Monday, 23 February 2015

Transmission of Ebola viruses: What we know and jumping the black swan

Last week a review was released entitled Transmission of Ebola Viruses: What We Know and What We Do Not Know. The review, which is listed in the Opinion / Hypothesis section of mBio, was penned by by Michael T Osterholm and a large team of Ebola experts. You may know him from such articles as What We’re Afraid to Say About Ebola and What we should — and shouldn't — be worried about regarding Ebola or his entertaining seminar at the Johns Hopkins Bloomberg School of Public Health Ebola forum.

First up a few random points from me...
  • This is basically a good review of the historical literature on transmission of Ebola virus and some other ebolaviruses. By the way, this literature is based on real experience, observation and experimentation, defining our understanding of how Ebola virus has transmitted among humans.
    It's worth noting that there have been no concerns made public, nor any new transmission data from the epidemic in West Africa, which indicate changes in the way Ebola virus spreads from person to person
  • This review is an opinion/hypothesis piece so it has a lot of room to move. The language fairly clearly defines where the thinking strays into areas without any actual data to support them. Look for phrases with words like "possible", "could", "postulated", "may", "suggesting" and "can"
A quote from the new review by Osterholm
and experts. Highlighting is mine.
  • Does anyone actually care whether we use words like aerosol, airborne, droplet, droplet nuclei, wet droplets or propelled to mean "not by touch"? I'm not sure any more, but I think they should. Words have meaning and slightly different words carry subtley, yet importantly different meanings. It's important to keep in mind who the messages relating to public health should ultimately try and reach - that would be the public. Experts, comparatively few in number, already have an innate sense of the differences between the words above, right? Right?! Well, many do anyway. Trying to change language or redefine a target in the midst of an epidemic, is at best bad timing and at worst it seems self-serving (although to what end I cannot guess). 
Suggested ways in which an ebolavirus can spread from a known EVD case to a new person. The most likely route is suggested by the thickest arrows with solid outlines while the least likely or most improbable route is indicated by the thinnest arrow with a dashed outline.
Click on image to enlarge.

  • Ebolaviruses are not just blood-borne viruses in humans like HIV is for example; they are not just gastrointestinal viruses like norovirus (although droplets play a role here too); they are not considered by anyone to be airborne viruses like influenza virus
    What they are, in a transmission sense, is a hybrid of the first two - reaching high loads in the blood and the gastrointestinal system. To me, these shared features make it more clear why a different level of personal protective equipment (PPE) is needed than would be considered essential for caring with patients with just one or other type of virus
  • One distinct viral group may remain infectious for a longer period, shorter period, or not at all compared to another distinct viral group, in droplet nuclei - the air-dried (gel-like mix of proteins and salts..and infectious or non-infectious virus) form of droplets that have not yet hit an object or the ground.
  • The figure of just 1-10 viruses being required for an infection to take hold has generously been bandied about during the Zaire ebolavirus (the EBOV|Mak variant) epidemic of 2014/2015. But some overlook a simple component of this apparently easy infection process; 1-10 viruses landing on a cell is not the same as 1-10 intact infectious viruses being emitted from an infected host, travelling out of the host's infected cells in a drop of blood, semen, urine, sweat, saliva, diarrhoea or vomit, retaining infectivity while passing through various environmental conditions, onto a new host's mucosal surface, perhaps indirectly via a hard surface, getting past that body's innate immune defences and eventually attaching onto and gaining entry into that new host's cell, successfully replicating within it and then infecting neighbouring cells to establish a new infection. It may take thousands or hundreds of thousands of viruses in that initial drop of infection material to get those 1-10 infectious virus particles to start a productive, symptomatic human infection.
    We know little about this part of the story outside of the laboratory
  • On that theme, there is much in general we still do not know about the ebolaviruses and Ebola virus disease (EVD). Direct contact with virus-laden fluids or a needle-stick injury are still considered to be major routes for acquiring an ebolavirus infection but direct mucosal contact with propelled droplets may occur at distance further away than the old 3ft/1m rule.(6)
    Truly airborne dried or semi-dried droplets that contain sufficient infectious Ebola virus, can be inspired and can result in an upper or lower respiratory tract infection that progresses to become systemic EVD in humans....have yet to be found. They may contribute to infections, but it will be very hard to prove that this is a transmission pathway that exists as a thing separate from droplet transmission. The authors sort of note this difficulty too; both droplets and droplet nuclei result from coughs, sneezes and explosive vomiting and diarrhoea.
    The suggestion that droplets are produced from the respiratory tract and then inhaled by another person (6) resulting in EVD is really straining the use of "improbable"
  • I've written about some of this stuff before - on the distinct issue of Ebola virus and pigs here, on droplets and droplet nuclei here, the complexities of contact here, on seeking some better words here and on previous versions of this theme by some authors of this latest review here and here and I'm not going to rehash all of that here! I invite you to read those posts
Mixed messages..

A problems I have with this review is this line in the abstract..
We also hypothesize that Ebola viruses have the potential to be respiratory pathogens with primary respiratory spread.
While Osterholm and expert colleagues round off the review by clearly stating that airborne ebolavirus transmission is an "improbable scenario", and that droplet transmission is plausible (I don't disagree with the latter statement), parts of the rest of the review struggle to tow that line quite so clearly. The media seemed to have struggled to find that message too..

It is 'very likely' that the Ebola virus will spread through airborne particles, experts say
Daly Mail

Limited airborne transmission of Ebola is ‘very likely,’ new analysis says
Washington Post


..although one bright light in the gloom managed extremely well..

No, A New Scientific Report Does Not Say That Ebola Is Now Airborne
Vice News

Prof Vincent Racaniello noted in his blog post about the review that we understand what viruses do now, by what we have observed them to be capable of doing in the past

Do ebolaviruses actually have the potential to shift to a primary method of spread that occurs via droplets or droplet nuclei and spread like a rhinovirus, influenza virus or the measles..to name a few? If no virus which we humans have ever watched has changed its method of spread so dramatically before, why would this particular one do it now? Well, why wouldn't it, you may well ask? Because it takes more than some genomic mutations and drift to do this. At some point we need to remember that each virus comes with its own toolset and it doesn't usually have a lot of replacement parts or upgrades in a satchel over its capsid. It can only tweak its component parts so much and so far before it reaches the limit of what it "is". Could one virus become another virus? Maybe it could. I look forward to becoming Superman myself. What would it take to overcome whatever biological throttles have existed on the ebolaviruses prior to so much human spread, for a virus to stop spreading primarily by fluids resulting from certain host disease processes, to being spread mostly by inspiration of respirable droplets? Certainly something we've never seen before and something in need of a utility belt and  can of bat EBOla repellent. Again, we're not just talking about some "genotypic changes"; the ebolaviruses would need to accumulate a plethora of stable genetic changes to make that sort of transition, possibly in combination with changes in the disease processes within its host...us.

An opinion by any other title...

Despite the review being an opinion piece, it seems to have some trouble owning up to its own real opinion; that Ebola viruses can spread by a new route and cause new disease. The title really should have reflected the content better in this regard. In approximate number 5,800 words included 440 (8%) on animal transmission studies which are mostly about aerosol spread; 925 (16%) devoted to defining aerosols and droplets and trying to change the paradigm; 670 (12%) about what we need to learn, which includes some content on aerosol transmission; 670 (12%) on a respiratory transmission hypothesis. So a sizable chunk, nearly half of the content, is heavily focussed on educating us abut Ebola and aerosol transmission. The topic is additionally reinforced within every other section as well. So why hide what the article was really focussed on; not the general transmission of ebolaviruses, but transmission via an as yet unproven-route? The authors note that an "aerosol" contains all the different droplet sizes and degrees of droplet wetness and that this entire range is propelled out of us via cough, vomit, diarrhoea and by  aerosol generating mechanical procedures. We agree on that bit. But once the bigger wetter droplets fall away and one is not standing unprotected within their range, is there an infectious virus left in the drier smaller droplet nuclei which are held aloft by air currents until they impact with something or someone? 

Have we ever seen Ebola virus infections caught by people walking into a room after an infected case has left it...as is the case for measles or rhinovirus, truly airborne transmissible viruses? Or is droplet spread only occurring in close proximity to the source? This is another point the authors raise-that being close to someone who just vomited may result in breathing in larger droplets that are infectious but have not yet fallen to the ground. How will we ever know that this is not a propelled droplet instead? Explosively coughed or vomited material can travel a sizable distance as well? So we still await some evidence to support the musing that inhaled droplets carry infectious ebolavirus in them, and that they are distinct from the more likely impacting of propelled droplets. Propelled droplets are likely a key reason that updated PPE guidelines recommend against any exposed skin and the use of eye protection, gloves, boots and a respirator; the yellow suits that will forever be linked to EVD in West Africa. But even those suits don't support that Ebola virus has been, or is showing new signs of, spreading primarily via a respiratory route?

What I could not find in this new review was a more thorough discussion - and some hypothesis and opinion - of the risk associated with how healthcare workers acquired their infections when outside of Ebola treatment units or in western hospitals. Also absent was opinion on the practical risks of semen remaining infectious, or harbouring viral RNA as was found in 2014 in a returning asymptomatic convalescent man [3] (sexual transmission has not been documented [11]). I would very much have liked to read some hypotheses on the role infectious urine might play in urban settings lacking no sewers and with densely co-located populations, since urine has been shown to remain infectious for longer than blood, in a detailed case study from Germany in 2014.[3]

Wrap up...

So to summarize, coming into contact with virus-laden body fluids either by touch, perhaps via an intermediate surface (a fomite; unproven) or by having these fluids propelled onto you (as yet unproven), are considered the main risk factors that comprise the overwhelming majority of human-acquired ebolavirus infections. Current PPE guidelines are designed to combat these and if western hospitals are any guide, they work well - although it's a tough comparison given the different carer-to-patient ratios in western hospitals compared to outbreak conditions in west Africa. 

What role "respirable droplets" or droplet nuclei play in transmitting ebolaviruses between humans awaits evidence but nothing points to a role for an airborne route of infection in west Africa.[6] Hopefully some studies will be looking very hard at this question. Nothing hints at any changes in  EBOV/Mak that could result in it becoming a "respiratory pathogen with primary respiratory spread" capability.

I recommend reading a few other recent reviews and articles to get a more rounded view [7,8,10,12] and if you want to see droplet, aerosol and airborne get smooshed together into an undifferentiated mess, that's in print too.[9]

References...
  1. Transmission of Ebola Viruses: What We Know and What We Do Not Knowhttp://mbio.asm.org/content/6/2/e00137-15
  2. Experts suspect Ebola virus sometimes spreads by air
    http://www.cidrap.umn.edu/news-perspective/2015/02/experts-suspect-ebola-virus-sometimes-spreads-air
  3. A Case of Severe Ebola Virus Infection Complicated by Gram-Negative Septicemia.
    Kreuels B, Wichmann D, Emmerich P et al.  N Engl J Med. 2014 Dec 18;371(25):2394-401
    http://www.nejm.org/doi/full/10.1056/NEJMoa1411677
  4. Ethical issues in isolating people treated for Ebola
    http://www.ncbi.nlm.nih.gov/pubmed/25588871
  5. 2007 guideline for isolation precautions: preventing transmission of infectious agents in health care settingshttp://www.ajicjournal.org/article/S0196-6553(07)00740-7/pdf
  6. Ebola virus disease in Africa: epidemiology and nosocomial transmissionhttp://www.ncbi.nlm.nih.gov/pubmed/25655197
  7. Understanding Ebola Virus Transmission
    http://www.mdpi.com/1999-4915/7/2/511
  8. Chains of transmission and control of Ebola virus disease in Conakry, Guinea, in 2014: an observational study
    http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(14)71075-8/abstract
  9. Ebola, through air or not through air: that is the question
    http://www.ncbi.nlm.nih.gov/pubmed/25646157
  10. Review of Human-to-Human Transmission of Ebola Virus from the US CDC
    http://www.cdc.gov/vhf/ebola/transmission/human-transmission.html
  11. Sexual transmission of the Ebola Virus : evidence and knowledge gaps
    http://www.who.int/reproductivehealth/topics/rtis/ebola-virus-semen/en/
  12. What we know about transmission of the Ebola virus among humans from the WHO
    http://www.who.int/mediacentre/news/ebola/06-october-2014/en/