Welcome to our website!

This site was made by a group of University of Edinburgh Medical students who studied this subject over 10 weeks as part of the SSC.From the outset, we would like to certify that this website is our own work, and that we have authorisation to use all content (e.g. figures / images) used in this website. Our tutors for the duration of the project were Laura Butler, Harriet Talbot and Hannah Ramsay.

The project we chose asks the question: “Ebola: what makes it so dangerous?”

In order to answer this, we had four key aims to address:

How did Ebola come about?

How does it spread?

How does it affect its victims?

Is there a cure?

Our website contains several sections that reflect our aims, comprising of:

1. Epidemiology – overview of all outbreaks of Ebola, both past and present.

2. Pathophysiology – what Ebola is, how it affects its host and how it is transmitted.

3. Management - vaccines, drugs and therapies that may cure Ebola.

4. Ebola in the west – how far will Ebola spread, what global measures are being taken to halt its spread, when might it disappear?

Having claimed more than 4,800 lives, it is apparent that the spread and severity of Ebola has been underestimated. It will take a global effort to stop this disease in its tracks, and we believe that our project shows hope in this. Please use the links at the top of the page to navigate through our sections.

A hand-drawn image detailing Ebola's presence in Africa:Ebola drawing

Total Word Count = 10540Word count minus appendices = 5981

Epidemiology

Ebola has been around for a long time, with the first known outbreaks taking place in 1976, occurring almost simultaneously in Sudan and the Democratic Republic of Congo (formerly Zaire). As documented in the Lancet in 19771, it was differentiated from Marburg virus (a similar virus causing acute haemorrhagic fever) by indirect immunofluorescence. It was given the name Ebola in reference to a river in the Democratic Republic of Congo, near to where the first examined sample of Ebola virus was collected.

The Sudanese outbreak is well documented in a report by the WHO2. The paper states that 284 cases of the virus were recorded in this outbreak, with a mortality rate of 53%. It describes the initial objectives of the WHO team brought in to help control the virus, which included finding out the means of transmission within humans and the collection of blood from infected individuals for testing and potential treatment of further cases. The Zaire strain of Ebola appeared towards the end of 1976, affecting 318 and killing 2803. At that time it was assumed that the Zaire and Sudan strains were the same, but it was recognised that the illness caused by the Zaire ebolavirus had “fewer respiratory symptoms, a shorter clinical course, and a higher fatality rate.3” A study documented in The Journal of Infectious Diseases details some of the first tests carried out to prove the existence of two strains. The Zaire strain was much easier to isolate in cell culture, and had a much greater infectivity and potency among suckling mice, thus providing substantial proof of difference in strains4.

Following these initial outbreaks, Ebola haemorrhagic fever in humans remained virtually non-existent for approximately 15 years. Another strain was identified however in a group of imported monkeys in Virginia in 1989, providing scientists with evidence that monkeys were a potential reservoir of the infection5. Ebola re-emerged from its perceived dormant period between 1994 and 1997, resulting in a total of 5 outbreaks; three in Gabon, one in the Democratic Republic of Congo, and one in the Ivory Coast. The latter was where the Côte d’Ivoire subtype was first encountered. The experiences of the first individual infected are well documented in a Case Report by The Journal of Infectious Diseases, which includes the clinical course of the disease and treatment/interventions provided6. The paper raises the point that it is difficult to identify and successfully diagnose a new tropical disease such as this strain of ebolavirus, due to the similarity of its symptoms with malaria and other diseases. It also highlighted the need for improved national surveillance and laboratory testing around the world to aid with early identification of new disease outbreaks/epidemics6.

The Kikwit epidemic of 1995 provided scientists with the first real chance to study an outbreak of ebolavirus as it progressed7. International teams recognised the important role of close contact in the passing on of infection, citing exchange of bodily fluids by various means and the touching of cadavers as two important risk areas for transmission7. Investigations at this time failed to reveal the ‘true reservoir’ for ebolavirus, but there was encouraging work done with regard to the production of experimental filovirus vaccines7. Perhaps most intriguingly of all, this paper comments on the challenges faced by local health systems during the epidemic. Despite massive aid effort and training of sufficient healthcare staff during the epidemic, much of the aid had dried up within 3 months of its conclusion, along with a reversion to old techniques by healthcare workers. Perhaps later outbreaks were made worse by a lack of training and resources. Outbreaks of significance post 1995 include the discovery of the Bundibugyo ebolavirus strain in Uganda in 20078, and the current outbreak, which was declared a Public Health Emergency of International Concern in August 2014 by the World Health Organisation.9

A map showing all outbreaks of Ebola prior to 2008

Taken from: http://en.wikipedia.org/wiki/Ebola_virus_disease…Copyright: http://commons.wikimedia.org/wiki/File:EbolaSubmit2.pngDate accessed: 24/11/14

Knowledge gained from previous outbreaks may prove useful in influencing the management of the current outbreak. Previous outbreaks have been stopped by minimising the ability of the virus to be transmitted, along with the early identification and isolation of patients that present with symptoms of the disease.10 What is most discerning currently is that whilst this knowledge exists on how to stop Ebola, the outbreak has surpassed all previous outbreaks in terms of distribution and mortality, and this is set to continue. 11 It has been estimated that the reproductive rate of the current Ebola outbreak lies between 1.34 and 3.65, which is consistent with values calculated for past outbreaks.12 Values above 1 suggest that the virus has the ability to infect significant proportions of the population if sufficient interventions are not in place.12 The results of such calculations need to be interpreted with caution, as the transmission rate of Ebola decreases exponentially when control measures are implemented.13 However, bearing this in mind, why is the prevalence of the current outbreak so much higher than previous outbreaks? It has been noted that there was an underestimation of severity, with countries at the source perpetuating the outbreak through ineffective health-infrastructures.10 There is also an apparent weakness in the ability of the international community to counteract such a fast spreading disease.

The improvement of health infrastructure in the worst affected countries is one way in which the tide of the current outbreak can be stemmed, and future outbreaks prevented. It is argued that the

costs of doing this would garner considerable benefit in terms of initiating an effective response, which would far outweigh the social and economic impact Ebola is currently having.11 However, many questions remain unanswered with regards to Ebola, such as its reservoir, pathology and the three dimensional structure of the virus. Nonetheless, with an average of 1.49 years between outbreaks, it appears Ebola is here to stay.12

References: http://studentblogs.med.ed.ac.uk/2014-ssc2a-c3/?p=14

Pathophysiology

BackgroundAs previously discussed in the 'Epidemiology' section, the Ebola virus (EBOV), formerly the ‘Zaire’ ebolavirus after where it was first discovered, is the most deadly of the five named virus species that fall into the genus Ebolavirus1. The five species of the Ebolavirus are: Zaire ebolavirus, Sudan ebolavirus, Reston ebolavirus, Côte d’Ivoire ebolavirus, and Bundibugyo ebolavirus2. These belong to the family Filoviridae, and order Mononegavirales3.

EBOV is the single member of the species Zaire ebolavirus. It is the most understood and researched virus of the five, due to its large outbreaks throughout Sub-Saharan Africa. With a case fatality rate of 78%4, there has been much study of its pathological effect on humans, with particular interest on ‘ebola haemorrhagic fever’ (EHF), which usually leads to the death of those infected.

Clinical ManifestationsThe Ebola virus has an incubation period of 2-21 days (mean of 4-10) 5, with an average time of death at 10.2 days after onset of symptoms6. Early symptoms of EHF include: fever, myalgia, vomiting, diarrhea, and abdominal pain. These symptoms are often accompanied by mild hypotension, postural hypotension, vasodilatation of the conjunctivae, and flushing of the skin7.

As the fever progresses, vascular damage and capillary leakage gives rise to nondependent oedema and large effusions into body cavities, such as the pleural and peritoneal cavities8. In the terminal state, the patient appears obtunded and begins to enter shock. Late symptoms of shock include tachypnea, aneuria, and normal/subnormal body temperature. In 41% of patients in terminal state EHF, there are haemorrhagic manifestations9. Haemorrhagic observations include conjunctiva bleeding, petechial rash (bleeding into the skin); epistaxis (nose bleed), haematemesis (vomiting of blood) and melena (dark/black faeces)9.

Overall, general manifestations of EHF include rapid and abrupt onset of symptoms, shock, fluid redistribution, disseminated intravascular coagulation (DIC) and absence of an antibody response to the virus12.

Attached is our hand-drawn diagram of the clinical manifestations.Symptoms of Ebola drawing

Transmission, Target and PathogenesisAt symptom onset, the measured titre of Ebola virus RNA in the blood increases logarithmically10. This RNA is present in bodily fluids and varies by fluid type. Across a variety of studies Ebola virus RNA has been detected up to 101 days after symptom onset in semen, 33 days from vaginal swabs, 29 days from rectal, 23 days from urine, 22 days from conjunctival swabs, 21 days in blood, 15 days

in breast milk, 8 days in saliva, and 6 days on skin10. However, these studies were conducted with a minimal number of subjects so it is possible that Ebola RNA could be present in these fluids for longer than the times specified above.

Ebola RNA is spread through direct contact with infected individuals. This can be with that individual themselves, their bodily fluids or their dead body. Once contact has been established the Ebola virus RNA enters the body via mucosal surfaces or injured skin, then by haematogenous (blood) and lymphatic spread it infects macrophages/monocytes and dendritic cells (immune cells) in nearly every organ of the body11.

Infection of monocytes triggers a secretion of pro-inflammatory cytokines (IL-1B, TNF-a, IL-6) and chemokines (IL-8, GRO-a), chemical mediators involved in co-ordinating an immune response. Particularly important are the inflammatory mediators TNF-a, IL-6, and GRO-a, that cause endothelial reorganization when released by virally-infected macrophages. This restructuring creates inter-endothelial gaps, increasing endothelial permeability and causing oedema12. Other inflammatory mediators trigger coagulation cascades in the blood that lead to various problems, including DIC.

SurvivalSurvival of Ebola virus infection is associated with three factors: a) an antibody response against the virus; b) cell-mediated immunity to the viral GP (glycoprotein) antigen; and c) clearance by CD8 T cells13.

Fatal outcomes often involve rapid infection and apoptosis of macrophages and dendritic cells, releasing toxically high concentrations of pro-inflammatory cytokines and chemokines. This loss of key immune cells, essential in controlling and guiding the immune response, lead to impaired T cell priming and proliferation. T cells are vital for both eliciting an antibody response from B-cells (helper CD4 T cells), and targeting and killing infected cells (cytotoxic CD8 T cells) 13.

Overall, without adequate priming and production of T cells and rapid eradication of the virus, no immunity ensuring survival can be produced.

References: http://studentblogs.med.ed.ac.uk/2014-ssc2a-c3/?p=14

Management

There are two main approaches to the management of Ebola - medical treatments and prevention. At present there are a limited number of options, but several have shown promise in the early stages.

Medical TreatmentsOne potential avenue for treatment of Ebola patients is ZMapp. ZMapp is a mixture of three distinct monoclonal antibodies which recognise the Ebolavirus antigen1, thus helping to kill the virus. The drug has been used during the recent outbreak in a number of cases, showing promise where it has been used, and has potentially helped save the lives of 2 American aid workers and one British nurse who all contracted Ebola and survived after using ZMapp2-4. However, an African doctor who was treated with the same drug later died2, as did a Spanish priest5. No trials have actually been

conducted to see whether ZMapp is an effective treatment in humans1 and it is still classed as an experimental treatment.

Although no human trials have been undertaken using ZMapp, there have been several studies conducted on animals to test its use for treating Ebola. One such trial by Olinger et al. showed that using ZMapp could provide protection for Rhesus Macaques infected with Ebolavirus, even when administered 48 hours after infection.6 It showed that 10 out of 13 infected animals survived when given treatment, compared with only 1 in 5 controls. However, the study had a very small sample size and the data was collected over three separate experiments over different time periods, meaning they may not have all had the same conditions. The paper is also not clear on how the animals for the study were selected, indicating a potential source of bias.

Following on from this trial, Qiu et al. showed that ZMapp can be used to cure Rhesus Macaques of Ebola, even when given up to 5 days post infection.7 18 macaques who were injected with the Ebola virus survived after being given doses of ZMapp 3 days apart, with some not receiving it until 5 days post infection.7 The sample size for this study is larger than that of the first study, and this trial follows and builds on this work, showing that ZMapp can be successful when administered up to 5 days after catching Ebola in macaques, further to the 48 hours determined by Olinger et al. However, the small number of controls means that the untreated animals are not representative of the full picture - had more controls been used it is likely some would have survived naturally, leading to a different mortality rate than that found in the trial.

The existing literature on ZMapp is scarce, and as no research has been done on humans, we cannot say for certain that it will be a good drug to treat Ebola in humans. The studies discussed show very promising signs and certainly indicate it could be an effective treatment. However, the fact that the studies were conducted on macaques, coupled with the small sample sizes, mean that no cast iron conclusions about human use of Zmapp can be drawn, and further research will be needed to fully prove its effectiveness.

Another treatment area which has been explored is the possibility of giving blood transfusions from patients who have had Ebola and survived, thus transferring the antibodies they produced in fighting it8. During the 1995 Ebola outbreak in the Democratic Republic of Congo, a study was conducted in which 8 Ebola sufferers were treated using transfusions from recovering patients9. They found that it was an effective treatment, with the mortality rate for those treated being 12.5%, much lower than the mortality rate for the whole outbreak, which was around 80%9. However, each patient was also given lots of other treatment (antibiotics and supportive care for example) as well as ZMapp, so it is impossible to tell what really made the difference. This, along with the very small sample size and potential for biased selection of patients (it was not made clear how this was decided) mean that this may not be an accurate reflection of the effectiveness of the treatment.

Blood transfusions have been utilised during the current outbreak, with some success10,11, having been named by the WHO as the best potential method for treatment currently12. Whether it will prove effective on the large scale remains to be seen – the current research shows promising signs but is not enough to say for definite that it will be. Large scale clinical trials will be needed to show beyond doubt that it is a good technique to use, and we will no doubt come to learn over the coming months of its clinical effectiveness.

PreventionA slightly different approach to treating Ebola is to prevent it through the production and distribution of a vaccine. At present, there is no approved vaccine for Ebola, however there has been substantial activity regarding the development of one. A study showed that giving a recombinant vaccination containing a respiratory pathogen and the Zaire strain Ebola virus (EBOV) to rhesus monkeys protected 88% of the animals against severe hemorrhagic fever and death caused by EBOV13. However, the HPIV3 vector is too common a human pathogen, and the widespread seroprevalence to this virus in adults would decrease its effect. DNA vaccines expressing the envelope glycoprotein (GP) or nucleocapsid protein (NP) genes of Ebola virus were also evaluated in adult immunocompetent mice - 78% survival of subjects was achieved after four vaccinations14. The GP and NP vaccines when compared showed that approximately the same level of protection could be achieved with either vaccine14. However a major limitation of the study was that only female mice were used, as the safety and immunogenicity must be confirmed in males too.

There is evidence of vaccines that have a safe and immunogenic effect on humans, but the sample sizes in these clinical trials have been small15,16. More testing is required to remove the element of chance, but the results are helpful in the vaccine’s development as randomisation and double-blinding removed a lot of possible bias. Martin, J.E. et al.’s clinical trial in 2006 stated that more work must be done on replication-defective adenoviral vector vaccines15. This was studied and proved to be safe and immunogenic by Ledgerwood, J.E. et al. in 2010, but additional non-human primate and human studies must be conducted in order to find a vaccine suitable for broader populations16, as the population sample in this study was mainly healthy caucasian adults.

Trials are now underway in Oxford with 60 volunteers being injected with a vaccine containing a small portion of genetic material from the virus - it will not trigger disease but will prompt the production of anti-EBOV antibodies17. The vaccine is being developed by GlaxoSmithKline and the US National Institutes of Health, and is being fast tracked so that it could hopefully be used to immunise health workers in affected areas by the end of 2014.17

There are several reasons as to why treating Ebola virus is so difficult. One barrier is the lack of capacity in treatment facilities, containment methods and diagnostic tools18. The recent surge in cases has stretched resources and hospital beds are filling up. There have been facilities in West Africa where one physician was responsible for 30 to 50 moderately to severely ill Ebola patients19. With no vaccine currently available, other effective prevention methods must be implemented.

The transmission of the Ebola virus also makes its treatment difficult, as it is highly contagious (although not airborne). Close contact with the bodily fluids of an infected person causes transmission, such as during health-care procedures, home care or traditional burial practices. In Guinea, approximately 60% of cases have been related to these burial practices, with women being most affected (as they are the principal care-givers there)18. There is also a high level of population mobility in West Africa, with people travelling between different villages, increasing the potential for spread20.

Fear may be another reason for treatment to be difficult. People may often refuse to accept their symptoms or diagnosis, as they do not want to deal with the consequences of being diagnosed with Ebola - this is similar to cancer patients in many Western societies20. Therefore, they do not consult a

doctor and remain undetected until their condition becomes severe enough to spread to others. Traditions can also cause people to seek herbal/homemade remedies rather than specialist help.

Picture showing proper infection protocol.

Taken from: http://en.wikipedia.org/wiki/Ebola_virus_diseaseCopyright: http://commons.wikimedia.org/wiki/File:VHFisolation.png Date accessed: 28/11/14

References: http://studentblogs.med.ed.ac.uk/2014-ssc2a-c3/?p=14

Ebola in the West

So far, it has been difficult to predict what threat the current Ebola virus (EBOV) poses to global health and security. Since its identification in 1976, EBOV outbreaks have been confined to areas in West Africa, with minimal exposure in the Western world. Papers written on Ebola before the current outbreak seem sceptical of its worldwide threat, naming it a “minor threat to global health”, and stating the disease to be “self-limiting”1, with the prevention of transmission being “in principle, straightforward.”2 However, this attitude is being questioned in the light of recent events, where

EBOV has managed to spread further than expected, overcoming supposedly fool-proof prevention methods.

UK PreventionSince the outbreak of EBOV in March 2014, high income countries (HIC) such as the UK and the USA have been bombarded with dramatic news stories such as ‘Ebola WILL reach Britain’3 and ‘SHOCKING: CDC Admits 100-150 People a Day Entering US from Ebola Infected Countries’4 - but is there any truth to this? Since the outbreak was declared a public health emergency on August 8th,5 the UK has been implementing a series of action plans and preventative measures to stop Ebola entering the country. How fool-proof these interventions are, however, is questionable when looking at the recent transmission in the USA despite precautionary measures.

One of the most recent UK measures is screening at airports and Eurostar stations for those from affected countries, costing around £9 million to implement.6 Although reassuring the public, this has been highly criticised by experts, goes against WHO advice and potentially creates a false sense of security.7 Flaws are also evident when looking at the recent USA cases: the questionnaires could be falsely filled in, as was the case with Thomas Duncan when he denied being exposed to EBOV on screening forms. Furthermore, the second nurse diagnosed with EBOV after treating Duncan was allowed to board a flight with a 37.5°C temperature due to it not reaching the 38°C guideline of the Centre for Disease and Control (CDC), further emphasising the screening test’s futility.8 Airport screening can also be very ineffective - in the 2003 SARS outbreak, airport screening failed to detect the only positive case, potentially because they screened before boarding the plane, which may be less effective than screening on arrival.9

Protocols are also being put in place by British hospitals to meet the state of “national preparedness” required by International Health Regulations5, with four main hospitals in the UK being “put on standby” in case of EBOV spread.10 London’s Royal Free Hospital has the most sophisticated isolation ward, successfully treating the repatriated British nurse who became infected in Sierra Leone. Workers throughout NHS hospitals are being sent guidance handouts for suspected cases, emphasising the need for a travel history of presenting patients and the need for every member of staff to familiarise themselves with the hospitals’ specific guidance.

As mentioned, the effectiveness of these measures in stopping the virus is questionable when looking into the recent spread of disease in the US, who seemingly followed similar protocol. On closer inspection of the treatment of Thomas Duncan and how the two nurses subsequently contracted the disease, it becomes clearer rigorous protocol may not have been followed, with medical records suggesting health workers had exposed skin and were not required to wear full body suits during initial treatment.8 This information needs to be interpreted with caution due to contrasting reports, and certain parties having reason to exaggerate mistakes made. Furthermore, there has been suggestion that the NHS would be more efficient at responding to EBOV than the USA’s private health care system; Britain’s preparation was recently described as “superb”, with the government’s access to all health workers through the NHS making communication much easier.7 In addition, there have been suggestions that the initial discharge of Thomas Duncan was due to his inability to pay - not a factor in the NHS – although again this does not come from official sources and needs to be treated with caution.11

Worldwide actionIn the USA, compulsory 21-day quarantine periods have been declared for any health worker or traveller who may have been exposed to the disease, following the positive diagnosis of Dr Craig Spencer after working in Guinea.12 Legal action is also being taken against those not adhering to quarantine periods; one nurse who defied her quarantine after returning home from a Sierra Leone MSF mission is now under questioning by the state government.13

Mauritania has recently closed its borders with Mali after a 2-year old recently succumbed to the disease in Mali.14 Countries identified to be high risk, including the two mentioned, have been told to make preparations in case they are subject to any cases.15-16

Joanne Liu, head of MSF, and Peter Piot, the identifier of Ebola, have both called for “quasi-military intervention”, believing it crucial in keeping the epidemic under control. Many troops have been provided from the US, UK and Germany.17 , with army medics being flown out to set up high-standard treatment centres for infected health workers. 18

WHO workers gear up to go into an Ebola isolation ward (Lagos, Nigeria)

Taken from: http://en.wikipedia.org/wiki/Ebola_virus_epidemic_in_West_Africa#mediaviewer/File:WHO_in_PPE.jpg Date accessed: 09/10/14Copyright: http://commons.wikimedia.org/wiki/File:WHO_in_PPE.jpg

Why are high income countries (HICs) helping to combat EBOV?There may be alternate motivations for HICs to fund Ebola research and patient care other than purely humanitarian reasons. Perhaps due to morality - the resources required are relatively small, and all HICs are able to help “curb the epidemic”.19 Another reason is research – originally much of the research on Ebola in the USA was due to a mixture of fear of spread and bioterrorism.19 The current outbreak requires new specifically targeted research, and HICs cannot carry out this research without also providing aid, as this could be seen as exploitation. There have also been some statements made suggesting that vaccines and treatments would probably already exist if Ebola

affected many people in HICs, as it would make “research financially attractive to drug companies”, with one man describing this as “the moral bankruptcy of capitalism”.20

More recently, HICs have increased incentive for trying to combat Ebola, with many healthcare workers from these countries becoming infected on top of the already high numbers.21

How did it achieve such devastation?An underestimation of the effects of Ebola may have damaged the initial response - the WHO did not launch their current ‘joint response plan’ until the end of July 2014, despite MSF and other organizations naming the outbreak “out of control” in June.20

As well as this, conditions in the affected countries are considerable factors as to why EBOV has achieved such devastation. Healthcare workers have had to deal with “numerous issues” including “weak health systems... few staff... little equipment” making surveillance and care almost impossible without outside help.20 Furthermore, the affected countries, among the poorest in the world, are having to steer their budget towards the Ebola epidemic, leading to treatment of other diseases being put aside. Recent estimates have shown that a good facility treating 70 patients requires a minimum of 250 health workers,21 an impossible feat in countries such as Sierra Leone whose have around 3 doctors to every 100,000 people.22 Moreover, decades of conflict have left residents distrustful of authority and restrictive guidelines,23 causing people to “escape surveillance systems, hide symptomatic family members and flee treatment centres.”21 Fear has made Ebola all the more dangerous.

References: http://studentblogs.med.ed.ac.uk/2014-ssc2a-c3/?p=14

Conclusion

Over the past ten weeks, our group tried to answer the question “Ebola: what makes it so dangerous?” To achieve this, we guided our research towards addressing the following questions:

How did Ebola come about?

How does it spread?

How does it affect its victims?

Is there a cure?

To show how we answered these questions we have summarised each of our sections, addressing their key findings.

EpidemiologyThis section covered the history of Ebola and its previous outbreaks, and how the responses seen may exacerbate Ebola’s lethality. As far back as the mid-90s it was recognised that improvement in national surveillance and laboratory testing around the world was needed to identify new outbreaks and epidemics - this did not happen. Another challenge faced by local health systems was a lack of training and resources - massive aid efforts and training during epidemics (particularly Kikwit 1995)

were ineffectual afterwards, as money dried up soon after the epidemic and healthcare staff reverted to old techniques. Perhaps the current crisis could have been avoided if the money and specialist training remained. With the benefit of hindsight it is clear there is weakness within the international community in combatting disease, with a need for increased cooperation between countries. Increased cooperation, as well as a greater understanding of the pathogen, will help us gain control over Ebola.

PathophysiologyOur research for this section made it apparent that loss of key immune cells and impairment to T cell priming and proliferation were the main causes of death in those infected by the Ebola virus. Several aspects of its pathophysiology explain its lethality. Firstly, the short time from onset of symptoms until death gives little time to identify, assess and successfully treat people with the disease. Secondly, the early symptoms that people present with are not indicative of Ebola infection, leading to late diagnosis of the disease. This allows infected individuals to continue to travel and interact with others. This illustrates why a vaccine is paramount – without prior immunity, prognosis is poor.

ManagementThis section discussed the different treatment and preventative measures currently being explored to tackle Ebola. ZMapp was discussed - trials carried out on rhesus macaques (small sample sizes) produced relatively high levels of success. Despite this, the literature available on ZMapp is scarce. Thus, with no human trials, we cannot conclude whether it would be an effective treatment method. Next, blood transfusions were explored. They have been touted as the best potential method of treatment by the WHO, however, only small scale trials using them have so far been performed. Therefore, we are not yet able to conclude whether they will be a useful form of treatment in the long run.

Vaccines have already shown promising results in preliminary tests. Animal trials have shown potential in this area, and a number of human clinical trials have already taken place. However, they were once again carried out on small sample sizes not representative of the broader population. Vaccines containing a small amount of genetic material have however shown particular promise, prompting the development of one such vaccine by GSK and the US National Institutes of Health. They hope to roll it out to health workers in affected areas by the end of 2014.

It is clear that prevention is better than cure. Avoiding exposure to bodily fluids of those infected is the best method of prevention. Risk of exposure increases during healthcare procedures, home care, travel between villages (West Africa has high levels of population mobility) and burial practices. Interestingly, 60% of cases in Guinea have been related to burial practice alone. These aspects need to be targets for improving prevention; however ending these habits will prove difficult.

Ebola in the WestOur research into whether Ebola could become a threat in more developed countries showed many countering arguments, from newspaper articles pronouncing international spread of the disease to

research papers dismissing the possibility of it arriving. We concluded that because high-income countries have fewer risk factors for the spread of Ebola, i.e. weak health systems and unsafe burial practices, the disease would not become an epidemic to the same extent as in West Africa. Despite this, our protocol and prevention guidelines are not fool proof - one off cases leading to small outbreaks are a possibility.

Overall ConclusionsSo – what makes Ebola so dangerous? It is, in reality, a combination of several factors, all of which have been discussed in this website. A major component is the disease itself: its severity, easy mode of transmission and the lack of treatment options available. But perhaps the main reason EBOV has become so widespread is the environment in which it has multiplied in – the poor health infrastructure, distrust of health systems and government and lack of trained staff and funding. It has been suggested that Ebola will soon become part of daily life in West Africa, but we can only hope that the efforts of the WHO, MSF and the international community will be enough to curb this epidemic.

An image to show global spread of Ebola.

Taken from: http://en.wikipedia.org/wiki/Ebola_virus_epidemic_in_West_Africa#mediaviewer/File:Map_of_Ebola_Outbreak_-_1_October_2014.svgDate Accessed: 28/11/2014Copyright: http://commons.wikimedia.org/wiki/File:Map_of_Ebola_Outbreak_-_1_October_2014.svg

Reflections on the ProjectBefore we began the project, we set out clear objectives that we wanted to achieve. These were:

To learn about the recent outbreaks of Ebola

To learn how to carry out and present a critical appraisal

To improve team working skills

To improve our researching ability

To learn how to put together a comprehensive website

To get an idea of what Ebola might be like in the western world

To improve knowledge and understanding of statistical tests

To improve confidence of working in a group setting

In order to fulfill our first objective, we divided our research into focused areas (i.e. pathophysiology and transmission), allowing us to explore all aspects of the disease in detail. This exposes not just a single reason why Ebola is such a threat, but many. Additionally, when we shared our findings together, we gained a more holistic understanding of the topics we researched.

Furthermore, the experience of having to present our own critical appraisal was daunting, but it gave us valuable experience in being sceptical of our research later in the project. It taught us a range of skills: using a critical eye on research papers’ claims and findings; adopting a careful and methodical research approach to finding papers; understanding statistical tests; extracting strengths and weaknesses from papers; and ultimately weighing up whether a paper was valid and useful. As a result, we feel that we have fulfilled the second, fourth, seventh and eighth objectives.

Moreover, from working in sub-teams in our research, to intertwining all the sections together for the website, teamwork was vital. Knowledge of each section was shared among the group, giving a common understanding for discussions and decision-making. Therefore as the project progressed we achieved our third objective.

Before SSC2a, the majority of our group had had no experience with designing, creating or using their own website. However those who had experience of this shared their expertise with the rest of us, and we now feel confident that we have gained this invaluable skill, fulfilling the fifth objective.

Finally, although it was not one of our specified aims, the group was intrigued by what effect the Ebola outbreak could have outside of West Africa. This was critically relevant for the current crisis, particularly with regard to international aid. Consequently we made one of our research sections encompass this topic (‘Ebola in the West’), thus fulfilling our sixth objective.

Final WordThank you for taking the time to read over our website, we hope it has been an informative experience for you. Find below a list of links directing you to additional areas of our website.

Group Critical Appraisal:http://studentblogs.med.ed.ac.uk/2014-ssc2a-c3/?p=10

Contributions:http://studentblogs.med.ed.ac.uk/2014-ssc2a-c3/?p=8

Information Search Report: http://studentblogs.med.ed.ac.uk/2014-ssc2a-c3/?p=12

Word Version:http://studentblogs.med.ed.ac.uk/2014-ssc2a-c3/?p=6

Weekly Diary

The following page details our groups week to week activities relating to our SSC2a project on Ebola.

Week 1

The group met up for the first time, all were introduced to one another including our tutors.

We discussed the SSC2a handbook and related to our project in order to define what our goals should be.

We discussed the "Critical Appraisal" section in great detail and decided that, each week, 2 members of our team would perform an individual appraisal on an Ebola related journal article of their choice.

We discussed basic statistical tests related to epidemiology and set out the task of researching these tests in order to better understand our individual critical appraisals.

We set out a task to decide what topics to include within our project.

Week 2

We discussed and finalised our research topics for the project and split them amongst the team members. The topics decided were: Treatment, Epidemiology, Pathophysiology and Ebola vs the Western World.

Set 2 individuals to each tackle a topic. This was split as follows: Treatment: Pavel and Greg, Epidemiology: William and Henry, Pathophysiology: Timothy and John, Ebola vs the Western World (Genevieve and Ailsa).

We decided that only one person should be responsible for the website, John was nominated for website upkeep.

We decided that in addition to our weekly meeting with our tutors we would meet up again but only with our partners for our respective section.

Discussed the Ethical Assessment form, decided it was to be completed for next week.

Timothy and Genevieve performed their critical appraisals.

Week 3

We finalised and submitted our ethical assessment form.

We discussed the recent outbreaks of Ebola (Dallas and Madrid) decided to set a week 4 limit on inclusion of any new data or article.

Discussed the sections we set out in previous week, tasked to think about a word limit for our own sections in relation to the 6,000 word overall limit.

Everyone tasked to research their own task and bring forth a summary of it at the next meeting.

John and Ailsa performed their critical appraisals.

Week 4

Discussed and summarised each of our individual research sections. Set a deadline of 04/11 for finishing our sections.

Set word limits for each section these are as follows: pathophysiology (1000), epidemiology (1000), treatment (1500), Ebola vs the west (1000).

We decided to leave 1500 words for our introduction and conclusion. These limits are movable and are not set in stone.

We set meetings with our section partners for the coming week to encourage continued progress.

Henry and William performed their critical appraisals.

Week 5

There was no meeting in Week 5. Each pair spent this week working on their own sections in order to have it finished for 04/11 - week 6.

Week 6

The team brought together all of their finished individual sections. The group discussed the word counts of each respective section and compared them to our initial word target.

Some groups were over their word count and others were under, no cutting needed to be done as overall we were only just over our set word.

We read over everyone's section to check for potential errors and proper referencing.

The group came together on the group critical appraisal, writing up and uploading it.

The group discussed what still needed to be done with regards to the website and set targets for week 7.

Week 7

The group met up - with all sections finished - and edited the website.

The group set the few remaining tasks to be completed: Website (John), Information Search Report (Greg and Pavel), Introduction (Timothy), Conclusion (Will, Henry. Genevieve and Ailsa)

With the final tasks set, the team set a deadline of next Tuesday for having all of these tasks finished: where we should be able to give the final touches to the website.

Week 8

The final tasks have now been completed, the next two weeks will likely have no meetings and will be spent improving layout of the site.

We have a final task of finding one image to add into our relevant sections.

Week 9

Everyone has found their relevant images and they have been added to the completed website.

Week 10

Website is complete!

Here are our scanned ethical forms:Ethical form (page 1)Ethical form (page 2)Ethical form (page 3)

Critical Appraisal

"Treatment of Ebola Haemorrhagic Fever with Blood Transfusions from Convalescent Patients"

The aims of this study were to determine whether a blood transfusion from a convalescent patient can be used to treat patients with Ebola effectively. Another objective was to determine whether the death rate is reduced when this measure is taken. The study was carried out during the 1995 Ebola outbreak in Kikwit, Democratic Republic of Congo. Eight female patients, with Ebola, between the ages of 12 and 54 were treated with blood from five male convalescent patients.

The study was a small scale clinical trial, conducted to assess a new area of treatment during an outbreak. The small sample size may reflect the lack of blood available. There were no controls – the intervention was simply given to 8 patients and their outcomes assessed. The intervention was simply a blood transfusion from a convalescent patient – the blood contained no Ebola antigen, but contained IgG and IgM Ebola antibodies. This was determined using ELISA testing, which is an accurate test. There was no randomisation or blinding in the trial, but given the nature of it, this wasn’t really appropriate anyway.

The outcome measure was to see whether the patients treated with the transfusions survived. As this is a very simple measure, no statistical tests were used to analyse results. As there were no

controls, the fatality rate for the treated patients (found to be 12.5% - 7 out of 8 patients survived) was compared with the rate for the whole outbreak. This was around 80%, so overall the study found that patients who received the intervention had significantly better outcomes.

There are several potential sources of bias in the study. The patients who received transfusions were all ill towards the end of the outbreak, and by this stage, the general care for Ebola patients had improved, excluding the blood transfusions. Healthcare workers had better knowledge and practiced methods, and had access to antibiotics and antimalarial drugs. This means that patients who were ill towards the outbreak would have been more likely to recover anyway, and the study population’s survival may not be down to the transfusions. It is also not clear in the paper how the eight patients were selected. This may mean that the organisers could have chosen patients who were more likely to get better anyway, patients with milder symptoms for example, leading to a misrepresentation of the intervention’s effectiveness.

This study addresses the aims and objectives well, and uses appropriate methods to work towards a conclusion. It has a small sample size however, which means we can’t say for certain whether the method will work on a large scale. Additionally, in the discussion, the paper refers to other patients out with the study who received transfusions with much less success, many of them dying. This indicates that the method may not be as effective as the study results indicate.

We also can’t say which aspect of the transfusion made the difference: antibodies against Ebola is the most likely reason, but it could also be that transfused blood contained more clotting factors to help stem bleeding, or that the blood transfusion was effective for prevention of shock

The initial signs from this study are good, showing that treating patients with blood transfusions is successful. However, further research will be needed to test this further and ascertain that it is an effective measure. Limitations with study mean that we can’t take this as cast iron evidence that it is an effective treatment, and while opening up areas for further research, it has not definitely concluded anything.

Contributions

Pavel Sharma co-wrote the “Treatment” section, with particular research emphasis on vaccinations. He was responsible for compiling the weekly minutes, and formatting the references.

John Henderson co-wrote the “Pathophysiology” section, with a particular focus on transmission. He was responsible for co-ordinating the website, and was the main line of communication with the course organisers when faults in the website technology were noted.

Greg Swan co-wrote the “Treatment” section, looking closely at non-vaccinating treatments. The paper he looked at for his individual critical appraisal was chosen unanimously by the group for our group critical appraisal. He helped educate the group about it so that everyone could contribute towards the finalised appraisal.

Genevieve McMahon initially suggested the idea of doing an “Ebola in the West” section - and consequently co-authored it. She looked at how the West is trying to protect itself from the threat of Ebola. She also helped write the conclusion.

William Rea co-authored the “Epidemiology” section, and analysed the other sections to create “mini-summaries” which were used to write the conclusion.

Timothy Brook co-wrote the section on “Pathophysiology and Transmission” - primarily focussing on pathophysiology. He also wrote the introduction and helped refine the final conclusion.

Ailsa Campbell co-wrote the “Ebola in the West” section - looking particularly at how Western countries are intervening in West Africa to control the spread of Ebola. She wrote the reflections and redrafted the “mini summaries” to form the conclusion. She also created the hand-drawn cartoons.

Henry Millar co-authored the “Epidemiology” section, and worked to streamline the final website to eliminate repetition and promote flow. He assisted William in writing the “mini-summaries”, and found several images for the website.

All group members were involved with the proof-reading and final formatting of the website.

Information Search Report

As a group, we looked at our aims and discussed different aspects of the topic that we wished to include in our report. We amassed our current knowledge on these areas and identified areas where further research was required. We got an overview of the topic through internet searches and reading current news articles due to the topicality of the subject. Each group then was able to identify areas within their section that were of the most importance.

We used various resources to search for information. Medline, PubMed and Google Scholar were identified as possible ways to access primary resources such as clinical trials and original research papers. We also used news articles and journal articles due to the topic of research being current - websites included BBC News and nature.co.uk.

For PubMed and Google we used keywords with Boolean operators to narrow down the search and find appropriate articles (eg ‘Ebola AND treatment’). When using Medline, our search strategy included using an advanced search, combining umbrella terms and then limiting it to only display what we were interested in. For example, when searching for clinical trials on Ebola vaccines our search terms were ‘Ebola Vaccines’ and ‘Hemorrhagic Fever, Ebola’ which were then exploded. We combined these using an AND operator and limited the results to ‘Clinical Trials, All’. This resulted in 3 articles which were of high value.

When locating full text journal articles, we were able to use various journals (such as Nature) that the university network had access to. Overall, a comprehensive and up-to-date pool of information was obtained through primary resources (e.g. clinical trials, observational studies, case reports etc.) and also recent news and journal articles and expert opinions.

Word Version

Please find our word version for this project below:Ebola SSC word version

References

Header Image

http://en.wikipedia.org/wiki/Ebolavirus#mediaviewer/File:Ebola_virus_virion.jpg Date accessed: 29/11/2014. Copyright: http://commons.wikimedia.org/wiki/File:Ebola_virus_virion.jpg

The following list contains each of the references sorted by their relevant section.

Epidemiology

1. Johnson KM, Lange JV, Webb PA, Murphy FA. Isolation and partial characterisation of a new virus causing acute haemorrhagic fever in Zaire. The Lancet 1977; 309(8011): 569-571. (Primary Research Article)

2. World Health Organisation. Ebola haemorrhagic fever in Sudan, 1976. Bulletin of the World Health Organization 1978; 56(2): 247-270. (Case Report)

3. World Health Organisation. Ebola haemorrhagic fever in Zaire, 1976. Bulletin of the World Health Organization 1978; 56(2): 247-270. (Case Report)

4. McCormick JB, Bauer SP, Elliott LH, Webb PA, Johnson KM. Biologic differences between strains of Ebola virus from Zaire and Sudan. Journal of Infectious Diseases 1983; 147(2): 264-267. (Primary Research Article)

5. Jahrling PB, Geisbert TW, Johnson ED, Peters CJ, Dalgard DW, Hall WC. Preliminary report: isolation of Ebola virus from monkeys imported to USA. The Lancet 1990; 335(8688), 502-505. (Case Report)

6. Formenty P, Hatz C, Le Guenno B, Stoll A, Rogenmoser P, Widmer A. Human infection due to Ebola virus, subtype Cote d'Ivoire: clinical and biologic presentation. Journal of Infectious Diseases 1999; 179(Supplement 1), S48-S53. (Case Report)

This paper documents the clinical course of Ebola in an infected individual in great detail. It records the symptoms experienced by the patient on each particular day, as well as any interventions used and the results of physical and laboratory tests. However, the report only comments on one patient with Ebola, and so their reaction to the virus may not be indicative of the response of others to the virus.

7. Peters CJ, Peters JW. An introduction to Ebola: the virus and the disease. Journal of Infectious Diseases 1999; 179(Supplement 1), ix-xvi. (Review Article)

This review article comments on the history of Ebola virus up until the Kikwit outbreak, which it covers in great detail. It tells of the exploits of teams of scientists in searching for the routes of transmission, potential reservoirs and sources of therapy/prevention. It also provides an interesting commentary on the struggles of local health systems to contain the outbreak.

8. Towner, JS et al. Newly discovered ebola virus associated with hemorrhagic fever outbreak in Uganda. PLoS pathogens 2008; 4(11), e1000212. (Primary Research Article)

9. Public Health England. Information for healthcare workers: Ebola in pregnancy 18 October 2014 Available: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/365184/20141020_PHE_Information_on_Ebola_in_pregnancy_V1_0_2.pdf Date accessed: 30/10/2014 (Information leaflet)

10. Ebola Editorial: Ebola: Time To Act 9 September 2014 Available: http://www.nature.com/news/ebola-time-to-act-1.15878 Accessed: 30/10/2014 (Review article)

11. World Health Organisation. Ebola response roadmap situation report. 31/10/2014 Available: http://apps.who.int/iris/bitstream/10665/137424/1/roadmapsitrep_31Oct2014_eng.pdf?ua=1 Accessed: 01/11/2014 (Online WHO article)

12. House T. Epidemiological outbreaks of Ebola outbreaks. Jha P, editor 2014, 2014-10-17, 13:04:42. (review article)

13. Althaus CL. Estimating the Reproduction Number of Ebola Virus (EBOV) During the 2014 Outbreak in West Africa. PLOS Currents Outbreaks. 2014 Sep 2. Edition 1. doi: 10.1371/currents.outbreaks.91afb5e0f279e7f29e7056095255b288. (review article)

Pathophysiology

1. Who.int. WHO | Ebola virus disease [Internet]. 2014 [cited 23 October 2014]. Available from: http://www.who.int/mediacentre/factsheets/fs103/en/ (Secondary source: online WHO article)

2. Kuhn J, Becker S, Ebihara H, Geisbert T, Johnson K, Kawaoka Y et al. Proposal for a revised taxonomy of the family Filoviridae: classification, names of taxa and viruses, and virus abbreviations. Archives of virology. 2010;155(12):2. (Secondary source: online PubMed Central journal)

This journal provided extensive research about virus taxonomy.

It was recent in its publication and cited many articles that further guided my research.

A weakness was its specificity with regard to the Ebola virus, as many other viruses were discussed in the paper.

3. Kuhn J, Becker S, Ebihara H, Geisbert T, Johnson K, Kawaoka Y et al. Proposal for a revised taxonomy of the family Filoviridae: classification, names of taxa and viruses, and virus abbreviations. Archives of virology. 2010;155(12):5. (Secondary source: online PubMed Central journal)

4. Paessler S, Walker D. Pathogenesis of the viral hemorrhagic fevers. Annual Review of Pathology: Mechanisms of Disease. 2013;8:413. (Secondary source: online Annual Reviews journal)

This was the most useful paper in my research. It provided a comprehensive review on current research regarding viral haemorrhagic fevers.

It cited numerous original research articles, which were also useful for my review.

5. Feldmann H, Geisbert T. Ebola haemorrhagic fever. The Lancet. 2011;377(9768):851. (Secondary source: online Lancet journal)

6. Paessler S, Walker D. Pathogenesis of the viral hemorrhagic fevers. Annual Review of Pathology: Mechanisms of Disease. 2013;8:414. (Secondary source: online Annual Reviews journal)

7. Paessler S, Walker D. Pathogenesis of the viral hemorrhagic fevers. Annual Review of Pathology: Mechanisms of Disease. 2013;8:412. (Secondary source: online Annual Reviews journal)

8. Bwaka M, Bonnet M, Calain P, Colebunders R, De Roo A, Guimard Y et al. Ebola hemorrhagic fever in Kikwit, Democratic Republic of the Congo: clinical observations in 103 patients. Journal of Infectious Diseases. 1999;179(Supplement 1):3. (Primary source: online journal from the Journal of Infectious Diseases)

This journal provided primary information on EHF with regard to an outbreak. It was relevant and informative.

It was useful in that it accurately described manifestations of EHF in a human outbreak of Ebola, with strong analysis and testing to diagnose EHF.

However a weakness of the journal is that it only looked at 103 cases; a small sample size that does not well reflect the population.

9. Towner JS, Rollin PE, Bausch DG, et al. Rapid diagnosis of Ebola hemorrhagic fever by reverse transcription-PCR in an outbreak setting and assessment of patient viral load as a predictor of outcome. Journal of Virology. Apr 2004;78(8):4330-4341 (Secondary source: online CDC article)

10. Bausch DG, Towner JS, Dowell SF, et al. Assessment of the risk of Ebola virus transmission from bodily fluids and fomites. The Journal of Infectious Diseases. Nov 15 2007;196 Suppl 2:S142-147. (Secondary source: online CDC article)

11. Paessler S, Walker D. Pathogenesis of the viral hemorrhagic fevers. Annual Review of Pathology: Mechanisms of Disease. 2013;8:418. (Secondary source: online Annual Reviews journal)

12. Paessler S, Walker D. Pathogenesis of the viral hemorrhagic fevers. Annual Review of Pathology: Mechanisms of Disease. 2013;8:416. (Secondary source: online Annual Reviews journal)

13. Paessler S, Walker D. Pathogenesis of the viral hemorrhagic fevers. Annual Review of Pathology: Mechanisms of Disease. 2013;8:418-419. (Secondary source: online Annual Reviews journal)

Management

1. Centers for Disease Control and Prevention. Questions and Answers about Experimental Treatments and Vaccines for Ebola. http://www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/qa-experimental-treatments.html (accessed 25 October 2014) [CDC website article]

Useful summary document from a reliable source, useful for initially gaining a background to Ebola. It gave a good introduction to treatment and gave some other useful sources to initially expand our knowledge.

2. BBC. Ebola kills Liberia doctor despite ZMapp treatment. http://www.bbc.co.uk/news/world-africa-28925491 (accessed 26 October 2014) [BBC News article]

3. Rayner G. British Ebola sufferer William Pooley given experimental drug ZMapp and sitting up in bed. The Telegraph. August 26 2014. http://www.telegraph.co.uk/news/worldnews/ebola/11057096/British-Ebola-sufferer-William-Pooley-given-experimental-drug-ZMapp-and-sitting-up-in-bed.html (accessed 26 October 2014) [News article]

4. Lock H. Ebola Outbreak: British survivor William Pooley returns to Sierra Leone to fight the disease. The Independent. October 19 2014. http://www.independent.co.uk/news/uk/home-news/british-nurse-who-survived-ebola-will-fly-back-to-sierra-leone-to-fight-the-disease-9804625.html (accessed 27 October 2014) [News article]

5. Gallacher J. Ebola: Experimental drug ZMapp is ‘100% effective’ in animal trials. http://www.bbc.co.uk/news/health-28980153 (accessed 23 October 2014) [News article]

6. 6. Olinger G, Pettitt J, Kim D, Working C, Bohorov O, Bratcher B et al. Delayed treatment of Ebola virus infection with plant-derived monoclonal antibodies provides protection in rhesus macaques. Proceedings of the National Academy of Sciences. 2012;109(44):18030--18035. [Primary research paper]

7. Qiu X, Wong G, Audet J, Bello A, Fernando L, Alimonti J et al. Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp. Nature. 2014;. [Primary research paper]

A paper from a study showing that ZMapp could be used to completely cure 100% of rhesus macaques with advanced Ebola virus disease. It is very relevant as ZMapp is a promising new form of treatment, but has a small sample size which may make it unreliable.

8. Sabin L. Blood transfusion: What is the Ebola treatment – and how does it work? The Independent. October 22 2013. http://www.independent.co.uk/life-style/health-and-families/health-news/blood-transfusion-what-is-the-ebola-treatment--and-how-does-it-work-9809980.html (accessed 24 October 2013) [News article]

9. Mupapa K, Massamba M, Kibadi K, Kuvula K, Bwaka A, Kipasa M et al. Treatment of Ebola hemorrhagic fever with blood transfusions from convalescent patients. Journal of Infectious Diseases. 1999;179(Supplement 1):18--23. [Primary research paper]

Useful paper on blood transfusions in treatment in Ebola, as it is the only primary research paper on this area. It is limited by its very small sample size and lack of controlling other variables, but is still an informative paper.

10. Eleftheriou-Smith L. Ebola Crisis: Why is an infected Texan nurse being treated by blood transfusion, and how does it work? The Independent. October 15 2013. http://www.independent.co.uk/news/science/ebola-crisis-why-is-an-infected-texan-nurse-being-treated-by-blood-transfusion-and-how-does-it-work-9795641.html (accessed 25 October 2014) [News article]

Useful and informative news article which explains the theory behind blood transfusion treatment and shows how it is being used during the current crisis.

11. Bennett S, Langreth R. Ebola outbreak: Blood of survivors could lead to cure, says WHO. The Independent. August 19 2014. http://www.independent.co.uk/news/world/africa/ebola-outbreak-blood-of-survivors-could-lead-to-cure-says-who-9679449.html (accessed 26 October 2014) [News article]

12. Butler D. Blood transfusion named as priority treatment for Ebola. http://www.nature.com/news/blood-transfusion-named-as-priority-treatment-for-ebola-1.15854 (accessed 25 October 2013) [News article]

13. Bukreyev, A., Rollin, P.E., Tate, M.K. et al. (2007). Successful topical respiratory tract immunization of primates against Ebola virus. Journal of virology 81(12): 6379-6388. (Primary research article)

14. Vanderzanden, L., Bray, M., Fuller, D. et al. (1998). DNA vaccines expressing either the GP or NP genes of Ebola virus protect mice from lethal challenge. Virology 246(1): 134-144. (Primary research article

15. Martin, J.E., Sullivan, N.J., Enama, M.E. et al. (2006). A DNA vaccine for Ebola virus is safe and immunogenic in a phase I clinical trial. Clinical and vaccine immunology 13(11): 1267-1277. (Clinical trial)

16. Ledgerwood, J.E., Costner, P., Desai, N. et al. (2010). A replication defective recombinant Ad5 vaccine expressing Ebola virus GP is safe and immunogenic in healthy adults. Vaccine 29(2): 304-313. (Clinical trial)

This was a useful resource as it provided encouraging results in the safety and immunogenicity of an Ebola vaccine on human subjects

17. BBC News Health - Ebola vaccine trial begins. URL: http://www.bbc.co.uk/news/health-29230157 [Accessed: 27/10/14]. (News article)

18. World Health Organization - Barriers to rapid containment of the Ebola outbreak. URL: http://www.who.int/csr/disease/ebola/overview-august-2014/en/ [Accessed: 27/10/14]. (Website article)

This article on the WHO website was very interesting as it explained some of their difficulties in trying to prevent and treat the Ebola outbreak in West Africa. Coming from a well-known, reliable organisation, their ideas were highly valuable.

19. Chertow, D.S., Kleine, C., Edwards, J.K. et al. (2014). Ebola virus disease in West Africa — clinical manifestations and management [online]. N Engl J Med DOI: 10.1056/NEJMp1413084 [Accessed: 6/11/14]. (Perspective article)

20. Medecins Sans Frontieres - Struggling to contain the Ebola epidemic in West Africa. URL: http://www.doctorswithoutborders.org/news-stories/voice-field/struggling-contain-ebola-epidemic-west-africa [Accessed: 29/10/14]. (Website article)

Ebola in the West

1. Kinsman, J. “A time of fear”: local, national, and international responses to a large Ebola outbreak in Uganda. Globalization and Health. 2012; 8:15. DOI:10.1186/1744-8603-8-15 (accessed 16 October 2014) (online journal article)

2. Barriers to trust. Nature. 2014; 511(7508):126. DOI: 10.1038/511126a (accessed 16 October 2014) (editorial)

3. Naish J. Truth about incurable virus that's just one plane ride from Britain: Experts say statistics show Ebola WILL reach Britain. The Daily Mail. Thursday 31 July 2014. http://www.dailymail.co.uk/health/article-2711462/Ebola-Q-A-How-no-cure-deadly-disease-statistically-likely-eventually-reach-Britain.html (accessed 17 October 2014) (newspaper article)

4. Hoft J. SHOCKING: CDC Admits 100-150 People a Day Entering US from Ebola Infected Countries. Weblog.http://www.thegatewaypundit.com/2014/10/shocking-cdc-admits-100-150-people-a-day-entering-us-from-ebola-infected-countries-video/ (accessed 17 October 2014) (online blog)

References 2 and 3 are very unreliable due to coming from biased newspaper articles, but we have just used them here to highlight certain news titles rather than for any solid facts.

5. Gostin L. et al. The Ebola Epidemic - A Global Health Emergency. JAMA. 2014;312(11):1095-1096. DOI:10.1001/jama.2014.11176. (accessed 16 October 2014) (online journal article)

6. Boseley, S. WHO warns 10,000 new cases of Ebola a week are possible. The Guardian. Tuesday 14 October 2014. http://www.theguardian.com/world/2014/oct/14/who-new-ebola-cases-world-health-organisation?CMP=EMCNEWEML6619I2 (accessed 15 October 2014) (newspaper article)

7. Booth, R. UK to introduce Ebola screening as death of Briton reported in Macedonia. The Guardian. Thursday 9 October 2014. http://www.theguardian.com/world/2014/oct/09/uk-screening-airports-ebola-symptoms (accessed 12 October 2014) (newspaper article)

8. Gambino, L. Second Texas nurse with Ebola transferred to special facility. The Guardian. Thursday 16 October 2014. http://www.theguardian.com/world/2014/oct/15/ebola-second-texas-nurse-transferred-atlanta?CMP=EMCNEWEML6619I2 (accessed 16 October 2014) (newspaper article)

Although many of these references are news articles instead of cited scientific research papers, due to the current and changing nature of the disease many of the factors discussed are too recent to have papers written on them, meaning we had to get many of our facts from news articles. We have considered this when writing our section though and have tried to ensure we included only facts, or if subjective opinions have been included we have mentioned the possibility of bias within the section.

9. Ebola: Lessons from SARS, the flu, and HIV/AIDS - Communities Digital News [online]. Available from: http://www.commdiginews.com/health-science/ebola-lessons-from-sars-the-flu-and-hivaids-27549/ [Accessed 11/10/2014] (online article)

10. Tran, M. What is the risk of Ebola in the UK? The Guardian. Wednesday 8 October 2014. http://www.theguardian.com/world/2014/oct/08/ebola-what-is-risk-in-uk (accessed 16 October 2014) (newspaper article)

11. Swaine, J. Ebola crisis: Texas hospital apologises for failures in handling of first patient. The Guardian. Thursday 16 October 2014. http://www.theguardian.com/world/2014/oct/16/texas-hospital-sorry-ebola-case-errors (accessed 17 October 2014) (newspaper article)

12. Ebola Outbreak: Cases pass 10,000, WHO Reports - BBC News [online]. Available from: http://www.bbc.co.uk/news/world-africa-29769782 [Accessed 25/10/2014] (news article)

13. Ebola Outbreak: Nurse Kaci Hickox defies quanantine - BBC News [online]. Available from: http://www.bbc.co.uk/news/world-us-canada-29836550 [Accessed 30/10/2014] (news article)

14. Ebola Response Roadmap Situation Report - World Health Organisation [online]. Available from: http://apps.who.int/iris/bitstream/10665/137376/1/roadmapsitrep_29Oct2014_eng.pdf?ua=1 [Accessed 30/10/2014] (situation report)

15. Fifteen countries are at risk of Ebola outbreak, says WHO - British Medical Journal [online]. Available from: http://www.bmj.com.ezproxy.is.ed.ac.uk/content/349/bmj.g6305 [Accessed 17/10/2014] (online journal article)

16. Only the military can get the epidemic under control: MSF head - British Medical Journal [online]. Available from: http://www.bmj.com.ezproxy.is.ed.ac.uk/content/349/bmj.g6151 [Accessed 10/10 2014] (online journal article)

17. Operation Gitrock: first UK army medics fly to Sierra Leone - British Medical Journal [online]. Available from: http://www.bmj.com.ezproxy.is.ed.ac.uk/content/349/bmj.g6237 [Accessed 14/10/2014] (online journal article)

18. WHO convenes industry leaders and key partners to discuss trials and production of Ebola vaccine - World Health Organisation Media Centre [online]. Available from: http://www.who.int/mediacentre/news/releases/2014/ebola-vaccines-production/en/ [Accessed 30/10/2014] (news article)

19. Rid, A. Emanuel, E.J. Why Should High-Income Countries Help Combat Ebola? JAMA. 2014; 312(13):1297-1298. DOI:10.1001/jama.2014.12869. (accessed 8 October 2014) (online journal article)

A clear paper stating the possible reasons high income countries may give money towards combating Ebola. However, although it has many clear references it makes some rather broad statements without giving an example of where this has been shown or why they say it to be true, meaning perhaps the paper may not be fully trustworthy.

20. The Lancet. Ebola: a failure of international collective action. The Lancet. 2014; 384(9944):637. DOI: 10.1016/S0140-6736(14)61377-5 (accessed 12 October 2014) (online journal article)

21. Chan, M. Ebola Virus Disease in West Africa — No Early End to the Outbreak. N Engl J Med. 2014; 371:1183-1185. DOI: 10.1056/NEJMp1409859 (accessed 14 October 2014) (online journal article)

22. Doctor to Patient Ratio in Africa. http://www.africapedia.com/DOCTOR-TO-PATIENT-RATIO-IN-AFRICA (accessed 16 October 2014) (statistics table)

23. Anthony S. Fauci, M.D. Ebola — Underscoring the Global Disparities in Health Care Resources. N Engl J Med. 2014; 371:1084-1086. DOI: 10.1056/NEJMp1409494. (accessed 16 October 2014) (online journal article)

A good paper outlining the progression of the current Ebola outbreak and the potential influences, though it does broadly state the unlikelihood of the disease spreading further and has only a few references

I would like to point out that I (John Henderson) have tried multiple times to space out each individual reference as seen in the above section for "Management", to improve overall presentation. However, the website is not letting me do this. Please take this into account upon marking. Thanks.