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Neither market nor farm poultry all that positive for H7N9; songbirds the culprit...?

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Following on from yesterday's post, "If not poultry then what?", I thought it worth noting the impressive numbers from the Chinese Ministry of Agriculture.

From 2013:

  • 1,630,000 poultry and environmental samples tested
    • 88 POS; all from live bird markets
    • None from poultry farms
From 2014, to date:
  • 33,400 poultry and environmental samples
    • 8 H7N9 POS; all from live bird markets
    • None from poultry farms
The other alternative to answer the question in my heading; the testing methods are at fault. 

No detail of what approach has been used to obtain these numbers in the links below. Viral culture and serology with some PCR have been noted before. I'd wager culture yields chicken scratchings compared to PCR for detecting virus in he wild; but serology has successfully been a pillar upon which animal testing rests. So that's why the numbers above are such a quandary for the epidemiologist who reads about the high frequency of links between human disease and exposure to poultry.

It would be nice to see some technical papers on antibody test testing (development and validation) at some point. If only to reassure everyone that the testing methods are doing what testing methods should be doing.

See #3 below for influenza PCR discussion at WHO.

Sources..
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H7N9 snapdate: cases in 2013 vs 2014...[UPDATED]

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Since I started tracking this beastie (the same time I started this blog) in April 2013, I've tended to use weekly data - because more is more!

This one presents the data by month and it really highlights that - at least to date - human infections with H7N9 have been focused on a single month. 

That's not really a seasonal thing (although it is a colder month) - just opportunistic - to my mind anyway. An opportunity last year that seemed to have been lost to H7N9 by market closures, cessation of the movement of its host and the encroaching warmer weather. 

With markets now closed in Zhejiang and Shanghai, we should see some impact taking effect once a 2-week period has passed, which is 2-weeks from the 24-Jan. 


Click on image to enlarge.
Plotted by week of disease onset or date
reported if onset data unavailable. Keep in
mind that, on average (n=199/273 data points)
there are around 9-days between illness
onset and case announcement.
Today signals the end of the 1st week; 7-Feb the second week. At the very least, Zhejiang-acquired cases should wither by the end of that period & hopefully an effect will be visible leading up to it. It may still take another week to 10-days to see that trickle through the reporting system (see figure legend). Last night we saw 4 new cases announced from Zhejiang province. Fewer than some weeks, more than others.

So Zhejiang is our sentinel for an impact from market closures. The place to keep an eye on in the coming weeks as an indicator of H7N9 activity in the region. Or it might just all be down to warmer weather shooing the H7N9 away! But at least we have last year as a guide of what to expect this year. If you can expect anything from influenza.

And just to add, there are also cases acquired in areas with active markets and those acquired at rural farms etc during the mega-travel period that is the Chinese spring festival....weeell, let's  just observe and see how those chickens fall as they do.
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If not poultry then what? [UPDATED]

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Maybe China needs to look at other
animals, both within market 
environments and at the source farms 
(using sensitive molecular tools as they 
have been), to find the "smoking chicken" 
(shamelessly stolen from Mike Coston)...
which may not be a chicken at all.
Mike Coston has written a nice post about the Chinese MOA denying that there is any proof of direct transmission of H7N9 from poultry to humans. 

Technically, they are of course correct. 

We have yet to see a human put in a cage downwind, but separated from, a flock of infected chickens or duck or geese to see if the human acquires H7N9 infection and disease. Nor have we seen any card-playing lockdown transmission scenarios to investigate aerosol, droplet and direct transmission routes. 

Nonetheless - if you take a look at a snippet of my list of H7N9 cases compiled from various public sources, "poultry" contact is mentioned...a lot; 72% of those rows (if you exclude the 19 awaiting WHO notification data; see below for update). 

 Of course it may be a "poultry" euphemism or a translation error (I'm asking @WHO) for contact with any feathery creatures, so song birds and wild birds may be the source in the markets....or another animal altogether of course but I think something non-feathery would have shown up as a pattern by now.

 [UPDATE] Gregory H�rtl notes..
Only one way to tell what's happening now; get more samples and RT-PCR them. Serology is historically solid and well relied upon, particularly in the world of influenza surveillance. See expert comments on this in a recent CIDRAP article here. I'm just not convinced its providing enough sensitivity at a suitable speed to feed the needs of rapid response and control measures for an emerging virus like an influenza. A virus which is spilling into humans from somewhere not yet convincingly defined to everyone's satisfaction. 

But I'm new to flu and am coming at this from an endemic human virus detection and characterization angle. I may be waaay off point.

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H7N9: Zhejiang in 50 cases...

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Click on image to enlarge.
A quick look at the same number of cases (50) during the same period of time (2-months) in Zhejiang province, across 2-years. In 2014, between 23-Nov to 23-Jan, H7N9 case numbers surpassed 50 whereas in 2013 H7N9 cases did not reach 50 during the 1st wave.

Back on the 23-Jan it did not look like it would make it. Things move fast in influenza-town and prediction is a mug's game.

All a bit arbitrary, yet it is another indicator in addition to starting earlier and from more provinces than in March 2013, that H7N9 case numbers will be higher in 2014 than we saw last year and may well tear through the human case tally for that other "bird flu", H5N1.

As @influenza_bio noted on twitter this evening, there have been a lot of farmers listed in the FluTrackers case list of late.

A quick tabulation shows that 9.5% of FT cases between #1 & #137 have "farmer" in their description while none do between #139 & #177. However, 33.3% of the cases between #178 & #274 are described as farmers. What type of farmer, and how thoroughly this description was initially reported in the provincial media release is completely unknown so take this paragraph with a big grain of chicken salt.

There have been 6 new H7N9 cases added tonight, so far including 2 deaths, one among the new list and 1 of a previously reported case.
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H7N9 snapdate: new charts for sex and age distribution and region of acquisition...

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Two new charts.


Click on image to enlarge.
Firstly, the "age pyramid", a revised and combined version of the age and sex distribution charts for 265/267 H7N9 cases to date. This one comes with many thanks to Shane Granger for helping me learn a new trick. Please follow him @gmggranger or visit his chart-tacular blog, Random Analytics at http://gmggranger.wordpress.com/.


Secondly, we have the latest map of the H7N9 hotzone; adjusted to account for Zhejiang tipping over the 100 cases mark (new colours!), and for the addition of a new province into the world of H7N9 human infections; Guangxi. This marks the first new region and 13th to generate cases overall, since 9-Aug-2013. 

H7N9 has thus crept sideways towards the west and as FluTrackers noted, Guangxi shares a border with Vietnam. An entire other country. The first shared land border since we learned of H7N9 I think. I'm no expert in this topic, but trade in poultry and tourists between these two regions seems commonplace, as noted here, here and to the extent that research such as this study (and its references) indicate H5N1 sequences are shared between the regions.

Do we know if Vietnam actively employs laboratory methods to screen poultry for H7N9, H9N2, H10N8 screening of their birds? I suspect we'll learn soon if not.

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MERS-CoV antibodies in dromedary camels from Dubai, UAE, as far back as 2005...

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Alexandersen and colleagues from Canada and the United Arab Emirates (UAE), writing in Transboundary and Emerging Diseases, recently described detecting antibodies to the MERS-CoV, or a close relative 

Their study is distinguished from similarly themed reports because it uses camel serum samples which are not as diluted. The thinking is that these may yield better indications of weaker positives. 

It also differs in that it has not undertaken all the various validation steps used in many of the antibody studies I've listed below, to convince the dubious reader that positive results are not due to some other coronavirus that may be yielding a cross-reactive and thus falsely negative result.

MERS-CoV RT-PCRs were negative on extracts of serum aliquots.

The authors could not determine where or how the camels may have been exposed to infection, other than it had been prior to the beginning of sampling in 2005. 6 camels from North America ("likely" originating from Australia) were antibody-negative reinforcing the fairly localised nature of MERS-CoV's (or it's close relative) likely origin.

So far we've read of antibodies in camels that are not convincingly present in other animals including sheep, goats, chickens, cattle, horses or camels from outside Europe, America of Australia. These antibodies react with, and sometimes neutralise the infectivity of, MERS-CoV (or a very close relative). This list now includes dromedary camels from:


With this much data behind us, camels currently sit at the top of the MERS-CoV (or some other novel CoV)-positive "animals-tested-to date" list.
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H7N9 snapdate: charts bonanza...[UPDATED]

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Now that I see Mike Coston's tweet and blog post, it's fairly safe to assume that all the cases have been announced for today (tonight/morning, my time). I should be working on my seminar, but I'm doing this instead. Apparently that makes me a "data wonk"...a definition I just learned tonight from CDC Director Dr Tom Frieden....
Click on image to enlarge.
Precise dates for the last 3-4 weeks may change as (a) cases are still
being announced retrospectively and (b) the WHO updates lag
a little behind as they collate and add in valuable additional data.
So let's update a few H7N9 charts.

Firstly, weekly confirmed cases, and case accumulation over both waves of H7N9 infections. Don't be fooled by that terminal dip though-it will rise as cases are sorted by onset date that are yet to be advised in WHO's disease outbreak notifications.


Click on image to enlarge.
Secondly, is the case fatality chart. This one's reliability is particularly "wobbly" at present since there are as many as 21 deaths that cannot be linked to a case announcement at present. 
FluTrackers has a nice turn-of-phrase; "We've lost visibility" on these numbers in China. Equally, identifying cases that have been discharged from hospital relies entirely on the provincial media releases; Google translate really excels at nonsensical sentences with these. A total of 66 deaths (if that is the number currently) produce a proportion of fatal cases (PFC) of 25% or the 226 total cases; trending back up again.


Click on image to enlarge.
Thirdly, we have the updated chart for region of H7N9 acquisition. This shows Zhejiang, after a quiet day this week, continuing its steep upward trend, accompanied by a resurgent Guangdong and a staggering yet rising Fujian and Jiangsu provinces, Shanghai municipality and some occasional cases in Beijing and Hunan province.


Click on image to enlarge.
Fourthly, and lastly for this post anyway, the H7N9 case with age charts. 

Some of the detail required for reading these 3 charts can be found at my previous post using this figure.

Suffice to say that the flurry of new H7N9 cases in southern and eastern China has highlighted the age bias once again; few cases under 20-years of age, many cases >60-years. 

I do wonder what a prospective RT-PCR study of specimens from mild respiratory illnesses and from asymptomatic community members in the <20-year age group would yield. Possibly more positives that are not being "seen" with the more immediate hospitalizations and severe illnesses. 

I also wonder how the intensive care capacity is coping with all these critical and severe cases. Of course H7N9 is far from a prominent influenza in many parts of the world right now. 

At the end of 2013, H3N2 and H1N1 were predominating among China's seasonal influenza infections. H7N9 is just an added and worrisome burden; yet it is thankfully a burden that is not transmitting among humans in an efficient and sustained manner.

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A date with Middle East respiratory syndrome coronavirus (MERS-CoV)..

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Click on image to enlarge.
Do regions that host transient high concentrations
of MERS-CoV (or a related virus)-positive animals play a
key role in the sporadic and geographically widespread
human infections?
This article in the Saudi Gazette was referred to me by a kindly commenter to a recent MERS-CoV post I wrote 24-Jan here.

It notes that August (through to December - see Ref #5 below for a lot of info on dates) is the date-harvesting season. When I received this comment, new MERS-CoV case announcements had ceased; a lull which, as I also wrote on the 24-Jan, I could not understand given that there had been no publicized steps to interrupt any type of transmission chain. 

Now we are seeing some publicized cases again, but it's clearly out of sync with date picking season. Nonetheless, I thought it might be worth looking at regional activities that may gather potential animal sources/vectors and humans, together , possibly addressing links in my disease acquisition scheme above; in particular links between dates, bats, camels and humans. No baboons this time around (I'm expecting a Tweet).


Click on image to enlarge.
Buraidah is located slightly north of 
central Saudi Arabia.
Buraidah (Buraydah) hosts the world's largest date festival in August/September and the Qassim date markets are a feature of the region as is agricultural in general.

Buraidah (population >600,000) is the well connected capital of Qassim Region (see map to the left). Qassim region is described as having plentiful water and, clearly, lots of palm trees as well as other fruit trees and wheat. 

Something else Buraidah has going for it? The world's largest camel market. Those are the beauties that seem to frequently have antibodies to the MERS-CoV (or a very similar virus that probably isn't any known coronavirus but reacts really specifically in MERS-CoV antibody-detection assays designed to detect the MERS-CoV but mainly in animals localized to the Arabian peninsula where most human MERS-CoV cases have been documented). Antibodies indicate past (about 1-2 weeks or more usually) exposure to replicating virus, with or without overt signs of disease in the host.

Recently there was also the the "Palm and Tree Date Festival" in Riyadh (15-16 Jan) and the "King Abdulaziz Award for Camels Beauty Contest" (26-Nov to 4-Jan) in Hafar Al-Batin.

I've made brief mention of the possibility of dates having a role in transmission (ingestion, self-inoculation or perhaps aerosolizing virus off bat-contaminated dates during their preparation?) previously here and here.

While this is all speculative, these latter events coincide a little with a small uptick in noted, and "social media suggested", MERS-CoV human cases.

So here's a speculative story:
  • A nexus point, like Buraidah, with its central, well-connected location (transportation-wise) serves or once served as an "inoculation station" for susceptible camels exposed to infected bats
  • Bats may be more reproductively active or in greater numbers because of higher concentrations of flowering insect-attracting date palms and other fruiting orchards in this region/at certain overlapping times (not actually sure if there is overlap)
  • Camels are brought in, sold and then return to herds all over the region. 
  • During their time in the markets, some camels become infected with the bat MERS-CoV and go on to infect their herd
  • Rarely, humans in close contact with their camels also get infected (it does happen - Ref#7) 
  • Rarely, some infected humans infect other humans
  • Rarely/frequently (unknown proportion) infected humans become severely ill and "show up" as hospitalized cases who get tested for MERS-CoV. 
As I said, twice, its all speculative and as also I've said, infection events are pretty rare. If nothing else, that bulleted list may address the geographically widespread and rare nature of human case distribution to date.

End of speculation. For now.

Sources..
  1. Saudi Gazette story
    http://www.saudigazette.com.sa/index.cfm?method=home.regcon&contentid=20130819177328
  2. Date markets
    http://www.youtube.com/watch?v=QJDBDmziikY
  3. Tourist information
    http://sauditourism.sa/en/About/Pages/k-Cities.aspx
  4. Events and festivals
    http://sauditourism.sa/en/Events/Pages/default.aspx
  5. 2012 Al-Rasub article on date festival
    http://www.alrasub.com/ksa-qassim-hosts-worlds-largest-date-market/
  6. Many, many date details
    http://postharvest.ucdavis.edu/files/71533.pdf
  7. Clinical course and outcomes of critically ill patients with Middle East respiratory syndrome coronvirus infection
    http://annals.org/article.aspx?articleid=1817260
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Freeze those chickens....

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As 8 new H7N9 cases are announced today we see a very welcome comment from Hangzhou City's mayor, Zhang Hongming...
"Hangzhou is planning to close live poultry trading markets permanently and promote the supply chains of frozen poultry products instead"
If Zhejiang Province can carry this off, it would be perhaps the single biggest intervention and risk mitigation step possible. 

Centralising poultry slaughter and providing chickens in a partially prepared and refrigerated/frozen condition could buy the time needed for research to catch up with public health needs. This could include further enhancing farm, market and human screening and finding the feathered or furry fiend(s) acting as the source(s) for these putative zoonotic transmissions (also for H5N1, H7N7, H9N2, H10N8, etc). 

Such change would also radically reduce the chance of selecting more efficiently transmitting human-adapted flu viruses by simply reducing contact between the large numbers of birds (and other animals) and humans occurring on a daily basis in the market environments and through the transport and slaughter of live birds throughout their heavily populated surrounds.

The changes in social behaviour and habits required the Chinese are huge, but such change should be considered as being as great an investment in the future health of the local and global populace as vaccines have proven to be.

Source...

  1. Xinhua
    http://news.xinhuanet.com/english/china/2014-01/27/c_126071190.htm
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Influenza H7N9 in the news....

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Some snippets of information about H7N9 from China in recent releases include:

  1. The description of H7N9-induced disease has changed in 2014 from an "infectious disease" to a "communicable acute respiratory disease". For what that's worth.
    Still technically infectious, just more about what sort of disease.
  2. 7 patients have died with H7N9 infection in 2014
  3. The incubation period for signs and symptoms to develop after H7N9 infection is 3-4-days; if patients develop severe pneumonia, it will be 3-7-days after signs and symptoms begin
  4. Chinese Vice Premier Liu Yandong said
    "China will strengthen monitoring on live poultry, continue vaccine research and development, tighten international communication and cooperation in epidemic prevention and control, and publicize disease information in a timely manner"
  5. "DNA rapid tests" (PCR-based) suggest a batch of chickens being imported into Hong Kong from Foshan, Guangdong may be H7 positive. H7N9? Further testing is ongoing. [Update - looks like they were POS as Hong Kong has suspended imports and will cull 20,000 chickens already there]
  6. 12 cases in Zhejiang province have died from H7N9 in 2014 alone! I have 2 listed. 7 in total 2014. Looks like we've lost traceability on the numbers again.
Sources...
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Zhejiang: more live bird market closures...

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FluTrackers have posted a report originating from the Ningbo evening news in China stating that more markets in Zhejiang province, in the regions below, have been closed for cleaning and disinfection in an attempt to bring the Province's H7N9 outbreak under control...

These regions have already suspended trading...
  • Hangzhou city (which I noted here)
  • Xiaoshan District
  • Yuhang District
  • Jinhua
  • Shaoxing City
This new report notes closure of the following markets in the "main city of Ningbo" from 26-Jan..
  • Haishu District
  • Jiangdong District
  • Jiangbei District
  • Yinzhou District
Exotic bird imports and pigeon flying has been banned.
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H7N9 Welcome to Week #50....

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Media preview
Chart of weekly cases from @influenza_bio

Let's play duelling charts!! My colleague on Twitter, @influenza_bio, (whom you should follow if you are not already - he's got a knack for (a) getting across some nice flu-facts in a easy-to-understand way and (b) he rants - who doesn't like a ranter!?! That sounded less weird in my head.

Today's chart update from me shows the avian influenza A(H7N9) virus weekly and accumulation case chart. In case I haven't mentioned this lately, the human cases of infection by this newly emerged (in humans) virus is all from south eastern China. 

Given that cases keep on coming, this chart has changed a lot in a few days. The last chart is now already 4-days old. Ancient. See it here.


Click on image to enlarge.
My latest chart lists 246 cases and is based on the FluTrackers curated list (to be found, and checked regularly, here) and includes all recent WHO update information which provides some extra details - including date of onset of illness and hospitalization since late October. WHO has a few cases to catch up on.

These are useful additions since cases can be noted in the media or by the relevant ministries or public health institutions many days after the illness manifested in the patient and even after they were admitted to a hospital, usually in pretty poor medical condition. 1 more was added form Jiangsu last night that missed those charts.

I've arbitrarily listed the 2 "Waves" of H7N9 cases - if there is an official designation for dates, I'd be happy to hear of it.

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Zhejiang province surpasses 100 avian influenza A(H7N9) cases...

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As of tonight's 2 additions, my tally shows Zhejiang province on 101 H7N9 cases, 41.2% of all 245 human infections confirmed to date. The BBC recently noted 55 deaths which would result in a PFC of 22%. This continues the lower trend we've seen in the PFC for a while now; the result of a sharp increase in new cases but few deaths among those.

In reality both the Zhejiang and the total case numbers are very likely a massive underestimate of the actual number of human infections, but until we have any actual lab testing results, we won't know that for sure and can only speculate on what's "out there" based on our experience, extrapolation from other outbreaks, epidemics and pandemics, 60+ years of respiratory virology research and a touch of logic.

Overall, in the most active of the case acquisition periods of 2013, we saw case numbers rise an fall abruptly...


  • Week 5: 7 cases
  • Week 6: 17 cases
  • Week 7: 29 cases
  • Week 8: 40 cases
  • Week 9: 22 cases
  • Week 10: 6 cases
In 2014 we seem to be right in amongst that now as we (in Australia) see out Week 49..

  • Week 45: 6 cases
  • Week 46: 26 cases
  • Week 47: 33 cases
  • Week 48: 12 cases
  • Week 49: 17 cases
We are still seeing a few cases with illness onset in Week 47 (6-Jan to 12-Jan) so tat could yet reach Week 8's levels, or more unless the market closure start to show an impact soon.
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The return of the H7N9 case chart timeline...

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Click on image to enlarge.
Please note, this chart is based on publicly available data and its completeness
suffers accordingly. It is provided as a guide only. Each black line (y-axis;
FluTracker's case numbering is used for comparability) represents a single, laboratory-confirmed
H7N9 patients' journey through time (the bottom, x-axis).  Data on patient discharge dates were
particular patchy in 2013 and I have yet to update what is available onto this chart (please ignore the terminal coloured dots for now)

...and its associated headaches.

This is a chart the really relies on complete data to be of full use.

I just had a look at the 2013 chart...you can find it here... which was last updated 02.06.2013. It's clear from that figure that detail on when H7N9 cases leave hospital was pretty scarce at the end of the first outbreak; or I couldn't find it. There has been a tally described in the past - around 86 cases discharged I think - but which cases is largely unclear.

So you can see that a lot of the 2013 patient's timelines trail off into infinity. By now those ill people would have been discharged or are part of the fatal cases list. Interesting that that link above describes a case that was hospitalized for 67-days, before succumbing.

Today I began the next case timeline chart for 2014. It's still a work in progress as I have yet to trawl through the cases to see which have been described as discharged (some definitely have) and I have not yet included those cases who were not admitted because illness was mild or without any obvious signs of disease at all.

As you can see from the new chart of 82 cases with a date of illness onset of 01-Jan-2014 or later (you'll need to click on it to appreciate the detail), the number of fatal cases, to date, is much lower tan it was in 2013's first wave of H7N9 infections.

It would not be surprising to find that most cases remain hospitalized in 2014 as the majority have been initially described as critical, severe or serious in this second round. I wonder how the contacts of these case are faring?

I will try to flesh this out in the coming weeks. Hopefully we remain as red dot-free as we are now.

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