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%).12 There 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.)
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.)