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H7N9: the dotted lines that make sense of things...[CORRECTED]

Click on image to enlarge.
The latest H7N9 case-per-day chart shows that the trickle of human cases of confirmed avian influenza A(H7N9) virus infection is becoming a drip. The tap? My money is still mostly with the market closures. What precisely in the markets is the source of human H7N9 acquisition? Dunno, but the consensus seems to be poultry; songbirds also look pretty good though. It doesn't have to be, and is unlikely to be, just 1 thing of course. We know that this virus, as with other avian influenza viruses, can be shared around among bird species. It can even go into a human and that isolate be used to infect a bird again. See my recent post on some of this.


Click on image to enlarge.
What's also particularly intriguing, among the many interesting aspects of H7N9's acquisition and spread among humans, is that we're seeing much more "shouldering" in the Wave 2 epidemic curve than we did in Wave 1's.

Instead of the precipitous decline we saw back in 2013, we're seeing a drop down to ~10 cases per day, but then a slower decline the rest of the way. Is this because we started human cases from more sites this time around?; because markets took longer to close after the cases numbers began to climb?; is it related to markets being closed at different times, in different ways, in different locales? Who knows?
Cases by region acquired, per week, with different
 regions highlighted by coloured lines and the 
total case number in the background (grey).
Wave 1 and Wave 2.
Click on image to enlarge.

Dr Katherine Arden suggested I have a look at what's happening in each Province or Municipality and see whether any particular place can shoulder the blame for the shouldering. And that does seem to be the case if you look at the adjacent chart. Guangdong province seems to be the major culprit contributing to the shoulder effect. 


Cases by region acquired, per week, with different
 regions highlighted by coloured lines and the
total case number in the background (grey).
Wave 2 only.
Click on image to enlarge.
In the zoomed-in version that focusses on Wave 2 alone, we can see that the Wave 2 "peak" has in fact 2 peaks; the 1st peak dominated by Zhejiang province cases and the 2nd driven by a surge in Guangdong provincial cases. Guangdong cases took longer to drop away, and are in fact still being reported, possibly because the major poultry markets there were closed later than in Shanghai and Zhejiang province and only temporarily for a clean. Or perhaps the bird outbreak @influenza_bio and I discussed has a source in Guangdong province?

It's all speculation beyond the data we can actually plot.

Google Flu Trends: not so perfectly predictive?

I'm no expert at the algorithms that go into the search giant's Google Flu Trends (GFT) predictive website so take what follows as a very superficial opinion. It does not surprise me at all that a recent paper in Science [1], backing up previous chatter on this subject [2], finds GFT is is not very accurate. Specifically, it has been overestimating peak influenza levels compared to more traditional laboratory-confirmed cases (itself only a subset of all cases) and influenza-like illness presentations to Doctors (a non-specific method of trying to identify influenza from a swarm of other ILI-capable viruses). 

A note: this recent paper is more a look at big data and whether it deserves our complete trust yet (it doesn't, is the message) than it is an analysis of how best to predict influenza virus activity in the future.

It would be fantastic if we could have a predictive system that could work around the need for actual testing of sampled people and give us an informed guess as to what flu was doing, how long it would be doing it, how severely it would do it and when it might start and stop doing it...I just don't have a lot of faith in predictive things like this. Perhaps I've just entered into a grumpy middle-aged male phase of my life....but I think that if we want to find out what's happening, we don't need to look too much beyond simply (not so simple when it comes to lab capacity and funding of course) upping the level of testing and typing that we do.

Even now, the current situation in Queensland of a 2-fold increase in influenza virus notifications compared to the mean of the past 5-years does not really show up so clearely on GFT.


Given that so many variables will contribute to a person's choice to search for "flu" (or whatever related text GFT includes in its algorithms), it makes perfect sense that a website showing flu activity in your area that is based on that component of the results, will be an over-estimate, especially during the peak times of flu activity. Why then? Imagine the impact on search when the media is most active in trying to get your pageviews using headline banners with "killer flu" or "early flu season" in them. People don't just chat over the back fence in response to those headlines any more, they go looking to the internet to provide their answers, news and sometimes poorly communicated facts. This will not just indicate that the have the flu, it will reflect concern that they may get it at some point in the future.

GFT also taps "real" flu data from real testing labs and Doctors clinics. This means its performance is probably not "off the rails" wrong, just overly influenced by non-infectious factors at peak times.

Are the inflated results positively affecting flu vaccine uptake I wonder? That would be a good thing. Might even have an impact on the size of the peak season.

Of course, no one knows what the actual numbers of flu cases in the community are; because flu is not always a serious disease that leads us to get a sampled collected and tested. The serious disease gets to a hospital and does get tested. these get added to notifications. Sure, influenza virus can cause a more serious outcome than many other respiratory virus infections, especially in certain groups, including death on occasion. There are also many mild infections that fly "under the radar". Those numbers won't be accounted for anywhere except through modelling. Perhaps the overestimate isn't that much of an overestimate; very hard to actually know that.

It's that damn iceberg tip again. 

References...

  1. http://www.sciencemag.org/content/343/6176/1203.summary?rss=1
  2. http://www.nature.com/news/when-google-got-flu-wrong-1.12413

The decline of H7N9 Wave 2: some thoughts on why it may be different from Wave 1...

Influenza virus and influenza the disease certainly give scientists a run for their limited money when it comes to predicting what either will do from year-to-year, country-to-country or outbreak-to-outbreak. 

And just when you think you know enough, things change. 

This morning my Twitter stream was fed by a sparkling rivulet of informed comment by @influenza_bio ("A biologist"follow him if you don't already) on the subject of why H7N9 cases are falling. @influenza_bio groups together a few great points:
  1. H7N9 cases are declining.
    Agreed, I think Wave 2 ended almost a month ago.
  2. Overall, influenza-like illness (ILI) visits in China have declined.
    A clear parallel, but is it causal? ILIs provide a general guide to influenza circulation (general, because other viruses cause ILI which is basically fever + upper and or lower respiratory signs and symptoms - so a very broad but useful good guide
  3. Is the drop in human H7N9 cases linked to the end of a (silent) outbreak in birds (poultry, waterbirds, songbirds, both...)?
    Finding data on specific bird migration dates in the region is difficult. See here and here for some generalizations. Seems very reasonable.
  4. Live bird market closures cannot be the only cause of a drop in H7N9 cases otherwise we'd expect to see cases in other areas continue to rise (presumably areas where markets are not closed).
    If we compare Zhejiang to Guangdong, then we can see that the delay in closing Guangdong's bird markets seems to have manifested as a delay in slowing of human cases; most recent H7N9 case acquisitions have indeed been in Guangdong (a major poultry producing area in southern China) whereas cases in Zhejiang which, like other eastern coastal regions shut their markets earlier and "permanently", generally speaking, have dried up.
  5. If H7N9 human case decreases were linked solely to weather, then how could we explain the peak in 2013 which extended into late April whereas it looks to have peaked well before that, in early Feb, in 2014?
    Given that the seasons have not differed between the years (or have they?), I'd suggest we look more at the start of the 2 Waves; Wave 2 commenced earlier in 2014 than did Wave 1 in 2013, but the precipitous decline of both outbreaks of human notifications seemed to have been more closely tied to market closures than dates on a calendar. Of course markets are stocked with H7N9 infected birds and that which links to outbreaks at the supply end unless poultry acquired their infections at markets and then spread that between markets by bird movements which can extend right across southeast China. Why did it start earlier is a key question for me.
@influenza_bio finishes with the comment that...

As I've learned from @influenza_bio, many factors go into humans acquiring a particular influenza virus at a particular time/season, and probably no single thing is responsible for all events for any given outbreak. Phew. But that's why we don't have influenza infections all the time and it underpins why they peak at a certain time.

Human acquisition of influenza virus is related to:

  • How a person is exposed to the virus (aerosol from upper respiratory tract coughs and sneezes or self-inoculation from contact with contaminated surfaces)
  • Whether the virus survives long enough to be inhaled/self inoculated which is in turn linked to virus subtype and strain and environmental temperature and humidity (see some more on that in a guinea pig model here)
  • The host and their immune state and general health, smoking, underlying diseases etc
  • How much virus enters the host and where it "lands" and makes a footing in the host's respiratory tract
  • The spaces we share with infected people and how fast and well the air is filtered/exchanged in those spaces
  • The virus subtype in terms of what receptor it prefers and where those might be located throughout the respiratory tract.
  • For avian influenza in humans there is also the type and length of exposure to the animal hosts and their environment

Not an all inclusive list I'm sure, but you get the point. Influenza viruses are a complex beast, made more so by the fact that any given subtype could be represented by a range of strains indicating a variety of stabilities, preferences for receptors, antiviral susceptibilities etc. 

So I complete agree with @influenza_bio, more bird surveillance would indeed be a very important step in understanding what is happening in and perhaps predicting the risk of, human outbreaks of this and other avian influenza viruses.

Influenza in Queensland, Australia: 24-Feb-2014:03-Mar-2014.



Image adapted from Geoscience Australia,
The Australian Government.
Autumn is upon us as the temperatures drop and we've had several days of showery weather in Brisbane.

The Courier mail (and my local radio) media note that "swine flu" (H1N1pdm09 presumably) cases are dominating across Queensland in what may be an early flu season; 85% of notifications are influenza A virus subtypes, and "most" are the "H1N1 swine flu strain". That's the influenza A virus subtype which the northern hemisphere has been battling.


In the previous week's Queensland Health Statewide Communicable Disease Surveillance Report the higher than average number of influenza notification was apparent (unfortunately they don't carry subtyping data).


See my previous post on this uptick in 24-January ([2]; Summer down here). 

By higher, I mean that that there have been 2.4X more notifications in Queensland (840 year to date based on onset date; 85 cases in this reporting week) than the mean number over the past 5-years (the mean for the time period spanning 24-Feb to 02-Mar in the previous 5-year period is 348.8). In fact Queensland seems to be leading the pack for flu notifications this year to date.

This time in past years we have seen these notifications..
  • 840 case notifications in 2014
  • 516 cases by this time in 2013
  • 233 cases by this time in 2012
  • 820 cases by this time in 2011
  • 104 cases by this time in 2010
  • 71 cases by this time in 2009
...highlighting that there have been other large years, but also much smaller (testing bias perhaps?) tallies in other years.

Keeping in mind that these are total numbers, not proportions of samples tested. Presumably this is the basis for the media comments of an "early flue season". Cairns, Gold Coast, Logan and Moreton Bay public health unit areas are the source of notifications and it seems the more recent data add Townsville and Cape York as hotspots.

I guess the next publicly released QHSCDS Report will have these updated total numbers in it so stay tuned. 


At the end of the 2013 flu season, H1N1pdm09 comprised just 15% of all notifications (although most Flu As were untyped), <1% in 2012 [4]. Queensland followed New South Wales and Victoria in total laboratory-confirmed notifications for 2013 [4]. 2013 was a late-starting, shorter flu season compared to 2011 and 2012 [4].

Whatever the small details however - get that flu shot - it will be available from next week. An advertising campaign is about to kick off for flu vaccination but in the meantime have a chat with your GP about flu vaccination options. It really is worth preventing the severe disease, and sometimes fatal disease, that can come along with an influenza infection. Not just for you, but for your children, those around you who are pregnant, your partners and parents as well as for the wider community. 


This is one of the relatively few diseases we can attack with just a simple jab.


References...

  1. Queensland Health Statewide Communicable Disease Surveillance Report 3-Mar-2014
    http://www.health.qld.gov.au/ph/documents/cdb/weeklyrprt-140303.pdf
  2. Influenza in Queensland, Australia...
    http://newsmedicalnet.blogspot.com.au/2014/01/influenza-in-queensalnd-austraia.html
  3. Up to 85 per cent of current Queensland flu notifications are H1N1 swine flu
    http://www.couriermail.com.au/news/queensland/up-to-85-per-cent-of-current-queensland-flu-notifications-are-h1n1-swine-flu/story-fnihsrf2-1226851854384?from=public_rss
  4. Australian influenza report 2013 - 28 September to 11 October 2013 (#09/2013)
    https://www.health.gov.au/internet/main/publishing.nsf/Content/cda-surveil-ozflu-flucurr.htm

An update on avian influenza A(H7N9) virus cases in humans: Week 56

As we currently stand (this minute), there are 389 laboratory confirmed human cases of infection including perhaps 122 deaths (31% PFC). 

H7N9 cases are mostly noted in older males (Average age 54-years; Wave 1 57-years; Wave 2 53-years) with the major risk being exposure to birds and "poultry markets" (commas because it is not just poultry being sold at these markets). No sustained human-to-human transmission has been noted and no specific vaccine exists although one is coming soon apparently. Oseltamivir or zanamivir are useful antivirals while adamantanes are of no use because H7N9 is resistant. to them. The second wave has peaked but we are still seeing a shoulder off the main peak from Wave 2; smaller numbers of cases each week (no longer occurring every day), often from regions other than those with closed poultry markets or with only recently closed or temporarily closed markets.


First chart.
Click on chart to enlarge.
First chart: where is H7N9? It's in Southeast China, most cases having been acquired in Zhejiang province (139/389 cases; 36%) during both Waves of human infection and Guangdong province is currently a very close second place (95/389 cases; 24%).



Second chart.
Click on chart to enlarge.
Second chart: where has H7N9 been focused over time? We can see from this chart that Zhejiang and Guangdong provinces have accrued H7N9 cases most rapidly. While Zhejiang featured in both waves, Guangdong is of Wave 2. It will be interesting to see what happens if there is a Wave 3; without finding and controlling the source of human acquisitions and if the birds with the virus continue to have the virus, I expect we will see future waves.


Third chart.
Click on chart to enlarge.
Third chart: the waves of an outbreak. Wave 1 was 2013 while Wave 2 started in Oct-2013 but really kicked off in Jan-2014. Cases dived in Feb-2014 but there are still sporadic cases being reported each week. The Week (#53) beginning 17-Feb-2014 saw 8 cases followed by 7, 4 and 0 for subsequent weeks. Keeping in mind that there are around 4-12-days (currently averaging 8-days overall) between onset of illness and when a case get confirmed by a laboratory (or reported publicly if no specific lab date is available), we may see a few more cases assigned to the last week of February yet.


Fourth chart.
Click on chart to enlarge.
Fourth chart: Age and sex of H7N9 cases. The age pyramid shows a decidedly upside down pyramid indicating that H7N9 disease is one of the older age bands. It also shows that it is a disease of men morseo than women.


Fifth chart.
Click on chart to enlarge.
Fifth chart: age by week and proportion female. This is an interesting one. There was a dip in the proportion of female cases for the week the week beginning in 3-Feb (right hand y-axis) which bounced back up a week or two later. 

Sixth chart.
Click on chart to enlarge.
Sixth chart: H7N9 cases per day and the rolling average. The decline in Wave 2 cases continues with multiple recent days recently in which no new cases occurred.

H7N9 and human infections: not just a paltry matter

Jones and an all-star cast of colleagues from Hong Kong, Shenzen, Beijing and Tennessee have looked at songbirds and their susceptibility to a human isolate (infectious virus recovered from a human case of H7N9 influenza) H7N9 infection (1).

But before I note the good bits of their study, this paper is one of importance for adding a lot to our understanding of how H7N9 is jumping to people from poultry/live bird/wet markets. It's also a great reference if you want to better understand influenza and birds overall. 


We've read much about human cases of this avian virus having had contact with "poultry" and bird markets and  from that we assume that poultry are the pool in which H7N9 is swimming (reservoir); but where did the poultry get it from (source/natural host)? Its also interesting to note that: 
  1. Very few poultry test positive for the virus; may simply be because of a test-based problem including using a test that is insensitive or sampling from the wrong end of the bird (testing the cloaca instead of throat as was discussed ). 
  2. Looking at the sequences of the H7N9 gene segments suggested that wild birds (bramblings) played a part in the evolution of the virus currently infecting humans in south east China (4)
  3. Pigeons have tested H7N9-positive (2,3)
So it might be that at least some of the human exposures are not from poultry but from other birds.

The authors of this latest article note the songbirds are common pets and so are in close contact with their owners. In the wild, such birds are likely to interact with farm birds.

Some key findings of this new study are:
  • A/Anhui/1/2013 was the strain used for H7N9 studies; it was an isolate from a human but early on and similar to bird (6) strains. H5N1 (A/Vietnam/1203/05) and H3N8 (A/songbird/Hong Kong/SV102/2001) were also used for comparisons
  • Zebra finches (Taeniopygia guttata), society finches (Lonchura striata domestica), parakeets (Melopsittacus undulates) and wild-caught house sparrows (Passer domesticus) were kept isolated for 3-weeks prior to experiments to let any naturally acquired infections burn out; none of the birds had antibodies suggestive of previous infection by an H3, H5, H7 influenza A virus (is that low prevalence normal?)
  • Birds were inoculated with 105 50% egg infectious doses of virus via nose, eye and mouth (that should do it) and then put in the same cages, sharing water and food, with uninfected birds
  • Virus testing was by growth using eggs (3/sample collected)
  • All inoculated birds shed virus (only) from the oropharynx; finches shed most virus at 2-days post inoculation (dpi); parakeet viral shedding could be detected by culture for 2-days and from finches for 6-days
  • Communal water troughs yielded culturable virus; zebra finches shed most virus but water consumption and drinking frequency were not measured and may have differed among bird species
  • No virus could be detected at 8dpi
  • 1 sparrow showed signs of disease and died; 1 zebra finch died without signs of disease (some loss of appetite)
  • Birds in contact with infected birds did not often acquire infection but when they did, they also shed via the oropharynx
  • In finches that were killed for organ testing, virus was mostly found in the trachea; some was isolated from brain and eye tissues of 1 society finch and in the small and large intestine and a high titre form the lung of the other. H7N9 was grown from the brain, lung and intestines of zebra finch. H7N9 was not found in surviving sparrow organ tissues; in the dead sparrow, some H7N9 was found only in the lungs
  • Nearly all inoculated birds mounted a specific antibody response to H7N9 after inoculation. Among the contact birds, 3/3 zebra finches, 1/3 society finches (had highest amount of antibody), 2/3 sparrows and 0/2 parakeets mounted a response to virus indicating that they were infected but did not show signs of illness nor did they shed virus, at least at culture-detectable levels
So songbirds, can be infected by a human H7N9 isolate, they can shed the virus into the environment, they can die (presumably) due to H7N9 infection, 33-66% of songbirds in contact with an experimentally infected songbird acquire aninfection (even if it was rare to grow infectious virus from that contact which may be a sensitivity issue of the testing) and they mount an immune response to the infection. Given that H7N9 acquisition seems to be a numbers among humans, this degree of transmission among birds fits well.

It was also very interesting that water troughs often contained lots of shed H7N9 virus. This is not new in the world of influenza virus but its nice to cross the 't' for H7N9. The authors note that studies of transmission from songbirds to poultry via communal water sources are yet to be conducted. Seems like this would be a very important piece of the influenza puzzle and with broad application to future outbreaks and seasonality in birds via migration. 

Add to all of this that songbirds are present in many markets (thanks to @Crof, @Laurie_Garrett and @debmackenzie1 for supporting info via Twitter this morning; also see refs from Jones et al (1) and a related story from New Scientist (8)) and that older males are a key demographic for keeping songbirds as luck-enticing (and cute) pets. They are also over-represented among H7N9 cases (see adjacent chart). A good fit.

Another recent study (7) shows chickens and quail (a possible amplification host helping bridge the gap between wild birds and poultry) shed a lot of H7N9 after experimental inoculation via an intranasal route. Also, quail (but not pigeons) shed enough H7N9, for long enough, to pass it along to their contacts; less so ducks.

None of this may be very new to some of you, but it's nice to see data that confirm it all for H7N9. After all, as someone reminded me recently on Twitter, data is just how we roll.

It's not hard to see the circle of life for influenza viruses is there for the interpreting and that non-poultry birds may be important intermediate hosts of H7N9 and act as a source of other influenza A viruses. 

Just how many human cases of H7N9 are acquired by songbirds vs chickens/ducks/quail/geese remains unquantified....perhaps unquantifiable.

References...

  1. Possible Role of Songbirds and Parakeets in Transmission of Influenza A(H7N9) Virus to humans.
    http://wwwnc.cdc.gov/eid/article/20/3/pdfs/13-1271.pdf
  2. A summary of Influenza A(H7N9) virus findings in birds and humans
    http://newsmedicalnet.blogspot.com.au/2013/10/a-summary-of-influenza-ah7n9-virus.html
  3. Emergence of avian influenza A(H7N9) virus causing severe human illness - China, February-April 2013.
    http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6218a6.htm
  4. Sunny summer or birds on the wing?
    http://newsmedicalnet.blogspot.com.au/2013/05/sunny-summer-or-birds-on-wing.html
  5. Origin and diversity of novel avian influenza A H7N9 viruses causing human infection: phylogenetic, structural, and coalescent analyses
    http://press.thelancet.com/H7N9genetics.pdf
  6. Genetic analysis of novel avian A(H7N9) influenza viruses isolated from patients in China, February to April 2013http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20453
  7. Role of poultry in spread of novel H7N9 influenza virus in Chinahttp://jvi.asm.org/content/early/2014/02/20/JVI.03689-13.long
  8. Budgies may be behind latest spread of H7N9 bird flu
    http://www.newscientist.com/article/mg22129542.000-budgies-may-be-behind-latest-spread-of-h7n9-bird-flu.html#.Ux5CnvmSx8F

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