Saturday, 10 October 2015

Is the next Ebola virus revelation...reactivating infection?

Update #1 11OCT2015 AEST
Update #2 11OCT2015 AEST
Update #3 22OCT2015 AEST

Great. Are members of the Zaire ebolavirus (EBOV) species the most educational viruses of modern times or what? I mean, we've "known" about EBOV since 1976, but the West Africa Ebola virus disease (EVD) epidemic is the epidemic that keeps on giving - we seem to learn a brand new thing every few months.

And the latest is a doozy although we don't know many of the details yet.

So what do we know about this new finding of a seeming return of infection in a former EVD case? Or is this new disease because of damage from the old infection?

  1. A 39 year old nurse, PC, was originally infected with EBOV while working for 3 weeks in the Save the Children’s Kerry Town Treatment Centre in Sierra Leone. She did not show signs of illness until after arriving home in Scotland [1,11]
  2. PC was believed to have become infected while treating EVD patients in some way related to her use of a visor as part of her personal protective equipment, rather than goggles, [10]
  3. PC entered a Gartnavel Hospital isolation unit on 29-DEC-2014, and was subsequently flown to the Royal Free Hospital (RFH) in Hampstead, North London on 30-DEC-2015. She stayed there for around a month [2,4]
  4. During her time in the RFH, PC was treated with convalescent blood plasma and an experimental antiviral drug
  5. PC was declared free of EBOV and discharged from the RFH on 24-JAN-2015 but continued to report thyroid problems afterwards as she described just a week ago [3,4,12]
  6. On Monday evening, PC went to a GP service at Victoria Hospital with a temperature, headache, sore neck and sensitivity to light (photophobia). [15] She was sent home.
  7. On Wednesday 07-OCT-2015, PC was admitted to the Queen Elizabeth University Hospital (QEUH) in Glasgow, Scotland. Tests revealed that EBOV (presumably) RNA was present.[13] 
  8. On Friday 09-OCT-2015, PC was admitted to the RFH, 8 months and 15 days after being declared free of Ebola virus and discharged.[16]
  9. She is described as being in serious condition. However, it is unclear what her signs and symptoms were at presentation, or have become since.[4]
  10. On Wednesday 14-Oct-2015, PC's conditions was described as having deteriorated and was now classified as in critical.[16,19,20]
  11. On Monday 19-Oct-2015, PC's condition was described as improved.[16,21]
  12. On Thursday 22-Oct-2015, at a press conference made possible because PC had given permission for her case to be publicly discussed, PC was described as having significantly improved. She had meningitis and has received a "highly experimental" drug, GS-5734, under development by Gilead Sciences, and proven highly effective in the lab and in monkeys post-infection.[22,23,25,26]

Descriptions note that PC is "not thought to be contagious". Presumably this means she is not symptomatic with EVD and if so the testing that must have identified EBOV somewhere in her system must have does so from a part of her system that is not readily in contact with the environment. In one report, laboratory staff in Glasgow who handled PC's samples, were not wearing the most basic of personal protective equipment (PPE) for lab staff-gloves.[24] All of that side, she is once again isolated at one of the world's best infectious diseases hospitals.[4] 

There are also recent reports of PC having had thyroid problems after recovering-perhaps virus has been replicating in this tissue. PC's "condition is a complication of a previous infection with the Ebola virus".[4] Which leaves a lot of room for idle speculation but could just be that she is ill because of what the fallout from what EBOV previously did to a tissue/organ rather than because of EVD itself. Perhaps follicles in the scalp have been a site for virus replication, relating to her earlier hair loss. Another site may be the central nervous system...
All speculation. Again, nothing is known about PC's signs and symptoms of disease when she presented herself to the QEUH, what tissue(s) are involved in her current illness, which samples tested positive first, whether viral culture has been conducted or just RT-PCR and where the virus may have been replicating all this time. While we understand that some tissues are sites for EBOV persistence, there is clearly much more to learn about the frequency and full range of tissues that harbour infectious EBOV once it becomes undetectable in the blood.

Apart from how shocking and scary this must be for PC herself, another issue is how this will impact on the fragile processes of accepting of EVD survivors back into their West African communities. Extending the length of time that some male survivors are known to harbour EBOV already put pressure on their acceptance by some, but the potential for virus to return to the blood or other tissues - if indeed that is what has happened here - even after that time frame, will require a lot of communication to explain. It will be vitally important for this process that the facts underpinning what's happened here are deduced soon and communicated in ways that can be understood in West Africa. This is a chance for the World Health Organization to show off their shiny new intent to do better at communicating and reacting. 

This is not the first time EBOV has been found to persist in a convalescent former EVD case.[5,6,7,8,9] But this may be the first documented time that the virus has re-emerged from an immune privileged site and returned to the blood, possibly causing EVD symptoms in the same former EVD case (recent media article mentions that this is the 2nd such case[15]).

The comments about PC's photophobia are similar to those from Dr Ian Crozier - who was found to have persistent infectious virus in the aqueous humor collected by needle from the anterior chamber of his eye causing uveitis-14 weeks after his EVD diagnosis.[6,17] His blood did not become EBOV positive again.[17] The virus found in his blood earlier and his ocular fluid 14 weeks later were nearly identical-just five mutations differentiating the genomes. Could the eye be a site of PC's hidden virus also? Perhaps the central nervous system the reservoir given the meningitis-like symptoms PC's family mentioned early and which was confirmed 22OCT.[15,18] Again, lots of speculation. 

Shingles has been thrown up as an example of a similar disease that results from a virus recurring but it's not the same thing at all. Although, we don't know that with absolute certainty. The viruses are very different - that we know for certain. Varicella zoster virus (VZV) is the herpesvirus that first causes chickenpox (doctors call it 'varicella'), usually in childhood. The virus then goes dormant in your nerves. In this state, the virus is not producing full virus particles and so VZV no longer excites our (cellular) immune system, which can eventually "forget" it. Decades later (again, usually) after lying dormant and because of triggers and a lack of suitable immune memory VZV may arise from dormancy (reactivate) to produce lots of whole virus and cause shingles (doctors call this 'herpes zoster' - still the VZV though).[14] As far as we know, EBOV does not go dormant or become latent, but remains active at some sites, like the testes and the eyeball,[5,7] where our immune system is programmed not to venture in full force, so as to protect those sites from unwanted inflammation (in a nutshell). There may well be other sites.

Hopefully, more official key information will be made clear soon (as opposed to in the scientific literature weeks or months from now) as it will be vitally important for the continued management and support of EVD survivors in West Africa. It is also important knowledge for communicating real risks, and informing and toning down perceived but unrealistic ones. What falls into which category is however becoming harder and harder to discern.

I'll update this blog post as more information comes to hand.

References...
  1. http://www.bmj.com/content/350/bmj.h36.long
  2. http://www.bbc.com/news/uk-scotland-30629397
  3. http://www.independent.co.uk/news/uk/pauline-cafferkey-ebola-nurse-back-in-hospital-virus-can-live-on-in-tissue-for-months-after-recovery-a6687571.html
  4. http://www.bbc.com/news/uk-scotland-34483584
  5. http://virologydownunder.blogspot.com.au/2015/08/post-ebola-syndrome-or-just-chronic.html
  6. http://virologydownunder.blogspot.com.au/2015/05/ibola-and-speed-of-research-reporting.html
  7. http://virologydownunder.blogspot.com.au/2014/08/ebola-virus-in-semen-is-real-deal.html
  8. http://virologydownunder.blogspot.com.au/2015/03/liberia-enters-next-phase-of-ebola.html
  9. http://virologydownunder.blogspot.com.au/2015/03/catching-ebola-mistakes-messages-and.html
  10. http://www.theguardian.com/world/2015/oct/09/scottish-ebola-nurse-pauline-cafferkey-royal-free-hospital-london
  11. http://america.aljazeera.com/articles/2015/1/3/scottish-nurse-ebola.html
  12. http://metro.co.uk/2015/01/24/british-nurse-with-ebola-pauline-cafferkey-makes-complete-recovery-and-leaves-hospital-5035112/
  13. http://www.bbc.com/news/uk-scotland-34495250
  14. http://www.nytimes.com/ref/health/healthguide/esn-shingles-expert.html?pagewanted=all
  15. http://www.dailyrecord.co.uk/news/scottish-news/family-condemns-hospital-failures-after-6612236
  16. https://www.royalfree.nhs.uk/news-media/news/update-on-pauline-cafferkey/
  17. Persistence of Ebola Virus in Ocular Fluid during Convalescence
    http://www.nejm.org/doi/full/10.1056/NEJMoa1500306
  18. http://www.theguardian.com/world/2015/oct/21/ebola-nurse-pauline-cafferkey-condition-serious-but-stable-royal-free-hospital
  19. http://www.bbc.com/news/uk-scotland-34529575
  20. http://www.theguardian.com/world/2015/oct/14/ebola-nurse-pauline-cafferkey-critically-ill
  21. http://www.bbc.com/news/uk-34574899
  22. https://www.royalfree.nhs.uk/news-media/news/pauline-cafferkey-makes-significant-improvement/
  23. http://www.bbc.com/news/uk-scotland-glasgow-west-34592132
  24. http://m.eveningtimes.co.uk/news/13842874.Lab_staff_at_Glasgow_hospital_told_NOT_to_leave_the_country_over_Ebola_fears/
  25. http://uk.advfn.com/news/DJN/2015/article/68969936
  26. http://www.telegraph.co.uk/news/health/news/11945802/Ebola-caused-meningitis-in-nurse-Pauline-Cafferkey.html
Updates...
  1. Added dates for PC being initially released from the RFH and that she was tested at the QEUH; described "dormant" and qualified that chickenpox and shingles can occur at any times but usually as a child and adult respectively; provided references about chickenpox
  2. Updated information from Ref 15 including dates, new calculation of time between RFH 1st discharge and admission and some symptom information from family
  3.  Added CSF+Blood Tweet; some tiny bits of new info from the RFH press conference; links to GS-5734 info