Epidemiology without dates is just -ology...

Click on image to enlarge.
Data from the Kingdom of Saudi Arabia Ministry of Health MERS website.[1]

The above images give an indication of what the Kingdom of Saudi Arabia's Ministry of Health (MOH) considers to be case detail of immediate relevance to the public according to Prof. Tariq Madani, head of the scientific advisory board within the MOH's Command and Control Centre (CCC). 

Since the newly revised CCC MOH website came online, dates that describe key information have been absent (red dashed outline in the screen capture above). These dates include:

• Date when symptoms began
• Date of hospital admission
• Date when a new fatal case was first reported (allowing a link to be made)



Click on image to enlarge.
Where the re-defined 113 cases fall out across 2013 to
1st week of May, 2014.[3]

• Date when a recovered case was first reported (allowing a link to be made; actually this one hasn't ever been present)

Sure, we only had these dates for a short period, and relied heavily on the World Health Organization's (WHO) Disease Outbreak Notifications (DONs) to fill in and "scrub" the data once it was submitted to them, but it was so great while it lasted. 

I have had many emails and Tweets noting how useful its been to others to see those data distilled into more digestible graphs and charts. These notes have come from both the public and from other scientists too.

This latest change to the MERS information provided us,  came after a report on 3-June[2,3]. That is also the entry between where there were dates included [orange] and where dates stopped being included [red] again, in Part A above. The report described a review which started in May and found 113 un(publicly)reported MERS cases (see the bar chart above). Interestingly, 55 of these cases were either not sent to, or were not confirmed by, KSA governmental laboratories (thus should be better listed as probable cases IMO) while 58 results just hadn't been sent to the MOH, who "sign off" on the final reporting of MERS-CoV detections. Great that the CCC is able to track these down and admit to them. Good work. 

Not so great that 33 of the 55 cases are included in this tally despite not being able to be confirmed. 

In response to the "found 113", I halted my charting activities for MERS-CoV that week. I won't be resuming charting until the very long-awaited WHO's DON fills in the gaps on over 400 cases[6].

Much has been made by the media, some of it with comments from me[2,8], of these events. Some have noted that there is now a new sense of transparency about. While I don't argue with reports and comments about a range of collaborative efforts now/already underway (which is great news) and the need to acknowledge things when they improve, I do question how the retraction of some key data, essential for public epidemiology efforts, data that were fine to be included (inconsistent as they were even then) previously, can be labelled as transparency. I certainly do not think those actions meet up to this statement (bolding is mine)[3]...

"Based on the findings of the review, the Ministry has already put in place a number of measures to ensure that best practices of data gathering, reporting, transparency are being strictly observed.."

I've stated before, for H7N9[4] and for MERS[5] that we, the public, do not have a right to such data, even though its deidentified and the privacy of the patient is protected. We may feel entitled, but we are not. So long as the WHO and appropriate Committees or experts are aware of the facts and can judge the risk to the world, then that is the main issue.

Of course, I'd much rather we lived in a world where such relatively innocuous data were available, and complete. But whether or not we get to play with useful and rich data is a separate issue to the difference between saying something is so and it actually being the case. 

There has been an increase in the presentation quality (prettiness) of data but a decrease in the data presented, since the CCC website came online. That's a fact. 

References...

1. http://www.moh.gov.sa/en/CCC/PressReleases/Pages/default.aspx
2. http://uk.reuters.com/article/2014/06/12/us-saudi-mers-failings-insight-idUKKBN0EN1I520140612
3. http://www.moh.gov.sa/en/CCC/PressReleases/Pages/mediastatement-2014-06-03-001.aspx
4. http://virologydownunder.blogspot.com.au/2013/04/h7n9-cases-in-china-to-be-reported.html
5. http://virologydownunder.blogspot.com.au/2014/01/keeping-patient-privacy-at-fore.html
6. http://www.who.int/csr/don/2014_06_13_mers/en/
7. http://news.sciencemag.org/asiapacific/2014/06/research-teams-clash-over-too-similar-mers-papers

*POSSIBLY NOT* Country #22 to have been paid a visit by the MERS-CoV: Bangladesh [UPDATED x2]

Looking like this result could not be confirmed 

by external testing.

June 20th 

The case, a 53-year old male (53M) returned to Dhaka, Bangladesh on 4-June from New York (the United States of America), via Abu Dhabi (United Arab Emirates). He became symptomatic on 6-June and was hospitalized 9-June.

Director of the Institute of Epidemiology, Disease Control and Research (IEDCR), Prof. Mahmudur Rahman, speculated that 53M was likely to have contacted MERS-CoV in the UAE. It's not clear whether he transited through the Abu Dhabi airport (apparently he was at the airport for 3-hours, h/t @influenza_bio; seems like a very unlucky acquisition then[4]), or stayed there for some time. 

If new Bangladesh #MERS patient truly contracted #MERS in Abu Dhabi airport or on an airplane, this suggests a spreader was also traveling.
— A biologist (@influenza_bio) June 15, 2014

It's also not clear how long he stayed the the USA for. The WHO have been informed, according to reports.

A 2-day incubation period is a bit on the short side for MERS-CoV though. Eagerly awaiting the WHO DON on this case.

[UPDATE] It looks like this sample could not be repeated. If I read any further announcements I'll post them here buit for now it appears that the two samples may have been false positive results. How that could happen I'm really not able to imagine. But we'd need to know more about the testing to answer that.

Sources...

1. FluTrackers thread
   http://www.flutrackers.com/forum/showthread.php?p=537546#post537546
2. Treyfish's H5N1 pandemic information news blog
   http://swineflumagazine.blogspot.com.au/2014/06/more-on-bangladesh.html
3. The Daily Star
   http://www.thedailystar.net/mers-detected-first-time-in-bangladesh-28635
4. Channel NewsAsia
   http://www.channelnewsasia.com/news/health/bangladesh-reports-first/1162024.html

MERS-CoV in the blood....

The Middle East respiratory syndrome coronavirus (MERS-CoV) is, at its core, a respiratory virus. Well, as far as we know it is anyway. But, like other respiratory viruses (see an earlier post on rhinoviruses), MERS-CoV can be detected in the blood....a so-called "viraemia". In some cases this is identified in other virus infections in parallel with the viral load being generally high, perhaps indicating that virus is replicating beyond the body's ability to contain and control it at the site of initial replication. 

Perhaps, and MERS-CoV may be a good example of this, so-called extra-respiratory spread of a respiratory virus occurs when it has a penchant for blood vessel cells (they present its receptor or have something in their cellular machinery that aids virus replication) or some other ability to specifically get beyond the respiratory tract. 

However it occurs, the result is a much wider spread of the virus around the body; blood being something that is widely traveled! We already know that MERS-CoV has a love for growing in kidney cells so extra-respiratory spread may create a perfect storm for delivering this little bomb to a site where it can create even more havoc than in our airways. If those kidneys are already a bit bashed about, say by diabetes, then the blast radius is perhaps increased that much more.

A new paper just out in Emerging Infectious Diseases [1] is the latest to highlight viraemia, or pedantically because its viral RNA in the blood, RNAemia and its role in detecting MERS-CoV.

A lower respiratory tract (LRT) sample (bronchoalveolar lavage; BAL) was collected from a 66-year old man (66M) who returned to Tunisia after after a 5-week visit (20-March to 28-April) with his daughter in Qatar, interspersed with a pilgrimage to Mecca (Makkah; 27-March to 04-April) in the Kingdom of Saudi Arabia (KSA). 

66M arrived back in Tunisia 28-April with an acute respiratory illness which progressed and from which the LRT sample was collected. A subsequent X-Ray identified cellular infiltrates in his lungs. His 30-year old daughter (30F) stayed in Qatar. His 34-year old son (34M), a nurse, cared for him both at home and later in the intensive care unit as his disease progressed, eventually ending in his death from multi-organ failure. He was buried 13-May and his daughter returned from Qatar for the funeral. 66M's LRT sample was not positive for MERS-CoV and he had no other respiratory viruses (not detected using PCR testing which may have been more appropriate). His daughter and son were positive for MERS-CoV so 66M was described as a "probable" case (travel, signs & symptoms, and at least subsequent contact with MERS-CoV cases). The incubation period for his illness placed 66M in Qatar at the likely time of acquisition of virus and his son was likely to have acquired his infection from his father in Tunisia. The daughter may have acquired the virus from her father while he was in Qatar or from a related source in Qatar (but seems to have been a Qatar-related acquisition of some sort). 66M's wife, 2 other well children and his son's wife were not MERS-CoV positive 5-weeks later (but then they were unlikely to have tested positive so far out from the event). 

Afterwards the US CDC tested a serum sample (tested 5-August-2013, blood taken 9-May-2013) by reverse transcription real-time polymerase chain reaction (RT-rtPCR), and it was positive. This - the case the cluster is resolved. Got a better appreciation for the amount of work that goes into tracking this stuff down in detail?

But this was not the first time a MERS-CoV diagnosis was obtained retrospectively, or as part of a study, using RT-PCR (conventional or real-time) on serum (cell free blood) rather than a respiratory tract sample. Just a note, the presence of viral genome (or bits thereof) identified by RT-PCR does not guarantee that infectious virus was in the blood, only that viral RNA could be detected there.

• Case No. 1 from the original hospital cluster of MERS cases in Al-Zarqa, Jordan in March-May 2012, was identified thanks to retrospective RT-rtPCR (CDC version) on a convalescent serum sample.[2] 
• The 2 French MERS cases (1 imported, 1 locally acquired from contact) had RNA in their blood (UpE RT-rtPCR); the patient who died was positive for at least 4-weeks while the surviving patient cleared viral RNA in the 1st week after symptom onset.[3] 
• Two cases imported into the Netherlands from the KSA were found to have viral RNA in their blood for days; Case #1 from day-0 after diagnosis until at least day-9 and Case #2 from day-1 until at least day-5.[4] In this study viraemia outlasted virus detectability in the faeces but was detected for as long as virus in throat swabs of Case #1. RNA was not detected in the urine.[4]

Serum may be a useful sample, not just to determine whether antibodies to MERS-CoV develop(ed), but to help detect MERS-CoV RNA, as a surrogate for infectious virus, when a respiratory sample is not available. 

The finding of MERS-CoV RNA in the blood so frequently, among those studies that have looked, may also indicate it is a useful marker of disease severity as seen in the French cases. Serum is already a sample recommended for collection for antibody studies.[5] Let's see if these papers can trigger a little more looking back at those samples, which are hopefully stored in freezers somewhere. 

Anything that helps nail down "probable" cases and better define the pathogenesis of MERS-CoV is a good thing. 

References.... 

1. Family Cluster of Middle East Respiratory Syndrome Coronavirus Infections, Tunisia, 2013 http://wwwnc.cdc.gov/eid/article/20/9/14-0378_article.htm
2. Novel coronavirus infections in Jordan, April 2012: epidemiological findings from a retrospective investigation
   http://applications.emro.who.int/emhj/v19/Supp1/EMHJ_2013_19_Supp1_S12_S18.pdf
3. Distinct Immune Response in Two MERS-CoV-Infected Patients: Can We Go from Bench to Bedside?
   http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0088716
4. Middle East respiratory syndrome coronavirus (MERS-CoV) infections in two returning travellers in the Netherlands, May 2014
   http://www.eurosurveillance.org/images/dynamic/EE/V19N21/art20817.pdf
5. http://who.int/csr/disease/coronavirus_infections/MERS_Lab_recos_16_Sept_2013.pdf?ua=1

1 of these papers is pretty much exactly like the other...[UPDATED #2]

This is a strange one. 

Today, a New England Journal of Medicine (NEJM) paper [2] came out and received a vast amount of media coverage. 

It seems as if all the other recent press, the camel kissing videos, camel advocates decrying the link between MERS-CoV and their beauties and camels being included in risk assessments...have just primed the world for the next scientific paper. 

And then this new paper came out showing MERS-CoV infection of a farmer and of his camels and a likely direction to that infection of camel >> farmer. And, it came out in the highly prestigious NEJM - this folks, is one part of what a high impact factor is all about - wide exposure and broad coverage. You really get your research out there.

Apparently neither of us are actually
Jeddah camels 'cause we're wearing too
much bling.

Twitter and the mainstream media have lit up with lines like "direct evidence that MERS comes from camels", "new report offers strongest evidence yet that MERS virus spreads from camels to people", "1st evidence that a new deadly virus has been transmitted from a camel to people".
There is a problem though. It's not reeeally any of those things.

These are both studies of what looks to be the same infected human (a 43-year or 44-year old man depending on which report), hospitalised at King Abdulaziz University Hospital in Jeddah on 3-November-2013, owner of a herd of 9 camels, some of whom were sick, sampled at around the same time (I presume, otherwise why sampled at all?).

The only major differences (there are smaller differences) between the 2 reports is which camel yielded sequence - it seems to have been Camel G for Drosten's lab and Camel B for Madani's - they even seem to have used the same identification scheme for the camels! The NEJM paper also has some human serology data that were absent from Drosten's study; determined using an immunofluorescence assay, although not confirmed as MERS-CoV specific using the more specific neutralization test.

Oh, one other big difference.

Memish, Drosten and colleagues got their paper out online around 20-March-2014 (2-months 15-days earlier [UPDATED]).

But let's also look at the sequence release/modification date too. This is the date when the researcher's virus sequence data, submitted to the public sequence database GenBank prior to the paper being published, is available. For Azhar and Madani and colleagues, that date was 1-May-2014 (sample taken 5/8-Nov-2013) and for Memish and Drosten and colleagues, 24-March-2014 (could only access 3 fragments; sampled 9-November-2013).

NOTE: This Editor's Note was added (9-June) to the NEJM paper:

The patient and camels discussed in this article are also described in Memish ZA, Cotten M, Meyer B, et al. Human infection with MERS coronavirus after exposure to infected camels, Saudi Arabia, 2013. Emerg Infect Dis 2014;20:1012-5.

I'm sure there are at least 2 very interesting stories behind this little event.

References...

1. Human Infection with MERS Coronavirus after Exposure to Infected Camels, Saudi Arabia, 2013
   Ziad A. Memish, Matthew Cotten, Benjamin Meyer, Simon J. Watson, Abdullah J. Alsahafi, Abdullah A. Al Rabeeah, Victor Max Corman, Andrea Sieberg, Hatem Q. Makhdoom, Abdullah Assiri, Malaki Al Masri, Souhaib Aldabbagh, Berend-Jan Bosch, Martin Beer, Marcel A. Müller, Paul Kellam, and Christian Drosten
   Emerging Infectious Diseases
   http://wwwnc.cdc.gov/eid/article/20/6/14-0402_article.htm
2. Evidence for Camel-to-Human Transmission of MERS Coronavirus
   Esam I. Azhar, Ph.D., Sherif A. El-Kafrawy, Ph.D., Suha A. Farraj, M.Sc., Ahmed M. Hassan, M.Sc., Muneera S. Al-Saeed, B.Sc., Anwar M. Hashem, Ph.D., and Tariq A. Madani, M.D.
   New England Journal of Medicine
   http://www.nejm.org/doi/pdf/10.1056/NEJMoa1401505

MERS-CoV charting on hold after 113 new cases reported without details...[UPDATED]

With the announcement overnight that a bunch (133 detections including 92 fatal cases) of old laboratory confirmed MERS-CoV detection had been found, but without any specific data to identify them, I will not be posting any further MERS-related charts. I believe there is a big WHO Disease Outbreak News update coming soon and it will provide all the detail - we bloggers will need to take a week off from our day jobs to add this detail to our line lists - but I'll resume charts some time after those data appear.

This is all obviously being dumped at the feet of the stood-down Deputy Minster of Public Health whose reputation for total control was well reported. Let's not forget that the Minister, Abdullah al-Rabeeah, was stood down 21-April by King Abdullah. If Prof Memish, who had been moved off the advisory committee when the new Acting Minster of Health took the reins, had the total responsibility (that many attribute to him) of ensuring every lab result was identified and reported and he was in charge of overseeing and releasing those data - then blame away! But that would also mean that the Ministry of Health is not a Ministry, but a one-manistry. I'd like to  believe that was not the case. Was the Ministry really under the complete control of just one Deputy Minister? It's never that simplistic.

This latest event, 6-weeks later and including cases from 2013/2014, points to reporting systems and data collection and collation pipelines that failed miserably. Given the inconsistencies of case reporting by the MOH, I don't have much trouble believing this is not a cover up but an administrative stuff-up. 

Sounds like I'm defending Prof. Memish too - which is not my intention. I do not know the facts. But I'm not sure anyone outside the KSA MOH does. Wouldn't it be great to live in a world where someone came out and just told it like it was? While Prof Memish obviously loved a good paper, and that was his chosen method of science communication (I've talked about that as a less-than-ideal route for public health matters), I personally have no evidence for or against the scope of his control over this latest debacle. 

Highlights of 113 retrospectively added (orange)
laboratory-confirmed detections of MERS
(including 92 deaths)
added to the cases already knwon (blue)
Chart from KSA MOH CCC [3]

A final note. These data [3] are presented on the new-look Ministry of Health's Control & Command Center (CCC).[1] It's a new website address so update your links. 

Let's wait and see whether the CCC lives up to it's name.

References..

1. Saudi MERS data review shows big jump in number of deaths
   http://in.reuters.com/article/2014/06/03/us-health-mers-saudi-idINKBN0EE1N820140603?feedType=RSS&feedName=health&utm_source=dlvr.it&utm_medium=twitter&dlvrit=309303
2. Kingdom of Saudi Arabia Ministry of Health Command and Control Center (CCC)http://www.moh.gov.sa/en/CCC/PressReleases/Pages/default.aspx
3. Update in Statistics: Ministry of Health Institutes New Standards for Reporting of MERS-CoVhttp://www.moh.gov.sa/en/CCC/PressReleases/Pages/mediastatement-2014-06-03-001.aspx

MERS-CoV by week...good luck Professor Memish

We are now in the 116th week since MERS-CoV caused known illness in a  human; a week that has seen the loss of Professor Ziad Memish from the frontlines of the war on MERS. 

Thankfully it was not a physically fatal loss, but rather a "standing down". Not only is Prof. Memish the father of Mass Gathering Medicine, but he has been the public and global face for the mischief caused by MERS since the beginning.

Insights from the Front Lines. UPMC Center for Health 

Security presentation by Dr Ziad Memish on MERS-CoV.

August 21, 2013

I tip my hat to a very prolific and expert writer who has in his time covered every aspect of the emergence of this virus. He has produced about 40 journal articles on MERS-CoV in just 2-years..so far. 

I and others have been critical of the speed with which information about MERS and the MERS-CoV has materialized and I stand by that. But I admit to never having walked a mile in Prof. Memish's shoes so that may be unfair.

I also realize that this one person had a lot to do. He bore the brunt of being the front man, the scientific communicator, the collaborative nexus and also the punching bag for the hits that came when things didn't go well or go fast enough; today's announcement is probably the culmination of those hits. Whether or not Prof. Memish was adequately supported in his role, I have no idea, but I personally feel The Ministry of Health needed more engagement with it's stakeholders, the people of the Kingdom, but also with the world at large. I don't know that any one person can adequately do all those things nor should he be blamed for all those failings. 

We shall see how Prof Memish's successor goes. I'd personally hope that they start a dedicated media Unit that can become a more public face for MERS and other health issues in the Kingdom. I'd instruct that Unit to have an active presence on Twitter. But not just on Twitter ; engaged with Twitter. Many people have ideas that could help inform and educate-listen and learn from them. And update the Coronavirus website with some "work in progress" banners. I think some official hints or comments about what is coming down the pipeline would be very useful and calming. And try find some mainstream media writers who will do the occasional 1 on 1 interview - sometimes the quick grabs can be a killer for trying to get the bigger picture out into the world. Plus, a lot of people like knowing more about "that person over there". Its a big media-driven world out there. Use it. Be novel and innovative with it. You've cleaned out your house now. Do something new and exciting with your abode.

So, to wish Prof Memish the best, I post a chart. I can't buy him a coffee from my chair on the other side of the world far away from all the action-but I would if I could. I'd love to sit and have a chat with him about it all. I also very much hope he has someone he can he can vent to, or with, at the end of the day. I know that without my family, I'd have gone mad many years ago! 

This is not a new chart to anyone who reads these pages. And it's not one that screams of an outbreak out of control. It's a chart that shows the continued cessation of an outbreak. In fact, one that seems to be under control, at least for now. And given that the biases in reporting are probably no different now from what they were 6-weeks or 18-months ago, I tend to trust that it is under control. 

Perhaps this is a fitting send off for a man who seems like he just wanted to do the best he knew how to, to help his people. I hope he can still do that in whatever role is next up for him. Just as I've always hoped for that for Prof Zaki as well.

Now to see what comes next for MERSville.

A chart for Professor Ziad Memish.
Click on chart to enlarge.

MERS-CoV detection and age...

Just a few different ways of looking at age of living and deceased MERS-CoV people, globally, since 2012.