World War Z: a study in extreme epidemiology.

I saw this at the movies Thursday night. I really enjoyed the movie - really delivers on its zombie promise and adds the story of a father trying to look after his family.

It struck me though that it's also a great story of what would happen if, instead of anthropomorphising viruses into beings that wish to do things...you gave them a pair of legs and let them decide what to do...which it turns out is to transmit, transmit, transmit! So, some irreverent thoughts on how a Z virus might fit in the current context of virus outbreaks..

1. Diagnosis would be a doddle. No need to painfully design, optimise and validate a catch-all PCR for the virus based on one sequence you got from the internet, or to keep that assay ahead of mutation-defeating viral evolution. There would be pathognomonic signs of disease - eyes rolling back into the patient's head and turning white, a strange web-like pattern of blood vessels under a pallid skin tone, very bad teeth, spasmodic limb and jaw movements, disregard for personal safety when colliding with objects at speed, an ability to rapidly accelerate, disregard for heights, a hideous squeally noise on inhalation (which also prevents the virus from spreading stealthily) and the very urgent need to bite any piece of you that it can. Any 3 of these should be a diagnostic triad.
2. Molecular epidemiology won't be necessary to track viral change. Nor will it be possible in the time you have left. No need to find the best and most diverse gene segments to sequence, no reason to use next generation/high throughput sequencing to characterize the entire genome, create phylogenetic trees and look for the impact of a multitude of tiny amino acid changes....because, you know, who cares how much worse could the virus get!?
3. Monitoring virus transmission will be much easier. Turn on the TV or radio and follow how many countries have not yet been over-run. Oh, and that banging on your door is probably not someone asking you to switch your power company or coming to talk to you about religion.
4. Calculation of the basic reproduction number (R₀) should be made much simpler. It would be any number >1, rising continually until someone can successfully enact sufficient cranial damage upon the infected case. Definition of a super-spreader becomes much more obvious. Oh, and there are no asymptomatic cases.
5. The need to argue about and decide upon the best way to calculate a Case Fatality Rate\Ratio would be relaxed. Every case dies...unless they already have a fatal disease. There is no time for hospitalisation...and anyone left in the hospitals wants to bite you.
6. No need for arguments about, and delays due to, Material Transfer Agreements. Every country has its own cases, no-one wants to claim sovereign rights over the virus and there is no longer a biotechnology or manufacturing industry left to profit from diagnostic kit or antiviral developments down the track. The track has been eaten.
7. Some of the variables needed to grow the virus for in vitro study are well defined: inoculation period-12 seconds to 10 minutes; favoured temperature-your body's; preferred cell type: does it really matter at this point?!
8. Animal models are no longer needed for disease studies. Human models are plentiful. Unfortunately there won't be time for ethical approvals and no way to get informed consent. Additionally, your lab will need a large plexiglass-enclosed holding chamber in the middle of it. No real need to study transmission methods through. Generalising to "transmission occurs via a bite" is probably enough - the number or bites or whether a small bite is as effective a transmitter as a big one may be a study for another day.
9. Treatment options are limited to removal of the bitten area along with 10cm of the neighbouring tissue. Do so within 5 seconds of infection or else look for a source of acute cranial trauma.
10. Prevention is also limited to inoculation with a deadly micro-organism...or having a pre-existing terminal condition. The former will be easy to find in any WHO research facility apparently, just look for a cold room vault. Any vial of serum-coloured, non-frozen liquid, adjacent to a drawer of syringes, should do the trick. Probably best if you can find an antibiotic or functioning antiviral somewhere first.
11. Detailed date data on illness onset and death are unnecessary - they will likely be the same day and probably today, or perhaps yesterday. This also removes frustration that your only information on new infections comes from cases being published through the scientific journals...rather than mainstream or social media.

Make you wonder?

Read More

Two new MERS-CoV cases in the Kingdom of Saudi Arabia.

I'll have to update the numbers and graphs again as a second announcement from KSA today identifies a 41M from Riyadh and 59F from Al-Ahsa governate, both in intensive care units.

This brings the total to 90 cases, 78.9% from KSA (also claims 86% of deaths, of those with identifying data) 7.8% from UAE, 61.9% with data are male and the PFC falls further to 50.0%

Read More

MERS-CoV proportion of fatal case chart.

Finally got around to this graph, one of my favourites from those I made for H7N9.

It shows the change in "Case Fatality Rate" (or PFC as I've taken to calling it here) over time. You will be able to see the graph more clearly on the MERS-CoVpage later today. It shows the very changeable PFC. Currently it is declining as death reports have slowed while the number of laboratory detections, including more that are mildly ill or with no signs and symptoms at all, continue to rise.

Read More

Latest article from CIDRAP: new H7N9 animal studies & comment from VDU EiC.

Shameless self-promotion - but very cool when someone asks for your opinion about something you are interested in.The CIDRAP article by Lisa Schnirring covers the newly released paper by Zhang and colleagues of the Prof Hualen Chen's uber-group at the Harbin Veterinary Research Institute, China.

To quote myself...to myself....

The study reinforces that even 'lowly' or inefficient transmission-only 33% of ferrets, for example-is still transmission," Mackay said. "That proportion would lead to a lot of human cases in densely populated or frequented areas.

And just look at these numbers: 10,703 samples from 30.03.13-02.05.13, collected from poultry markets in all the key H7N9 provinces and municipalities. All (I said all!) were inoculated into eggs. 238 influenza viruses (136 Newcastle disease viruses as well) of which 52 were influenza A(H7N9) virus. They then sequenced the complete genome of 37. Phenomenal work.

While I am no expert on what each and every influenza mutation does (I'm thinking about making a table on the flu page), I was interested in how closely related all the genomes were (<4% nucleotide difference between them all) and that the major differences are at the level of amino acid changes. Also, there were no amino acid changes noted after animal inoculation or transmission. Does this mean the virus is already happy in its own skin?

Although highly similar, the most diverse genomes (those with <99.5% identity to the H7N9/Anhui/1 strain) came mostly from the Shanghai principality. Does that mean anything in terms of site of ground zero? The site of "youngest" viruses perhaps? PB1 seemed to be the most variable H7N9 segment in terms of nucleotide differences.

In the future it might be informative to look at genetic comparisons of complete H7N9 genomes from mild/asymptomatic cases and those from moderate/severe/fatal cases. As well as considering what other viruses and bacteria are in these two groups and whether virus:virus or virus:bacteria interactions may play a role in more severe outcomes.

And this study confirms that of Belser (see below) - if you're a mouse, don't get H7N9!

I haven't looked myself, but it would also be useful to know whether the recommended H7N9 PCR-based assay targets remain conserved in the latest genomes.

Read More

MERS-CoV count reaches 88 [UPDATED].

The addition of 2 new cases in the KSA and 4 in the UAE (2 asymptomatic and 2 mild illness) lowering thePFC to 51.1%.

[UPDATE] According to Crawford Kilian's latest info, the four UAE cases are all Doctors caring for the recent 82M case (FluTracker's Case #82 coincidentally). Does this qualify as a super-spreader, 1 case and 4 transmitted infections?

Read More

MERS-CoV cases #82 and #83 are mildly ill outpatients.

Hat tip to Crawford Kilian.

Two new MERS-CoV cases reported on the Kingdom of Saudi Arabia's Ministry of Health website.

Both cases are from Asir (Southwestern KSA), the 42F (F=female) is possibly a healthcare worker and the other, a 26M, had contact with another MERS case. No dates. No details of which case.

The KSA has now hosted 86% of known MERS-CoV cases. 64% of all cases with data being male. The new PFC is 53.6%.

Read More

The first MERS-CoV novel is almost written!

And Crawford Kilian, in releasing his inner editor, has the complete framework.

All that's missing is one monkey with a disproportionately amount of blood from which we can purify vast quantities of antibodies to cure new and existing cases...and reverse any existing tissue damage, and remove the likelihood of any sequelae. Okay. So this is why I'm not a writer. Expository dialogue indeed.

Now go read this entertaining article - Crawford is a writer.

Read More

(formerly pandemic) H1N1 is a seasonal influenza virus these days.

Some people look aghast when I suggest a pandemic virus could now be "just" a seasonal virus...but here is the word from the H�rtl's mouth...

.@pandemie6 #h1n1 is no longer a pandemic but a seasonal virus. it is to be expected that it returns in winter.
� Gregory H�rtl (@HaertlG) July 17, 2013

Printed words from the mouths of others, including some good points, can be found here.

Read More

WHO declares no eMERSgency?

Hat tip to Master Corin Mackay for title help.

The 2nd meeting of the International Health Regulations (IHR) Emergency Committee concerning MERS-CoV, convened by the WHO Director General with a new special advisor added (Ms Karen Tan, Senior Director, Public Communication Division, Ministry of Communications and Information, Singapore) and several affected State Parties (France, Germany, Italy, Jordan, Kingdom of Saudi Arabia, Qatar, Tunisia and the United Kingdom) on a party line, unanimously decided not to declare a Public Health Emergency of International Concern (PHEIC). 

The Committee will reconvene in September, or earlier if needed. By September we'll have given the MERS-CoV every chance to spread by providing it with millions of people to jump to, from wherever it comes, at the hottest zone of infection, the KSA. If cases do not take off after the Hajj, one would think the immediate risk for a MERS-CoV pandemic would drop significantly.

Based on these views and the currently available information, the Director-General accepted the Committee�s assessment that the current MERS-CoV situation is serious and of great concern, but does not constitute a PHEIC at this time.

Read More

A drug to stop rhinovirus (HRV) infections in patients with chronic obstructive pulmonary disease (COPD)?

For those who don't know, the HRVs are the most frequent infecting agents (that we know of) of the human upper (and perhaps lower but that work is not done) respiratory tract (URT).The first HRV was isolated in 1953 in the UK and the viruses were soon burdened by the label "common cold viruses". This was largely because early studies were conducted in adults who generally have milder outcomes.
There are about 77 genetically distinct HRV-As, 60 HRV-Cs and 30 HRV-Bs - that's nearly 170 distinct viruses (includes serotypes and genotypes)! Imagine 170 distinct coronaviruses.

In the past they were classified by the type of cell they infected/receptor they used into major (most of them used ICAM-I as the receptor) and minor (the rest; use VLDL-R as the receptor) groups. Sequencing is the preferred method to classify them today.

The receptor for the HRV-Cs remains unknown and they do not grow in routine cell lines instead needing more advanced culture methods. Because of this, studies predating 1988 (the first published PCR primers) generally don't account for the HRV-Cs, even though they were there and causing infections.

A.Prof Eva Kathryn Miller and I recently reviewed the HRV-Cs in some detail. Around 70 distinct HRV genotypes can circulate at a single place over a year...depending on the population being studied. I and others have found that to be the case in both the community and in hospital-based populations.

A recent article from Yamaya and colleagues suggests that a mucolytic drug (stimulates surfactant production and release to help the airways clear themselves of gunk) might be of use in treating HRV infections in COPD patients at least.

Exacerbations, which are mostly due to viruses, are the main contributor to disease burden in patients suffering from COPD, as they are in those with asthma.

The drug, ambroxol hydrochloride is already thought to reduce the frequency of URT disease and may reduce ICAM-I expression. The authors tested this using a major group HRV, HRV-B14 and found reduced release of virus, ICAM-I levels and reduced viral RNA levels.

Prophylactic use may inhibit HRV-B14 infection and modulate the inflammatory response to infection. Many of the differences were moderate (mostly arithmetic rather than logarithmic), albeit statistically significant.

It would be interesting to see what effect the drug has on other major group HRVs, minor group HRVs and on the hard to culture HRV-Cs.

Read More

Crack commando epidemiologists, swab shipping and bat bums.

I'll leave you to read the content that this derives form on Crawford Kilian's, ever entertaining blog.

Read More

What threat of an eMERSgency: its all in the language.

A thought-provoking piece from the keyboard of Helen Branswell on the language the WHO are lumbered with, to describe something that currently accounts for 0.000001% of the world's population.

Read More

MERS-CoV numbers by area - UPDATE.

Let me preface this release with the statement "I hate doing this!" "This" being the use of data that are the best I can find, but not the best we could have. I've been spoilt by H7N9 which, at least initially, but not lately, was filled with dates. Seems like the only dates being publicly discussed in relation to MERS-CoV cases are those the bats may be contaminating.

However, the number of cases without any obvious dates of illness is steadily climbing towards half of all cases so I've decided to bite the bullet and make a second graph of MERS-CoV cases by site of infection to highlight the increases.

The new update uses Dates of Onset (DOO) where available but is augmented by Dates of Reporting (DOR) for the remainder (still missing 1 case). While this is inaccurate, it does serve the purpose of showing where the cases are accumulating from, and roughly how quickly that is happening, at each location.

As an example of how the two datasets compare, I've excised a part of my Excel sheet to show you that the trends (left column = new chart data DOO+DOR; right column = DOO data only) remain, even if the numbers change. It also highlights the biggest cluster of missing DOOs which dramatically to increase in number after the week beginning June 9th. Anyone know why or what changed?

The new chart, produced with my thanks for the extra dates found at Flu Wiki's MERS-CoV page, will be placed, in a larger size, above the current version that uses only DOOs, on my MERS-CoV page, and both will be kept updated.

Read More

ProMED in need...

Many of us get important early, validated global information about emerging infectious diseases, disease outbreaks or novel cases from the Program for Monitoring Emerging infectious Diseases (ProMED) email alerts.

ProMED mail lies between those sites which never seem to close down and constantly update us about infectious diseases (I'm looking at you awesome FluTrackers) and those more heavily-moderated representatives of larger bodies, such as the WHO's Disease Outbreak News.

But nothing comes for free and so to maintain the ProMED website, mailouts and Tweets, they run an annual ProMED-mail Internet-A-Thon. MERS-CoV...hate that guy?....well it's discovery was announced to it's 65,000 followers via ProMED mail.

That's just one example of information that made a tangible difference to the speed with which the world could respond to an unknown pathogenic entity.

Only 235 people donated last year, surely we can do better than that in 2013!

I strongly recommend donating today, right now even. I just did. It's PayPal enabled (link above) and it couldn't be easier to give to this, the only open-access, scientifically and clinically moderated collaborative source of information of its kind.

Read More

Resp virus causing gastro but little respiratory symptoms...

Hat tip to Secret Squirrel D for this.

To add to my first two post's today,this paper by de Jong and colleagues in the New England Journal of Medicine details a 4-year old male (4M) who presented with a 2-day history of fever, headache and diarrhoea which after admission progressed; cough, then to coma and death.

4M was found to have systemic influenza A(H5N1) virus infection (viable virus was isolated from cerebrospinal fluid, throat and rectal swabs and were RT-PCR positive).4M and his sister (9F who died 2-weeks previously but had no diagnostic specimens collected) were diagnosed with acute encephalitis.

Chest X-rays were normal and 4M exhibited some lung sounds suggestive of infection after transfer to a paediatric referral hospital and he went on to respiratory failure.

This highlight my earlier points: respiratory viruses could spread from gastrointestinal disease and encephalitis has a lot of causes in addition to the usual suspects.

Read More

India's Acute Encephalitis Syndrome (AcEnSy).

Hat tip to Crawford Kilian for the idea from his earlier post

According to an excellent article at the New York Times and from regular articles on PubMED and Crawford Kilian , there is an annual epidemic of encephalitis of undefined origin that sweeps through India peaking around mid-May, each year.

It is not clear what is being routinely tested for ("known causes of brain swelling" is not very informative) or what resources are available to the laboratories and patients in this region(s) of India. Some detailed postings to emerging disease sites like ProMED might attract some suggestions and encourage much needed discussions in an open forum that could help the hunt.

There are many infectious potential causes of such disease and from the article, many, many potential sources for acquiring such pathogens, which includes a wide range of viruses. Some of these viral culprits have only recently been discovered - the picornaviruses - klassevirus, parechovirus cosavirus and the Saffold viruses - among many better-known viruses.

The NYT article notes that the US CDC is collaborating on a project to seek a cause(s). Hopefully that will yield solid leads before another year passes and more children succumb. Beyond financial issues underpinning PCR-based diagnostic testing, it is hard for me to understand why this has not been tackled in a collaborative manner, earlier. Obtaining basic knowledge ("what is causing this disease?") may not be a sexy topic for grant funding, but it is the cornerstone on which a solid public health foundation is built.

To know and understand what bug (I mean virus, but I include bacteria!) you face you could:

• Screen for known bugs using existing PCR assays
• If unsuccessful, hunt using next generation sequencing technology
• Characterise the culprit if it's new or if it's a variant of something already known - get the genome, feed that information back into assay design to make sure your assay works properly and that the first hit wasn't luck, design a second and third assay to different regions of the genome to provide detection redundancy, continue searching to find all the strains
• Create serological assays to determine the nature of infection by measuring antibodies
• Incorporate the new target into the existing diagnostic menu - and keep revising that menu
• Publish the results, update your peers, modify your patient management and advisories and include social media to keep everyone up-to-date.
• Do lots of other high-tech research which I know only a little about, to understand what the virus does in, and to, its host

Without the tests you can't know what's contributing to disease (circular I know) and without knowing it's contribution, how will you ever get expensive diagnostic kit and drug design research off the ground?

Read More

A great way to spread gastrointestinal viruses?

Readers of this blog will have read my comments about those occasions when we get virus infections that do not make us sick - so-called "asymptomatic" infections.It won't take a great leap of understanding then to see the potential for contact, droplet and aerosolized spread of such infections from a person who is suffering from vomiting and diarrhoea due to another cause.

In this instance, read the story Crawford Kilian posted on over-eating as a cause for hospitalisation during Ramadan. Given that we know respiratory viruses (it's a given that gastrointestinal viruses are!) can end up being shed through the intestine on occasion, and we know that viruses can reside and be transmitted through droplets and aerosol (which can remain suspended in a room for some time, with their tiny passengers remaining infectious), this could be an inadvertent cause of new infections, especially among healthcare workers but also other in- and outpatients visiting hospitals that may already be over-crowded.

With incubation times extending up to 12-days or so, these sites in the Persian Gulf States may see a spike in such infections in less than a fortnight.

Read More