H7N9 keeps changing and mingling and mixing...

A new report in Eurosurveillance out today has once again raised the spectre of a pandemic H7N9 spread. 

Not just for what the Meng and colleagues from China and the United States have shown in their detailed analysis of the PB1 gene segment of (mostly) avian influenza A(H7N9) viruses from humans birds and the environment in 2013, but also for what they have indirectly highlighted: a massive absence of 2014 H7N9 sequence data on GISAID or GenBank sequence databases. 

Being asked for comment, which I provided in 2 stories linked below (2 and 3), I dug into the sequence databases and was stunned (yes, really!) to find that there are hardly any sequences available from H7N9 gene segments or genomes this year.
Given that this year's human case tally of H7N9 infections has surpassed that of 2013's 1st wave, I find that really surprising, and confusing. Also given a few subtle pattern changes that I've been writing about of late including the shifting age balances, sex ratios, fewer farmers, more family clusters, apparently limited impact on human case numbers from market closures >2-weeks ago...I would have said keeping our eye on the genetic ball was more important right now than ever.

What's going on?

Meng and colleagues use the PB1 gene to highlight changes to H7N9 resulting in 4 genetically distinct clusters with links through time and geography. 

There seems to be continued and active change in H7N9 based on analysis of this 1 segment. Not surprising for a virus whose genes exist as a deck of 8 cards, each capable of its own drift changes, just waiting to be shuffled but the next already-occupied host it enters.

I really wonder how much of the virus we knew of as H7N9 in 2013 has changed and what the virus we know in 2014 is like by comparison. 

The only way to answer that will be to see and analyse the sequences from 2014. And hopefully, do that soon. 

These bits of viral genetic material don't just make pretty trees (or hard to see ones like in he Eurosurveillance article), they identify significant changes to the virus that signal potential for, or real, change in transmission, disease type and severity, site of preferred replication and our likelihood of successfully detecting the virus using sequence-dependent, PCR-based diagnostics.

Sources...

1. Eurosurveillance article.
   http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20699
2. CIDRAP story
   http://www.cidrap.umn.edu/news-perspective/2014/02/h7n9-cases-pause-new-report-details-reassortants
3. Bloomberg News story
   http://www.bloomberg.com/news/2014-02-13/pandemic-potential-seen-in-gene-changes-of-bird-flu.html

H9N2 confirmed in 86-year old Hong Kong citizen living in Guangdong province...

Influenza A(H9N2) virus, another "bird flu" but this usually causing mild signs and symptoms of infection, has been confirmed in an 86-year old man reported Dec-30.

The man's underlying illnesses were added to by chills and productive cough from 28-Dec when he was admitted to hospital with a fever.

Sputum tested positive for H9N2. Not sure if an upper respiratory sample was tested.

He had no recent contact with poultry and no contacts have shown signs of illness.

Mild human cases in Hong Kong have previously been reported in 1999, 2003 and 2007 and imported cases in 2008 and 2009.

As ProMED moderator CP (Craig R. Pringle) noted, enhanced surveillance in the region is likely to continue to pick up all sorts of H and N viruses and variants. Interesting watching these pop up - especially if they remain as mild infections, unlike H7N9 has so far.

Sources...

• Centre for Health Protection, Hong Konghttp://www.chp.gov.hk/en/view_content/32802.html
• South China Morning Posthttp://www.scmp.com/news/hong-kong/article/1393266/86-year-old-man-infected-h9n2-avian-flu
• FluTrackershttp://www.flutrackers.com/forum/showthread.php?p=518167
• ProMED AVIAN INFLUENZA, HUMAN (165): CHINA (HONG KONG) H9N2 FOLLOW-UPhttp://www.promedmail.org/direct.php?id=20131231.2145404
• ProMED AVIAN INFLUENZA, HUMAN (164): CHINA (HONG KONG) H9N2http://www.promedmail.org/direct.php?id=20131230.2143709

Influenza A(H7N9) in Zhejiang, Dutch DURC and dogs..

With the second H7N9 case (see FluTracker's thread) in Zhejiang, located only 13km from the earlier case, things seem to be picking up where they left off in late April. Poultry exposure seems key to this latest case who was a farmer who engaged in poultry trading. That word, trading, also sparks concern. It suggests that the farmer was exposed to poultry coming from, or going to, somewhere else. H7N9 is on the move. Both patients are very unwell.

Zhejiang province had the steepest rate of case acquisition back then and reached the highest H7N9-confirmed case number as well. 

Looks like this province is going to be a key battleground for the next wave of H7N9.

Meanwhile, Eurosurveillance continues its fantastic coverage of this and the Middle East respiratory coronavirus  and H7N9 outbreaks. It already has a paper online (less than a week turnaround) of the earlier Zhejiang H7N9 case in a 35-year old male (35M) which includes a note about the subsequent Zhejiang case! Outstanding work to the researchers and the publishing team. Quality publication almost in the time it takes to write blog post!

This journal certainly highlights how quickly detail research results and analysis, when submitted to peer review, can be published. 

Click to enlarge. The laboratory turnaround
times for H7N9 detection (where suitable date
data exist) since the outbreak began in early 2013. 

• 35M was identified though the surveillance system for unexplained pneumonia
• He was not a farmer and had not had close contact with another probable case. The laboratory turnaround times on this case was 7-days. A 2.2 day improvement on the rolling average I stopped calculating May 6th.
• The most likely source of exposures was a trip to rural region of  Ningbo city where he may have been in contact with animals. But that was 10-days prior to onset which would make it a long incubation period. 35M remains unconscious so further detailed tracking of exposures is not possible
• The virus was >95.5% identical to H7N9 from earlier in the year but with 5 hitherto unreported mutations in the neuraminidase (NA) gene. 2/9 bird market samples were also H7N9 PCR-positive but could not be sequenced due to low viral load

Meanwhile, Reuters reports on Albert Osterhaus and Ron Fouchier at the Erasmus Medical Center who are firing up the "gain-of-function" studies to look at what would be required for H7N9 to become a pandemic virus; essentially changing the virus to look for increased transmission. This work will be performed in an highly secure, enhanced biosafety Level 3 lab. Which of course doesn't change the subject matter - but does define how difficult it would be for that to escape. It's not convincingly clear why this virus needs to be given an evolutionary push, rather than "reverse-engineering" those influenza viruses that have previously been pandemic viruses - or some other approach with less risk of creating a virus that if it escaped, would cause a pandemic. Well, to me at least...but I'm no flu expert. You can find much more on dual-use research of concern (DURC) in Laurie Garrett's latest writing over at Foreign Affairs.

And to add to general influenza virus concerns, Sun and colleagues report in Infection, Genetics and Evolution, that infectious H9N2 (isolated using embryonated chicken eggs), strains of which has been implicated in providing genetic material to H7N9, can be isolated from dogs. The isolate was called A/Canine/Guangxi/1/2011 (H9N2). Between 20% 45% of dogs were found to be antibody-positive to H9N2. A range of dogs seem to have been virus-positive with signs and symptoms including loss of appetitie, cough, sneeze, nasal discharge and raised temperture. Some were asymptomatic. Cats next please?