Old thread was too long.
[http://www.pnas.org/cgi/content/full/98/12/6883|Pattern of mutation in the genome of influenza A virus on adaptation to increased virulence in the mouse lung: Identification of functional themes]]
I promised Tom DVM a brief summrary of the paper above:
After reading that paper and thinking about what we know about H5N1 so far, I think
the human sequences are still almost the same as the avian sequences. Except for the Indonesian cleavage site. But apparantly the virus with the old cleavage site was more virulent in the latest cluster.
Tom DVM at 23:31 (in old thread):
The problem then becomes what is going on with the secondary and tertiary cases. You would think that they would be as infectious as the index case and therefore they would repeat the pattern and maybe start infecting community members and hospital workers.’‘“
Doesn’t make sense, does it? If you ask me, a major flaw in the super-shredder hypothesis is that it requires flogging the evidence: early caregivers were limited to blood relatives, there is a “goldilocks” infectious stage, later caregivers took greater precautions, etc.
What I like about the genetic susceptibility alternative is that it doesn’t ask us to get quite so creative.
anonymous, almost the same? First, how do you know what the human sequences are in Indonesia? Most of them haven’t been released. Second, define almost. Only a few changes are likely necessary for H5N1 to adapt to humans.
I’ll never understand why the tags work sometimes, and fail sometimes. Here’s another attempt at formatting the block I quoted from Tom:
“‘’Here’s how I see it. The index case is a super-shedder or a very efficient spreader and this must be in respiratory droplets. The person must be infectious, by this mode of action, for a relatively short period of time. Therefore, the only persons who would contact the person at this time would be family members. Community doesn’t get it because the person is not infectious in the early stages. Healthcare workers don’t get it because the person is not infectious in the later stages.
The problem then becomes what is going on with the secondary and tertiary cases. You would think that they would be as infectious as the index case and therefore they would repeat the pattern and maybe start infecting community members and hospital workers.’‘“
Hi I have a question for the group in general, and Tom DVM or any other folks that might have clinical animal knowledge in particular. Here is an article abstract describing H5N1 infection and the organ degradation in some wild birds, and it made me wonder if the virus was passing into the general lymphatic system via the intestinal tract. Thus could this be extrapolated as possible mode of full-body infection in mammals also? Could it constitute a possible route from gastrointestinal, then to throat tonsils, then to upper (or lower) respiratory infection in human index cases - thence to surrounding humans to create a cluster?
Also, what are “cecal tonsils” in birds? Are they tonsil-like material that are found in the cecum? If so this is interesting, because we know that tonsils are part of the lymphatic system. After the article abstract is a brief snip from a website about the lymphatic system. Thanks ahead of time!
________
J Wildl Dis. 2005 Jul;41(3):618–23. Highly pathogenic avian influenza in magpies (Pica pica sericea) in South Korea. Kwon YK, Joh SJ, Kim MC, Lee YJ, Choi JG, Lee EK, Wee SH, Sung HW, Kwon JH, Kang MI, Kim JH. National Veterinary Research and Quarantine Service, Anyang, Kyunggi 430–824, South Korea.
Highly pathogenic avian influenza (HPAI) is an extremely infectious, systemic viral disease of birds that produces high mortality and morbidity. HPAI was diagnosed in the three dead magpies (Pica pica sericea) submitted to the National Veterinary Research and Quarantine Service. At necropsy, the prominent lesions were multifocal or coalescing necrosis of the pancreas with enlargement of the livers and spleens. Microscopically, there were severely necrotizing pancreatitis and lymphocytic meningoencephalitis. Influenza viral antigen was also detected in areas closely associated with histologic lesions. Avian influenza virus was isolated from cecal tonsils and feces of the magpies. The isolated virus was identified as a highly pathogenic H5N1, with hemagglutinin proteolytic cleavage site deduced amino acid sequence of QREKRKKR/GLFGAIAG. To determine the pathogenicity of the isolate, eight 6-wk-old specific-pathogen-free chickens were inoculated intravenously with the virus, and all birds died within 24 hr after inoculation. This is the first report of HPAI in magpies.
PMID: 16244075
from http://www.lymphomation.org/lymphatic.htm
“Secondary lymphatic tissues control the quality of immune responses. Differences among the various lymphatic tissues significantly affect the form of immunity and relate to how antigens (bacteria, virus, fungus, etc.) are acquired by these organs.
- Lymph nodes are filters of lymph,
- the spleen is a filter of blood, and
- mucosal associated lymphatic tissues acquire antigens by transcytosis to lymphoid tissue from the “external” environment across specialized follicle-associated epithelial cells.” Source: geocities.com
“Lymphatics are found in every part of the body except the central nervous system. The major parts of the system are the bone marrow, spleen, thymus gland, lymph nodes, and the tonsils. Other organs, including the heart, lungs, intestines, liver, and skin also contain lymphatic tissue.” - gorhams.dk
Racter, the index case was in close physical proximity to the secondary cases - small room, no ventiliation, overnight. This is likely why there were so many secondary cases. I suspect that if one of the secondary cases or the tertiary cases had been locked up in a room with no ventiliation with a lot of other people, the spread may have worse, perhaps much worse. This is not to discount the importance of genetic susceptibility, I just don’t think it explains why so many secondary cases.
Racter, the italics only work on one paragraph at a time. If there is a space between lines, the tag fails.
monotreme, that’s what WHO said. Also Andrew Jeremeijenko said it before. One human sequence from Indonesia is already known. And we clearly see it in the Qinghai-strain-sequences. Almost the same means: the human sequences are no more different from the nearby avian sequences than the avian sequences differ from each other.
WHO update 16 31 May 2006 http://tinyurl.com/mbat6
For all the twisting and turning that has been done trying to explain the clusters, especially the one in Indonesia the simplest explanation seems to be that some very few people are susceptible to this disease and that this susceptibility runs in families.
Areview of what is known.
Note that nine people stayed in the North Sumatra house on April 29th. A niece and a male family friend were not infected. This lobbies against the super shedder argument.
The brother who later got sick and his wife moved between two villages and no one else including the wife were infected. Those who died were sick for approximately six days preceding their death. This is a sufficient time for some of these people to be walking around spreading the disease. Fifty-four potential family and close friends were not infected. There are 400 residences (X 3 people per family = 1,200 people) in the N. Sumatra village were not infected. This suggests that one needs to have some sort of biological weakness to get the illness.
There are 220 million people in Indonesia and using the unofficial count perhaps 500 people have been infected. If unobserved cases are used perhaps 1,000 people (wild guess) have had the disease. This is a very small percentage of the population when it is considered how closely these people live to their animals.
It has been noted that one cannot get the virus from eating sick animals. However, if people slaughter and eat sick animals people do smell the slaughtered animal before eating. At the least they breathe the air after slaughtering. Of the millions who could get the disease only very few people actually become ill.
I think that what is needed is to determine why only some people are susceptible.
beehiver, birds are infected in the intestine. Mammals are usually infected in the lungs. In rare cases maybe in the intestine, but this is unclear. Only days later other organs are infected too. It was found, that the virus survives in blood other than normal flu. So it seems that it travels in blood.
JoeW, some people are better shedders, some are more suspectable of being infected. It doesn’t seem that any of these groups i.e. the receivers is so rare. Even when they are related there is some chance for genetical differences and we won’t expect so many cases in a family when good receivers were so rare.
Ok, I take it back: I do understand. About the tags, that is. Thanks.
I still don’t understand why people living in the tropics would spend nights shut up in unventilated rooms.
Agreed and note that even a good super shedder (N. Sumatra) was not able to infect everyone in the close quarters. So there is some sort of interaction here.
Racter -one word answer to that from living down south in the summer - BUGS!!!
Monotreme – at 08:36
Back to the original paper, I thought it was very interesting that the polymorphisms to make the strains more virulent weren’t always the ones that we’d expect and that some were unexplainable.
I was especially moved by the following quotes:
The parallel polymorphisms clearly point to some rules-based system, don’t you think?
“one word answer to that from living down south in the summer - BUGS!”
I guess they don’t have high-tech stuff like screens in Indonesia.
The literature I have reviewed dating back nearly 20 years seems to draw a picture. To be really virulent, the bug needs to be able to infect multiple tissues. The paper recently published on viable H5N1 virons in blood and serum (sorry, I don’t have the cite right now) indicates to me a generalized viremia, which is unusual in influenza. Recall the idea that typical influenza A infects the respiratory epithelium, and then only through and from the apical (“air side”) end of the epithelial cells. The appearance of the bug in other tissues (including the blood) is starkly alarming.
I am intrigued by Montreme’s assertion of an occult mammalian reservoir. Could be - but considering the state of surveillance and reporting, it seems to be also likely that this thing is moving through (and killing) folks unoticed in one or more oppressed, poverty-racked, war-torn and starving population where is is quietly passaging and adapting.
Sarge:
At this point, that may be slightly abusing the privilege of extrapolation; as far as I know, there are only a handful of examples ever involving live virus (versus RNA fragments only), and only one involving H5N1.
The multi-tropism of H5 and other virulent influenzas is well-studied and is a chief concern.
In a phrase, we’re just looking at too many things that can go wrong. Too many moving parts.
Something is going to break when you introduce this bug into a body.
Maybe Humans are the ‘occult mammalian reservoir’.
Tom,
Turn off your monitor for a little while. We’re not ready for that eventuality yet.
Racter -
Touche’. However, what I’d genuinely like to know is how does the bug move around to all of the organs that it has been observed to attack if now through the blood?
‘not’, not ‘now’ - ham fingers!
H5N1 has been observed in the plasma.
Sarge, the lymphatic system, same as blood for a highway, and closer to the mucus in the lungs.
TRay-
No pumps in the lymph system, requires body movement to move fluids.
I wonder if we could track the speed of movement of a viral particle thru the lymph v. the circulatory system?
I was reading a post with a link to a necropsy report on infected birds today and recalled seeing something about lymphatic degradation. That’s why I mentioned it.
Tom,
Continuation of my post at 01:12 a.m.
Now, as for my thoughts on the secondary and tertiary cases and the lack of spread. One cause could be the weakened state of the virus or unlike how many would have us think, some type of human antibdies. We know avian flu has been around a long time. Maybe aome human resistance has been formed. Not nessicarily the exact sequences, but close enough to create resistance. I really think it is the weakened state of the virus and how far it has to travle to spread. Just wait till it makes like the old Jefferson’s sitcom and moving on up.. into the upper lobes of the lungs. Can I say… not far to go or very long to wait if it hasn’t already (areas of the world wehaven’t heard from. Tight now, the buck is alright (maybe), but it will stop here. gina
P.S. Please excuse the typo’s. gina
Thanks Gina. I know there is an answer but it hasn’t popped into my head yet, maybe I’m not in the right frame of mind at the moment.
I don’t think there is evidence of anything in the way of protective antibodies from previous infections, but again that is theoretical which doesn’t necessarily make it true. There will be no actual proof until after the pandemic develops.
I wondered myself about the virus losing virulence as it radiates out from the index case. I was going to ask Monotreme but just hadn’t got around to it.
If it exhausts itself after one passage, that would be the best news I have heard in the last two years. However, infuenza viruses didn’t become the most effective and efficient pathogen in the world by acting in this manner.
Must be another answer to the question.
I agree that the lymphatic system is a candidate - especially if the bug has a way to hitch on WBC’s. I wonder if we could radiographically or fluorescent tag the bug and observe it in a couple of models (swine, murine, ferret, avian). I haven’t seen any studies.
The disturbing thing though is that by whatever route, the virus moves around. Viruses aren’t motile, so they are hitching along in either blood or lymph, and these aren’t places we are accustomed to seeing influenza, are they?
On the subject of spread - my discussions with a number of knowlegable folks leads me to believe that the size of the innoculum can offset whatever difficulties the bug has in initial infectivity - maybe by overwhelming the presumed alpha 2,3 binding in mucins? It seems that the bug has farther to go in perfecting its adaptation for rapid airborne H2H, but it closer now than at the beginning.
Tom,
Let’s not giveup on this. I think we are closer than we realize. There is a missing link in all of this and I personally want to know what it is before it makes it’s next jump. I just wish I had more information from countries holding back. As someone has already said, “The quiet is deafening”. Living where I do, I feel I’m in the eye of a hurricane. I honestly hope it is just my internal alarm telling me to back away for a short while. At least until I can see the forest. I know how you feel, it has been bugging me for a while too. gina
Thanks Gina.
I’ve been in these kinds of connundrums many times before…where you know there is an answer to the disease problem facing you but you can’t find it.
The best thing to do is to …Stay Calm, Be Brave, Wait for the Signs (Tom King-Native Canadian Writer- Dead Dog Cafe).
We wait and we watch for the girders and the rivets!
We have the tools, now we need the materials.
Tom, Gina,
I was just reading another thread and a couple of posts clicked a thought from back in my old reactor operation days. I know nuclear is a bit more micro than viral theory, but see if this parallel makes any sense?
When we split atoms we don’t actually split them at once or evenly. There is a range of so-called daughter products from each fission (like variations in virus reproduction from imperfect copy in a host cell). More so, the fission does not happen at the instant the neutron hits the nucleus of the atom. Instead, there is a period of time that it binds to the target and imparts its energy, which actually destabilizes the atom before the energy is too great and it splits.
Could we be looking at the virus having “lag time” once it enters a cell before it can efficiently set up shop and make replications. Maybe an environmental or chemical parameter it has to overcome because it isn’t “human” yet? That could give cause for the time delay in some index cases becoming spreaders, or just being isolated single infections. Ultimately it would adapt, provided it didn’t kill too much host tissue before the time delay cycled, but a time delay in some ways is worse. It would let the infection “go deep” before it launches into replication, and after a finite amount of damage wouldn’t the shedding be effectively cut off by reduction of deep lung tissue (my dad died of lung cancer and it was hell giving him hospice care til the end knowing what was going on).
That could explain the limited transmission time frame. But that would also favor increasing chances of “daughter product” mutations that may be compatible with lymphatic transfer, because coughing is a mechanical pumping action. Those nasty little beasties could end up in any tissue. I know that normal flu can end up in muscles and other tissues. This could be like a viral “real estate agent” showing new neighborhoods as it cruises the body in lymph during that post-spreader, pre-death phase. And as in nuclear fission, some of the daughter products are also spontaneously fissionable. We could have H5 variants trying to operate in other system tissues.
I’m referring to the beehiver – at 09:59 post earlier in this thread. That was so telling because the virus seemed to have literally eaten large varieties of tissue in the same animal.
Just wondering…
I was told, when I visited the health dept., in a nearby city…that they expected to have a West Nile epidemic here…a few years ago. Instead, they found that many people had built up an immunity to this virus. Is it possible to get immunity any other way, then from an active infection or vaccination? Obviously we didn’t have a community full of West Nile victims, although at one point, it looked like that may happen and it has been a long time since I heard of any cases…either animal or human. The gentleman I spoke to said they were completely surprised at this finding.
Could people build up immunity from less pathogenic H5 viruses, that may not have been detected? Maybe we have been exposed to some ourselves, since poultry is a main source of most peoples diets.
Sarge:
That is a not uninteresting question, but I’d say that it is still reasonable to conjecture that this bug’s ability to infect such a wide range of organs is an artifact of its inability to infect in a timely manner those cells which it most needs to infect in order to be efficiently passed from one human to another. If and when this virus emerges in a pandemic strain, that strain will be the descendants of those virons best adapted to infecting those cells, and the descendants of those virons favoring cells found in other organs or blood or lymph will — while their cousins go on to global fame — languish in the brutal but dead-end business of wreaking system-wide havoc throughout their hosts’ bodies.
When a new environment is being explored for the first time, the generalists are likely to enjoy much of the early success (for that matter, the generalists are those most likely to be exploring new environments in the first place). But that glory soon fades once the specialists really get their game going.
By the time we figure out what the virus is doing at this stage of its evolution, it won’t matter so much any more. We’ll be dealing with a pandemic strain, and the rules will have changed. (Or not, and we’ll be feeling a lot less pressured to come up with answers immediately).
Racter-
How would you feel if I told you that I believe that multi-tropism is a feature, a well-conserved feature, of H5N1 and that there is little likelihood IMO that this feature will be reduced when transmissibility becomes more aerosol.
I believe that the two features, respiratory particles and extensive multi-tropism, will co-exist peacefully in the PF51 strain and direly in the host.
We aren’t looking at a generalist virus; we are looking at a multi-discipline specialist.
while the virus also spreads by blood,feces,lymphs eating carcasses all the successflu flu-pandemics so far did spread respiratory.
So, when H5N1 wants to go pandemic it should choose this way. When we forget for a moment how virulent H5N1 is, suppose it were as mild as common flu, would our bets for a H5N1-pandemic decrease ? I guess, yes. People were more talking about and more afraid of H7N7 or H9N2 or reappearing of H1N1
Anonymous at 05:16 -
I don’t think anyone would disagree that H5N1 might not be The Bug that starts a highly lethal pandemic, and that there are other candidates. However, the existential threat is H5N1 and that seems to be the place to focus right now.
Racter -
I appreciate your perspective. I have opined elsewhere that the pandemic must follow a trajectory, else the host becomes extinct. The trajectory traces the struggle of the virus variants - between virulence and long-term survival, much as H1N1 must have. My concern then is ‘how big is the area under the curve’ - how many of us die while the bug sorts out this little intramural struggle?
when the virus infects a human, this human either dies or is immune. Both are equally bad for the virus in short terms. In the long run it might overcome the immunity by mutations. But for H5N1, why should it matter a lot whether the host dies once it stops sheading virus ? It could even be an advantage with carcass-eaters who might become infected or spread the virus.
Hi everyone. I read through an article yesterday about influenza receptors in chickens that rather surprised me. The researchers tested chicken colon and lung cells for presence of 2,3 receptors (usually characterized as avian) and 2,6 receptors (usually characterized as human or mammalian, in the upper respiratory system).
What they found was: chicken colon cells - 87.07% were positive for the 2,3 linkage; and a surprising 95.01% were positive for the 2,6 linkage.
chicken lung cells - 94.91% were positive for the 2,3 linkage; and 72.67% were positive for the 2,6 linkage.
So to some degree, a large proportion of all chicken colon and lung cells displayed receptors for both 2,3 and 2,6 types of viral linkages. Different types of tissues displayed different proportions. It seems that when scientific articles say “such-and-such avian cells display a preference for 2,3 linkage”…well that would only be a preference…it does not rule out the presence of 2,6 linkages.
Considering that quail are also found to posses both types of receptors, this lends more weight to the possibility of land-based poultry being in the category (along with swine) of influenza “mixing vessels”. The article about quail is at PMID no. 16325879. From the abstract: “we found that, in addition to the presence of sialic acid alpha2,3-galactose (SAalpha2,3-gal) linked receptors, there are abundant sialic acid alpha2,6-galactose (SAalpha2,6-gal) linked receptors in quail trachea and intestine”.
It would seem from this, that the implications for human infection are significant (or, for infection of chickens from humans and/or other mammals!). If anyone wants to read the 4-page article from the researchers that tested the chicken colon & lung cells, you can access it at http://tinyurl.com/qars3. And not to worry, you don’t need the Korean characters to read it.
beehiver. Thanks. You have confirmed what I have suspected for some time. Humans like to have things in a neat little box, but nature never works that way; it is usually muddled, overlapping and messy. I remember hearing a description of how many genes humans shared with I believe a ‘slug’ or some similar animal and the similarities were amazing. It should come as no surprise that we have more similarities with chicken genes than differences.
anonymous. That is a really good point.
NS1:
Life is a tradeoff. To get one thing, you must give something else up. Always. Whether viruses qualify as life forms is debatable; whether they are subject to this universal law is not. Generalization and specialization are expressed as a gradient, and “multi-discipline specialist” is really just another way of saying “generalist”. We cannot speak of what will or will not be conserved in a pandemic strain until we see it, but the simplest of logic demands that some of what is presently conserved will be lost, else we would be in the throes of a pandemic already.
Certain points in design-space act as “attractors”, which is why human designers working completely independently of one another often arrive at essentially the same design — among the available choices, certain ones are just what works best. If those influenza viruses — all of them — which historically were the most successful at infecting lots of humans did so by virtue of specializing in certain types of cells, it may not be because they were somehow “less than” H5N1. Remember, a virus gets extra points for compactness in its genome.
beehiver, I think, chickens are not the animals where the virus forms and mutates. Quails probably neither. Maybe ducks ? How is it in ducks ? And how is it in humans ? I won’t be surprised if we (some of us?) also have 20% alpha 2,3 in the upper airways …
anonymous. Exactly, and this overlap between species,would allow a mechanism to adapt to humans without actually infecting them.
Selective evolution can occur without the species being infected at all…once again proving that…we’re screwed!!
Tom, assume 2.3 vs. 2.6 is 80% vs. 20% in ducks and 20% vs.80% in humans.
Now the virus walks through long chains of d2d2d2d2d… and mutates
and reassorts and recombines. Now it jumps to chickens and goes
…d2c2c2c… usually killing them. Not many mutations occur in
the chickens before if goes c2h.
There is not much reason for the virus to be adapted to humans
at this point.
It might start to mutate inside the human now.
Although this E627K did form in the bird-Qinghai-strain,
probably increasing virulence in humans,
but that’s another story, it has nothing to do with the alpha 2,x
receptors. The S227N mutation might occur in humans and under
favourable conditions (superspreader…) maintain and form
h2h2h2h…-…- pandemic . I don’t know whether S227N is sufficient
(probably not) or whether some other mutations are needed for
a pandemic strain.
anonymous. I don’t understand exact mutations but here’s my point.
1) the current state of the science doesn’t have a clue what produces virulence and transmissibility or not. Even if they release every exact sequence and every gene for every strain is sequenced, they will not be able to tell how far it has progressed to a pandemic virus because they don’t have a clue what components produce a pandemic virus.
2) The argument has been that it wouldn’t jump species because it would have to infect humans to have a directed evolution. In my opinion all it takes is a threshold to be passed to allow the evolution in humans. The cross-over of receptors allows the critical mass to be attained to allow what we both agree is more targeted mutations once a sufficient toe-hold has been attained in humans.
3) I think you are right about virulence vs transmissibility and whether virulence has to go down in the move to a pandemic virus with transmissibility. Well, we’ve been on the voyage for nine years (a short time in the earths life) and virulence is going up rather than down.
However, my point is that the virulence is so high now that even if it drops by 80%, we are still screwed…therefore to me it really doesn’t matter because it will be much higher than 1918 not matter where it ends up landing.
anon at 1010 re: “the human sequences are no more different from the nearby avian sequences than the avian sequences differ from each other.”
please- I’m dumb- what does this mean? what are the implications?
1) they do have some clue. (but never enough) They might get some ideas from the published sequences, but this is unclear.
2)yes, the species-barrier argument looks silly now.
That “threshold” could be almost continuous or still contain some barriers
3) careful with the 9-years argument. We still have not much h2h2h..
and thus no chances for the virus to adapt. This will change in a pandemic.
The MIDAS computer simulations or the RMS-model assumes a CFR smaller
than 2% in USA. I wonder how they come to this estimate or whether this
is just to calm down the press+public ?
Grace, the virus doesn’t actually mutate a lot inside the humans.
No more than it does in birds. It doesn’t adapt to humans
while infecting them. (yet)
And there is not much evidence yet for some other intermediate hosts
like swine or cats where H5N1 were already established with long chains
of s2s2s2s2…2h or c2c2c2c2…2h
When we ignore the strange thing with the Indonesian cleavage site, that is.
I’m not sure how to explain this. Looks unusual.
But that’s just one small point-mutation and not important in the phylogenetical statistics.
Yes, we have many genes in common with a slug, a chicken, and even a bannana. “Catcher In The Rye” and “Oliver Twist” also have in common many English words and even entire phrases, but they’re not the same story; the order and timing of the expression of the elements is at least as important as the elements themselves.
Due (theoretically, and controversially) to the 70+k y.a. “bottleneck” (legacy of an ancient influenza pandemic, perhaps), the human genome contains far less variation than would otherwise be expected — yet we regard the nuances as significant when they affect mathematical aptitude, bra size, or predisposition to diabetes, schizophrenia, or sickle-cell anemia. With some things, it doesn’t take much difference to make a lot of difference.
We look at surface structures on cells because we can; it’s “where the light is good” — but we must be cautious with the conclusions we reach. Beneath the surfaces of cells, a whole bunch of stuff is going on about which we still understand very little, and as the effects of those inner workings propagate upward through the entire system, our lack of understanding propagates upward along with them. What’s worse is that we most often start from the other end: we find statistical correlations indicating that this or that trait has a genetic component, and we try to trace that component to its source — a feat which must be attempted against the background noise of environmental influences (somewhat paradoxically, since the background isn’t just noise, but a critical element itself in the ultimate outcome of gene expression).
It’s a certified Ball-O-Confusion.
anonymous. My point about the nine year period is that while it may be an eternity for us humans, it is less than a blink of an eye in earth, biologic time…
…H5N1 will take its own sweet time but may no mistake, there is going to be a pandemic sooner than later.
A CDC computer model in 2004, concluded that the range of deaths from the next pandemic would be 2–7 million. The WHO jumped on this like flies to **** and the end result was that sovereign regulatory agencies around the world are still saying that a pandemic is fiction and that countries loose more people to smoking each year then they will ever lose to a pandemic.
We should take these computer models and drop kick them off the nearest precipice.
Racter. I completely agree.
H5N1 might never go pandemic. Webster said : even chance. The computer models are still useful, but we need also those with higher CFR. I guess, they just dare not to publicly speak about it ?!?
anonymous.
I guess then I’m going to have to disagree with Dr. Webster on two accounts 1) his place in history depends upon his release of the sequences and 2) there is a 100% chance of H5N1 having an influence on emerging or existing seasonal influenza’s in the very near future.
The computer models are useless.
You want real predictions…use a human mind or better…a team of minds.
I agree with gs that computer models can be useful, perhaps the biggest drawbacks being the sort of logical errors which tend to occur when the results are interpreted by human minds — assuming, that is (which it is seldom really safe to do) that flawed assumptions are not transparently written into the models. It is in fact the power of the computer as an extension of the human brain which has driven much of the advancement of our knowledge of these things during recent decades, and much of the hope that we will ever achieve a thorough understanding of such complexities as genetics, protein folding, cellular processes, and immunity (and the ways in which they interact) surely lies in better mastery of these tools. We just need to keep in mind that we aren’t there yet, and that just as is the case when unaided human brains are employed, reality is what it is, and even the best models are just models.
Hi Racter.
The problem is now we have given them yet another escape route…Oh, it was the computer models fault.
A revisionist history maker’s dream.
TOM DVM: Maybe you can answer a question for me. Am about mid-way through “The Great Influenza”. They talk about the pre-virus waxing and waning over a period of a year before it really hit. They stated that a virus can often go “underground” to grow its viralence. How does this happen? I thought a virus grew by affecting more hosts. How can it grow during dormancy? Is it recombining and picking up on other traits needed to become pandemic?
Do you think this is what we are currently seeing in Indonesia. First a rash of new deaths and new clusters, then nothing. Is this the virus going temporarily dormant only to come back stronger. Comments appreciated.
Hi Janet excellent question. I have not read The Great Influenza yet. I’m not sure if I want to.
It might be helpful to remember Dr. Osterholm’s comment…H1N1 and H5N1 are ‘kissin cousins’.
If you think of seasonal influenza’s they usually disappear in the summer time to return each fall and winter season in the Northern Hemisphere.
H5N1, over the past nine years, has followed this same general pattern.
When H5N1 goes dormant, it can be circulating in wild bird species (think Q.Lake last summer to the fall when it broke out with the migrating ducks).
Unfortunately, H5N1 now has several options and several species in which to go dormant or to circulate asymptomatically for indeterminate periods.
I think in a sense these natural systems follow a pattern similar to humans approaching a war. First there is only whispers…then the talk of war waxes and wanes slowly getting steadily louder until the background noise is deafening…then the war starts.
With respect to H5N1, the virus will enter an area, then cause a localised outbreak etc. probably for the next little while.
I wouldn’t relax each time it goes away. When the WHO announced it was endemic in Asia, they were saying it’s here to stay…and if it’s here to stay then it will be definition have an effect on our lives..
…the only question left is when.
Janet Hope that helps. If you are still unclear just ask another question.
Tom DVM, What is your take on SARS? Do you think it could also be circulating in other animal species right now, possibly “waiting” for its opportunity to jump to humans again? Is it endemic in any parts of the world to your knowledge?
Hi Dejure. Haven’t seen you in a while.
I don’t think SARS was around long enough to be considered endemic in most of the world, but it has probably endemic in Guandong China where it emerged from.
SARS is a coronavirus. Coronaviruses are very stabile, probably one of the most stable viruses in the world. Even the scientists had a hard time believing that it was causing SARS until Dr. Osterhaus proved it by infecting Chimpanzee’s I think…
…the point is, as you probably know, a coronavirus is no influenza virus.
SARS is limited a little bit by it’s pathogenic characteristics.
Is it silently harbouring in wild animal populations in China…very likely.
Will it be back…very likely
Will it mutate to overcome its pathogenic limitations…very unlikely unless the world really has been turned upside down in respect to the mutation rates of pathogens.
Thanks, Tom DVM. I take it from your response that if SARS did come back it would be somewhat manageable as it was before. Correct me if I’m wrong. Curiosity has the best of me on SARS, however, and I don’t think it is too far off topic from H5N1. It seems there are many questions left unanswered as to why the coronavirus jumped the species barrier if, as you say, it is quite a stable virus. Which animals harbor SARS? Could the same ones be harboring H5N1? I’ve heard bats discussed in previous threads. Makes sense to me. I wonder if any vets are currently doing research in this area? But again, why did the carona virus mutate in the first place? Curious, isn’t it? It seems your profession is becoming more and more instrumental in answering these questions.
The benefit of a math / computer model:
Human experts are used to create a computer model to predict phenomena. The computer then out performs the individual human and a group of humans. Here is how it works: We ask humans to specify the rules they use and then determine the usefulness of these rules (via statistical analysis). Some rules are kept some are thrown away. Note that we may get one rule from three experts and another rule from four other experts.
All experts can be advised of the rules and the computer (math model) continues to outperform the experts. It has been found that “experts” with their vast experience continue to look for exceptional circumstances, well past the point of diminishing returns. Humans are often influenced by irrelevant information.
For instance, if the expert is diagnosing schizophrenia they will say the diagnosis is mitigated because this young, beautiful, articulate woman just “could not” have chronic schizophrenia. According to the math model the expert is wrong, according to drug treatment effects the expert is wrong and once again the math model (computer program) outperforms the human upon which it was based. BTW, the best experts are those recently out of grad school or still in grad school because they stay close to the rules!
The trick is knowing what to put in and the reliability of the measurements used. (This is where anonymous (alias GS) does not know what he is seeking.
Bottom line, math algorithms outperform humans by a very significant margin when you have good models.
Dejure. I don’t like SARS either, it’s just that it appears “somewhat manageable” compared to the monster H5N1…in a sense I guess its like comparing a ripple to a tsunami…but I’m with you, SARS went away a little to easily and suddenly the first time around.
SARS jumping the species barrier the way it did was a complete shock.
I should know who has been pushing the bat theory so I can give them credit, but at the moment the name escapes me…but it makes perfect sense because bats are in effect the link (the bridge) between birds and mammals, they group in very large numbers similar to domesticated chicken flocks and are warm-blooded, a bad combination for the development of new variants of existing viruses.
Veterinarians are more important now because Mother Nature is making us more important. Something is pushing mutation rates in bacteria and viruses, whether it is sunspots, global warming, over-population, the size and number of farms, increased contact between man and animals…who knows…
…we are talking about animal diseases…the physicians are standing on my toes, I am not on theirs.
Tom, your analogy to war just made me think of something. Remember “Shock and Awe” about 3 years ago. Huge build up, then silence, then BOOM!. With a pandemic capable virus, that type of “stealth” attack would fit a pattern of sudden outbreak of extremely deadly strains in separate locations, seeming out of the blue. That is what has me really scared the last couple of weeks. We saw the virus almost make it over the last hurdle, then slide back. Now, as I read several places, the “silence is deafening”. And Mt. Merapi is having larger outflows in th past 24 hours. Attention is focusing away from avian flu and toward Iraq, the stock markets dropping around the world, and oil prices dropping because usage is down. The world will be in “shock and awe” if it breaks out.
JoeW. You know I agree with most everything you say but on this one, I’m afraid I am going to have to disagree…give me a thinking, open minded human brain anyday!!
Thanks all on the genetics primer…
Tom DVM..I’m with you- we ask computers to tell us things that we already know. the conflict is when the computer tells us things we know to be wrong..human instinct has it all over a computer :(
TRay75. I made the prediction in Jan 2005 that the fall of 2006 and the winter of 2007 would be, in my opinion, when the pandemic would start.
Now, I don’t know any more or any less than anybody else, so I could be completely wrong…and I have not started prepping yet.
The point is you and I and we…should have a nice summer. Start worrying again on Sept 30 th.
Thanks Grace.
Yup, enjoy the summer with my kids, tell them how much I love them and what I hope for life for them in ways kids understand, just in case. That kind of prep will mean as much as anything and never go to waste. Off to a meeting.
TRay and Tom -
I don’t mean to cast aspersions on the honorable profession of veterinarians, but the prime players in the old US biowar programs were predominantly vets! That’s because all of the ‘good’ biowar agents are zoonoses (anthrax, brucellosis, glanders, meliodosis, VHF’s, viral encephalitides, etc.) They understood much better than MD’s the nature and potentialities of these bugs. That is why the importance of vets in the detection and control of many emerging/reemerging and novel pathogens is so important now.
For too long there has been a disconnect between the veterinary and human medical community. That needs to be rectified quickly in the brave new world, where bugs are lurking in the animal populations waiting to jump out at us bipedal types.
There was a time when most MDs would not use the new fangled tests for diabetes. The technology was baffling and useless. They preferred the old ways, sticky urine on the shoes and the taste of sugar in the urine. That was the way to diagnose diabetes. The human mind is good and can analyze many phenomena but when we can create a math model the model wins. That is not opinion that is fact.
Personally, I find it amazing that epidemiologists have not built a model for predicting influenza epidemics. The data with regard to predictors and the dependent variables are certainly available. The only thing I can conclude, without studying the field, is that their predictors are neither valid nor are the variables reliable. The generality of variables that could be used to predict influenza, as a disease entity that causes epidemics, cannot be very dissimilar whether one is predicting H1N1 or H5N1 it would appear that they all work in a similar fashion and must have similar requirements.
Perhaps you can explain why people versed in this topic are not using the history or prior similar diseases to predict the course of this one?
The one thing I have gotten from The Great Influenza so far is that influenza is clever. It is not some virus that just happens to mutate or die off. It is a virus that often lays-in-wait and comes back fully armed. This is what happened in 1918….just when everyone thought the milder strain that was predominant in Europe and America was over…WHAM!
JoeW: I agree that we should be able to take what was learned back in 1918 and program the data into a computer for some working model for what is happening now. I also agree with TomDVM that it does not take a rocket scientist to figure out that this thing is not going away on its own. It may go into hiding, but it is not retreating only getting stronger.
Apparently Epidemiologists are indeed limited in their abilities as indicated below.
Infectious Diseases: preparing for the future\\
OFFICE OF SCIENCE AND INNOVATION
S9: State-of-Science Review –
Predictive and real-time epidemiological modelling
Dr Matt Keeling – University of Warwick
Consider trying to make an accurate model for a human airborne infection (say influenza). Such a model would need to account for variations in transmission temperature and climate, capture the day-to-day movement and interaction of individuals, and encompass the variability in susceptibility due to genetic factors or past
infections. Even if such a model could be built, the chance nature of
transmission would still prevent perfect prediction. Therefore, epidemiological
modellers are faced with an impossible task; the best they can achieve is to
bound the range of plausible epidemic behaviour, predicting which future
outcomes are likely and providing confidence intervals for any characteristics
of interest. Page 4
http://tinyurl.com/qex3j
It seems to me that perhaps epidemiologists should be predicting the likelihood of an individual becoming infected based on past infections. If a sufficient number of individuals could be predicted then one could categorize this level of infectivity as an “epidemic” or by some other name. A sufficient number of epidemics would lead to the conclusion that a “pandemic” is eminent. This is one place to start.
Tom, I’ve been at it again…thinking…dangerous.
Basic: this virus has servived throuth adaptation and has evolved to the point of going H2H. Now it looks like another fluhas developed in Indonesia. Next step for this virus…gene swaping. With both flues in humans and the proximity and conditions around both…you finish it and tell me I have an over active imaginatio…Please. gina
That, Gina, is exactly the scenario for “shock and awe”. I don’t think I’m going to sleep well the next couple of nights, again! And Mt. Merapi is becoming more active the last 24 hours, with the lava dome growing. No one is looking at the micro because the macro is becoming a bigger immediate threat.
Hi Gina. No, you’ve probably got it about right.
I am not that good with numbers and am not a virologist so others can correct me if I make a mistake.
When they say there is a pandemic coming they do so with good reason. There is an H3N8 outbreak in North America from a very stable flu jumping from horses to dogs. There has been H7N1 outbreaks in Holland, the US and Canada. There is H5 and also I believe recent outbreaks of H9.
H5, H7 and H9 are classified as high pathogenic subtypes?
The WHO confirmed H5N1 is endemic in Asia. This statement was overlooked but is extremely important when assessing H5N1’s future damage potential. It can do it on its own, it can pick up little pieces of other viruses (recombination) or it can pick up whole gene segments (there are eight in a virus).
So you are right about the many possibilities. The two I wouldn’t want to get together are H7N1 anbd H5N1. H7 also killed it’s first human in the late 1990′s; a veterinarian in Holland. When they did serology in families and close contacts and poultry workers, they had 700 positive tests. Therefore, H7 has everything that H5N1 needs.
The H3N8 in North America is also troubling because of the close contact and therefore chance of infection between kids and their pets.
I agree with your hypothesis Gina, there are many possibilities now for H5N1, not least of which is gene swapping; one side benefit of gene swapping would almost certainly be decreased virulence.
http://www.pikiran-rakyat.com/cetak…006/08/1102.htm
Dr. Nidom, the “Form of the Virus already 2,6″ Since the spread of bird flu to humankind stuck up, Dr. drh. C. A. Nidom M. Sc. To one of the informants that results of his research were often made the reference. Together with the development of the case of this illness, “HOMEWORK” carried out the special interview through the researcher’s e-mail to Avian Laboratory Tropical Disease Center influenza and the biochemical Part & Molecular Biology the Medical Faculty the Airlangga University Animal, Surabaya, on Monday night (5/6). Along with his interview extract. Was bird flu to humankind at this time still being spread from the poultry? How far the possibility of the spread of the bird flu virus between-humankind and like whether his scientific explanation? This question was very interesting. Actually the direct spread from the poultry to the person really was difficult. This difficulty was caused by two matters that is receptor relations and spesifisitas the receptor and the difference of the temperature between the person and the poultry also were different. Therefore, I carried out the research in the month February-March 2006. This research was helped by Tokyo University. The aim of the research to know whether the circulating virus in the field, only had the shape of the virus from the poultry that is had spesifisitas the receptor alfa 2,3 or that had spesifisitas the receptor alfa 2,6 that is the virus that could infect direct to the mammal (the pig and humankind, etc.. ). The sample that I the test came from the poultry, the pig, and humankind. From 100 samples, there is 20 that succeeded in being turned on and evidently 11 among them had spesifisitas the receptor 2,6. Meaning that, these viruses had the capacity immediately could infect humankind without must from the poultry before. Moreover, some of the samples had the amino acid lisin in the number 627 proteins PB2, that meaning that the virus could be stable in the temperature of the human body. Because of several matters above, the direct spread to humankind without through the poultry very possibly happened in Indonesia. However, continued to have to be researched to the person who was infected by this bird flu virus. All the poultries and humankind that was infected by this virus will experience was sick? Not all the poultries that were infected by the bird flu virus were sick. Often I encountered the chicken without the sign was sick, appeared healthy,
Who said 2 by 4 to the head moment last night? Commonground, thanks.
Re: Commonground’s post, So, Dr. Nidom believes that H5N1 did mutate enough to spread H2H in Indonesia and, unlike before, the virus has adapted to the temperature of the human body? Also, although it is not suprising, it appears he detected asymptomatic H5N1 chickens.
Hi Commonground. How did you choose your name?
The most troubling part of your post is the last two lines…”Not All the poultries that were infected by the bird flu virus were sick. Often I encountered the chicken without the sign was sick, appeared healthy.”
For H5N1 to really take off, it needs to infect animal species asymptomatically (without making them sick).
We know from the serology that it is not happening in humans. We know it was happening in some species of migratory waterfowl. We know from serology that it is happening in pigs and probably other mammals…and now you have provided information that it is occuring in poultry…not good if true.
Hi Tom DVM, I chose my name because we all share a “common ground”, this blasted H5N1. There is another post, at another site, but I am not one to copy someone else’s work and place it in another site….. I would appreciate any input from this article, as I don’t know much about Science. But I follow Niman and I know the 2,6 is not good at all. That means it’s in the upper throat and nose, right? Not the lower lung?
Commonground. That finding may explain the transmissiblity or H-H-H in Indonesia. However, I never really bought the receptor argument. It seemed a little to neat for my liking…nature is usually a little messier than that. It was mentioned on a thread today, I’m not sure which thread now, that birds have both types of receptors in their bowels and lungs…so that adaption to humans could indeed occur in chickens and the finding in chickens could explain how the 1918 H1N1 made the jump directly to humans (it was a pure avian virus).
Anyway, nice to know you…stick around.
Thank You, you are very kind….
Hi ya’ll! Ar yu takin bout them pur sik anmuls. Sorry, couldn’t resist. I want you to know that that is southernred neck. That was also my way of taking a deep breath.
Tom, I think I would have prefered you telling me I’m crazy. Because that is already a known fact. Trying to stay with or ahead of this virus is a gray matter distorier. But thank you for telling me what you did for it’s better than not knowing for sure.
Commonground, Thank you for the species/virus update.
Well, I’m off for a little while to put the finishing touches on the BbQ Bird. Such revenge! gina
http://www.recombinomics.com/News/06080602/H5N1_Indonesia_RBD.html
Commentary
Altered Receptor Binding in H5N1 Bird Flu in Indonesia?
Recombinomics Commentary June 8, 2006
This difficulty was caused by two matters that is receptor relations and spesifisitas the receptor and the difference of the temperature between the person and the poultry also were different.
Therefore, I carried out the research in the month February-March 2006.
This research was helped by Tokyo University.
The aim of the research to know whether the circulating virus in the field, only had the shape of the virus from the poultry that is had spesifisitas the receptor alfa 2,3 or that had spesifisitas the receptor alfa 2,6 that is the virus that could infect direct to the mammal (the pig and humankind, etc..) . The sample that I the test came from the poultry, the pig, and humankind.
From 100 samples, there is 20 that succeeded in being turned on and evidently 11 among them had spesifisitas the receptor 2,6.
Meaning that, these viruses had the capacity immediately could infect humankind without must from the poultry before.
Moreover, some of the samples had the amino acid lisin in the number 627 proteins PB2, that meaning that the virus could be stable in the temperature of the human body.
The above translation of an interview with CA Nidom from the Airlangga University Vetereinary School in Surabaya is cause for concern. The comments indicate that 20% of the samples tested had virus (presumably H5N1) and 55% of the positives had a 2,6 receptor specificity, indicating they had an increased affinity for human receptors in the upper respiratory tract. In addition, many had PB2 E627K, which allows the H5N1 to grow at lower temperatures.
Earlier reports described E627K in one of the initial samples from Jakarta, A/Indonesia/6/2005(H5N1). There was additional speculation that the high levels of H5N1 bird flu in the nose and throat of victims in Medan were also due to E627K.
The above comments indicates thee are differences in receptor specificities in the H5N1 isolates from Jakarta. The comments above to not break down the number of H5N1’s with 2.6 specificities, but H5N1 can readily recombine and exchange such information, so finding that specificity in H5N1 in any of the tested species is cause for concern.
Media Source Link
Phylogenetic Tree
large numbers!
very large numbers!
Thank God someone like Nidom is getting sequences. It may still be in private hands, but verbal report is a lot more alarming than WHO. How do we reconcile the difference? WHO saying no mutations towards human adaptability and Nidom saying half of the samples have the orientation to a2.6. We need a better interview, some English media like the New York Times had better get on this! Tell ‘em Niman!
>>>The sample that I the test came from the poultry, the pig, and humankind. From 100 samples, there is 20 that succeeded in being turned on and evidently 11 among them had spesifisitas the receptor 2,6. Meaning that, these viruses had the capacity immediately could infect humankind without must from the poultry before>>>
It seems to me it would be helpful to know, of the 100 samples, how many were from poultry, how many from pig, how many from humans. Then you would see if the origin of the sequence has any direct correlation to the receptor site.
I would like confirmation of this information from another source. Machine translations introduce some interesting phrases that don’t make sense. We have asymptomatic chickens and pigs with both temperature and upper airway infection capability directly to people. I also get out of this that the author thinks the pandemic may be right before our eyes. It is not going to be a good weekend for me. Glad I have no appointments for tomorrow. I am going to be on the lookout for more information on this.
I agree, petperson. It would be interesting to see how many pigs have viruses with 2,6.
Close thread for length. Continue here