Friday, 8 May 2015

iBola and the speed of research reporting during outbreaks and epidemics...

My thanks to Dr Judy Stone who pointed out the New York Times Health article.[1]

Ebola virus takes advantage of privileged sites

The New England Journal of Medicine (NEJM) has been one of the greatest publishers of high quality clinical information throughout the Ebola virus disease (EVD) epidemic in 2014. 

NEJM has just published an article on a 43 year old male physician who was evacuated from Sierra Leone after an EVD diagnosis, for treatment at the Emory University Hospital Serious Communicable Disease Unit (SCDU). But 14 weeks after his EVD diagnosis, he developed eyesight and hearing problems and was found to have infectious Ebola virus, and viral RNA...In. His. Eyeball.[2] No viral RNA was found on his conjunctiva or his tears. He hearing loss was on the same side as his declining vision.[1] 
An approximate timeline of the Emory patient.
Coloured balloons with vertical lines indicate specific dates.
The absence of a vertical line indicates a general time frame only.
Click on figure to enlarge.
Emory has treated at least four EVD cases evacuated to the United States [17] and has done so with exceptional care and enviable professionalism.[19] They produced a protocols website that became a beacon to the world's public health efforts to prepare for an imported case of EVD.[18] 

This latest finding may go a long way towards explaining some of the issues suffered by survivors of EVD - headaches, eyesight and hearing issues, muscle and joint pain, tingling or other sensations and extreme weakness. Some of these symptoms have affected 50% of survivors by some counts.[4] 

Eyesight problems may not be a long term effect from damage during the earlier infection, but the result of a persistent infection - active virus replication at body sites like the eyeball, that have immunological (e.g. expression go anti-inflammatory chemicals) and physical methods (e.g. cellular barriers) of keeping out molecules, viruses and bacteria, but not necessarily host cells.[5,6,7] Such sites do not usually have a strong inflammatory immune response to pathogens - perhaps to avoid the collateral damage that occurs during inflammation. Should a pathogen get into one of these sites, perhaps by riding in via an immune cell it infected, it can set up house for an indeterminate amount of time and with an unquantified spectrum of damage - from direct viral cell deaths to inflammation. It may also be difficult to get a drug into these sites because of the very discriminatory barriers mentioned earlier. Apart from the eye, such protected tissues include the testes (and we know Ebola virus can be maintained there for half a year) and brain and they are very generally described as 'immune privileged' sites.

The NEJM study also reported that the patient's semen contained RNA at 44 days after illness onset, and was still being monitored at publication. During his initial illness he had received the Ebola virus RNA-binding drug, TKM-100802 (or 'TKM-Ebola'[15]). It seems - for this one case anyway - that TKM-Ebola did not prevent persistence in at least two privileged sites.

This was not the first time an eye infection of this sort, called uveitis (inflammation of a region inside the eye), has been described in the EVD literature. In a study published about four years after an EVD outbreak in the Democratic Republic of the Congo, four ophthalmologist-confirmed cases were described. They developed symptoms between 42 and 72 days after onset of EVD, but no virology testing was reported.[9] In 1975, a report described a Marburg virus isolate grown from a fluid sample from the eye of a female with uveitis nearly three months after EVD onset.[10] All cases recovered their sight following treatment with atropine and steroid.

Apart from the NEJM story being a fascinating discovery and a tribute again to Emory's tenacity in trying to understand EVD, I have two concerns:

  1. According to the Disclosure forms attached to the NEJM article and signed by the authors, the article was likely submitted around February 2015 (amendment: Dr Varkey-lead author, confirmed via a Tweet to me, that the paper was submitted in January). It's now May 2015 and the EVD epidemic, while vastly reduced in scale compared to what it was in December, is ongoing. There have been growing reports of clinics devoted to dealing with the survivors of EVD and the description of post-Ebola syndrome is also growing.[8]
  2. The New York Times article included the following (bold is mine)...

    Dr. Jay Varkey, an infectious-disease specialist who had handled much of Dr. Crozier’s care, got special permission from the Food and Drug Administration to use an experimental antiviral drug taken in pill form. (The doctors declined to name it, preferring to save that information for future publication in a medical journal.)

    There is currently no evidence for or against any successful intervention using this unnamed drug. But the fact that the authors are considering publishing its use in a separate article could be interpreted as there being a chance it was helpful. Also, because the drug was obtained with special permission - it needed the drug company to agree to it being named. Perhaps they did not. But if this drug helped, it is a drug that should be made known, or available, to all who are seeing and treating EVD survivors. If the drug was of substantive use, then it might also be of helpful for survivors in Guinea, Liberia and Sierra Leone for slowing/eradicating virus in other immune privileged sites. I hope the company is considering this at least as urgently as vaccine companies did, before they eventually ramped up production of their products.
Publishing can often be slow 

The traditional process of publishing research results through scientific journals is a lot slower than many would like. This four month lag is an example of that. There are some journals that are faster than others and some that are slower. Publishing in some journals is traditionally considered to guarantee (you and) your data greater exposure. Some journals are where your data go to die. This is not just because of the journal per se, but also because of your data and because some journals are watched more closely than others by those who can make the complex science more understandable - the science communicators. They write the stories that draw attention to the big discoveries.

But peer-review is an important part of publishing quality science. Peer reviewing - finding expert reviewers who will review a manuscript in their own time and getting them to return their comments in a reasonable time frame - it is quite a challenge and it can be the cause a lot of delay to the process of manuscripts becoming published papers. It is also often argued that peer-review is a broken system, nonetheless it is (still) what we have now.[11,12,13]

Publishing should sometimes be fast

When there is an active or ongoing outbreak of infectious disease, knowledge is power; the power to perhaps help save lives, reduce the burden of the disease, halt transmission, find the source, change the diagnostics, manage infected patients differently, alter the message, use a new drug - generally the power do good things for people at risk, as fast as possible. 

On these occasions when time is so important to health, putting new data related to an outbreak through the scientific publication pipeline may be the least effective way to get important messages out in a timely manner. Before and after an outbreak - whatever - but during the outbreak - think differently. We've seen some great leaps in free genomic (viral sequence) data from Ebola virus variants - with the important detailed scientific papers following up later.[14] We still have a way to go to embrace not just a culture of openness, but one of speedy openness.[16] Not just for sequence data but for clinical data and for use of investigational drugs at times of crisis too.

All of the important aspects of the latest Ebola virus findings may have been passed quickly along to public health institutions that disseminate the information and act upon it if and as necessary. Nonetheless such behind-the-scenes information has remained behind-the-scenes. 

While eye surgery is unlikely to be very frequent in west Africa, a risk is now known for ophthalmologists who may operate on, or collect samples from, EVD survivors. We now know of at least two immune-privileged sites that can harbour infectious Ebola virus, many months after signs of disease have passed and the surviving patient has left care; the other site being the testes.[20,21] 

Could the central nervous system be yet another site? Could much of the remaining post-Ebola syndrome symptoms be related to virus replicating here causing headaches and nerve-related pain and tingling/burning?[8] Perhaps Emory medical researchers are working on this next.

Ebola virus continues to challenge us as we learn important lessons about managing its many and newly discovered impacts on the health of the host. This virus excels at revealing and exploiting our weaknesses. For something that is not alive, it has certainly played merry havoc in showing up our many failures to communicate.

References...

  1. Weeks After His Recovery, Ebola Lurked in a Doctor’s Eye
    http://www.nytimes.com/2015/05/08/health/weeks-after-his-recovery-ebola-lurked-in-a-doctors-eye.html?smid=tw-share
  2. Persistence of Ebola Virus in Ocular Fluid during Convalescence
    http://www.nejm.org/doi/full/10.1056/NEJMoa1500306
  3. Mystery ‘post-Ebola syndrome’ emerges in West Africa
    http://www.japantimes.co.jp/news/2015/05/03/world/science-health-world/mystery-post-ebola-syndrome-emerges-in-west-africa/#.VUwe9vnzp1N
  4. Sierra Leone: Helping the Ebola survivors turn the page
    http://www.who.int/features/2014/post-ebola-syndrome/en/
  5. Immune privilege or privileged immunity?
    http://www.nature.com/mi/journal/v1/n5/full/mi200827a.html
  6. The testis in immune privilege.
    http://www.ncbi.nlm.nih.gov/pubmed/16972897
  7. Immune Privilege of the Testis: Meaning, Mechanisms, and Manifestations
    http://link.springer.com/chapter/10.1007%2F978-3-0348-0445-5_2
  8. Mystery ‘post-Ebola syndrome’ emerges in West Africa
    http://www.japantimes.co.jp/news/2015/05/03/world/science-health-world/mystery-post-ebola-syndrome-emerges-in-west-africa/#.VUvhNfnzp1N
  9. Late Ophthalmologic Manifestations in Survivors of the 1995 Ebola Virus Epidemic in Kikwit, Democratic Republic of the Congo
    http://jid.oxfordjournals.org/content/179/Supplement_1/S13.long
  10. Outbreake of Marburg virus disease in Johannesburg
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1675587/
  11. Scientific Peer Review Is Broken. We’re Fighting to Fix It With Anonymity
    http://www.wired.com/2014/12/pubpeer-fights-for-anonymity/
  12. Is the Peer Review Process for Scientific Papers Broken?
    http://time.com/81388/is-the-peer-review-process-for-scientific-papers-broken/
  13. Is Peer Review Broken?
    http://www.the-scientist.com/?articles.view/articleNo/23672/title/Is-Peer-Review-Broken-/
  14. Using Genomics to Follow the Path of Ebola
    http://directorsblog.nih.gov/2014/09/02/using-genomics-to-follow-the-path-of-ebola/
  15. Ebola: Tracking the Latest Measures Against a Killer
    http://sciencewatch.com/articles/ebola-tracking-latest-measures-against-killer
  16. Data sharing: Make outbreak research open access
    http://www.nature.com/news/data-sharing-make-outbreak-research-open-access-1.16966
  17. Status of U.S. Ebola cases
    http://apps.washingtonpost.com/g/page/national/status-of-us-ebola-cases/1406/
  18. Emory Healthcare Ebola Preparedness Protocols
    http://www.emoryhealthcare.org/ebola-protocol/ehc-message.html
  19. Emory's "Team Ebola" to receive National Patient Safety DAISY Award for exceptional nursing
    http://news.emory.edu/stories/2015/04/team_ebola_npsf_daisy_award/
  20. Ebola virus in semen is the real deal....
    http://virologydownunder.blogspot.com.au/2014/08/ebola-virus-in-semen-is-real-deal.html
  21. Ebola virus in the semen of convalescent men
    http://www.thelancet.com/journals/laninf/article/PIIS1473-3099%2814%2971033-3/fulltext?rss=yes