Monday, 29 September 2014

The numbers are underestimates...

Ebola virus numbers.

Sorry but D'uh - yes the numbers during the Ebola virus disease (EVD) outbreak happening since December in Guinea then progressing to Sierra Leone, Liberia, Nigeria and Senegal....are an underestimate. 

Of course they are! 

How could they possibly not be?

Have you not watched a single documentary or news video detailing how heartbreakingly difficult it is to visit and help the people of West Africa, to characterize and gather those case numbers, to take, transport and test samples?

The suspect cases are an underestimate. 
The probable cases are an under-estimate. 
The fatal cases are an under-estimate. 

The only thing that is spot on is the laboratory confirmation numbers, because they are what they were when someone wrote them down having had some semblance of control over the steps to acquire them. 

But let's put that underestimation into context. 

"The tip of the iceberg"
Image originally provided by Gregory Haertl, WHO.
Click to enlarge
Influenza case numbers each year are also an under-estimate. 

In fact, some of those, the subtyping numbers, are deliberately so because it's too expensive and wasteful to subtype every single laboratory confirmed case - so a sample of cases are tested and that is assumed to reflect the subtype distribution for that region during that period. 

But seasonal influenza case numbers as a whole are a huge underestimate. Influenza does not drive everyone to a general practitioner nor to a hospital. Some infections with influenza virus don't even produce noticeable symptoms at all. They are still infections. They just don't get counted. So influenza A virus, possibly the most tracked of any respiratory virus, is underestimates. And that's okay. 

Well, measles too, in the respiratory virus department. 

The latest big bad is the species D enterovirus 68 (EV-D68). But the paltry few detections of it (identified by genotyping) that have reported across the United States are likely a monstrous underestimate. In fact we have very little idea of a normal denominator for EV-D68 detections so it's hard to even know if 2014 is seeing all that big a change in its spread and distribution. Usually the enteroviruses (includes rhinoviruses) cause common cold-like illnesses and only get sought out in the great detail from a research point of view.

Middle East respiratory syndrome coronavirus (MERS-CoV) cases or the emerging influenza A(H7N9) virus cases are all underestimated as well. 

The population of your state or country is an underestimate too you know?

This is because we cannot capture every single case of infection, or person, at once. 

So the next time you are about to say "the WHO numbers are an underestimate" as if that is a revelation or an unexpectedly horrible thing you can also lay at their doorstep - please just don't. It's not smart, new or unusual.

You might as well say the world is round; underestimation of infection numbers is just that well established a fact. It's just by how much, and frankly that doesn't even matter too much because the trends can usually be easily seen, or quickly extrapolated.

Perhaps you did not know all that before. But if you have read to here, you do now.

The control gap...

v2 300914
I have a theory.

This theory is meant only to apply to disease outbreak/epidemic/pandemic situations, and then only to those which include fatal cases.

This theory of mine has only emerged since I've been plotting Ebola virus cases numbers from the West African epidemic. I precede the explanation with the caveat that there is very probably already a well developed, well-known actual epidemiology term to describe this theory. But I'm not a trained epidemiologist and this is just a blog, so please forgive me my ignorance.

The theory goes that when a gap grows between the number of new cases being reported and the number of deaths or laboratory confirmations in that population, despite the outbreak having been going for a while, this represents an indication that control of the situation is slipping, or has been lost. 

Mind the gap.

This "control gap" - my term, so don't expect to find it anywhere official or that knows of that which it speaks - can also appear when looking at suspected or probable cases of disease X, and the number of those that have been confirmed by a laboratory test.

Other explanations for the control gap may exist of course; testing may be scaled back deliberately, reporting of deaths may have been deliberately throttled for some political reason. So it may not reflect being "out of control" as much as someone else being "in control".

Probably still more variations that I have not thought of at all.

Ebola virus disease (EVD) in Liberia.

In the graphics below I've used the accumulation of World Health Organization data for Liberia, up to 23-Sept. 

First up - the fold increase in total case numbers (suspect+probable+laboratory confirmed) compared to the fold-increase in the distance between that total and the total number of laboratory confirmed cases alone. This distance, or the "control gap|lab", has widened over time. It has widened because total cases have climbed more steeply than the number given a laboratory confirmed diagnosis of EVD. 

For whatever reason(s), laboratory confirmations are not keeping pace with the total case numbers, and they seemed to start slipping at the end of July. 

I suspect a principal reason - and I'm not on the ground of course, so this is all speculation and second-hand knowledge - is that laboratory capacity is overwhelmed. 

Other reasons include that samples might not always be collected or that many recent clinically defined EVD cases are actually due to something clinically similar to EVD, but not an Ebola virus infection. If it were this last one though, the total numbers would be readjusted downwards as new diagnoses were made...if the laboratory has time to make those of course...so I doubt it as a major role.

The control gap|lab
A.) Ebola virus disease case graph for Liberia showing the accumulation of total (suspect+probable+laboratory confirmed) cases (pink line; left y-axis) and deaths (blue line; left y-axis), the laboratory confirmations (green line; left y-axis) and the proportion of fatal cases (right y-axis) at each reporting date (x-axis). The size of the gap between laboratory confirmed cases and total cases is indicated for a range of reporting dates, using a vertical green drop-line.

B.) The drop-lines have been copied and aligned and the amount they have grown has been measured using a scale bar so that the fold-increase can be compared to the first reporting date used, 8-July. The fold-increase value is written at the top of each drop-line. Along the bottom (enclosed within a grey box) are the case numbers at each reporting date examined and the fold-increase (in bold) compared to the 8-July baseline.


Next up -the fold increase in total case numbers (suspect+probable+laboratory confirmed) compared to the fold-increase in the distance between that total and the total number of deaths. The control gap|deaths comparison finds that the deaths and the total cases don't diverge as much as total cases and lab confirmations do. 


The control gap|deaths
A.) Ebola virus disease case graph for Liberia showing the accumulation of total (suspect+probable+laboratory confirmed) cases (pink line; left y-axis) and deaths (blue line; left y-axis), the laboratory confirmations (green line; left y-axis) and the proportion of fatal cases (right y-axis) at each reporting date (x-axis). The size of the gap between laboratory confirmed cases and deaths is indicated for a range of reporting dates, using a vertical blue drop-line.

B.) The drop-lines have been copied and aligned and the amount they have grown has been measured using a scale bar so that the fold-increase can be compared to the first reporting date used, 8-July. The fold-increase value is written at the top of each drop-line. Along the bottom (enclosed within a grey box) are the number of deaths at each reporting date examined and the fold-increase (in bold) compared to the 8-July baseline.

So with that visualization under our belt, there is another, less laborious way to look at this, by graphing the numbers, rather than the gaps.

What we see when we plot the fold-change values against report date is that total cases lost control as we suspected, but deaths are less obviously out of control. From 9-Sept onwards the gap has widened a little more consistently. Before that though the deaths did not dramatically drift away from the rate at which new cases were being added.

I'll graph Sierra Leone, Guinea and Nigeria in the next day or two. Nigeria should serve as an example of how this looks for a country in which EVD is definitely in control. 


Graphing the control gaps


Friday, 26 September 2014

MERS-CoV data request: A response from the Ministry of Health

Four days after I posted a blog requesting missing data on retrospective Middle East respiratory syndrome coronavirus (MERS-CoV) detections and deaths, I received a response. 

Dr Anees Sindi, Deputy Commander of the Command and Control Centrer, Ministry of Health, Saudi Arabia replied. With his permission, I have reproduced his reply below.
______________

Sent: Tuesday, 23 September 2014 6:36 PM
To: Ian M Mackay
Subject: Re: your request for missing data on retrospective MERS-CoV detections

Dear Dr. Mackay,

I’m writing in response to your blog posting entitled “A request for missing data on retrospective MERS-CoV detections.”

Thank you for acknowledging the steps that the Ministry of Health’s Command & Control Center has taken to ensure members of the public -- including researchers around the world -- have access to real-time information about MERS-CoV cases in the Kingdom of Saudi Arabia.

These daily postings are a small step on our journey toward full transparency. We want scientists to have access to the data they need to produce meaningful publications that advance our understanding of this disease for the benefit of mankind.

With that in mind, I am happy to inform you that the Ministry of Health is in the process of preparing additional data for public release. I will follow up with you once we have a confirmed release date.

Collaboration with the international research community is a key pillar of our work. In addition to sponsoring more than 30 research projects focused on MERS-CoV, the Ministry of Health has opened its doors to academics and experts from the World Health Organization and U.S. Centers for Disease Control & Prevention. MOH shares more data with the WHO than is required under the International Health Regulations, and we stand ready to support other scientists with an interest in better understanding coronavirus.

Thank you again for your interest in our work.


Best Regards,

Dr. Anees A. Sindi
Deputy Commander
Command and Control Center, Ministry of Health
Saudi Arabia


______________

This is fantastic news and I am very excited to hear that we may soon be able to complete the data picture for MERS-CoV. 

I am most grateful to Dr Sindi, the Minister and the Ministry for taking my request seriously and for replying to it so quickly.


With these data in hand, many of us will be able to build better epidemiological picture of the timing, spread and impact of MERS-CoV over the past 2 years as well as more specifically quantify MERS among fatal cases. 

These data do not answer all the questions we have of course, but they definitely answer some, and for that I'm thankful.

This social media thing does seem to have some impact.

Monday, 22 September 2014

Ebola virus, HCWs infections and personal protective equipment..

Co-authored by Dr Katherine Arden.

No one could offer anything but our deepest and most heartfelt thanks and a feeling of pride in the selfless, essential and humanitarian work being done by healthcare workers (HCWs), both local and international, in West Africa.

But they have paid a high price for this work, as they always do in emerging disease outbreaks.


WHO Ebola virus disease
numbers up to
14-Sept-2014
Of the >5,300 people reported as infected by the West African variant of Zaire ebolavirus (EBOV) to date, around 315 have been HCWs. Both numbers are very likely an underestimate. Half of the HCW cases have died. I don't know just how many HCWs there are in Guinea, Liberia and Sierra Leone who are dealing with the EBOV outbreak. I do know that these deaths are as horrible as each of the losses among non-HCWs, and are also worrying for those trying to recruit the many more HCWs needed to expand care of ill patients.


This week a commentary article on the Centre for Infectious Disease Research and Policy (CIDRAP) website delves into this issue by suggesting an improvement to HCW respiratory protection.[1]


Two quick things first:

  1. The World Health Organization (WHO) defines human transmission of Ebola virus as being by direct contact (between mucous membranes or a break in the skin and the blood and other body fluids of an infected individual via physical contact or by wet material being propelling onto mucous membranes or skin breaks) and by indirect contact via contaminated surfaces.[3,4]
  2. When dealing with patients, the WHO recommends wearing gloves, a disposable impermeable gown to cover exposed skin, a waterproof apron over any gown that is not impermeable or when undertaking strenuous activity, facial protection to prevent splashes to the nose, mouth and eyes including a medical mask + eye protection (visor or goggles) or a face shield and medical mask.[3]
The CIDRAP article's authors claimed a belief that there is scientific and epidemiologic evidence that Ebola virus has the potential to be transmitted via infectious particles. Unfortunately they don't make a convincing argument to support their belief-nor could they, since no data currently exist to for any claim that an Ebola virus is transmitted between humans by an airborne route. So we're left with a commentary based on those beliefs, and some speculation.

Some collaborators and I wrote about Ebola virus not being an airborne virus based on what we know and what's been done to answer this question before.[2] I'll first add that if it were an airborne virus, we would likely be seeing many, many more cases-"Compared to this Ebola outbreak, the H1N1 swine flu had already spread to an estimated 10,000 times as many people in its first 10 months" noted United Kingdom virologist Ben Neuman.[13] H1N1 being an influenza A virus; a real airborne virus. In our post, we noted that big wet droplets (part of an "aerosol"-a messy term that may not be well understood by the public...or some scientists...that includes big wet droplets and small rapidly drying droplets) can be propelled at a mucous membrane or fall to the ground to contaminate surfaces.


A schematic of the makeup of an "aerosol".
From [2]
Big wet propelled droplets can contain infectious Ebola virus and are included in the established risk messaging. Hence the need for droplet precautions.

We also know that from every human aerosol, after the heavy larger droplets fall to the ground or impact on a surface, the remaining lighter droplets very quickly dry to form droplet nuclei (these can be gelatinous, gooey, or water-free). It's these droplet nuclei that can linger for hours or more in the air. We know that droplet nuclei can be made to contain infectious Ebola virus under lab conditions[8] thus droplet nuclei produced by an infected human may contain Ebola virus. We can't say with certainty that they do or do not. However, as far as we have been able to tell, infection of humans and resultant disease from inhaling lingering droplet nuclei, has not occurred. And when an airborne route was investigated using infected and uninfected non-human primates housed nearby but without direct contact, no infection via an airborne route was found to have taken place.[9]


When putting one's faith in the belief that a different piece of PPE will prevent or significantly reduce HCW infections, one has to wonder if that will empower a false sense of security among HCWs in the field where the infections are happening. Most of the studies looking at aerosol of Ebola virus do so in temperature and humidity-controlled laboratories with lots of lab grown virus.


And relying on one added component raises a few questions for me:

  • Could the faith in this one extra precaution threaten the very important, meticulous care required when donning, using, and removing contaminated PPE-of any sort?
  • What role does a lack of the basics, like soap and clean water [10], play in HCW infections?
  • Could an additional extra safety measure really have a major effect on reducing the known risks involved with treating Ebola virus disease (EVD) patients, such as the long hours, tiredness, the constant and pervasive tension of imminent exposure, the oppressive heat, delirious and sometimes violent patients and the ease with which one can self-inoculate?[6]
  • Does the extra safety measure even have a role in reducing risk associated with HCWs who are unknowingly infected while not wearing PPE?[7]
How much do the things listed above, mostly unrelated to having a hi-tech battery-powered breathing apparatus on your hip, contribute to the tally of HCW infections?

Glaringly, the authors overlooked mentioning that early on, many HCWs may have had few or no masks at all and few other essential barriers such as those listed by WHO above, to protect against direct contact. They also did not mention the lack of HCW training in the use of any of that equipment if available, and did not highlight the lack of experience HCWs had dealing with EVD patients. These HCWs had (and may well still have) direct contact with very ill EVD cases, and got infected. What fraction of HCW infections resulted from absent or incomplete PPE and training versus the HCWs that they believe became ill while wearing full droplet precaution PPE?



Embedded image permalink
MSF designed suit of PPE.
Graphic tweeted by the
Washington Post.[5]
Others have also made note of the disparities between the imagery of a biosafety level 4 (BSL4) laboratory researcher working in a negatively pressurized, airlocked laboratory within a tethered, airtight suit (probably unnecessarily high precautions [13]) versus highly biocontained single patients being shipped home on dedicated planes (kept somewhat contamination-free using isolators) to rich nations for specialized support and treatment versus Médecins Sans Frontières (MSF) workers who use respirators (specialized face masks that fit more snugly and contain more layers to better filter what is breathed in) instead of surgical masks versus the WHO recommendations of standard precautions which include a surgical mask. Notably, the WHO recommendations vary according to the type of risk one is exposed too [see pg 96-7 96 of the 113 pg PDF at [3]).[10] There clearly is a range of thinking and messages here. But equally, there are a lot of different applications to cover, and no way for every need to be specifically catered for by one guideline. If everyone could agree on such a thing anyway.

I share the concern of many over the deaths of HCWs in West Africa. They may still be unnecessarily exposed to virus due to the lack of enough PPE. They may not have enough training to understand how easy it is to become infected. They may not be given the message that during an EVD outbreak as monstrous and different as this one, many heavily populated areas have been included for the first time resulting in very real risks of infection occurring outside the hospital setting, not just inside it. There are also real risks of infection in supposedly EVD-free hospital settings like maternity wards.[11] There are many, many non-airborne related risks for HCWs.


We freely admit that we are not trained in the use of PPE for treating Ebola patients; just for working with actual respiratory and blood borne viruses in PC2 & PC3 laboratory settings, respectively. Still, some may find this post irrelevant.
By all means stop and read that disclaimer on the right about this blog not providing medical advice. You come here of your own free will and this blog is not part of any Organization's reference list when they write PPE guidelines...because it's a blog.

But for what it's worth, I would follow the MSF lead if working in the battlefield of a 100+ bed treatment facility. In an ideal world with unlimited and readily available resources, a more roomy and breezy head covering that allows patients to see your face and which can be worn for longer periods would be useful. You can see an image, provided by 3M, of this battery-powered air-purifying respirator (PAPR) accompanying the CIDRAP post.


However....first and foremost, and well before we get to this level of hair-splitting based on speculation and belief and no evidence of an airborne virus-I'd be wanting to make sure there was a minimum level of disposable PPE actually available for use by every HCW and the appropriate education about how to use it and about all the risks for acquiring EBOV infection.

Reasons for HCW infections are many and varied. As much as we may believe or wish it were so, no single act or change will circumvent these risks nor these infections.


References..

Saturday, 20 September 2014

MERS risk reduction and signs of illness to watch for during hajj and umrah...

I love a good infographic and this one ticks a lot of boxes for getting a clear message out about the Middle East respiratory syndrome (MERS) disease and how to avoid catching and spreading the MERS-coronavirus (MERS-CoV).

Thanks World Health Organization.


World Health Organization poster describing risk of infection
 and how to identify when you might have MERS.
Of course, I'd be happier if the poster specifically suggested putting more distance between people and potentially infected camels, rather than just avoiding "close contact".

Granted, close contact can include spending time in the close, but not physically connected, "personal space" of a camel. But "close contact" is, in my opinion, one of those infectious disease terms that needs to be made more simple and clear. Like "aerosol" and "airborne", "close contact" gets a little lost when translated to the people who are at actual risk from infection.

Friday, 19 September 2014

To the Saudi Arabian Ministry of Health: A request for missing data on retrospective MERS-CoV detections

From: Ian M Mackay

To: The Office of the Minister of Health, Kingdom of Saudi Arabia

I write to humbly ask for your help on a matter of infectious disease communication. I ask that you please consider completing the already near-complete public data picture for all retrospectively confirmed cases of Middle East respiratory syndrome coronavirus (MERS-CoV) that have occurred on your soil. I ask that this be publicly released for analysis, and suitably acceptable citation, by all. The Ministry of Health has already made a number of advances in tracking and communicating new cases of MERS-CoV, addressing criticisms along the way. But there remain some small but epidemiolgically important gaps in an otherwise complete set of data that could be easily closed.

Today, the 19th of September, I make note of the Command and Control Center announcement of the discovery of 19 MERS-CoV cases, identified after retrospective analysis of cases.[1] This adds to the 113 MERS-CoV detections announced 3rd June 2014.[2] I also note the reference to removal of a duplicate case and two false positive cases. In addition to these items, there have been many identified deaths that cannot be linked to publicly announced cases because key date data are no longer published along with the time of death announcements, as they once were (see example [3]).

So I ask if it is possible for you to publish a minimum set of deidentified details from cases that have not been fully described by the World Health Organization Disease Outbreak News reports. I suggest an open access spreadsheet on the CCC website.  I do not ask that any compromising or identifying data be included nor do I believe there is a need for identification of hospital or treatment facility. I would be happy to help identify these cases if that could be of use. 

These data include:

  • Age
  • Sex
  • Date when symptoms began
  • Date of hospital admission
  • Date when a fatal case was first reported (allowing a link to be made)
  • City where case likely acquired

The Command and Control Center website and its updates on contemporary MERS cases have evolved into an essential global asset for many international researchers and for the global public, each of whom are still trying to understand this emerging virus. What I suggest here would add even more reach and value to your efforts to keep us all informed. 

As the custodian of over 90% of MERS case data, the world wholly relies upon your transparency, good will, expertise and willingness to openly share it. I believe a complete set of MERS-CoV data have great potential to engage more researchers from around the globe. These links may help identify new and interesting patterns that could be of use to Saudi Arabia and other Middle East and African nations trying to improve control of MERS-CoV now and in the future.

Thank you for reading this.

Yours sincerely,

Ian M. Mackay, Ph.D.
Virologist
Science communicator
ian.mackay.im (at) gmail.com


  1. http://www.moh.gov.sa/en/CCC/PressReleases/Pages/Statistics-2014-09-18-002.aspx
  2. http://www.moh.gov.sa/en/CCC/PressReleases/Pages/mediastatement-2014-06-03-001.aspx
  3. http://www.moh.gov.sa/en/CCC/PressReleases/Pages/mediastatement-2014-05-24-001.aspx

Thursday, 18 September 2014

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/





Monday, 15 September 2014

Happy 2nd birthday Middle East respiratory syndrome coronavirus (MERS-CoV)...

Its been 2-years since Prof. Ali Mohamed Zaki sent his email to ProMED notifying them of a novel coronavirus. That email was published 20-Sept 2012.[1] 

A year ago we had 138 cases and 58 deaths. Today we have 856 cases with perhaps 306 fatal (36%).

I won't rehash what I said a year ago - I invite you to check that out over at the 1st birthday post.[2]

Suffice to say the past year has been, to my mind anyway, mostly about:

  • Camels
  • High level job "shuffling"
  • Controversial parallel publications
  • Very problematic infection prevention and control issues.
The latter leading to the relatively huge number of MERS-CoV detections and deaths in Saudi Arabia and to some exported detections and cases. The one constant over both years has been that the MERS-CoV is a pitiful spreader among humans. MERS-CoV is nonetheless a virus that is very capable of inducing fatal outcomes, especially among older males with underlying diseases.

Has MERS-CoV gone away? No. Of course it hasn't. MERS has, mostly. That's the disease, not the virus. For now anyway MERS cases are sporadic, although still geographically widespread. 

MERS cases fell to zero cases per week for a number of weeks this year following containment of the Jeddah-2014 outbreak. Nonetheless, this is a virus of camels that seems to  spread, rarely, to humans and when in us, it has not been in any rush to mutate into the pandemic SARS-like threat many once worried about. 

Camels are where this virus likely remains. And there have been no signs that that has in any way changed. The latest information suggests camels have been harbouring MERS-CoV for at least 30-years.[3] This, as with a great deal of the research to date, is knowledge gained mostly thanks to the efforts of international research teams and their funding

So Happy 2nd Birthday you opportunistic, spiky little killer. I'm once again wishing Dr Zaki well and congratulating him on co-parenting the birth of this novel coronavirus. This year I also wish Prof. Ziad Memish well and congratulate him on seeing the infant virus through to toddler age.

Oh, and 2-years on, I still see no sign that the contentious patenting issues were any sort of hindrance to diagnostics or actual research. Just sayin'.

References...

  1. http://www.promedmail.org/direct.php?id=20120920.1302733
  2. Happy 1st birthday Middle East respiratory syndrome coronavirus (MERS-CoV)http://virologydownunder.blogspot.com.au/2013/09/happy-1st-birthday-middle-east.html
  3. MERS Coronavirus Neutralizing Antibodies in Camels, Eastern Africa, 1983–1997
    http://wwwnc.cdc.gov/eid/article/20/12/14-1026_article

Sunday, 14 September 2014

The proportion of fatal cases (PFC)...

This is excerpted and altered a little, from a more influenza A(H7N9) virus slanted article to be found here. But I think it deserves its own page.

In July 2013 I coined a term on VDU to avoid the use of the term Case Fatality Ratio/Rate/Risk (CFR). 

My term was the Proportion of Fatal Cases (PFC). I use the term on VDU and have published it an article.[1] I have no expectations that anyone else will use it although I notice it made an appearance in a HeathMap story[2] by Maia Majumder.

The PFC is a percentage calculated as the currently known number of fatalities divided by the number of total lab-confirmed cases including fatalities, regardless of whether surviving cases are inpatients (hospitalized) or outpatients.

The PFC is just a number - it's not meant to imply that every case that ever happened is included - it never could. It does not account for those cases who will die later on, either directly or indirectly, as a result of their infection but who may be alive at the time of calculation. 

The PFC is a snapshot to be used before an outbreak is done and dusted. It is meant as a guide to what is happening right now using the data we can get our hands on. Sometimes that means lots of data and sometimes they are very limited or just plain behind closed doors.

The CFR makes use of the number of recovered cases in its denominator.[3] So it's important to know survivor numbers. As suggested above, this requires that all the people who will recover from their infection, have recovered (and been discharged) from their infection. 

Using the CFR early in an emerging virus/disease outbreak, when what usually brings in outbreak to our attention is death, is great for selling papers, but not helpful realistic in a bigger picture sense. 

The CFR is most useful at the end of an epidemic/pandemic, but not so much when data-in-hand is poor during the early days of many outbreak. 

Of course, some will take a PFC and multiply it by the world's population as an estimate of how many are going to die if the virus reaches pandemic levels. That's not helpful or accurate. Just accept it as that snapshot of what's happening now.

References...
  1. J. P. Dudley and I. M. Mackay. Age-Specific and Sex-Specific Morbidity and Mortality from Avian Influenza A(H7N9). J. Clin. Virol. 2013. Nov;58(3):568-70. ePub Sept.
    http://www.ncbi.nlm.nih.gov/pubmed/24091087
  2. http://www.healthmap.org/site/diseasedaily/article/estimating-fatality-2014-west-african-ebola-outbreak-91014
  3. http://en.wikipedia.org/wiki/Case_fatality_rate

Saturday, 13 September 2014

The wind beneath my Ebola virus.... [UPDATED]

Only a couple of weeks ago the report in Science presented 99 genomes representing some of the thousands of those circulating in Sierra Leone this year.[1] I say thousands because each infected person has a range of subtley different viral variants among the billions of viruses per millilitre of blood that all compete to be the champion. The words "mutant" and "ebolavirus" are now hard to avoid. And of course as soon as you talk mutations, you can only see one endgame - a virus that is easily transmissible and turns us all into zombies. spreads across the world in a pandemic and kills as many as 80% of those it infects. Yes, its seems the proportion of fatal cases (PFC) in West Africa may not be as simply calculated as most of us were thinking these past months. When we take into account that Ebola virus disease deaths occur in people that were part of a case tally days earlier (if they were counted of course) when the total case numbers were smaller, the PFC inflates. How much, we don't really know.

And so the story of mutants was brought full circle today thanks to Dr. Michael T. Osterholm. In a very nicely written piece for the New York Times,[2] Dr. Osterholm, ventured behind the scenes to crack the door into the world of whispered discussions, shadowy frappé meetings by chino and beige blazer-wearing figures, many of whom were men with with thinning hair. Yes, he found where the real virologists hang out and what were they discussing at length? Why they were talking about how soon it would be until Zaire ebolavirus was going to mutate and become an airborne killer virus identifiable only through watching big wall-mounted LCD screens as they are rendered in red because of the fusion of rapidly growing dots, spreading across a map of a world filling rapidly with infected hosts. Or red dots. Or something. Okay, some of that was from me.


Only problem is, I think he may have entered the tinfoil hat room next door to the (but very similarly attired) room full of virologists. Maybe not. Hard to tell sometimes. But seriously.


For sure, a virus changes over time. It will change randomly through mutations that happen because viruses, especially those with genes/a genome made of RNA, are always making errors in their gene/genome copying and sometimes those errors make the virus better at something. Viruses may hold on to those changes in response to all sorts of pressures on them. These genetic sequence changes sometimes results in change to the proteins that make their structures and enzymes. Sometimes the changes may revert back as pressures go away or new ones come to be. It's a constant micro-environment of change; evolution on fast forward.


We should also keep in mind ebolaviruses didn't come down in the last shower. They are viruses that are happy in their own envelopes...and natural host(s). But mutational changes can impact on how the viral "bits" assemble and release from the cell and perhaps on how the virus causes disease, where virus replicates in the body, how it interferes with the host immune system's attempts to interfere with it, how hardy it is, how well it replicates in response to temperature and so on. 


A virus doesn't "think" about any this of course. It doesn't plan to do the nastiest thing to us that we can imagine when it jumps into us from an animal (a zoonosis). Headlines might make you think otherwise. These changes happen because, in a new host species producing many subtley different viral variants all vying for supremacy, the virus with the mutation(s) that allow it to get out from under some sort of controlling pressure or to do something better than the earlier viral versions, wins the day. The winner thrives, makes more of itself or does it better, and passes to new hosts.


A virus may keep more of these mutational changes while it is "settling in" to a new animal host species if they help that process. It may be under more pressure to adapt to slightly different environments, different receptor structures, temperatures, immune responses - all sorts of things may created a different environment from the one the virus came from and so it may need to make use of more mutations in order to "find its footing". Or fail and not find a home in the new host.


There can be all sorts of new and negative pressures to try and avoid or adapt to for a virus. So ebolaviruses seem to naturally infect bats, not us, and in bats the infection does not seem to cause a whole lot of disease. Of course we don't know a whole lot about how bats spread virus among themselves. Perhaps they do it via an airborne route. The theory then goes that humans or other forest animals including chimpanzees, gorillas, porcupines and antelopes may eat the bats or bat/virus-contaminated fruit. We, and those animals, do get sick.


Another unsure thing, a sizable knowledge gap you might call it, is whether an ebolavirus would actually be under any pressure at all to keep the mutations that change its proteins, site of replication and disease course which result in it being:

  • More stable in dried droplets
  • Shed in higher concentrations from the upper respiratory tract
  • Able to trigger more coughing or sneezing.
Each and all of these major changes might be necessary to create the mythical airborne Ebola virus. The outcome? Creation and propulsion of more droplets from an infected human, that dry down and linger in the air (the airborne part) while still containing infectious ebolavirus, and enough of it to result in human infection and disease. Phew. That is an unbelievable series of huge changes, even for a "sloppy" replicating RNA virus. 

I think we all understand that a virus doesn't "know" that these changes would provide better spreading outcomes and we now know that Ebola virus already spreads very well between bats and in humans (see the West Africa outbreak numbers which have not at any time been linked to a different or unusual spread of virus compared to any earlier outbreak[11]). To date, airborne spread has never been found to happen naturally in the dissemination of Ebola virus disease in humans. That is some kind of significant considering it does not take a lot of virus to start an infection through direct contact and considering there have been non-human primate transmission chains in the forests for a long time.

Each of those changes to the virus and the host's disease might happen by a series of accumulating mutations over time. But is their pressure to keep each of them? And really to be airborne, these changes would need to co-occur and do so without any trade-offs that meant the 'new airborne virus' was negatively impacted in some other area of its attachment, cell entry, replication, interference with the immune response enzymatic efficiencies etc. 


We do already know that in the lab, under laboratory conditions, with lab animals, lab equipment, plenty of lab-grown virus and a closed space with a lot of aerosol (probably some of which is wet droplets, not just droplet nuclei, meaning not truly airborne conditions), an Ebola virus can be forced to infect non-human primates. I've written about that previously.[3] 


And yet even when it was sought, no sign of such airborne infection has been found to occur naturally among humans. Direct. Contact. 



So I think it was a stretch to expend so many words on the chances of an airborne virus emerging rather than one that causes more bleeding, or less diarrhoea, or more vomiting, or more shedding in sweat, or having lower viral loads, more rash, more hiccups etc. 

Many additional things could result from mutational changes. We know next to nothing about the mutations recorded from the 99 genomes in Sierra Leone.[1] So why all this focus on one specific yet really quite complex outcome of viral air travel instead of many/any others? I don't know. But hey, now we have indeed been able to talk about this aspect some more, so good one Dr O! 


Others have come out to comment too. 


  • Dr Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases in the US noted that "it’s fundamentally unlikely"[9]
  • Dr Amesh Adalja, University Pittsburgh said "it may not be the best path for the virus to take"[10]
  • Dr Derek Gatherer of Lancaster University in the UK noted an airborne Ebola virus would need a "conjunction of coincidental, unlikely events" [10] 

  • Dr David Heymann, Chair of the Health Protection Agency in the UK stated "No one can predict what will happen with the mutation of the virus", reminding us that "The virus's epidemiology is consistent with transmission via bodily secretions and excretions, which is exactly the same as other past epidemics".[11]
  • Prof Vincent Racaniello, a virologist at the College of Physicians and Surgeons at Columbia University stated "We have been studying viruses for over 100 years, and we've never seen a human virus change the way it is transmitted."[12]

Dr Osterholm did hit some other nails flush with the timber though. West Africa needs fewer promises to defeat Ebola virus and more plans that include actual rapid mobilization and on the ground experienced leadership to make inroads into getting beds for sick people and tracing contacts. Two key items on a long list of things to do better (in my opinion).

Thankfully some promising signs are appearing. The scope of this outbreak has now been guesstimated - 20k-100k cases.[4,5,6,7] I list this range rather than extending it to much higher levels [8] because I do still have hope that things will improve and interventions will turn the exponential case growth curves away from the sky and back to the horizon, sooner rather than before entire nations are destroyed. Because that's what is coming without successful intervention.


Money is being freed up and arriving from all over and more resources are slowly moving in to the region. Resources needed just to keep the people safe who have come from all over the world, including the nations of Africa, to care for the overwhelming numbers of sick and sickening people. Not to mention the money needed to prevent more infections. More specific and insistent pleas for defined numbers of healthcare professionals are also being broadcast. Drugs and vaccines are closer than they have ever been to use in humans. They may be our only hope to stop this virus.


If the many thousands of people predicted to die from a virus that is killing 4 in 5 confirmed cases (see the Medicins Sans Frontieres tweet below) is not enough reason for stopping the spread of Ebola virus, then stopping this particular evolving variant before it does change into something worse or more ingrained to the communities all over Africa and beyond, really is. 


While this Ebola virus variant may never make the changes necessary for it to go airborne, it has shown signs of relatively rapid change and that was relatively early in what looks to be a very long chain of human-to-human-to-human-to-human... transmission. Each person allowing the virus to adapt further, if that's what it needs to do.


Such a long transmission chain, from 1 animal>human infection, has never been recorded before and so we are indeed in new territory when it comes to the ebolaviruses. For now at least, the Ebola virus in 5 countries in and around West Africa has the upper hand. This tiny self-assembling unthinking, randomly mutating thing is totally dependent on our cells to replicate itself - and we are not doing enough to starve it of those cells. 


It clearly doesn't "need" to be airborne to spread efficiently.


References...
  1. http://www.sciencemag.org/content/345/6202/1369
  2. http://www.nytimes.com/2014/09/12/opinion/what-were-afraid-to-say-about-ebola.html?smid=tw-share
  3. http://virologydownunder.blogspot.com.au/2014/08/ebola-pigs-primates-and-people.html
  4. http://currents.plos.org/outbreaks/article/estimating-the-reproduction-number-of-zaire-ebolavirus-ebov-during-the-2014-outbreak-in-west-africa/
  5. 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/
  6. http://healthintelligence.drupalgardens.com/content/predicting-number-cases-ebola-virus-disease-outbreak-countries-widespread-and-intense
  7. http://news.sciencemag.org/health/2014/08/disease-modelers-project-rapidly-rising-toll-ebola
  8. http://www.dw.de/ebola-threatens-to-destroy-sierra-leone-and-liberia/a-17915090
  9. http://time.com/3342305/airbone-ebola-not-happening/
  10. http://news.yahoo.com/could-ebola-become-airborne-153701091.html
  11. http://www.dailymail.co.uk/health/article-2753421/Real-risk-Ebola-virus-mutate-AIRBORNE-disease-expert-warns.html
  12. http://www.vox.com/2014/9/19/6543157/ebola-is-unlikely-to-go-airborne