Monday, 28 April 2014

H7N9 Snapdate: some quick charts...

Click on image to enlarge.
I don't have a lot of time tonight so this is just a quick post of some updated charts with a few summaries of some key features of the influenza A(H7N9) virus situation in south-eastern China. At writing it was at 432 detections with media reporting 128 deaths

Click on image to enlarge.
Guangdong is where H7N9 is still most active and it is this province that is the source of the continued cases trickling off Wave 2's peak.

Most H7N9 cases overall have been in Zhejiang and Guangdong provinces but lately, post-peak of Wave 2, there has been continued activity in Jiangsu province including a recent healthcare worker with no mention of "contact with poultry"; the absence of which stands out in World Health Organisation (WHO) reports because most cases are followed by affirmation of that phrase.

Click on image to enlarge.

In  the  survival chart above we see that most of the fatal cases, shown in red, are defined by an older age. Unfortunately, a lot more of the fatalities have been reported through the media without identifying details (48 of 128), than have come through official Chinese channels and out via the WHO. This lack of detail makes it impossible to clearly link a lot of the deaths to the case announcements. Only the custodians of these data know what this chart should really look like. NB: Since making the chart this morning I've found a handful more case details at FluTrackers, but public detail on fatal cases remains the weakest of any of the H7N9 data.

Click on image to enlarge.
We can see in the weekly chart on the right that the two H7N9 waves differed in timing, the width of their bases (more cases in Wave 2) as well as how "tight" their peaks were. Wave 2 has tailed off, but continues to spit out cases, while Wave 1 comprised both a steep climb and a steep decline in human cases.
Click on image to enlarge.

If we zoom in on Wave 2 we can see by looking at cases per day in the chart on the left, that between 0-4 illness onsets per day are being reported, as they have been since late Feb-2014. 

Is this the legacy of those regions whose live bird markets remained open or were only shut temporarily for disinfecting and restocking? Those regions with markets that were shut for much longer, or for good, do not seem to have contributed much to the continuing leak of H7N9 infections despite being key contributors during the peak periods before markets were closed.

Click on image to enlarge.
In zooming in on Wave 2's cases by week, but this time based on the region of likely acquisition of infection, we see that Guangdong province (brown line) has been the most consistent contributor of human H7N9 infections both late during the 2nd of the Wave 2 peaks, but also after the peak's decline almost everywhere else in south-east China. There was considerable publicised unwillingness from poultry producers to permanently close markets in this Province, a location with a major role in the nations poultry production. And so this little experiment incubates further and I have little doubt we will see the impact of that unwilingness late in 2014. 

Click on image to enlarge.
As noted above, public H7N9 death data do not allow good linkage with official case announcement data for about 48 fatalities, so my second-last chart tonight uses both public and media-release numbers to try and illustrate how the proportion of fatal cases (PFC) has changed across both Waves. The PFC seems to be holding fairly steady now between 17% and 30% (depending on source of numbers).


Click on image to enlarge.
And finally we see that the age and sex distribution across all cases (both Waves) is skewed to wards older males. Same as usual. If we look at this distribution (ran out of time to put in here) for the fatal cases, it is much more tightly grouped around the >60-year olds, but that females appear to dominate males in deaths during Wave 2, whereas it was the other way around for Wave 1.

Sunday, 27 April 2014

If this is what MERS-CoV detections look like with more testing...what is the "normal" community level of virus?? [UPDATED]

The bar along the top depict how much time passed between each 100 cases.
Click on chart to enlarge.


For a virus that is chugging along without the aid of any new genetic changes, and perhaps showing up more often (a) because of enhanced testing and/or (b) because of a large-scale breakdown in infection prevention and control (IPC), this curve sure does depict the possibility that we had no idea how much MERS-CoV was transmitting among the population. Still a poor transmitter compared to an influenzavirus, because we have seen a few larger MERS-CoV studies than show few to no MERS-CoV positives, but still more people positive than we thought.

Can we really lay this rate of climb at the feet of poor IPC alone? Wouldn't that also mean that every other respiratory virus would do this too? Perhaps not if MERS-CoV was the only one capable of causing acute pneumonia. It isn't. So shouldn't all hospitals always be full of acute pneumonia and respiratory disease among older males with comorbidities? These are modern hospitals after all. Also modern doctors with great training and skills acquired from all over the world. Perhaps poor IPC plus enhanced testing is an option? Maybe. Probably most likely when combined with an outbreak that starts in April for an unknown reason.

What about this option, which focusses on testing alone? Better levels of testing are at last showing it like it really is in the Arabian peninsula? This options proposes that we've been underestimating the ability of MERS-CoV to travel from person-to-person, all along. An underestimation driven by testing only the "tip of the iceberg" of disease and just watching the rest of the iceberg from a distance? What if severe disease is only found in already ill older males and most (granted, not all) of the rest get milder or unnoticeable disease but do get infected? Yes, in the past 2 weeks 5,000 samples have been tested in the Kingdom of Saudi Arabia (KSA) to yield ~140 MERS-CoV detections (~3%). After the 2012 Hajj, 154 pilgrims were tested by Gautret et al and, despite a high proportion with respiratory symptoms (83%), none were found positive for MERS-CoV. At 3% in Jeddah, testing of the Hajjis should have yielded ~4 detections among this cohort if the distribution of MERS-CoV was at this level all the time. In screening 5,065 cases and their contacts (family and healthcare workers) over a year from 1st-Oct-2012, Memish et al reported 106 detections (~2%) and no significant rise in case detection rates over that year. So a very similar proportion of positive cases, and both Jeddah and this larger study have similar numbers and a roughly similarly broad population being tested. Of course, even endemic human CoVs are not always detectable every year at the same site. Some have a biennial periodicity.

So perhaps 2-3% prevalence, similar to endemic CoVs, is the magic number for MERS-CoV 
positivity? Which just leaves the question, why weren't more Hajjis positive last year? Or was that just a testing thing too?

Just wondering out loud here.

MERS-CoV genomes remain stable amid Jeddah outbreak cases... [UPDATED]

Thanks to Prof Christian Drosten for answering a major question about the sudden large rise in Middle East respiratory syndrome coronavirus cases. He did so in an email some hour back.

Based on 3 genome sequences from 30 samples that Prof Drosten has been working with, no significant changes in the genome of Jeddah variants could be seen compared to previous sequences. The spike gene, a likely indicator of viral change, is "100 percent identical" to key regions from earlier MERS-CoV genome sequences.

This swings the focus for finding a reason for the outbreak in Jeddah,  Kingdom of Saudi Arabia (KSA) and the cluster in Abu Dhabi, the United Arab Emirates (UAE) back onto asking about:

  1. What happened to infection prevention and control?
    And why does this seem to happen in April (2013 and 2014)  in particular?
  2. Has recent increased testing simply uncovered that which was already happening?
    Perhaps there have always been more MERS-CoV infected people and a slightly better efficiency of transmission than we expected based on past efforts which mainly tested the sickest and most obvious of cases of MERS. 

I'm also wonder a couple of other things. 

As I've asked before, how were these samples selected? In a ProMED announcement a short time ago (thanks to Crawford Kilian/@Crof for pointing it out) we learned that the 3 complete genomes are from early on in the outbreak. So that raises the question of whether the virus has remained identical to earlier strains, later on in the outbreak? 

Also, what do other seasonal human endemic respiratory viruses do in the Arabian peninsula? Are these sorts of outbreaks, but due to other viruses like influenzaviruses, parainfluenzaviruses, rhinoviruses, respiratory syncytial virus, metapneumoviruses or other coronaviruses etc also happen to this extent and with similar clinical impact? What is the occurrence of acute pneumonia like in the KSA and UAE?

I thank Prof Drosten for his efforts, efficiency and rapid (sample were only dispatched to Germany 14-Apr and we have 3 complete genomes already!) and open communication. And I take special note of his comments...

"In light of some of the recent comments implicating delays in following up on the outbreak it is worth considering the timing and the workload associated with careful testing and internal confirmation done in Jeddah. It is also worth mentioning that samples were already dispatched from KSA MOH Riyadh to Germany on [14 Apr 2014] -- just about a week after receipt of samples in Jeddah regional laboratory, testing, internal confirmatory testing, and transport to Riyadh. After dispatch from Riyadh, samples were not successfully delivered through customs in Germany with an administrative process that took 3 days (17 Apr 2014). The sequencing work in Bonn started only on [22 Apr 2014] for the simple reason that most of the laboratory staff (including myself) have been on Easter holidays. Sequencing of further samples taken at later time points in Jeddah is underway."
ProMED 20140426.2432140

For my own part in communicating a message of delay, I'd like to add that, in my opinion, there really should be some local viral genotyping in place by now and that should have been producing 2014 MERS-CoV variant sequences all year. A great deal of fuss might have been side-stepped if we new the virus wasn't a factor in the outbreak.

For now, based on these 3 complete genomes and Prtof Drosten's 25 other partial spike gene sequences, there is no indication that viral change occurred early on in the Jeddah outbreak. No MERS-CoV v2.0 in town. No "mutant killer virus" headlines that can withstand scrutiny. We next await some detailed evolutionary analyses from Prof Andrew Rambaut who has these sequences. They are also available at http://www.virology-bonn.de

Sources...

  1. ProMED post.
    http://www.promedmail.org/direct.php?id=2432140



Saturday, 26 April 2014

Ebola update: for 23-April, WHO update [UPDATED]

These data are tallies from all sites.
Specific numbers from towns and countries
can be found from the Update itsel.
Click on image to enlarge.
The latest figures tell a story of linear increase driven by Guinea. There is plateauing of the proportion of fatal cases (currently sitting under 60%). 

Testing continues and hopefully more suspect and probable cases will be discarded or confirmed in the coming days and weeks.

The Liberian component of the World Health Organisation report did not include death figures this time around. Thanks to +C├ędric Moro (@Moro_Cedric) who referred me to the UNICEF update [2] which does indeed report the death toll remains stead at 11 as charted.

Source...
  1. WHO-AFRO West African EVD update | April 23rd
    http://www.afro.who.int/en/clusters-a-programmes/dpc/epidemic-a-pandemic-alert-and-response/outbreak-news/4121-ebola-virus-disease-west-africa-25-april-2014.html
  2. UNICEF Report for April 23 for Liberia
    http://reliefweb.int/sites/reliefweb.int/files/resources/UNICEF%20Liberia%20SitRep%2019%20Ebola.pdf

MERS is a respiratory disease and MERS-CoV is a respiratory virus... PART I

The disease

Definition time.

The Middle East respiratory syndrome (MERS) is a disease (a change in the body away from normal function towards abnormal function) comprised of a bunch of signs and symptoms (the syndrome bit) that is identified in patients who turn up ("present") to their doctor/clinic/hospital with signs (things the doctor can see or measure e.g. coughing, sneezing or a fever with a temperature about 38°C) and symptoms (things the doctor can't see that may still be measurable or not e.g. lung inflammation upon X-Ray, muscle aches or chills but no measurable fever).
 

At the bad end of the disease spectrum, MERS is an acute community-acquired pneumonia (CAP; confirmed by X-Ray of the lungs) that progresses to be worse. "Worse" includes kidney failure acute respiratory distress syndrome, respiratory failure and multi-organ failure. MERS pneumonia cannot be told apart from acute CAP due to other causes.

Laboratory testing to confirm the presence of the agent you suspect, is essential. You can't confirm its absence, but you can say it was "not detected".
 

MERS is a particularly nasty disease for those who already have a disease that is chronic. These include diabetes, kidney disease, heart disease, hypertension, lung disease, obesity, malignancy and those who smoke or use steroids. This appears to more often include older males around the Arabian peninsula in whom the coronavirus that is assumed to cause MERS (MERS-CoV), has had a big impact, associated with the most severe forms of the disease and death. Neonates, infants, toddlers and children (up to 14-years) are in the minority of MERS-CoV detection to date (14 of 361 with age data, or 3.9%).

Over 85% of patients with MERS (remember: the disease, not the virus) have a fever >38°C, cough and chills or rigors (shaking episode) and all have an abnormal 1st chest X-Ray.

Around half have a runny nose and about a third have malaise (feel rubbish) and myalgia (aching or sore muscles).

A quarter have diarrhoea and a fifth have sore throat, nausea or vomiting.[1]


The virus.

While it has not been shown conclusively in humans, the MERS-CoV has been shown to cause MERS or a similar, although milder form of disease, in Rhesus macaques given an unrealistically large and I would argue, unrealistically located (the trachea) dose of virus preparation. So we work under the assumption that the MERS-CoV causes the signs and symptoms listed above, and/or causes our immune system to respond in such a way that respiratory disease is what MERS causes.

We talk about MERS being caused by MERS-CoV.

We also talk about flu being caused by influenzaviruses. To confuse matters though, there is no single "common cold virus" that causes the common cold so we need to specify that common colds can be caused by any respiratory virus (there just happen to be more rhinoviruses than an other respiratory virus so they mistakenly wear the brunt of that burdensome label even though they are also the main viral cause of much more severe asthma attacks).


Breathing in versus ingesting.

The MERS-CoV presents first as an acute respiratory infection, with some other things that develop or are exacerbated (pre-existing diseases in particular).

Even when atypical disease presents first and respiratory disease follows, that may simply be explained by other preceding or concurrent infections. Take the recent Greek imported case of MERS from Jeddah, Saudi Arabia. He presented first in Saudi Arabia with fever and diarrhoea and was also subjected to an X-Ray and found not have no pneumonia. He had visited his wife in hospital there and she had been diagnosed with typhoid fever. He was also given antibiotics to combat that bacterium based on a positive test. He then travelled to Greece whereupon he presented to Athens hospital with fever and low blood oxygen levels indicative of viral pneumonia. That was confirmed by an X-Ray. This can be interpreted as an atypical presentation of MERS...or perhaps just MERS following typhoid or a even an acute viral gastroenteritis. Very little testing of faeces was described for the latter possibility and so we don't know. And into the void walks hand-waving.


Sources...

  1. Middle East Respiratory Syndrome Coronavirus (MERS-CoV): A Perpetual Challenge
    http://www.annsaudimed.net/index.php/vol33/vol33iss5/631.html
  2. A CASE OF IMPORTED MIDDLE EAST RESPIRATORY SYNDROME CORONAVIRUS INFECTION AND PUBLIC HEALTH RESPONSE, GREECE, APRIL 2014
    http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20782

An update on the April outbreak of MERS-CoV...

We are in week 110 of the MERS-CoV outbreak event, that's 2.12 years and 386 cases including approximately 113 deaths (PFC of 29.3%, the lowest to date) since the first known cases became ill in Mar of 2012.

Just a few quick charts to keep track of things.

Virus detections continue to accrue at a double-digit rate, as has been the case each day except 2 (one of which was blip) between 18-Apr and 25-Apr this year. Thanks mainly to the Jeddah outbreak (no more calling it a "cluster")
Click on image to enlarge.

I've added the Mazayin Dhafra camel festival (United Arab Emirates; UAE) to the regional acquisition chart. It's a gathering that brings together ~17,000 camels. [1-6]
Thank you to @_abdullah88 and David Leith


Click on image to enlarge.
In the next 2 charts we can see the large and rapid rise in number of detections over the past 3 weeks, firstly by week. The cumulative average has also jumped (now at 2.88 cases per day across the entire period of MERS-CoV's emergence) as detections continue in higher numbers than ever before.
The underlined region (green) includes those detections which have
not yet passed through the World Health Organisation and
been "officially" announced to the world. His process usually,
and until late March, consistently, added valuable additional data.
Click on image to enlarge.


In the next chart we can see the zoomed in daily story for late March to April detections. That cumulative average (grey line) is steadily climbing but not at an exponential rate. We wait and see if human-to-human transmission increases as each of these cases makes contact with other people and the incubation period clock starts. If the virus is spreading even more efficiently than in 2013, that daily curve might start to look more like the weekly curves. Another few weeks should answer that for us.


Click on image to enlarge.
Healthcare worker (HCW) numbers have risen sharply (see below) during the April outbreak to a total of 84 detections, 7% of whom have died. 

Deaths (left) among HCWs now represent 1.6% of all MERS-CoV positive deaths. This jump in HCW detections has been fuelled by the Jeddah outbreak but also by the parallel HCW cluster among paramedics in the UAE; two as yet completely unexplained events.
Click on image to enlarge.

As ever I must note that the data are full of holes. 

In particular, the past 140 or so detections, despite being announced through a Ministry, lack sex, date of illness, date of hospitalisation or precise dates of detection if they were not ill (of which there have been a number of late).

This increasing number of detections may simply be due to increased testing of contacts, as we learned from comments by Dr Memish this past week.[7] Apparently until relatively recently, and despite comments that suggested more KSA laboratories were coming online made as far back as July/August 2013, contacts of confirmed cases have been mostly observed for signs of disease, and not sampled for laboratory testing. Testing has been limited to cases of pneumonia. This seems to conflict with recent accounts of larger sample numbers being tested (which I don;t have citation for right now), unless pneumonia is far more widespread in the Kingdom of Saudi Arabia (KSA) than we understand. 

Testing is key to understanding how widespread MERS-CoV is in the community and how well it actually transmits from human-to-human (-to-human-to-human- etc). 

It's not at all surprising that clusters spread and are not shut down quickly if no-one knows who has MERS-CoV and who has influenzavirus or rhinovirus or another coronavirus or even who has a MERS-CoV-positive mild yet perhaps still contagious infection that doesn't rate a second look. You can never understand an emerging virus when you miss out people that are infected-whatever their clicnial presentation. 

The previous level of limited and biased (toward only the most severe of disease) testing is reserved for say, annual influenza surveillance; a well known virus that circulates seasonally, as we fully expect it to, and for which we sample a sliver of the community pot. This are the cases that go to hospitals or just to family doctors, get tested, some viruses go on to get subtyped and we can use those proportions to extrapolate what's going on with that well-known human virus, to the rest of the community. We cannot do that with MERS-CoV yet because we don't know our enemy like we know influenzavirus.

Another point to make is that right now, the flurry of detections may be just a flurry of testing; better testing more accurately representing MERS-CoV circulation among humans in the KSA. A community-based study testing milder disease is essential to answer that. 

In the meantime we're left hanging between wondering whether changes to testing approaches is the reason for being about to reach the 4th 100 MERS-CoV detections in record speed, or whether it is a change in the virus that lets it spread better and further. Of course we don't know how many "rounds of infection" are going on with MERS-CoV just now because we are lacking information about how cases are linked together; who got infected from whom? Is it from a case to just a single close contact, or from a case-to-person-to-person-to-person....? 

Also, what is happening in camels during the first quarter of the year when MERS-CoV detection in humans seem to be at their lowest? It's now pretty clear that humans can acquire MERS-CoV from camels thanks to a recent article in Emerging Infectious Diseases by Dr Memish and colleagues that indicate a quite clear direction to acquisition.[8] But do camels undergo a seasonal outbreak of MERS-CoV and is that a regular and recurring thing? Is it related to camel festivals? Is it what has started the human infection waves in in April 2013 and 2014? We'd need widespread and ongoing camel (and human) testing to understand that. What about camel milk and urine; drunk regularly or used / collected / drunk for various reasons, respectively? Is it harbouring untold reserves of infectious MERS-CoV that gets ingested, then manifests in the vast majority of cases as a respiratory disease? We'll need some testing of those fluids to answer that, and perhaps a little common sense to interpret the results.

As usual, I present you the best of the data that I can lay my hands on yet find myself unable to give you many actual answers. At least I'm not alone in that so enjoy the hand-waving! 

One fact that I can share; the communication of events during what might be the most significant outbreak and cluster of cases of MERS-CoV to have happened in 2-years has been horrible, even by MERS epidemiology standards. 

Couldn't happen at a worse time really. Let's hope the new management at the KSA Ministry of Health have been awakened in time to avert an event on a much more global scale.

Sources...

  1. Avaxnews | Mazayin Dhafra Camel Festival | 21-Dec-2013
    http://avaxnews.net/touching/Mazayin_Dhafra_Camel_Festival.html
  2. Mazayin Dhafra Camel Festival | ABC Australia news | 21-Dec-2011
    http://www.abc.net.au/news/2011-12-21/emirati-men-look-through-a-fence-at-the-mazayin-dhafra-camel-fe/3741618
  3. Daly Mail UK | Even the winner of this competition will have the hump: Hundreds of camels snake their way through the desert for a beauty contest | 24-Dec-2013
    http://www.dailymail.co.uk/news/article-2528868/Theyve-got-humps-Hundreds-camels-snake-way-desert-theyre-driven-beauty-contest-Abu-Dhabi.html#ixzz2zxdhAqNb 
  4. DailyMail
  5. http://www.dailymail.co.uk/news/article-2528868/Theyve-got-humps-Hundreds-camels-snake-way-desert-theyre-driven-beauty-contest-Abu-Dhabi.html
  6. Newser.com | Dubai Sheik Pays $2.7M for Camel | April 2008
    http://www.newser.com/story/23945/dubai-sheik-pays-27m-for-camel.html
  7. Sydney Morning Herald photos of Mazayin Dhzfra festival| 23-Dec-2013
    http://www.smh.com.au/photogallery/travel/the-spectacular-mazayin-dhafra-camel-festival-20131223-2zu5b.html
  8. Soaring MERS Cases Cause Pandemic Jitters, but Causes Are Unclear
    http://news.sciencemag.org/health/2014/04/soaring-mers-cases-cause-pandemic-jitters-causes-are-unclear
  9. Human Infection with MERS Coronavirus after Exposure to Infected Camels, Saudi Arabia, 2013
    http://wwwnc.cdc.gov/eid/article/20/6/14-0402_article.htm

Friday, 25 April 2014

MERS-CoV partial spike gene sequences do not implicate viral change in April's Jeddah human case cluster

Stars highlight difference in scale at left-hand side,
 (x-axis) numbers. Seasons based on info [2]
Click on image to enlarge.
With a new article at ScienceInsider written by Kai Kupferschmidt (@kakape on Twitter)[1], it seems that the idea of a Spring start to human detections of MERS-CoV in Saudi Arabia is gaining some support from other scientists.

Springing into action...

The "pattern" of MERS-CoV detection seen in the chart still need some fleshing out wit more time. They might be heavily and unrealistically biased by the enormous number of recent hospital detections. However, it's worth noting that in April 2013, it was the Al-Ahsa cluster that added to detection numbers. In April 2014 it is the Jeddah outbreak started with a hospital cluster. What's that about? I say "detection" rather than cases so we don't get bogged down in whether they were ill or not at the time of sampling. In fact the pattern seems to be one that begins with a hospital cluster. 


I've tried to track down when Spring is in this region, and the chart - a rework of one I've been showing for a while now - overlays the seasons of interest.[2]



http://www.flickr.com/photos/xikita/48647105/in/photostream/
CC BY 2.0
Camels have a very long gestational period, up to 15-mths, which makes it difficult to know when a 1-2-year old camel, the ones most likely to acquire MERS-CoV and to shed virus, are around and mixing with humans. Jennifer Yang reported that most camel births occur between Nov and Jan and so their birthdays would fall on...well you can do the maths.

NOTE: The fatal case numbers in the past month, as with most data in the past month, are lacking detail which means I cannot plot them. Pleeease post scrubbed data from all April and late March detections soon WHO.


A pattern of animal to human to hospital to human..?


So could how about this summary of MERS-CoV movement among animals and people?



Young camels become infected within a year or so of birth > virus spreads to humans in contact with camels, a rare few of whom become ill > seriously ill cases shed virus and infect other humans in a healthcare setting > humans spread to other humans, severe illness showing up mostly in those who are already diseased due to something else (e.g. diabetes or cardiac issues)

Hospitals are an obvious starting point for this human-to-human spread to occur because of increased level of close contact and the concentration of already ill people.

But my question today is, as spread of MERS-CoV among humans has likely been occurring since at least 2012 (I suspect earlier), why such a big spike in detections in Jeddah now? Also, lest we forget, among that temporally-linked large cluster of paramedics in Abu Dhabi (being able to link that to Jeddah would answer an important question for me).

Part of the spike gene sequenced but not a sign of viral change...

We learned today, at very long last (I know it's been less than a month but these clusters seem to have been going on for years!), that a part of the MERS-CoV genome from 30/31 samples from Jeddah have been able to be amplified by Christian Drosten's group in Germany (collaborating with Dr Memish and the Kingdom of Saudi Arabia's Ministry of Health) using a separate assay that that used in screening (a safe assumption as spike is not a diagnostic screening target recommended by the WHO). That means that laboratory contamination is a less likely cause of case climb. It doesn't exclude it though. We call this a possible "false positive". It can be due to a reverse-transcription polymerase chain reaction (RT-PCR) being accidentally contaminated ;by some DNA from a previous test and showing up as positive result, when in fact there was no MERS-CoV RNA in that person. Contamination can also occur at the purification step, when (viral) RNA is extracted from the patient material and DNA (or RNA from another high viral load specimen) again contaminates the process. The latter will always be positive while the former may appear virus-positive in 1 reaction run and negative in another.

Sample selection for sequencing...

We don't know how the 31 samples tested by Drosten's lab were selected for packaging and transport to Germany. It is possible that only repeatedly positive samples were sent.


Schematic of a coronavirus virion.
Click to enlarge
In Kupferschmidt's article, Drosten informs us that there is nothing different or distinctive about the 2014 MERS-CoV partial spike gene sequences he's generated thus far when compared to sequences from previously sequenced MERS-CoV genomes in 2012 and 2013. This is not the end of that story though as we are not yet sure which part of the spike was sequenced and still have a lot of the genome to see before we can feel assured that the virus has not changed. We also don't know if sample selection has occurred from cases during the beginning, middle and later stages of the Jeddah cluster and thus whether these new sequence data accurately represent all the viruses circulating among detected in the Jeddah outbreak. But this is a good start.

Severe acute respiratory syndrome (SARS) and spike..


The ~4,000nt, region of the MERS-CoV genome 
that encodes the ~1,300aa spike gene is highlighted in 
pink. Schematic derived from the EMC-2012 variant 
sequence of MERS-CoV.
Click to enlarge.
With the SARS-CoV, evolutionary changes in the spike gene (especially between amino acids 75-1025 or nucleotides 224-3075) could be used retrospectively as a marker of the virus adapting though time,[5] perhaps towards a better transmitting variant among humans. Along with ORF1a, these two regions showed changes suggestive of adaptation from animal to human.[5] I'm not sure that we've seen that with the human/camel genomes sequenced to date have we? Does this reflect that the virus has already "settled in" to humans? Or does it mean that the spike region is just less informative for MERS-CoV than it was for SARS-CoV? To answer that we'd need older camel MERS-CoV sequence. With the new data we have for MERS-CoV, we begin to wonder whether we can exclude viral change. Hopefully that information will be forthcoming when compete genomes are sequenced and when we know more about which "part of the spike gene" was sequenced. Those details will probably be delivered via a rapid scientific publication.

So, a day full of new data and a mad day on Twitter. 

Thanks to @nika7k, @yasnot and @AB_Algaissi for very helpful Twitter exchanges on this topic this morning.

Sources...
  1. Soaring MERS Cases Cause Pandemic Jitters, but Causes Are Unclear
    http://news.sciencemag.org/health/2014/04/soaring-mers-cases-cause-pandemic-jitters-causes-are-unclear
  2. http://www.iexplore.com/travel-guides/middle-east/saudi-arabia/weather
  3. Tracking MERS-CoV through time: a spikey problem
    http://virologydownunder.blogspot.com.au/2013/08/tracking-mers-cov-through-time-spikey.html
  4. Saudi Geography and Climate
    http://fanack.com/en/countries/saudi-arabia/basic-facts/geography-and-climate/
  5. Molecular evolution of the SARS coronavirus during the course of the SARS epidemic in China
    http://www.ncbi.nlm.nih.gov/pubmed/14752165
  6. Camels likely source of deadly coronavirus, study shows
    http://www.thestar.com/news/world/2014/02/25/camels_likely_source_of_deadly_coronavirus_study_shows.html

Thursday, 24 April 2014

Dump the garbage...

Sharon from @FluTrackers and I had an exchange on Skype this morning - always a useful way to message, even with my high rate of typos - and we agreed (or perhaps I bullied) that there was little point to keeping  "TheUAE12" (as I've taken to calling the 12 cases announced in the Kuwaiti News Agency [1]) on the list. 

In the past I've also argued that if samples get dropped, such as when Spanish or other cases could not be confirmed as MERS-CoV-positive, for whatever reasons, that FluTrackers retain their case numbers and "count around them". So the numbers become discontinuous. Those arguments are based on the numbers having already become embedded among flublogians/coronablogians and this way they could continue to be trackable by those who have used them. For example, FluTrackers makes a note saying this case is now a probable case, not included in the tally as it could not be suitably confirmed or somesuch. This is akin to not making wholesale changes to the name of a virus because you no longer like the "look" of the name when it already has decades of published literature behind it and is in the head of every researcher in the field. 

I proposed to Sharon that the MERS-CoV detections over the past few days were not yet embedded enough to be missed. So we've cleaned our lists. The FluTracker's tally [2] now sites at 360 cases using Ministry and WHO data. And I follow that excellent list.

So my Tweets this morning (AEST) were about those numbers having now been deleted and the case list comprising ~6-days and 70 cases has been "moved up" to fill the gap, but the numbers remain continuous. The new list [2] is thus 12 cases down from a few hours ago, but that has little impact on April's surge of new cases

We think that some of TheUAE12 are included in recent WHO Disease Outbreak News posts but they are not linked to the announced 12, no-one could/would link them to the announced 12 and so retaining them as empty case numbers was pointless.

On with the show.

Resource...

  1. UAE Media Report: 12 New (Asymptomatic?) MERS Cases Detected
    http://afludiary.blogspot.com.au/2014/04/uae-media-report-new-asymptomatic-mers.html
  2. FluTrackers MERS-CoV line list | MASTER LIST
    http://www.flutrackers.com/forum/showthread.php?t=205075

And then that happened....

Noting to see here. Ignore the blip.
These are not the data you were looking for.
Click on image to enlarge.
I had a big post written about the lack of cases and how that was unlikely to be real and how hypothesis, hand-waving and guesswork rush in to fill a vacuum because nature abhors a vacuum and humans resent a void of information when they think there should be some..blahblahblah. 

So that's deleted. 


We have this instead. 



What seemed to start as a healthcare cluster
in late March in Jeddah hospitals and among
Abu Dhabi paramedics, seems to have shifted towards
cases appearing across a wider area than had been occurring
immediately before the clusters. Weather? Festivals with
camels? MERS-CoV variant 2.0 with altered transmissibility
characteristics? Multiple things? We don't know.
Click to enlarge.
MERS-CoV is a faster moving beast than a variant of the Zaire ebolavirus right now, and for something only acquired through "close contact", MERS-CoV seems to be punching well above its weight in April when talking about transmitting. I think MERS-CoV now needs to come with the ebolavirus tag of "numbers are subject to change". Right now, that change is all upwards and at a pretty rapid daily rate. April alone has nearly seen more cases than all those reported for all of 2013 (n=171). 

April certainly contains the biggest number of MERS case announcements ever. Apologies to the Buzzfeed article that came out overnight; numbers have moved a bit even since then. 2014 has already equaled all of 2012's and 2013's detections added together. Another interesting number, 23-Apr, it is the biggest single day of MERS-CoV case reporting ever.
Click on image to enlarge.

So let's all agree that the pattern of MERS-CoV detections has changed this month compared to any other month you want to point at.

But why? 


I have two main thoughts on that.


  • Option 1: MERS-CoV v2.0 spreads better than v1.0. We need sequences to address this. If the virus has changed then this may be the percolation of a virus with pandemic potential, and a sizable clicnial impact among a particular portion of the community, happening in  real-time. Or not. Suffice to say we need hose sequences yesterday to stay in front of that possibility and its global implications.
  • Option 2. Massive breakdown in infection prevention and control in some healthcare facilities, which has spread. The question I have about this option is why has it occurred in 2 geographically distinct places at once (Jeddah, Kingdom of Saudi Arabia [KSA] & Abu Dhabi, United Arab Emirates)? The fact that healthcare workers were intimately involved at both sites adds weight to close-contact, but also to their role as sentinels for emerging viruses, including v2.0 variants. And this much close contact? 
It's impossible to say which option, or if both, have contributed to the uncharacteristic and ongoing spike in cases. But we need to keep watching this closely for some answers since this is the most rapid development for MERS epidemiology since its discovery.

If the KSA Ministry of Health experts are serious about accepting ideas from outside, I have a few quickies:


  1. Please tell us what you're doing to control the cluster in Jeddah
  2. Please  tell us if testing methods or approaches have changed lately (more testing overall, different tests, testing instead of simply observing contacts..)
  3. Please tell us what you're doing to understand MERS-CoV, the virus, in 2014 (hint; sequence the Spike gene of as many viruses as you can get you hands on, do genomes later and release those data quickly; social media, WHO, Eurosurveillance or some other super-rapid journal for example)
  4. Please give us a reason, or a best guess, for why April is different from every other month since MERS-CoV was identified in 2012
  5. Please provide the WHO scrubbed case data more quickly and include sex/age/date of illness/animal contact[Y/N]/comorbidity[Y/N]/date of hospitalisation/region of KSA
  6. Please screen samples by PCR from the community, looking at asymptomatic, mild and moderate acute respiratory disease.
  7. Please publish some data on what other respiratory viruses do among older males with comorbidities (e.g. diabetes) in the KSA so we have a comparator for MERS-CoV

So let's all agree that the 1-day blip in case reporting was in response to changes in the Ministry and move on with hypothesis, hand-waving and guesswork. The void still exists of course, and we're all still living in it. Welcome to it fellow information seekers. Let's hope we get thrown a line soon. Because the daily double-digit case numbers now have me at "don't want to look away".


Click on image to enlarge.
I won't post a new sex chart as many of the April cases have no sex information attached to them. Here's the rolling average age per week based the 357/360 cases with data, including the influence of negative weeks. No obvious trend towards young cases?

Today saw 2 case releases in a single day (probably just catch up?) and the case load for MERS continues its ascent apparently unabated.


References...

  1. A Deadly Virus Is Spreading Around Saudi Arabia And It Might Be About To Go Global
    http://www.buzzfeed.com/sheerafrenkel/a-deadly-virus-is-spreading-around-saudi-arabia-and-it-might

Wednesday, 23 April 2014

Ebola update: some additional numbers for Guinea & Liberia from 20-April, WHO-AFRO update

Click on image to enlarge.
The case curves are flattening which is a good sign that he 2014 West African Zaire ebolavirus outbreak is being brought under control. 

Nothing new is happening in Sierra Leone-no new case onsets have occurred there since 6-Apr. Nothing has tested positive in Mali.

The previous SitRep [2] seemed to have lowered the Liberia case numbers but they have popped back up again - perhaps part of the "cleaning" of case data there - and that has made it "look" like a jump (contributing to the grey bar), when it may have been a more gradual rise.

The most recent activity is in Guinea, where the last cases isolated were on 20-Apr.

Finally, despite all the Tweets flying around about the virus having spread to Europe and "broken containment", that would not seem to be the case from the latest report. Oh and the lack of any credible source for that.

Source...

  1. http://www.afro.who.int/en/clusters-a-programmes/dpc/epidemic-a-pandemic-alert-and-response/outbreak-news/4106-ebola-virus-disease-west-africa-22-april-2014.html
  2. http://www.afro.who.int/en/clusters-a-programmes/dpc/epidemic-a-pandemic-alert-and-response/sitreps/4102-sitrep-2-ebola-virus-disease-west-africa-17-april-2014.html

Sunday, 20 April 2014

A situation well in control....?

Click on image to enlarge.
Is the slowly-spreading epidemic of MERS-CoV changing gears or are the vastly shortened times required to reach each 100 cases just a blip?

I don't know but here's a chart that tells a story of speed.


Ebola update: some additional numbers for Guinea from 17-April, WHO-AFRO update

These numbers slightly change the numbers I last posted from 18-April. 

A small uptick in deaths and lab confirmations and a change to the most recent illness onset which is now 17-Apr. The clock is still waiting to start on the 2-incubation periods required, without new cases, before the region will be declared free of Zaire ebolavirus.

18 healthcare workers are lab confirmed with Ebola virus disease, 6 are probables (24 in total) of which 15 have died (11 are lab confirmed).

Source..

  1. http://www.afro.who.int/en/clusters-a-programmes/dpc/epidemic-a-pandemic-alert-and-response/outbreak-news/4104-ebola-virus-disease-west-africa-19-april-2014.html

MERS-CoV cases and deaths by month and growing tallies: a look at the impact of 2 clusters on a "slowly growing epidemic"

The yellow star are to highlight that the 
y-axis (left-hand side values) in 2014
is set to a higher maximum value
than for 2012/2013.
Click on image to enlarge.
The 2 healthcare-associated clusters (paramedic cluster and Jeddah cluster) are the driving factors underpinning the case number spike in April. Cases in other regions are either linked or relatively few in number.

Click on image to enlarge.
With a dozen new cases noted by the United Arab Emirates (UAE) early this morning (my time) I've updated the case and epidemic curve chart below as well, again. This makes UAE the clear second place hotzone for MERS-CoV cases. 

Whether these cases, all asymptomatic, are liked to the paramedic cluster or just the result of enhanced testing (there was mention of contacts in the media release though) is unknown and awaits clarification as do more details on most of the recent 90 cases .


Click on image to enlarge.
And lastly for this post, a chart I last updated 18-Mar when there were fewer then 200 cases. Ahh the good old days. How a month and a couple of healthcare outbreaks change things. This shows the total cases, obviously driven by the Kingdom of Saudi Arabia, but adds on those from the UAE and Yemen as well. A very interesting feature here is the current proportion of fatal cases. The PFC sits at 32.7%; the lowest proportion of fatal cases in the history of MERS-CoV. Why? Because the denominator in that equation (total case numbers) has sky-rocketed without an accompanying rise in fatal cases. While some of the recent cases may yet succumb to severe MERS, the spike we've seen in cases without any disease or with only mild disease, who probably won't die, will offset that and the PFC looks to remain lowered. I would very much like someone to tell me whether these increased numbers of mild cases are due to a change in the approach to testing (contact me!) of people; more testing and less watching and waiting to see if contact and other become obviously sick. Either way - this is great to see.

So this last chart really hammers home one good reason to include asymptomatic cases in the tallies; we get to see the full spectrum of disease from MERS-CoV infection, including no disease at all

Knowing that gives us some much needed context when we see a headline that reads "killer virus spreads". 

Now if we just knew whether asymptomatic cases spread infectious virus either through occasional coughs or sneezes or by contaminating their environments. Baby steps.