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.

http://www.flickr.com/photos/xikita/48647105/in/photostream/

CC BY 2.0

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
http://www.dailymail.co.uk/news/article-2528868/Theyve-got-humps-Hundreds-camels-snake-way-desert-theyre-driven-beauty-contest-Abu-Dhabi.html
5. Newser.com | Dubai Sheik Pays $2.7M for Camel | April 2008
   http://www.newser.com/story/23945/dubai-sheik-pays-27m-for-camel.html
6. 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
7. 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
8. 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

Read More

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://newsmedicalnet.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

Read More

The case against over-interpreting MERS-CoV detection by month...

Click to enlarge. MERS-CoV cases plotted by month of
detection (global data; combining 2012 and
2013 confirmed detections).

There are a number of reasons why I started my post yesterday (my time) with "I'm the first one to say its way to early to be talking about the seasonal distribution". Let's look at some of those reasons today:

1. Where there are few positives in the chart, there has also been very little testing done. The first validated PCR assay was published in 27th September 2012. So Sept-Dec 2012 cases are few and far between for this reason.
2. We are not yet 12-months beyond the announcement of the discovery of MERS-CoV (then nCoV and subsequently HCoV-EMC/2012). It was announced via ProMED on the 20th of Sept and the first genome and clinical study went online 17th October 2012. So no real screening had been done before that time. Cases shown prior to Sept 2012 that identified were retrospectively and not the result of systematic screening
3. As far as I know, screening is still mostly done on a case by case (and contacts thereof) basis. We don't know whether MERS-CoV is circulating endemically in the KSA or any other peninsula country. This is an important data gap since it may be humans that are acting as the reservoir - for all we know
4.  If we look at my post prior to the seasonality chart last night, we can see that cases are climbing steadily - have been since April, and there is no real sign that there is a change in that climb by month. Some reduction of numbers July & August but September is shaping up to be a big month.
5. The spike in cases starting in April was related to a hospital outbreak (the Al-Hasa cluster). And things have rolled on since then. What triggered that outbreak or how the first case(s) acquired the infection remains unknown

So why draw the chart if it is not an accurate representation of true seasonality? Because it gives us an idea of how all the cases officially announced so far are falling out over time, based on the data we have. 

But it should not be over-interpreted. 

We'd need a much greater number of cases and probably a couple of years of surveillance (including community screening) before we could accurately define whether MERS-CoV appears with any seasonal recurrence. Nonetheless, the seasons, or events that happen with seasonal regularity, may influence the risk of exposure and spillover. Also, most of the other seasonal human CoVs occur at their peak every couple of years, and even then, some occur in very low proportions of specimens from people with acute respiratory tract infections. That may be irrelevant to an emerging CoV, or not, so it may take even longer before we can speculate on any seasonal regularity to MERS-CoV infections; if we don't first stamp out the virus altogether as we did with the human SARS-CoV.

So to conclude, before I have to find something and PCR it, given the small amount of data we have, and hints that it might be only the tip of that well referred to iceberg, the more we can extract from what we have the better our chances of finding some clues to the host and some risks for acquiring infection.

Read More

Can MERS-CoV seasonality tell us anything about acquisition of MERS?

Click to enlarge. Combined MERS-CoV cases for 2012 & 2013.

I'm the first one to say its way to early to be talking about the seasonal distribution of a new or emerging virus when there are only 124 cases worldwide. 

Right. 

Having said that, I thought I'd plot the cases by date of illness onset or (less satisfactorily) date they were first reported (even if that first was the report of a death). 

When combining the 15-months worth of case data for 2012 and 2013, the graph revealed a single "season" or at least larger numbers around summer in the Kingdom of Saudi Arabia (KSA). Because >80% of cases have occurred in the KSA, I have also listed a few festivals (some of which are frequented by camels) as well as the peak temperature variations and dust storm activity.¹ 

While I have no idea whether weather could be kicking up clouds of infectious CoV, it is an interesting co-occurrence, as are the presence of a number of festivals before case numbers spike. The Saudi Gazette commented that the risk of [acquiring?] bacterial and viral infections increases during dust storm season as do complication due to allergen exposure.

Of course we also know that some large clusters of cases have originated form hospital outbreaks and so environmental factors may play very little role at all. Or they might. Its impossible to say. But it is worth considering what could be happening up 2-weeks prior to a sharp rise in cases - if only to identify 1 index case that then ended up triggering a hospital outbreak.

1. Dust Storms in the Middle East: Sources of Origin and Their Temporal Characteristics. http://ibe.sagepub.com/content/12/6/419.short
2. http://www.magazine.noaa.gov/stories/mag86.htm
3. http://www.saudiaramcoworld.com/issue/200803/heads.high.htm

Read More

Flu-like symptoms on the rise in Qatar...

The Gulf Times notes a rise in cases of "flu-like symptoms" in Doha, Qatar. Dr Sameer Kalanden, a general practitioner (GP) notes a rise on cases coming to the clinic. He usually prescribes medication  or "an injection" to reduce the fever (please don't let it be antibiotics..oh. It is antibiotics). 

If there is no sign of improvement, even after a 2nd visit, he refers the case to Hamad General Hospital (managed by Hamad Medical Corporation; HMC).

Another GP confirmed the recent rise in cases with symptoms of "flu and common cold" rising "these days". He also refers cases with more severe respiratory disease to HMC.

So from that we might be able to conclude:

1. HMC may be the testing lab for Middle East respiratory syndrome (MERS) coronvirus (CoV) in Qatar. We also know that may/all MERS-CoV cases are confirmed by UK collaborators
2. That only the most severe cases of illness will be tested for MERS-CoV
3. GPs do not refer any other acute respiratory illnesses for MERS-CoV testing routinely
4. There is considerable concern about MERS in Qatar - but not a lot of structure to resolve that concern

This sort of anecdotal report is a great way to bring attention to what isn't being done, but it would be much more helpful to know what is being done in Qatar, given its recent local cases and deaths. 

As I understand it, Qatar is entering it's cooler months. Looking through the literature, there are not a lot of papers on respiratory viruses from Qatar. In one paper by Wahab and colleagues in 2001 in the Journal of Tropical Pediatrics, we see that HMC testing defined the peak season for respiratory syncytial virus (RSV) in children as November-January in Qatar (data from 1996-1998 combined, included 257 previously healthy children). 59.9% of these cases were diagnosed with bronchiolitis, 17.6% with pneumonia and 35.8% had an infiltrate in their lungs. RSV cases start rising from September though. The authors note this seasonality is similar to other temperate countries in the Gulf region. And this is just 1 virus of 200.

In another study, this year, in Archives of Virology, Althani and colleagues (Qatar University and HMC) tested 200 adults with asthma or chronic obstructive pulmonary disease (COPD) across winter (October 2008 to March 2009). While virus detections were relatively few (18% of patients), most seasonal viruses were present during this period - more so in asthma than in COPD. These included rhinoviruses, HCoV-229E, NL63 and OC43, parainfluenza viruses 1-3, RSV, adenovirus, influenza B virus and human metapneumovirus.

So this rise in cases noted by the GPs above may be nothing more than the usual start to the respiratory virus season, made to look more scary because of the recent MERS-CoV outbreak. Or it may be more than that.

I believe its time to be seriously considering what local laboratory testing capacity exists on the ground in the Arabian peninsula.

If the hajj stirs up case numbers, as many suspect it will, having limited to no ability to quickly resolve a flood of potential cases will result in a management crisis. Cases will accrue quickly and "probable", rather than "confirmed" will become the word of the day while trying to prevent spread in hospital environments.

If it looks like a duck and quacks like a duck, it may be just a rhinovirus. 

Case numbers will also be added to, as they always are when surveillance is heightened for a new agent, because seasonal endemic human respiratory viruses are circulating as well and those infections cannot reliably be discriminated from mild to moderate MERS-CoV using patient observation alone. 

Currently, MERS-CoV results in the Kingdom of Saudi Arabia may take up to 2 weeks to turnaround (if you follow me on Twitter you will have seen this time frame suggested to me last night). 

If the cases seen by the GP today were MERS-CoV positive, they would 1st need to return with a continuing fever before being tested and then that result would be revealed either too late to reduce the risk of a transmission event, or perhaps too late to be of use in applying novel antiviral treatments on that patient.

Time is of the essence. And more testing is paramount.

Thanks to @makoto_au_japon and @dspalten for bringing this to my attention.

Read More

Welcome to Week 7 of the H7N9 outbreak.

Week 6 was relatively quiet although more fatalities occurred than in Week 5 (3 vs. 2).

No new H7N9 cases with a date of onset in Week 6 occurred, and there were only 3 in Week 5 so confirmed case reports have dropped right back. Tomorrow is "tell-all Tuesday" (well, I'd like some more date data this time around) in which we hope to get a snapshot of cases over the past reporting week in China. No sustained human-to-human transmission, no new provinces or municipalities reporting cases. Reports suggest that with summer coming H7N9 cases will drop off. I'm not convinced given of that H1N1pdm 2009 peaked in the US during the warmer months - I think an emerging flu virus may well be able to buck the trend of seasonality. However, I suspect that seasonality is heavily influenced by virus:virus interactions in the community so it may depend on what other respiratory viruses are co-circulating now and in the coming weeks.

Read More