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Thank you for your response. I am digesting it!
What's starting to worry me is: where are the children and teenagers this year? Last year, if I can count, we had 8/150 people under the age of 20 (all but one of whom were actually under 10). This year, only one (case 200, the 5yo) out of 110, so far.
Could be chance, but could be that this year, children are less likely to be tested than they were last year. Or less likely to be positive. Or, of course, they could be genuinely less likely to be infected for some reason. I hope they aren't the missing vector...
last April they also tested lots of contacts.
That may have slowed down.
Now they just test at the hospital (?)
Great post. In full agreement.Sadly, today is the baseline because most prior information has been gathered so haphazardly as to render it incomparable. If we don't modify the process soon, even today will be a poorly functioning baseline for decision makers 5 years from now.
Polymorphisms that move between serotypes do not always correlate to functionally equivalent outcomes. An infective flu reservoir in a certain host determines the outcome. By studying with great scrutiny the disease process, the deepest picture of the pathogen and the human genetics of the host, science will begin to build a foundation around Gain of Function research.
That research will show patterns of polymorphisms, sets, that travel together and correlate to specific outcomes in identifiable scenarios. Although singleton changes at times have a dramatic impact, understanding the set of related changes is much more important to predicting the system.
How that information is used at the policy level will turn the tide of human health, either for the benefit of the citizen or against them.
Great post. In full agreement.
The situation - as I understand it (anyone feel free to differ)- is broadly that the 144 HxNy combinations in Type A AI (I am ignoring the new bat strains as I think they are removed from this mixing pool) fall into two broad groups one group (the larger 'primary' group) mainly circulates in Anseriformes (fresh water birds - Ducks) and the secondary group in Charadriiformes (shore birds - Gulls & waders). There is mixing between the groups, and with other Aves Orders, but each of the circulating H & N combinations has a 'home base' in one (or occasionally both) of these two groups. The primary group is of greater importance to mammalian infections as 'our' HAs are mainly from this group.
Both groups are ideally suited to the oral-faecal transmission route as they feed in the water into which they defecate, they often congregate into dense flocks (high viral loads) and include migratory species (wide geographic spread).
The first thing to note is that these birds take their flu sero-types in parallel while for us we seem to take them in series, each pandemic largely killing off its predecessor (yes I know we now have two due to the reintroduction of H1N1 in the '70s). Infection in the primary hosts is normally mild or asymptomatic allowing the sub-types in each group to mix freely with no real barrier to multiple infection in one host.
Flu's route to genetic diversity is two fold. Firstly the sloppy polymerase allows for poor fidelity in copying the vRNA creating lots of SNPs and secondly it does not seem to care much about virion assembly and is happy to mix RNAs from different infections leading to reassorments. Human reassortment have a very limited pallet as there are only two sero-types - plus extremely rare zoonotic infections. Most changes lead to unfit viruses but, as flu is parasitic, the cost of all these duds are born by the host not the virus.
As we have only had a few flu pandemics recently enough for us to know how to sub-type them and we have only very recently got surveillance in place to watch human zoonotic flu infections amongst the background we do not really understand the dynamics of pandemic emergence.
1918, 1957, 1968 and even 2009 all look like they reassorted straight into their pandemic form - or at least we did not spot them until there was sustainable H2H. For the first time we are now sequencing enough to spot the odd zoonotic infection amongst the background. H5N1, H7N9, H5N8, H10N8 are all ongoing and many others in the past. I think it unlikely that this is new behaviour, it is just we did not have the tools to look.
Now thinking a little about the 'zoonotic edge' of the avian virus pool.
For an infection to occur in a human they need to be exposed to an AIV that, as an absolute minimum, can infect a human cell most can't.
How do they get to the point where they can?
They drift, genetically, around the strain consensus by the methods discussed above. Of all those sero-types circulating at any given moment some will be close to an infectious form (in humans) and most will be far away. Also the line is not clear and most infections occur in either people who have been exposed to a very high viral load (farmers, vets etc.) or were immunocompromised to some degree. In an earlier post I pointed out pigs could be infected with H7N9 experimental, given a high enough dose at inoculation, but would not spread the infection either by contact or aerosol transmission.
If we look at H7N9 as an example there seem to have been a number of reassortments leading to a virus of which A/Anhui/1/2013 is representative. Presumably the parents strains were somewhere near my 'zoonotic edge', prior to their latest changes, and their progeny is now very close to the edge.
What happens now?
More change (hey it's flu' what did you expect). As the virus is not showing efficient H2H, in it current form, the AI strain will continue its genetic meander in its primary host(s) and either drift away from my 'zoonotic edge' or over it into pandemic territory (away from the edge should be more likely as it is likely closer to the bird index). The alternative route is that one of these human infection will develop, within its quasi-species, a variant that is better adapt and successfully start a cluster. The starting virus now is already a bit better adapted and its quasi-species can then capitalise on the advantage and jump again etc. A virus replicating in a host to which its is ill adapted will be under severe selection pressure and favour mutations that improve replication in that host (but not necessarily adaptations that improve transmission to a new host).
I am sorry this has ended up being so long but I thought it was important to cover as many aspects as possible as they all inter-relate. I hope some one will be able to pick holes in the logic of my model - it's how I learn and improve my mental model.
People in China do not interact with ducks, gulls and waders any more than other nationalities do. Especially if they are from an urban environment as many of the patients are. Well over 100 people have gotten sick in the last month.
What did they come into contact with that they all had in common????
I may not have been totally clear. What I am talking about here are two overlapping genetic pools or constellations of viruses. A search for Gull HA sequences in the database is going to throw up a number of HA which we don't often discuss like H4 & H16 plus some we do like H1. For a Duck you will get a wider range with lots of familiar numbers H1, 3, 5, 7 etc. All the other Aves Orders which include the Pigeon, Sparrows and Poultry etc I do not see as being as central to the flu story. They draw from one or both of these pools - and pass material back - but I suspect they are not where flu started and are less central to flu genetics. Although I have no data to back it up I also think they probably commonly host less sero-types than you would get in a Mallard which could be expected to host every subtype in the primary pool.Now I have a few questions. If the virus is now mainly in two bird types Anseriformes (fresh water birds - Ducks) and Charadriiformes (shore birds - Gulls & waders)
To this part I just do not know where we are getting infected from., then why aren't we seeing more human cases outside of China? What is the intermediary in China? If it is the song birds that old men keep as pets, then why hasn't it been found in samples taken from the homes of sick patients? Why don't all victims have a pet song bird? And the question that is truly baffling me is why no human cases farther than 800 miles from the first case after one years time? Shanghai to Hong Kong 765 miles. Shanghai to Beijing 769.5 miles? Most of the birds cited migrate. Is it possible there is some unknown reservoir that is neither song birds, Charadriiformes nor Anseriformes? NS1 you stated earlier that the virus should be looked at as multi host. I certainly intuitively must agree. People in China do not interact with ducks, gulls and waders any more than other nationalities do. Especially if they are from an urban environment as many of the patients are. Well over 100 people have gotten sick in the last month. What did they cone into contact with that they all had in common????