VDU's blog: persistent

Showing posts with label persistent. Show all posts

Monday, 12 October 2015

Jon Snow is remarkably well informed compared to us...

...because we clearly know almost nothing when it comes to the specifics of where Ebola virus (EBOV) can, in some portion of survivors, hide.

What triggers EBOV to come out of hiding? If indeed that is what it has done within PC, the United Kingdom nurse who seems to have recently become ill while (or due to) hosting a reappearance of EBOV in her blood - 9 months after her blood was defined as containing no detectable EBOV.

This is not a new infection - but a return of a virus that had not been cleared from its hidey hole(s).

There are obvious concerns to be discussed around this, including:

What triggered its re-emergence
Is this a strange and rare event or a more common one?
Was the virus hiding in PC's central nervous system (she has meningitis-like symptoms reportedly) or in another place or places?
Is the thyroid a site of persistence?
Did the mysterious antiviral treatment she was given alongside a plasma treatment in 2014/15 act to push the virus into hiding?
Has the activated virus mutated in any significant way during its holiday out of the bloodstream?
Can EBOV become truly latent or at least dormant (still producing proteins, but not infectious virus particles) when off the beaten track, or is it constantly replicating?
Is PC suffering from full-blown Ebola virus disease (EVD) now, or a disease due to tissue or organ damage from her earlier infection - although if she has detectable EBOV in her blood, one would assume it is EVD.
What the hell are a "lucky set of genes" in the context of a return to systemic EBOV infection?

Below are some known and some proposed/possible/unproven sites at which EBOV may linger, avoiding or not exposed to clearance by the full force of our immune response.

In the future, perhaps tomorrow, in a non-rich nation, will others become infected from a convalescent patient who experience a return of EBOV long after they were declared virus-free based on a their blood test results. Has that happened already? Will they be our colleagues, friends or family members? The sooner we hear more about what is going on with PC, the better prepared those on the ground will be to intervene. Also, those tending to convalescent health workers in countries around the globe.

Communication has always been a key issue for EVD and other emerging diseases. Have we been listening?

We know nothing but we can learn. Will we?

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?

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]
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]
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]
During her time in the RFH, PC was treated with convalescent blood plasma and an experimental antiviral drug
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]
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.
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]
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]
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]
On Wednesday 14-Oct-2015, PC's conditions was described as having deteriorated and was now classified as in critical.[16,19,20]
On Monday 19-Oct-2015, PC's condition was described as improved.[16,21]
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...

@amymaxmen I've heard she has a meningitis like syndrome, probably CSF is where #Ebola virus is replicating
— Ahmed Tejan-Sie MD (@AhmedTejanSie) October 9, 2015

@MackayIM @amymaxmen CSF and blood (later) positive
— Ahmed Tejan-Sie MD (@AhmedTejanSie) October 15, 2015

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...

Updates...

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
Updated information from Ref 15 including dates, new calculation of time between RFH 1st discharge and admission and some symptom information from family
Added CSF+Blood Tweet; some tiny bits of new info from the RFH press conference; links to GS-5734 info

Saturday, 8 August 2015

post-Ebola syndrome or just chronic Ebola virus disease...?

The number (y-axis) of confirmed EVD cases added
by each World Health Organization report
over time (x-axis) as of 06AUG2015.
See here for more graphs and tallies.
Click on image to enlarge

There are at least 13,000 people in Guinea, Liberia and Sierra Leone who have survived an encounter with the Makona variant of Zaire ebolavirus (EBOV) since December 2013.¹

But that’s not where the story, or the suffering, ends for these people.

Following the resolution of acute Ebola virus disease (EVD), there is the spectre of a lengthy period of subsequent symptoms, sometimes called ‘post-Ebola syndrome’ (I’d prefer post-Ebola virus disease syndrome or PEVDS), which is similar to that found among survivors from past outbreaks.^2,3

In Uganda in 2007, EVD survivors were more likely than controls to suffer from retro-orbital pain, blurred vision, hearing loss, neurological abnormalities, sleep disturbance, arthralgias (joint pain), memory loss, confusion, difficulty swallowing and chronic health problems.^4,5 These sequelae can reportedly persist for more than two years.⁴

In West Africa up to 50% of EVD survivors report these and other symptoms as well as fatigue, pressure in the eyes, uveitis (eye inflammation), blindness, hair loss, myalgias, swelling, menstrual irregularities, rashes and shooting pains.^6-11 Eye problems have been reported in around a quarter of survivors.¹¹ Anorexia was reported by 98% of survivors in a study of 105 participants with joint pain (87%) and back pain (46%) also common.¹² This study also reported difficulty in short-term memory (27%), headaches (22%), sleep difficulties (19%), insomnia (13%), dizziness (11%), abdominal pain (32%), constipation (14%), decreased exercise tolerance (77%), decreased libido (23%), and sexual dysfunction (20%).¹²There are also issues of stigmatisation, psychosomatic illness and a broader psychological impact among survivors, including depression and post-traumatic stress.^9,12

In at least a few of these instances of PEVDS, viral genome or infectious virus has been detected, sometimes at the site of disease – the eye for example.¹³ Because of this persistence of infectious virus at the peripheries and because of chronic pain, ongoing symptoms of acute disease and also the progression of disease as new symptoms – it may be prudent to stop calling this a ‘post-EVD’ syndrome and recognise this as part of EVD – redefining EVD into an acute phase and a chronic phase.

Much more work is needed to understand what causes the symptoms of chronic and evolving EVD. Some knowledge about the pathogenesis and transmission risks of EBOV is still lacking along with the lack of capacity in Guinea, Liberia or Sierra Leone to culture infectious virus. Physical containment (PC) or biosafety level (BSL) 4 laboratories are not available in West Africa, but are needed to work with known, high concentration samples and pure cultures of EBOV. That requirement appears a little excessive given the large number of humans who have hosted, cared for, tested or otherwise handled massive EBOV loads over the past 20 months – but responding to a crisis and planning to do research (also a much slower process) are two very different beasts.

Keep in mind that one privileged site, the testes, has not been a cause – as far as we know and have actively looked for – of more than a tiny number of EVD cases.¹⁴ We can of course academically argue that any case is one case too many and that one case is all that started this epidemic - but it would be helpful to have a better idea of the true infection risk posed by EBOV in these immune privileged sites, based on the published results of more testing.

In the case of EBOV in the eye (see here), tear fluids were not found to contain viral RNA, so infectious virus does not seem to be a significant risk to other people if contained within an intact infected eyeball – apart from causing ocular disease - but that is based on a single case study.

Apart from testes and the eye (perhaps the foetus/placenta), are any other fluids or tissues harbouring infectious EBOV for extended periods? Could synovial fluid be to joint pain what aqueous humour is to eye problems (h/t @gwendolbowling)? Can we assume persistent viral RNA detection equates to replicating infectious virus (yes, in my opinion)? What is the frequency of persistent infection among the 13,000 survivors? Exactly what anatomical and host factors are involved in persistent infection? Just how long does virus replicate after the acute signs and symptoms of disease have cleared?

Other viruses, for example Dengue virus and Chikungunya virus are known to cause chronic joint issues so this is not totally new ground, but the pathogenesis of that disease is also not nailed down. So, how will new chronic EVD knowledge be useful for other virus infections, including those that we may have not yet have considered to play similar roles at immune privileged sites or may not be typically associated with post-acute disease signs and symptoms?

In June, 2015, the National Institutes of Health in the United States launched the Partnership for Research on Ebola Virus in Liberia (PREVAIL) III study in partnership with Liberia’s Ministry of Health aiming to understand the long-term health implications of EVD.^15-17 There is a similar study in Guinea.¹⁸

As you’d expect, there are not yet any specific licensed antiviral treatments in routine use for persistent Ebola virus infection, just as there are none for acute EVD. But supportive treatment – treating the symptoms of disease rather than the underlying viral (or whatever) cause – is ongoing. Anti-inflammatory eye drops are used…but with caution.¹¹

The EBOV epidemic keeps teaching us new things; a very costly education.

References…

1. Ebola survivor meeting explores research priorities, 'biobanking'. Center for Infectious Disease Research and Policy, 2015. (Accessed 8/8/2015, at http://www.cidrap.umn.edu/news-perspective/2015/08/ebola-survivor-meeting-explores-research-priorities-biobanking.)

2. Kibadi K, Mupapa K, Kuvula K, et al. Late ophthalmologic manifestations in survivors of the 1995 Ebola virus epidemic in Kikwit, Democratic Republic of the Congo. J Infect Dis 1999;179 Suppl 1:S13-4.

3. Rowe AK, Bertolli J, Khan AS, et al. Clinical, virologic, and immunologic follow-up of convalescent Ebola hemorrhagic fever patients and their household contacts, Kikwit, Democratic Republic of the Congo. Commission de Lutte contre les Epidemies a Kikwit. JInfectDis 1999;179 Suppl 1:S28-S35.

4. Clark DV, Kibuuka H, Millard M, et al. Long-term sequelae after Ebola virus disease in Bundibugyo, Uganda: a retrospective cohort study. Lancet Infect Dis 2015.

5. Bausch DG. Sequelae after Ebola virus disease: even when it's over it's not over. Lancet Infect Dis 2015.

6. Free from Ebola, survivors complain of new syndrome. Reuters,, 2015. (Accessed 25/5/2015, at http://www.reuters.com/article/2015/02/04/us-health-ebola-survivors-idUSKBN0L81WA20150204.)

7. It's Like The Story Of Job: Ebola Survivors Who Continue To Suffer. NPR, 2015. (Accessed 25/5/2015, at http://www.npr.org/sections/goatsandsoda/2015/05/15/406748691/its-like-the-story-of-job-ebola-survivors-who-continue-to-suffer?utm_source=twitter.com&utm_medium=social&utm_campaign=thirteenseven&utm_term=artsculture&utm_content=20150515.)

8. Ebola: Surviving Survival - Life after recovery. 2015. (Accessed 25/5/2015, at http://www.msf.org/article/ebola-surviving-survival-life-after-recovery.)

9. Life After Ebola: Pain, Flashbacks, and 'Post-Ebola Syndrome'. Vice News. (Accessed 25/5/2015, at https://news.vice.com/article/life-after-ebola-pain-flashbacks-and-post-ebola-syndrome.)

10. Sierra Leone: Helping the Ebola survivors turn the page. 2014. (Accessed 25/5/2015, at http://www.who.int/features/2014/post-ebola-syndrome/en/.)

11. Ebola Survivors Face Lingering Pain, Fatigue and Depression. New York Times, 2015. (Accessed 8/8/2015, at http://www.nytimes.com/2015/08/08/health/ebola-survivors-face-lingering-pain-fatigue-and-depression.html?smid=tw-nytimesworld&_r=0.)

12. Qureshi AI, Chughtai M, Loua TO, et al. Study of Ebola Virus Disease Survivors in Guinea. Clin Infect Dis 2015.

13. Varkey JB, Shantha JG, Crozier I, et al. Persistence of Ebola Virus in Ocular Fluid during Convalescence. N Engl J Med 2015.

14. Christie A, Davies-Wayne GJ, Cordier-Lasalle T, et al. Possible sexual transmission of ebola virus - liberia, 2015. MMWR Morb Mortal Wkly Rep 2015;64:479-81.

15. Blood, Sweat and Tears: Study Will Watch Ebola Survivors. NBC News, 2015. (Accessed 23/6/2015, at http://www.nbcnews.com/storyline/ebola-virus-outbreak/blood-sweat-tears-study-watch-ebola-survivors-n377256.)

16. Study of Ebola survivors opens in Liberia. 2015. (Accessed 8/8/2015, at http://www.nih.gov/news/health/jun2015/niaid-17.htm.)

17. Ebola Virus Disease Survivors: Clinical and Immunologic Follow-up. ClinicalTrials.gov, 2015. (Accessed 8/8/2015, at https://clinicaltrials.gov/ct2/show/NCT02431923.)

18. Results of the meeting on survivors of Ebola virus disease. World Health Organization, 2015. (Accessed 8/8/2015, at http://terrance.who.int/mediacentre/presser/WHO-RUSH_Ebola_survivor_VPC_07AUG2015.mp3.)

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