits or assistance with delivery November 2015. Liberia was declared Ebola-free for the [55]. The United Nations Population Fund estimates that th third time January 14 2015 and has not reported any the Ebola epidemic will, either directly or indirectly, result new Ebola cases since that time [1]. Sierra Leone was in as many as 120,000 maternal deaths by the end of th first declared Ebola-free on November 7 , 2015. Two October 2015 [55]. new cases were reported in January 2016; following Another area of concern is psychological care for these cases Seirra Leone was declared Ebola-free on Ebola survivors and family members of Ebola patients th March 7 2016 [1]. Guinea was declared Ebola-free on [57]. The epidemic has created many psychological th December 29 , 2015, but reported five new cases in stresses beyond fear of the disease itself, including late March 2016 [1]. declining economies, closed borders and markets, and widespread hunger [58]. Discrimination against families West Africa after Ebola affected by Ebola and international stigma against coun- According to Médecins Sans Frontières (MSF; also known tries with widespread Ebola infections also contribute to as Doctors Without Borders), no one knows the true the development of mental health problems in affected number of deaths caused by the 2014–2015 Ebola epi- communities [58]. There is a severe scarcity of mental demic [52]. The lack of basic healthcare means that over- health workers in West Africa making delivery of effect- all morality rates have dramatically increased, in addition ive care even more difficult [58]. Currently, a shift in the to deaths resulting from direct viral infections [52, 53]. global health community’s attitude toward mental health For example, vaccination rates for common illnesses have is resulting in more funding for mental health programs, also dropped—it is estimated as of March 2015 over a and the WHO has started to address psychological care million more children will have not been vaccinated in its reports [57]. While these are encouraging signs, against measles than there were before the epidemic there is still a long way to go before Ebola survivors and began [54]. The number of people who lack food security families of Ebola victims receive adequate support. as a result of the 2014 Ebola epidemic is estimated to be in the hundreds of thousands and is expected to continue International engagement in public health to rise [53]. Prior to the epidemic, healthcare in these According to the WHO, Ebola in West Africa is an countries was severely underfunded– in 2012 the Liberian example of “an old virus in a new context”, which sums government spent $20 per person per year on healthcare, up some of the unique challenges faced during the Ebola Sierra Leone $16 and Guinea $9. This is far below the response in West Africa [23]. From early June to mid- minimum of $86 recommended by the World Health September 2015 the epidemic grew exponentially in Kaner and Schaack Globalization and Health (2016) 12:53 Page 5 of 7 Guinea, Liberia, and Sierra Leone, with national case warning and response system for outbreaks, increasing number doubling times between 16 and 30 days [23]. disease surveillance, and funding additional research into Against this backdrop, the scaling up of the international drugs, vaccines, and diagnostic tests, as well as creating a response to the West African Ebola epidemic began on system for accelerating the approval of these interventions th July 9 , 2014, when the United Nations Security Council during a crisis [60]. Jeremy Farrar of the Wellcome Trust, issued a statement expressing its deep concern about the and Seth Berkley of GAVI The Vaccine Alliance, argued Ebola epidemic and implored the international commu- that much more should have been done before this nity to provide prompt assistance to prevent the further outbreak, in terms of vaccine studies and vaccine approval spread of the virus [43]. protocols [61]. Funding for research and development of As of April 2015, there were 176 organizations operat- drugs and vaccines for diseases likely to cause future ing emergency programs in Guinea, Liberia, and Sierra epidemics, even though these are not the diseases that are Leone [59]. At this point, the total number of Ebola the most lucrative for drug companies, may be a key treatment unit beds exceeded the number of reported component of preventing future outbreaks [61]. Ebola patients and there were enough burial teams in place to ensure safe and dignified burials for all deaths Conclusions: what we have learned due to Ebola [59]. However, due to uneven distribution The 2014 Ebola epidemic in West Africa highlighted of these resources and the continued fear and suspicion major deficiencies in the ability of the international of Ebola treatment hospitals and burial teams in local public health and scientific communities to respond to communities, many patients were still going without infectious disease emergencies. It also provided a stark treatment or safe burials, resulting in new infections. reminder of the consequences of not investing in the According to the UN task force, the epidemic response development of healthcare infrastructure in developing needs to be tailored to adapt to the wide geographic countries. The current system of drug and vaccine devel- spread of Ebola even as the outbreak diminishes [59]. opment favors the development of drugs and vaccines According to the WHO, this outbreak demonstrated for chronic diseases that primarily affect people in the the severe lack of international capacity to respond to developed world, rather than diseases likely to cause public health crises [23]. It has been estimated that more epidemics. According to Currie et al. [62], the develop- than 30,000 children were orphaned by this epidemic ment of a mechanism for international cooperation in [23]. Access to routine healthcare has also been severely vaccine development and licensing is an urgent priority. effected by the outbreak, resulting in increased mortality The first step in preventing or minimizing future epi- from common and chronic illnesses [59]. One year after demics is to create an effective global monitoring system the official declaration of the 2014 Ebola epidemic, MSF for newly emerging pathogens. This relies on improving released a report critiquing the lack of international healthcare infrastructure around the world, resulting in a engagement with the epidemic response [52], specific- network of healthcare professionals who could serve as an ally, MSF president Dr. Joanne Liu who pointed out that early warning system for disease outbreaks. It is important the lack of international political motivation to intervene that knowledge from a variety of disciplines is employed in West Africa ended in July 2014 when the first case of to create a multifaceted approach to future outbreaks [62]. Ebola was diagnosed outside of Africa [52]. It was only Another important facet of the global response to disease at this time that the outbreak could no longer be seen as outbreaks is the rapid mobilization of personnel and a humanitarian crisis affecting a few poor countries in resources. Thirdly, the Ebola outbreak has demonstrated Africa, but instead began to be viewed as an inter- the risk that international mobility and air travel poses to national security threat to developed countries. This infection control, including the panic that can ensue when report by MSF also concluded that the interconnected- infected people move across international borders. The ness of the modern world means that world leaders can role of mobility and the importance of allocating resources no longer ignore health crises in distant countries [52]. to understand transmission and epidemiological risk has As a result of this epidemic, several influential edito- been underscored during the recent Zika virus outbreak, rials have called for renewed attention to international in part because of its previously unknown symptoms and public health issues. Bill Gates commented that the transmission dynamics (reviewed in [63]) problem was less that the current system did not work Ultimately the 2014 Ebola epidemic has shown that infec- well enough, but more that a system barely existed at all tion control measures can fail and that there is a significant [60]. In his editorial published in the New York Times, risk from infectious disease worldwide. 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Journal

Globalization and HealthSpringer Journals

Published: Dec 1, 2016

Keywords: public health; development economics; social policy; quality of life research; epidemiology; health services research

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