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expert reaction to case study looking at potential flare-up of Ebola infection a year after initial infection

Researchers publishing in Lancet Infectious Diseases present an outbreak report documenting the persistence of the Ebola virus after the end of widespread transmission in Liberia.

 

Dr Nathalie MacDermott, Clinical Research Fellow, Imperial College London, said:

“The Ebola epidemic in West Africa revealed to the scientific community the significant plight of Ebola virus disease survivors and the on going problems they may suffer.  Included within this is the potential for survivors to further transmit the virus through various bodily fluids, particularly through semen in male survivors.  While reports of transmission are rare from other bodily fluids, this report further adds to the literature of cases of Ebola transmission through survivors where there has been either re-activation of the virus due to an immunocompromised state or persistence of the virus in regions of the body that the immune system finds it harder to access.  This report also adds to the growing body of evidence for individuals infected with Ebola who show either subclinical or minimally symptomatic infection and who subsequently do not seek medical treatment resulting in them not being formally diagnosed with Ebola virus disease.

“While these reports are concerning they must be held in balance, in proportion to the large number of Ebola survivors in West Africa these transmission events are rare and likely become less frequent the more that time progresses after the initial Ebola infection.  A balance must be struck between ensuring health care professionals act with caution and ensure they are appropriately protected when treating unwell Ebola survivors or potential contacts of survivors, but not further stigmatising a group of people who have already suffered greatly and face significant stigma within their communities.”

 

Dr Derek Gatherer, Lecturer in the Division of Biomedical and Life Sciences, Lancaster University, said:

“Past experience with Ebola in central Africa has shown that large outbreaks are often followed by smaller ones in the same geographical region.  These ‘satellite’ outbreaks have traditionally been classified as distinct outbreaks by the WHO, but genome sequencing of thousands of viruses in the massive west African outbreak of 2013-2016 is now providing evidence that they are not independent.  Dokubo et al study one such satellite Ebola cluster that occurred in Liberia in November 2015.  Liberia suffered badly in the main wave of Ebola, having a very intense summer in 2014, but recovered quicker than the other two countries, with the end of the epidemic being declared in May 2015.

“How then is it possible to connect the November 2015 cluster with the main outbreak?  Two main lines of evidence are used.  The first is epidemiological contact tracing.  The cluster consisted of three individuals within a family – a father and his two sons.  The mother had antibodies against Ebola, indicating that she was a survivor from the main outbreak.  She was also unwell about a month prior to the rest of her family, but Ebola was not conclusively demonstrated.  During the main outbreak her brother’s family had been badly affected in July/August 2014, with three cases, and she had been involved in caring for her brother.  A plausible transmission chain can therefore be constructed between the main outbreak and the satellite cluster.

“However, given the gap of many months between these events, this scenario requires that Ebola virus had remained within the mother after she had recovered from her presumed (highly likely due to her antibody status) attack of the disease.  We have several other examples of such late transmission from survivors, but most of the focus has been on sexual transmission from males, where viable virus can be found in seminal fluid for several months.  Since the individual in this case was female, the implication is that other body fluids can similarly be sources of infection from survivors.

“The second line of evidence is molecular.  The virus that was sequenced in the November cluster is related to that sequenced from the relatives of the mother in the main cluster in August of the previous year.  Does this relationship prove the case?  Aside from sheer similarity, there is a further aspect of the sequence comparison that suggests it does: the sequence of the virus in the cluster does not appear to have accumulated many extra mutations between August 2014 and November 2015.  Viruses mutate when they replicate, so a long transmission chain tends to accumulate lots of mutations.  If the mother in the cluster had acquired her Ebola infection recently from another source, even from one in the same general area with a related strain of virus, we would expect far more mutations to have accumulated.  The virus isolated from her spouse and sons appears to have been in ‘suspended animation’ for over a year, and the most plausible scenario for that is that it was inactive within the body of the mother.”

 

Prof Trudie Lang, Director of The Global Health Network, University of Oxford, said:

“Outbreaks such as Ebola present challenges because we still do not fully understand the disease and how the virus behaves in the patients, such as how and where it remains within the body, and how it might present or when, if it becomes an active infection again.  One of the major barriers to our understanding these diseases is that there is such a low level of research capacity in these regions and so keeping this level of research evidence coming through is difficult, especially when the world has stopped watching.

“I flew back from Madagascar this weekend because we have been working to support the small numbers of local researchers as they prepare for another outbreak of the Plague, which happen often.  It is the same situation as we have with Ebola and so one of the key requirements is to support the country in developing its own capacity to undertake research.  For example, we found that disease surveillance is one of the major gaps in Madagascar, so this is the ability to spot outbreaks and understand who is affected, where and how many.  This is the first key step in the whole process of research that is needed, from identifying disease through to testing drugs and vaccines in clinical trials.  This work should be led and undertaken by the affected country.  The WHO said that unless these regions become the generators and not the recipients of health research data then there will never be any true improvements to public health.  That report was referring to everyday diseases of poverty that bring the highest mortality burdens to these regions.  However, the rest of the world only really notices this lack of capacity when it comes to disease outbreaks such as Ebola and the Plague, and therefore we should use this awareness and recognition of the problem to drive efforts to support countries, from building research skills and infrastructure to address all the diseases that impact them, including outbreaks such as Ebola.”

 

Dr Simon Mardel, Consultant, Emergency Department University of Manchester NHS Foundation Trust, said:

“Although the authors have listed just some of the alternative explanations for this apparent flare-up (and their efforts to exclude them from their analysis), and the scientific limitations of this study, and have clearly used the word ‘plausible’ in summing up the transmission risk, such details may easily be overlooked in its subsequent portrayal to the global community.

“Historically with Ebola and other dangerous viruses we have found other explanations for initially unexplained chains of transmission.  These have included poorly managed laboratory fridges, sample storage, or understandable family or community pressures to conceal what at first appeared a trivial contact history.  As one illustration, this patient’s co-incidental blood transfusion just prior to her ‘second’ illness, is likely to have involved the donated bags of blood being stored in a general purpose laboratory fridge from where they would be re-sampled for cross-match by technicians responsible for most if not all of the hospital lab work, and having to re-use most if not all of the glassware, syringes and gloves that we take for granted as being disposable in more affluent health care settings.

“It’s right to use case studies like these to highlight a potential public health risk, but we’d need far more evidence before it could be suggested that those who have survived Ebola could either be at risk themselves or represent a risk to their communities where this could potentially restrict people’s liberties, such as the right to play a full role in a community without any stigmatisation.

“This isn’t just a moral issue – complete reintegration of survivors back into the community is a major part of outbreak control.  Those of us who have worked in this field over many years have witnessed just how badly we can lose control of public order locally, or control of the wider outbreak, when communities receive only messages of fear.

“In the 2014/15 Ebola outbreak, phrases persistently carried by two of the world’s largest public health organisations stated Ebola is ‘a fatal disease’ and has ‘no cure’.  The survivors of Ebola need to be supported and cherished, not only for the work they often do in subsequent control efforts, but for being the visible proof that Ebola is treatable.  Having worked with survivors of these viral haemorrhagic fevers as far back as 1997, I would say that their potential to help and communicate is consistently underutilised.  Any communication that directs attention to them would do well to highlight their unique strengths along the way.”

 

* ‘Persistence of Ebola virus after the end of widespread transmission in Liberia: an outbreak report’ by Emily Kainne Dokubo et al. published in the Lancet Infectious Diseases on Monday 23 July 2018.

 

Declared interests

Dr Nathalie MacDermott: “I am a Wellcome funded Clinical Research Training Fellow investigating genetic susceptibility to Ebola virus disease.  I have no other disclosures.”

Dr Derek Gatherer: “Derek Gatherer has no conflict of interest in commenting on this paper.”

Prof Trudie Lang: “No conflicts of interest to report.”

Dr Simon Mardel: “I have no conflict of interest.”

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