Influenza in Queensland, Australia: 1-Jan (Week 1) to 8-June (Week 23)

Map of Queensland's Hospital and Health service 

areas. Adapted from

http://www.health.qld.gov.au/maps/hhs_facilities.pdf.

Click on image to enlarge.

Waaaay back on 18-March we looked at how influenza notifications in Queensland (population ~5mill) were above the 5-year-to-date (YTD) average. 

"Woopty Doo" some, perhaps very few, of you said. "That number means nothing until you look back at it later". 

So, let's look back at it now that it's later. 

It was Autumn then and now its Winter which is Flu season and also the season when we get some more public info on a handful of other  respiratory viruses circulating here in Queensland thanks to the collatory (I don't care if a dictionary doesn't recognize it) genius of the crew at the State of Queensland, Queensland Health (SoQ|QH).

So what's happening with flu Down Under? For all the detailed detail, I recommend you check out the Open Access document, Statewide Weekly Influenza Surveillance Report that spans up to Week-23 (that's the week ending 8-June; we're in Week 25 now)

Turns out its still 2x (well,  1.987x but who;/s counting?) above the 5-year-to-date mean. No, this is not a "I told you so" - just that it's interesting to see that on this occasion at least, autumn trends predicted a winter event. Still, its only early winter. We've also had a very warm and dry autumn (see the Bureau of Meteorology for more on Autumn) for those who like to link weather and influenza activity.

I like to look at virus interactions as driving their own seasons. How is that possible I eerily hear you ask (I'm not listening to the "Oh what a load of..." comments by  the way, so sit back down and put up your hand)? Well, they don't do anything themselves of course, but my theory goes like this...

When there are enough of us in the community infected by one virus (say respiratory syncytial virus [RSV]) and our immune-thing-a-me-whats-it is all fired up and producing an inflammatory response to rid us off said pestilence, that responsey thing offers a kind of "Shield's Up" effect. 

For a short while we feel like rubbish but we also don't let other viruses get in as easily because we're in an "antiviral state". Enough of us in that state and we get a kind of short-term herd immunity (a fairy died) - where the number of people fully susceptible to another virus (say, an influenza virus) is too small for it to get a good toehold in us and the population. This pattern among seasonal respiratory viruses is most often observed, in my experience, for viruses with an RNA genome like RSV, rhinoviruses and influenza viruses. 

Thankfully for my hypothesis, the data from SoQ|QH show a nice example of this pattern of viruses interacting with viruses within us, projected to the level of the community. 

A snippet from the State of Queensland, Queensland 

Health Statewide Weekly Influenza Surveillance 

Report  for 1-January-2014 to 8-June-2014.
Edited by Ian M Mackay, VDU.

Click to enlarge. 

Let's have a look at the adjacent figure I've mixed around from reference [1]. Hopefully I haven't broken any copyright laws in hacking pasting as I have.

Part A shows the notifications for influenza viruses in Queensland. Peaks and troughs, As and Bs. Cool

Part B shows some of the respiratory viruses, including RSV which has been having a bonza season this past autumn by the looks of things.

Can you see the pattern?

Part C is a cobbled together composite I made in Photoshop/Illustrator by laying B over A and making B partly transparent. It's a bit rough and has had the axis labels and legend trimmed off for clarity, but it makes the point. What it shows (to me anyway) is that when RSV numbers go up, influenza virus notifications head downwards. 

Is this due to RSV influencing influenza or influenza exerting its muscle on RSV? Can't tell from this sort of analysis. 

The fact that RSV can rise in the presence of influenza virus may speak to its dominance. But take a step back. Remember we're taking about people not cells in a dish. It may be that 2 distinct populations are at play initially; perhaps younger children with RSV versus older children and adults with influenza. Once infected people reach a critical mass, that virus may win out and "push put" the other.What's happening in a single household - kids bringing home one virus, parents another perhaps? That would be intriguing to know with these concepts in mind using molecular methods and longitudinal regular sampling of whole families, regardless of symptoms.

Statistically, when I've looked at this with other data, that negative association, more obvious and frequent between influenza virus and rhinoviruses, does reach significance. You can read one of my group's hospital-based studies in [4] and a collaborative community study in [5]. Rhinovirus seasons usually bracket influenza season. So I offer a different view of how seasonal viruses are seasonal. With the sources of variability I discuss above as well as genetics and differences in everyone's past virus exposures and immune-thing-a-me-whats-it status to each virus, some cross-protective, some not, some having got really sick last year, some not...its not hard to see how those virus seasons can shift around from year to year as well.

Yet another reason to test for viruses, and to include more than just 1 or 2 viruses in that testing; the more you test, the more you can observe and learn.

By the way, interferon-the major player in causing these virus:virus interactions, got its name because it could block a secondary viral infection much like those that I've described above, but on a population level.

Now, try and get some funding to do any research on that. I hate you if you do by the way (yes, I failed miserably).

References...

1. Statewide Weekly Influenza Surveillance Report, 1-January to 8-June 2014.
   http://www.health.qld.gov.au/ph/documents/cdb/influenza-qld-140101-140608.pdf
2. Queensland in autumn 2014: A warm autumn; coastal rainfall but dry inland of the Great Dividing Range
   http://www.bom.gov.au/climate/current/season/qld/summary.shtml
3. Do rhinoviruses reduce the probability of viral co-detection during acute respiratory tract infections.
   http://www.ncbi.nlm.nih.gov/pubmed/19376742
4. Community-wide, contemporaneous circulation of a broad spectrum of human rhinoviruses in healthy Australian preschool-aged children during a 12-month period.
   http://www.ncbi.nlm.nih.gov/pubmed/22829638

MERS-CoV detections by week...

Yeah, I got bored waiting. 

I finally came around to the fact that the data for MERS-CoV have always been so inconsistent that why worry about that now. So what about dates? I have no idea how long it will be until we see the WHO post data with dates for the hundreds of Kingdom of Saudi Arabia (KSA) cases we know nothing much about that occurred in the Jeddah-2014 healthcare outbreak. The WHO without Gregory Hartl is a much less interactive entity on social media these days. One person can make such a difference.

As it stands, the KSA Ministry of Health has clearly decided to hold fast on not releasing dates for symptom onset, hospitalisation and death for new cases; the new and improved Command & Control Center (CCC) colour scheme speaks for the data....instead of having the data....it seems.

Click on chart to enlarge.

So, the chart. It shows the end of the outbreak in western KSA...still...having been that way for a few weeks. Its hard to tell exactly when the cases have fallen out for the last 13 days or so, since we don't know when they became ill (which is what I use most often when plotting cases-and will again should those data ever become available). So take those dots over the last month with a grain of salt for now. I expect they will reduce in number as they sort into the preceding week(s). 

As I note in the chart - I do not include the "found113" cases here. They remain dodgy data for now. I'll also wait for the WHO to make sense of them.

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