Ebola virus disease (EVD) and the human desire to see the worst...

Criticism is easier from up here!

There are those who just seem to enjoy hoping for the worst.

Yes, I'm othering "those people" - I'm invoking a "them" category because their outlook is just too alien for me to understand. I can respect and often understand other points of view, different beliefs and skin colours, clothing styles - all manner of things. But I just cannot understand those who seem to be filled with a macabre desire to see pain and suffering triumph over efforts to defeat it. 

Some of us are lucky enough to live in a free country and write our every little thought and feeling down to share with the world. I'm doing that now. Some use that privilege to say 'I told you so'. There is no room in the lives of some people for mistake, misstep or shades of grey. It's ones and zeroes, yes or no, all or nothing. The binary belief of those so self-assured in their personal opinions that they don't need to look around or experience for themselves any of those roles they criticize; they just know. They can just tell.

Are these personal-views-made-public all that destructive? Maddening though they may be, they probably don;t do a lot of damage, no. Nonetheless I thought it worth writing my own opinion about a related example in a recent opinion piece posted by the New York Post, addressing some aspects of that Ebola virus epidemic you may have heard about during 2014. It's the one causing>18,000 cases (and growing), >6,800 deaths, collapses of already minuscule health infrastructure, deaths of many key healthcare workers, potentially disastrous impacts on birthing, schooling and vaccination programs and bans on festive season gatherings.

The NYP article was entitled "The great Ebola lie — Outbreak hyped for funding & media attention". 

No hype there though. 

The author, Michael Fumento, seemed disappointed and a little angry about a few things. These included:

• that EVD deaths had not reached HIV's 35 million
  That's a really good thing in case you were wondering. This use of an HIV statistic is a bit off though; AIDS is not an acute disease but an acute public health emergency was what the WHO quote referenced. Sure-I'm just playing with words. Also worth remembering that EVD acutely kills >70% of those we know have been infected during the 2014 epidemic. A bit different from the course some pathogens chart. The particular choice of a citation for that WHO quote was also interesting. Firstly, the quote had been used some weeks earlier but secondly the next sentence from the original quote was not present in The Week's article source yet it adds even more context by stating that "Never before in recorded history has a biosafety level four pathogen infected so many people so quickly, over such a broad geographical area, for so long". Together, that does paint a kind of unique picture.

• that EVD did not attain a rate of 10,000 cases per week, starting in the first week of December.
  Also, really good.
  The models have been discussed around social media and in the scientific literature for a while. For example, articles most recently in Nature and in the PNAS discuss how predictive models provide much needed guidance for planning the scale of a satisfactory intervention and predicting as well as gauging the impact of those interventions...among other things. Oh, and that 10,000 cases number was not pulled out of thin air at a press conference, it and more dire predictions can be found in other models including those discussed in Science, the Lancet Infectious Diseases, here and here, the New England Journal of Medicine, PLoS Currents|Outbreaks here and here and the CDC's Morbidity and Mortality Weekly. And elsewhere, if one asks around.

• that 2014's EVD epidemic had already peaked by mid-October when the WHO held a media conference.
  But if you look at more recent data from WHO - their weekly numbers are plotted below - it's pretty clear nothing but Nigeria had peaked. Later data shows that cases were still adding up in Liberia and in fact still are raging in Sierra Leone. Cases in Guinea seem to wax and wane and export travelling cases to other countries fairly consistently. The US was happening and Mali yet to happen. 

Weekly Ebola virus disease (EVD) suspect+probable+confirmed cases by
WHO reporting week, and country.
Click on image to enlarge.

Most of the author's apparent anger seems directed at WHO but also other "big public health" including the Centers for Disease Control and Prevention. The main guts of the article reduce down to...

You’ve been lied to, folks. For months.

But "lie" is specific and well-defined word. Oxford defines a lie as... 

An intentionally false statement

So in the author's opinion, the WHO & the CDC and perhaps others, each conspired by making conscious decisions to lie to the world and promote hysteria in order to...ummm....be rewarded with "billions of dollars"? BigPublicHealths' endgame was really just to make a buck from all that extra funding (much/most of which still hasn't materialized) by hyping up history's biggest ever EVD epidemic.

Or is it more realistic to see it for what it actually was; a (delayed) effort to try and light a fire under a sluggish international community? 

Perhaps all those dollars were part of a costed (perhaps using models?) proposal for a suitable response to fully shut down the epidemic and remove Ebola virus humans in West Africa before everyone gives up? Could it really be that simple? Yup. It sure could. Because a response to an outbreak, even when not in a rich Western nation, is an expensive and big deal. In rich Western nations, it's a lot more expensive and, judging by the response to a couple of cases in the United States, a much bigger deal. So I'm really stumped about the focus for the angst; perhaps there is a deeper reason in the NYP article that I simply missed by being simple. Naah, that's not it.

It's already been said, but just to repeat the point; disease modelling uses the numbers we have to predict what the numbers will be. The numbers we have are already old and cannot tell us how bad things could get. Bodies in the street give us an innate sense of bad, but models put brackets around that in order for cheque signers to get a quantifiable understanding of just how bad things will be tomorrow, next week or next year. Models predict what could be if nothing happens to change the trends extrapolated from the numbers we have in hand. Modelers have no qualms about saying they produce predictions. Models can also do some other stuff like predict how things could improve if we provide help, teach, support, learn and change our habits. In Ebolaville, the models were one part of the support underpinning a new message of urgency  that, it was hoped, would stir a slumbering international awareness - jolt it to life - and elicit the kind of response that, at least partly, eventuated. 

Were we lied to by bigPublicHealth so they could get a huge payday? No, of course we weren't. But we were shown what could come to pass if no funding appeared. Keep in mind that "funding" also includes resources-in-kind such as:

• labs
• vehicles
• planes
• food
• antibiotics
• oral (nasogastric and intravenous) rehydration solution
• pain relief
• personal protective equipment
• awareness & advertising campaigns
• phones and better comms for reporting results
• bleach
• water
• treatment units
• healthcare workers 

And despite the assurances of the author of the NYP article, there are a few past epidemics that have been contained, not by simply disappearing, but because of the heroic efforts of many in public health and patient care roles all over the world....and often with lots of money. Some epidemics have been nipped in the bud before they could bloom beyond an outbreak, thanks to dedicated people...and money. 

Wouldn't it be great if our public health could be protected for free? Sorry. Never gonna happen. The truth about Ebola in 2014 is that we may well have avoided the loss of many of the thousands of souls gone too soon, if we had just got the messages, awareness and money flowing sooner. But we'll never know that for sure.

Anyway, this is my opinion piece.  

Updating a model of a modern Ebola epidemic...

Professor David Fisman, University of Toronto, Canada published one of the excellent recent models designed to estimate where Ebola virus disease case numbers might be heading.[1] He has updated his model using the latest World Health Organization EVD data that includes up to 13-Sept.

This morning I awoke to find the fruits of his labour generously presented to the world via Twitter.

I'm constantly impressed by how much info can and is being provided for everyone to share, discuss and  constructively mull over. This is just the latest fantastic effort.


Prof Fisman's (@DavidFisman) model has provided a very close estimate when compared to the real figures on which it is, of course, based (Figure 1.). His estimates have not changed with the latest data. He calculates an overall R0 of 1.75, and 'd' (a value that can indicate the level of control; when d is zero, you have uncontrolled exponential growth) is at 0.0078. The d values for different countries in the outbreak, differ.

Figure 1. Showing that the model (black line) fits extremely well
to actual reported case numbers (red bars) to date

The projected end date is November 2016 with a final size of approximately 480,000 cases. (Figure 2) This is just based on current numbers and without knowing what interventions are coming not how successful they will be. Prof Fisman says his model currently predicts an epidemic peak in June-2015 at which time there could be 227,000 cases. By Jan-2015, projected case counts reach 28,450.

Figure 2. Extending the model into 2017.
Red curve (right y-axis): incidence by 15-day generation.
Blue curve (left y-axis): cumulative cases.

Keeping in mind that these numbers do not include deaths. The proportion of fatal cases (PFC) requires some further mathematical wizardry in order to account for the time between when cases present to a treatment facility, and when they die. 

Figure 3. Ebola virus disease cumulative curve for Nigeria.
The proportion of fatal cases is markedly lower than for
 the more overwhelmed countries. This does
not appear to be an artefact as most cases have
been laboratory confirmed.

It's not a simple division of deaths and total cases at the same time point (these are the crude percentages I report on VDU and which the WHO report-this reporting may change in the future). 

The addition of that calculation spikes the PFC to >80% at times (see the post by @maiamajumder post on HealthMap), but seems to vary to lower figures depending on country and population for example, in Nigeria (Figure 3). But whatever way you look at it, many people will die from Ebola virus infection, as well as all the other diseases and medical care needs that going with sufficient attention.

References..

1. Early Epidemic Dynamics of the West African 2014 Ebola Outbreak: Estimates Derived with a Simple Two-Parameter Model
   http://currents.plos.org/outbreaks/article/obk-14-0036-early-epidemic-dynamics-of-the-west-african-2014-ebola-outbreak-estimates-derived-with-a-simple-two-parameter-model/

A date with Middle East respiratory syndrome coronavirus (MERS-CoV)..

Click on image to enlarge.
Do regions that host transient high concentrations
of MERS-CoV (or a related virus)-positive animals play a
key role in the sporadic and geographically widespread
human infections?

This article in the Saudi Gazette was referred to me by a kindly commenter to a recent MERS-CoV post I wrote 24-Jan here.

It notes that August (through to December - see Ref #5 below for a lot of info on dates) is the date-harvesting season. When I received this comment, new MERS-CoV case announcements had ceased; a lull which, as I also wrote on the 24-Jan, I could not understand given that there had been no publicized steps to interrupt any type of transmission chain. 

Now we are seeing some publicized cases again, but it's clearly out of sync with date picking season. Nonetheless, I thought it might be worth looking at regional activities that may gather potential animal sources/vectors and humans, together , possibly addressing links in my disease acquisition scheme above; in particular links between dates, bats, camels and humans. No baboons this time around (I'm expecting a Tweet).

Click on image to enlarge.
Buraidah is located slightly north of 
central Saudi Arabia.

Buraidah (Buraydah) hosts the world's largest date festival in August/September and the Qassim date markets are a feature of the region as is agricultural in general.

Buraidah (population >600,000) is the well connected capital of Qassim Region (see map to the left). Qassim region is described as having plentiful water and, clearly, lots of palm trees as well as other fruit trees and wheat. 

Something else Buraidah has going for it? The world's largest camel market. Those are the beauties that seem to frequently have antibodies to the MERS-CoV (or a very similar virus that probably isn't any known coronavirus but reacts really specifically in MERS-CoV antibody-detection assays designed to detect the MERS-CoV but mainly in animals localized to the Arabian peninsula where most human MERS-CoV cases have been documented). Antibodies indicate past (about 1-2 weeks or more usually) exposure to replicating virus, with or without overt signs of disease in the host.

Recently there was also the the "Palm and Tree Date Festival" in Riyadh (15-16 Jan) and the "King Abdulaziz Award for Camels Beauty Contest" (26-Nov to 4-Jan) in Hafar Al-Batin.

I've made brief mention of the possibility of dates having a role in transmission (ingestion, self-inoculation or perhaps aerosolizing virus off bat-contaminated dates during their preparation?) previously here and here.

While this is all speculative, these latter events coincide a little with a small uptick in noted, and "social media suggested", MERS-CoV human cases.

So here's a speculative story:

• A nexus point, like Buraidah, with its central, well-connected location (transportation-wise) serves or once served as an "inoculation station" for susceptible camels exposed to infected bats
• Bats may be more reproductively active or in greater numbers because of higher concentrations of flowering insect-attracting date palms and other fruiting orchards in this region/at certain overlapping times (not actually sure if there is overlap)
• Camels are brought in, sold and then return to herds all over the region. 
• During their time in the markets, some camels become infected with the bat MERS-CoV and go on to infect their herd
• Rarely, humans in close contact with their camels also get infected (it does happen - Ref#7) 
• Rarely, some infected humans infect other humans
• Rarely/frequently (unknown proportion) infected humans become severely ill and "show up" as hospitalized cases who get tested for MERS-CoV. 

As I said, twice, its all speculative and as also I've said, infection events are pretty rare. If nothing else, that bulleted list may address the geographically widespread and rare nature of human case distribution to date.

End of speculation. For now.

Sources..

1. Saudi Gazette story
   http://www.saudigazette.com.sa/index.cfm?method=home.regcon&contentid=20130819177328
2. Date markets
   http://www.youtube.com/watch?v=QJDBDmziikY
3. Tourist information
   http://sauditourism.sa/en/About/Pages/k-Cities.aspx
4. Events and festivals
   http://sauditourism.sa/en/Events/Pages/default.aspx
5. 2012 Al-Rasub article on date festival
   http://www.alrasub.com/ksa-qassim-hosts-worlds-largest-date-market/
6. Many, many date details
   http://postharvest.ucdavis.edu/files/71533.pdf
7. Clinical course and outcomes of critically ill patients with Middle East respiratory syndrome coronvirus infection
   http://annals.org/article.aspx?articleid=1817260

The book of MERS has several chapters yet to write

Epidemic is a big word, and while it generally means "a rise in the number of cases above what you'd expect", you can see from the definitions below that there are many ways to spin the meaning. For the public at large, it generally means "bad scary stuff" and so it's important that we use this word sparingly.

An epidemic is defined by Oxford Dictionaries as:

a widespread occurrence of an infectious disease in a community at a particular time

..or more applicably..

a sudden, widespread occurrence of an undesirable phenomenon

...from Merriam Webster online...

affecting or tending to affect a disproportionately large number of individuals within a population, community, or region at the same time

...from Wikipedia...

In epidemiology, an epidemic (from επί (epi), meaning "upon or above" and δήμος (demos), meaning "people") occurs when new cases of a certain disease, in a given human population, and during a given period, substantially exceed what is expected based on recent experience.

The Middle East respiratory syndrome (MERS) was so-named back in May 2013, and prior to March 2012, there had been no known cases of the coronavirus (CoV) named for the disease it was associated with.

Yesterday we saw a detailed publication by Cauchemez and colleagues in the Lancet Infectious Diseases (LID). Accompanying that was an excellent piece in the Canadian press written by Helen Branswell which included some comments from the authors.

Click to enlarge. 
Accumulation of MERS-CoV lab detections by week (blue
mountain, left y-axis) and the accumulating deaths
(red line, left y-axis). The proportion of fatal cases is slowly
declining as fewer cases have died recently (ratio; black line,
right y-axis). No data exist for ~3 or so deaths and I include
the unconfirmed 2nd case in Kuwait for now.
Feel free to use, just cite me and here.

The key phrase slowly-growing epidemic, used by both, has been not-so-slowly appearing everywhere since then. Does that phrase accurately represent MERS to the world?

Yes, it does. If you have a look at the chart above, its been a steady increase ("blue mountain"), but despite the apparent steep slope of new cases, the steepest part of the mountain, extracted and plotted below, is in fact very linear. A steady but slow growth in cases. No exponential take off. No major deviations. So yes, there is an epidemic. And yes, it is slow. 156 (157 if 2nd Kuwaiti instance is confirmed) cases over 87 weeks in a country of 20,000,000+; a country that just hosted the biggest human gathering of the year (the Hajj) and a country which provides a launch point for around 18,000,000 travelers and a destination for almost as many. 

Click to enlarge.
A slowly growing outbreak of an emerging  coronavirus.
Cases have been accumulating worldwide but at a
linear rate since the week beginning April 7th.
Why the spike from this week? I'm not sure.
Feel free to use, just cite me and here.

But I think we need to be careful when throwing around the "E" word. An outbreak of an emerging virus may still be the best term to describe this chapter in the book of MERS. When someone asks on Twitter "to panic or not to panic"? (this was in reference to the latest MERS-map I posted) then I wonder if the correct message is being conveyed.
Another central message of the new LID paper was a no-brainer; well it was to me but perhaps I'm just too close to it all - in which case take this with a grain of salt.

I thought it was as obvious as the hump on a camel that where 1 case of a respiratory virus infection was detected, others were there to be found. After all, a virus needs us to survive - no us (which means no us actually harbouring infections, acting as a living incubator) then no more cases of the virus). Perhaps that's not obvious at all. Perhaps there is a lack of general understanding that our pathology laboratory systems do not test everyone with illness for even the "standard" endemic human respiratory viruses; that only those presenting to the right place, with the appropriate signs and symptoms, get a sample collected and get tested. This is apparently also true for MERS-CoV-which is by no means a standard virus. Do you go to your doctor if you feel mildly crook? Of course not - you go to work. What if you just have a fleeting headache, a stiff neck, feel a bit hot? Still going to work? Still going shopping? Still packing the kids off to school? Of course you are because we have these all the time and we have an immune system that does a wonderful job keeping it all mostly under control. Life goes on.
But you may be positive for a virus and you are a key part of the transmission chain. You are an incubator. A host.

So if routine testing is not geared towards finding out this extra information how do we find out what's going on in those who are not presenting with kidney failure or pneumonia; a relative small sliver of the population? Someone has to run a research study in which you enrol or get permission from people who are not very ill and sample them. Then you know something new about how widely the virus you are interested in is spread, for how long a person sheds it (if you sample the same person a few times during a month) and even how many other people get it (because all of a sudden your "contacts" become those of a less ill person and the numbers go up and you capture more of a picture of what's happening). So where are the research studies doing this?

When the illness is just some fleeting thing its no real problem. Especially when it's due to a virus we know all about and don't track for public health reasons (we track influenza virus positives, but the reality is you have to be sick enough to be tested in order to add to that pool of data). 

Click to enlarge.
A very exaggerated example of how failing to test mildly ill or asymptomatic
cases of infection in the community may confound our ability to make a link
between cases of severe illness leaving knowledge gaps. These gaps prevent our ability
to track spread of the pathogen and thus interrupt spread of disease.Feel free to use, just cite me and here.

But if that virus is not yet in a textbook, not yet understood, not yet weighed and measured against the viruses we are more familiar with, emerges from an unknown place, is not considered endemic and is often notifiable, then not knowing this basic stuff becomes a major hole in our knowledge and our ability to respond appropriately. This is where we (still) are, 87-weeks after the first known MERS-CoV positive. Guessing (however educated) at what's happening by extrapolation and modelling.

I guess not everyone knows that for every time there is a noticeably ill person infected with a "respiratory virus", it's fair to assume that there will be at least 1 or other who gave it to them, got it from them or got it from the one who gave it to them and who are not as sick or even considered sick at all. For MERS-CoV, they are missed and thus we have no idea how the virus is spreading. Just models. But we can make mathematically supported guesses to back up gut instinct, fair assumptions and logic.

The hallmark of, and big problem with, the MERS outbreak (an epidemic mostly for the Kingdom of Saudi Arabia [KSA]), is that testing has been LIMITED to those who have pneumonia, or another severe disease, and their close contacts. Back in August Memish noted that surveillance was focused on those with pneumonia which was again noted by a WHO representative yesterday.

Why, why oh why not test more people? Why?! Is it because "it's too costly to prospectively test people by RT-PCR unless they are (very) ill"? It might be for some nations, but the KSA is not one of those. 

If you don't test others then you see these modelling publications arise. Idle hands and all that. Yes, it is great to have a model to support what many of us think to be true. And as Fisman and Tuite note in their editorial accompanying the LID article..

..inferences based on the best available data, even if those data are imperfect, allow decision makers to follow optimum courses of action based on what is known at a given point in time.

The question is, can decision-makers sign off on any actions if they don't have actual data? If those data are not forthcoming, how can we ever test the validity of the MERS models?

For now at least, I think we can agree that there is just too little testing to know enough to write more than a few chapters of the MERS-CoV textbook. A book for which we do have a table of contents. Many viruses have emerged before this one and they have each taught us what pages to skip ahead to. Unfortunately, we seem to have a recalcitrant author for 1 or 2 chapters. 

Why palm tress in the MERS-CoV acquisition model...?

Click to enlarge. See more at earlier post.

I have palm trees drawn in as a sort of focus for my hypothetical acquisition model for the Middle East respiratory syndrome coronavirus (MERS-CoV). 

I first posted this graphic back in late August. It shows ways in which humans might acquire/have acquired the (probably) occasional MERS-CoV infection from an (suspected) animal host/intermediate host.

You can probably see from that paragraph, that this is just some crazy thoughts and there are no data that link them together.

I was recently asked why the palm trees? My thinking here was that date palms, and perhaps other flowering trees, may attract insectivorous bats as well as providing shade, and perhaps water if nearby, for animals and humans. This could create a point of cross-over between species - even if they don't directly co-mingle there may be opportunity to come in contact with contaminated excreta, saliva or partially eaten fruit or bugs.

How mice lie....

In a nice 9:40 video presentation to TEDMED 2013, H. Shaw Warren brings us up to speed on some of the shortcomings of using mice to understand our complex human immune responses to bacterial infection.

Some key points he makes are:

1. We use inbred mice. They "all look the same" because they are. That does not capture the diversity of responses to infection that we must deal with in trying to understand human infections
2. Mice are resistant to infection and inflammation requiring lots of material o be injected. This is not what happens in the wild (100-100,000x more resistant than humans)
3. Trauma and burns can be studied by examining gene responses in humans. These studies found poor correlation with mouse models.
4. Mice look very different from us, why wouldn't their immune responses be equally different?
5. Mice have evolved in environments rich in microbial exposures
6. Mice have large litter sizes and short gestational periods which would increase adaptive evolutionary cycles - perhaps they have adapted to tolerate larger inocula than humans
7. Mouse model success often determines whether a candidate drug proceeds to human trials. Some of these may work in humans
8. All of the drugs studied in mice that have worked, have failed in humans (I did not know that)
9. Mice still useful for gene, gene pathways, techniques and toxicity studies but extrapolating to complex human inflammatory disease networks may be a stretch
10. The scientific community should raise the bar in justifying a link between human and mice responses before proceeding

Very nice talk.

Thanks to @MsWZ for tweeting link

Low transmission potential for H7N9 that was....remains to be seen what will be

Chowell and colleagues mathematically model influenza A(H7N9) virus transmission in a new article in BMC Medicine.

They conclude that the basic reproduction number (R; the average number of new cases arising from each exiting case) remained much less than 1 (0.1) for H7N9 infections, indicating the virus from earlier this year did not have pandemic potential. I guess we also know that now because we're not the midst of a pandemic. Good test of the model I guess.

The authors note that their...

..very generic model only requires information on the date of symptoms onset and could be applicable to a variety of emerging infections that include spillovers from a putative reservoir and human-to-human transmission.

Unfortunately, one need only look at the MERS-CoV data to see that those dates can be as rare as hen's teeth (pardon the avian pun) in some instances. Models are wholly reliant on good data.

The authors link the decline in the H7N9 outbreak principally to live bird market closures; but if those controls are relaxed (as they have been, I believe)....we hold our breath to see what re-emerges as the weather turns colder, birds intermingle and humidity changes. If indeed any of those things are what might lure out a new round of animal-to-human infections.

A model of MERS-CoV acquisition (ver1)

With thanks to David Spalten (@dspalten) for discussion and considerations and AtRG for advice.

First we heard about Middle East respiratory syndrome coronavirus (MERS-CoV)-related viruses in bats in South Africa, then we read of antibodies in camels that reacted to MERS-CoV more than the most likely (known) other CoV to infect cattle, and most recently we were absorbed by the discovery of a probable parental strain of the MERS-CoV in the faeces of a Taphozous perforatus insectivorous bats.

We've also heard that most patients have not had direct or obvious contact with bats and we also know that pasteurised camel milk products should be safe. But that still leaves many stones unturned.

So if we can assume that the most likely route of acquisition of MERS-CoV is through the upper respiratory tract and that the spillover events come from animals (I'm including human-to-human exposures in this figure) then we need to consider how that might happen. I've included the animals above as well as baboons as they seem highly mobile, interact well with humans, visit mountains and caves (where bats are likely to hang out") and are found in the KSA. I've added ingestion but I don't really imagine how this could result in a respiratory infection, and MERS-CoV gastrointestinal involvement seems infrequent.

I don't live in the Kingdom of Saudi Arabia or in the Middle East and I do not profess to know much of the environment so what follows is "remote guestimation" at best. But I've thrown together some of the possible routes and animal players into a figure which may have some degree of reality buried in there somewhere. It may also spark an idea or two among those who do know what they're talking about.

So, here is my model of how humans may indirectly get a zoonotic infection from a primary or secondary animal host...

A model of MERS-CoV acquisition. Click to enlarge.

I'd be most happy to take suggestions for improvement of the figure. I know some of you like to use the graphics from the blog and Virology Down Under (which I strongly support, asking only for a specific reference to their source) so if they can be made more robust, I am very happy to do so. Get to me via the comment section below or on Twitter (see top right).