Biggest Middle East Respiratory syndrome coronavirus (MERS-CoV) case study to date

Assiri and colleagues from the Kingdom of Saudi Arabia (KSA) today described, in The Lancet, the clinical characteristics of 47 cases of MERS-CoV. The largest detailed analysis of MERS-CoV cases to date.

This report includes 20 cases more than that 27 reported previously by these authors, along with additional information on the first 27. 

The paper opened by noting that clinical data are scant and suggest that's because of the small number of cases since it appeared 15 months ago. The case numbers include all 90 known MERS-CoV cases. 1 new case was announced today.

Some key points from the paper...

• Nasopharyngeal swabs, tracheal aspirates and bronchoalveolar lavage specimens were taken by attending doctors
• Since June 15,  MERS-CoV has been detected in 16 ( 17.5% of the current tally of 91 cases) asymptomatic people as a result of screening contacts
• The authors note the need for rapid and accurate antibody tests to apply to case-control studies
• 45/47 (96%) of  cases had 1 or more comorbidities with diabetes, chronic kidney/heart disease and hypertenstion the most common among surviving cases
• All but 2/47 were citizens of the KSA
• Fever and cough were found in >83% of cases with shortness of breath in 72%
• Nausea, vomiting  abdominal pain and diarrhoea were present in 17-26% of cases
• Runny nose was rare (4%), sore throat (21%) and cough were occasional (dry-47%; productive-36%) and headache, chest pain and coughing blood were present in 13-17% of cases
• Chest X-Ray was abnormal in all cases
• Neither blood nor respiratory sample from any case had another virus or bacterium detected. That's an extraordinary finding. Co-detections around 20% or more are the norm, not the exception. This might indirectly flag the extent of the antiviral inflammatory response being mounted to MERS-CoV
• Time between symptom onset and sampling averaged  about 72-hours
• Real-time RT-PCR threshold values fro 37/45 samples ranged form 20-40
• Cellular laboratory findings revealed mostly normal neutrophil counts while just over a third had low platelet and/or white blood cells; lactate dehydrogenase and aspartate aminotransferase levels were raised in half of the cases
• The authors identify a large number of knowledge gaps and some that require urgent research including finding the host, source of exposure to it, what are the excretion and transmission dynamics, how best to sample, contain and manage patients

The authors write of a current absence of clinical and laboratory features to distinguish MERS-CoV cases from other respiratory infections. We have had very good viral detection methods for a while now, so its unclear which other tests they mean when they say "no tests are available" to exclude MERS (the disease) among patients with fever. That could also be said of any respiratory disease due to virus infection. For example, we know much about HCoV-NL63 and HPIV-3, but if a child presented with croup (associated with both viruses), we could not reliably distinguish which caused the disease using signs and symptoms alone. This is a problem common to all respiratory viral infections, not simply those due to MERS-CoV, and is best addressed using an extended panel of assays. Resources permitting.

Could anything biochemically, haematologically or clinically distinguish a patient as being infected by MERS-CoV rather than any other virus? Surely we are beyond trying to do that?

The paper does not mention whether there are sera available from all these cases to address the stated need for good, and well-validated, antibody-detection (serological) assays. As stated by others previously, KSA has the best sample population to make this happen. Without validation (testing antibody-detection assays using known positive as well as negative patent sera), the delay in producing a reliable assay and in getting a better grasp of who has been previously exposed to the MERS-CoV, what the real proportion of fatal cases is and the efficiency with which an infected person to pass on the virus (basic reproduction number, R₀).....remains out of reach.

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Belated Happy Birthday to Rosalind Franklin (1920-1958)

The 25th would have been Dr Franklin's 93rd birthday.

In 1952 while working at King's College in London, Dr Franklin captured images (including Photo 51) of the patterns made by DNA scattering X-Rays...which revealed a helical structure. 

The photo was the basis for James Watson, Francis Crick and Maurice Wilkins chemical model of DNA as double helix structure.

We who follow owe much to her hard work and devotion.

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MERS-CoV: new case and a death in previous case both from Asir Province

Hat tip to crofsblogs and FluTrackers

The Kingdom of Saudi Arabia (KSA) Ministry of Health (MOH) website announces a new case (83, no other details) and the death (no details at all; FluTrackers believe it could be case 66M¹, announced 26.07.13) in a previously confirmed case. Both from Asir province (population 1.9 million).

The KSA MOH website is having some issues just now though.

Cases now at 91 / Deaths at 46
PFC²: 50.5%

The MERS-CoV page on VDU has been updated with these numbers.

For general info, The World Bank lists the 2012 population of Saudi Arabia (2010 census) as 28.29 million.

 In 2007, the proportion of the KSA population:

• 65-years and older: 2.8%
• 0-14-year old: 32.4%
• 15-16-year old: 64.8%
• 1.37 males for every female.

For MERS-CoV cases (with data available) :

• Average age of cases (including deaths) is 53-years
• 65-years or older: 29%
• 3:1 males aged 65-years or older
• Males: 61.9% of cases; 77% of deaths are in males

¹66M-"M" means "year old Male"
² PFC - see earlier post

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Allergy to a Transformer's garbled signals

Transforming growth factor-� (TGF�) is a protein we secrete throughout most of our body which controls the growth, function and future employment of cells through binding to its receptor on them and creating a specific response inside the cell. It's also one of many very important managerial proteins called cytokines. It is involved in immunity (calms it down, stops it from over-reacting to foreign things) and asthma, among other things name a few.

Frischmeyer-Guerrerio and colleagues found that patients with a genetic disease called Loeys-Dietz syndrome (LDS), had high IgE antibodies, eosinophil numbers and T_H2 helper cells...all markers of and contributors to allergy. LDS is a genetic disorder in which TGF� receptor proteins are a bit wonky. LDS patients had incidence of asthma, food allergy, eczema, allergic rhinitis and eosinophilic gut disease.

In the case of asthma, I wonder if LDS patients also had more exacerbations. These are greatest burden of disease in those with asthma. Asthmatics are also known to have a predisposition to worse outcomes after viral infections, which reach higher viral loads, as if they were not being suitably attacked by the antiviral arm of the immune system.

The authors note how changes in just one gene can lead to complex changes that manifest as disease, because the altered, reduced or absent gene products can't partake in their normal activities further down its chain of action.

A drug called Losartan may be useful to alter the signalling due to TGF�. However, it has not been tested on LDS yet.

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Drug resistant bacterial terrorists worthy of alarm

Hat tip to Namraj for the education.

Maryn McKenna describes the rising alarm over our inability to stop infections by bacteria, because we have essentially run out of drugs to which they are sensitive. This is despite Doctors keeping in reserve the important drugs like carbapenems. But carbapenem-resistant Enterobacteriaceae (CREs) continue to spread, and kill.

Okay, so this is VDU - but viruses have a hand here too - one of the historic reasons behind overuse of antibiotics has been for  the (ineffective) treatment of  infections that were actually due to viruses-bad colds for example. Of course there are many other sources for antibiotics being flushed into the environment.

In on editorial in Nature, you can read of the rarity of new antibiotic discoveries in parallel with previous widespread use of antibiotics to aid growth of livestock.

And as we just spoke of bacteriophages earlier today...what ever happened to their use as bacteria-specific drugs? This was, and continues to be, a popular area of research in Eastern Europe according to the 2011 review by Harper and colleagues. Chemicals (antibiotic drugs) This overtook this area, as did regulatory and quality issues and the need for more comprehensive characterisation of them because some of the early work may have been rushed. 

Bacteriophage are looking like an ever more viable option in light of the growing crisis stories like those above highlight.

For example, there are recent papers describing the ability of bacteriophages to kill CREs including Klebsiella species - members of the Enterobacteriaceae. Recent phage success stories include killing of K. pneumoniae that mediate liver disease in mice and being superior to more traditional antimicrobials in treating burn wound infections in mice.

Oh, and Holmfeldt and colleagues just described the discovery of 12 new genera of phage comprising 31 phage from aquatic bacteria.

Time to get serious and turn the less conventional into conventional antibacterial options?

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You think you're under pressure?

The human herpesviruses (HHVs) have their DNA genomes poised to be fired into the cell with which they are docked, under pressures equivalent to 10s of atmospheres. These are the recent findings of Bauer and colleagues.  

Those protein capsids must be pretty tough.

So at least the early stage of DNA entry is a passive process; just relies on good old force.

This is the same way, and with a similar degree of pressure, that the bacterial viruses called bacteriophage, inject their genetic material through the much stronger cell wall and into a bacterium.

Big fleas have little fleas,

Upon their backs to bite 'em,

And little fleas have lesser fleas,

and so, ad infinitum.

And the great fleas, themselves, in turn

Have greater fleas to go on;

While these again have greater still,

And greater still, and so on.

"The Siphonaptera", from Wikipedia

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Editor's Note #9: End of a (very short) era - beginning of a much longer new one!

...and the beginning of a new one! For the first time in 6021-days (or 16-years, 5-months and 26-days since 28-Jan 1997 in fact), part of Virology Down Under (VDU) has moved off the University of Queensland's servers. 

*sniff*But its only this relatively new format, the blog bit, not the rest of the site. For some reason, actual blog professionals want to be able to link to some of my ramblings. Go figure! I hope this new format helps.
This move allows a better record of the articles....for me as much as you...and it definitely speeds up the process of writing...a lot as I don't have to edit all the blog entry's HMTL and CSS by hand. Phew.

Perhaps it will free up some more time to revamp the older pages too.

You will now be able to leave comments: perhaps ideas, corrections or suggestions and you can get update alerts via sites like bloglovin'.

There will still be search capability through a Google search box, and I'll leave The Freezer (old blog entries) intact. I will endeavour to move all the old blog entries onto this Google-based Blogger platform...but it may take a while.

The original core business of the VDU site - its pages providing more relaxed information on different viruses, DNA and PCR - will remain on the University of Queensland server, thanks to the Sir Albert Sakzewski Virus Research Centre. Only the blog component will be moving.
It's been a long time and lot of tech since I started VDU on my home 486DX Gateway Pentium II (128Mb RAM and 6.4Gb HDD). Let's hope this new home for the blog has the same legs.

Thanks to Crawford Kilian for the nagging impetus to make the blog more citation-friendly, to my wife, Kat, for the idea of a dedicated blog site for VDU (and much more) and to my boys Corin and Ronan for being brilliant...and for giving me the time during their school holidays in March to get this blog started! 

Many thanks for reading. Returning to normal blogging tomorrow.

Ian

Editor in Chief, Virology Down Under

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Open a box of mystery.

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The newest jaw dropping viral discovery is a big one - literally. Philippe and colleagues describe 2 protozoan-infecting megaviruses (possibly part of a proposed group, the family Megaviridae, in the future?).

These guys are not tiny, simple or only subtly different. One virus, Pandoravirus salinus (from marine sediment at the mouth of Tunquen river, central Chile) was 1,000nm long (shaped like an amphora), 500nm wide, has a genome of 2,473,870-base pairs and potentially encodes 2,556 protein coding sequence (CDSs), 93% of which were novel. They do not seem to have a capsid, rather a trilayered tegument.

The second discovery was named P. dulcis and was found in the bottom of a freshwater pond near Melbourne in Australia; it's genome was 1,908,524-bp, encoding 1,502 CDSs.

Some more info at the Megavirus page. 

Yeesh. The stuff we don't know...

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Ferrets are not small furry humans.

Zeng Guang, Chief epidemiologist at the Chinese Center for Disease Control and Prevention (CDC), commented on the recent H7N9 study from his own country (covered here)...

The findings are mainly based on animal tests in the lab that have not been witnessed or substantiated among the H7N9 human cases reported. So it shouldn't affect current intervention efforts or strategy at all

So far, no substantial evidence of H7N9 spreading among humans has been detected

And Zeng, back in April, made other comments about H7N9 transmissibility...

Humans' susceptibility to the H7N9 virus is only a little bit higher than to that of H5N1

Sure. I think we all understand that a tad over 130 cases in an area with 10s of millions people living in it, does not indicate a great deal of human-to-human transmission. As I noted yesterday, I wonder what active PCR screening of well human populations would yield?But ferrets are not supposed to be used for direct comparisons: 1 infected ferret in 3 exposures, under experimental conditions, probably does not equal 1 infected human in 3 exposures. Ferrets have tails, are much shorter, have a lot more body hair and a tendency to bite - not the usual description of a human. So there are other differences.

Ferrets are however, meant to be a great alternative to placing two humans in a cage separated by 7cm with one downwind of the other, inoculating one then harvesting tissues from them both to see where the virus ended up. Such human infections (reviewed here), acceptable for some viruses (e.g. rhinoviruses), would most likely yield the most relevant data to wild human infections. But we can't do that sort of thing for a virus we know to be detected in people who die. The risks to the participants are too high.

Also, we can and do inoculate ferrets and other animals with "unnatural" amounts and unnaturally pure preparations of virus to get the results we are after...in this case infection to let us observe transmission. Sure ferrets are not tiny humans, but we still have work to do to prove they are not a very useful indicator of what might be happening in the transmission of H7N9.

Let's turn Zeng's question around then: What evidence is there that 33% of ferrets being infected in various H7N9 studies, is not what happens to humans in the context of previous exposures, underlying diseases, the human immune system, chance encounters with animals and people, exposure to lower amounts of virus etc?

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New Influenza A(H7N9) case in Hebei, 1st for this province.

Hat tips to Crawford Kilian, FluTrackers and Mike Coston for extensive coverage.

In what is one of the most thoroughly reported single cases since we heard of H7N9, the weekend saw the confirmation of an H7N9 infection in a 61-year old female from Hebei province. I don't mean that flippantly, such a ferocious reporting response highlights just how jumpy this virus, and influenza in general, makes those who watch the webs.The patient, from Lanfang city, is now in a Beijing hospital, on extra-corporeal membrane oxygenation (ECMO) - this indicates severe disease with a need to support the heart and lungs in their task of providing oxygen to the body.  

The patient had not travelled outside of Hebei but lives near a poultry market.

No close contacts have tested H7N9 positive. She was reportedly situated in 2 different hospitals in Lanfang, before being sent to Beijing and tested for H7N9.

I've updated some key charts at the H7N9 page.

This raises a lingering question for me though. Many, many, many samples, both animal and human have been tested for H7N9 in China. As I understand it though, the human samples are mostly from those exhibiting signs or symptoms of illness or from contacts of those doing so. Would it not be a very useful study to add to these data a prospective PCR-based screening study of samples from "normal healthy" community populations/cohorts to see if H7N9 is circulating stealthily?

I respect the resources that it would take, but I also acknowledge the huge laboratory testing capacity currently available in China. It's phenomenal. These data would certainly add another piece to the puzzle.

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Thoughts and (many) questions on the 4 MERS-CoV UAE cases. [AMENDED]

Thanks to Prof Andrew Rambaut for pointing out my incorrect usage of R₀

4 new infections were detected from health-care workers (HCWs) in contact with a previously confirmed 82-year old male MERS patient-we've covered this previously.

My main question is: Does that mean the basic reproduction number (R₀) for MERS-CoV is creeping towards being greater than 1? If in fact 4 new infections arose from every case, on average, that would put the MERS-CoV up there with influenza, SARS-CoV and mumps.

While the R₀ is not >1, this was an informative small cluster of human infections. Basic protective measures may not have been taken in this cluster and presumably we can exclude pre-existing immunity as a moderating factor (although do we know that yet?).

I'm also assuming these 4 are otherwise "normal healthy" people, not suffering any major underlying disease(s), and so I'm having trouble imagining what stops this from happening all the time. Perhaps co-infections in which the MERS-CoV is the super-infecting (2nd) virus such that an innate and moderating immune response is already underway?

Perhaps the virus has recently changed to become more easily transmissible - we need more sequences from recent strains and more isolates in animal studies to confirm that or course. I'm not holding my breath that either of those will be achieved rapidly-although perhaps I should be holding my breath.

To me, and feel free to educate me on any of this post via Twitter (@MackayIM), this means we should expect to see more viral RNA-positives (regardless of symptoms since 2/4 here were asymptomatic) in contacts...doesn't it? What is the status of testing "less close" contacts? How far does the testing net get thrown I wonder?

Nonetheless, we don't see 4 new community infections from every case in the KSA. I'm assuming that the KSA MOH lab(s) uses the same PCR assay as that recommended by the WHO. 

Others have already noted that, on the data we have, MERS-CoV is unlikely to cause a pandemic.The most recent announcement of 2 cases of MERS-CoV provides an answer to that, one that is a typical KSA MOH site's communication:

It is worth mentioning that, the MOH has tested 64 samples recently, given that, all of such samples have been proved negative, May Allah be praised, except the cases that have been published.

No contacts positive there. So, at the end of the day, we can't extrapolate much from clusters, because when we consider the entire MERS-CoV population and all of it's tested contacts, we have an R₀ value <1. Still, the clusters do happen and this does highlight that numbers, tools and hypotheses are good as guides - they should not to be used without full regard to each specific pandemic, epidemic, outbreak, cluster or even individual case.

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