To continue a similar thread that got too long. A revised first post with discussion points from various contributors.
Are Human-to-Human and Mammal-to-Human Transmission the Source of Most H5N1 Infections in Humans?
Although we have been conditioned to believe that birds are the source of most human infections of H5N1, what is the evidence that this is so? Certainly, many, many birds have been infected. It is also true that a close association between infected birds and some patients have been observed. For example, the owner of a prize fighting cock applied mouth-to-beak resuscitation when blood was impairing the bird’s ability to breathe.
However, in most cases, the association between human patients and infected birds is either absent or very tenuous - some birds in the village died, or the patient ate chicken a week ago, or the patient walked past a chicken on their way home from work.
It also interesting to note that poultry workers who would be expected to have the most exposure are rarely infected. Nor do they have antibodies to the virus.
Many of the human cases involve clusters. One person is infected, there is a delay consistent with H5N1’s incubation period, and then one or more additional people are infected. Which is more likely, 1. first one person was infected by birds, then other family members were infected by birds, or 2. that the first person infected others? Also, why do we expect that it’s easier to get infected from birds than other people? If the spread from birds is fecal-oral, isn’t that route of infection also possible from human to human, especially caregivers? There are many viruses that are spread human to human this way. Think Norovirus.
Other mammals are also possible vectors. Here is a list of the mammals that have been shown to be infected by H5N1. Perhaps human infections of H5N1 are rare because it is really, really hard to get it from birds. But perhaps it’s not so hard to get it from mammals. There may be few human cases because relatively few mammals have been infected thus far.
Strains of H5N1 isolated from humans were more lethal to ferrets than strains isolated from birds reference. Why would this be? I had interpreted this to mean that the virus had mutated while in the patients to become more adapted to mammals. But, there is another explanation. Suppose the virus isolated from patients was more lethal to mammals (ferrets) because it infected the patients directly from mammals. This would have given the virus much more time to adapt to mammals.
Cat H5N1 sequences in Indonesia are apparently more similar to H5N1 sequences from humans than either are to H5N1 sequences from birds. What is the most logical interpretation of these results? I submit that there may be a mammalian reservoir for H5N1 in Indonesia and other countries and that H5N1 is under selection to adapt to mammals in this reservoir. Further, at least some of the human cases may be due to mammal-to-human infections. (See also Dr. Jeremijenko’s post at 23:14 in this thread, and here and here). In the recent large cluster of human cases in Indonesia, no infections of poultry were found in close proximity to the village where the outbreak occured. However, pigs with antibodies to H5N1 were found in this region reference. As Tom DVM, FrenchieGirl and DennisC pointed out, H5N1 infections in pigs would be particularly worrisome as these animals could serve as mixing vessels for the formation of a human-adapted H5N1 strain.
I cannot prove that specific human infections were due to human-to-human or mammal-to-human transmission. However, it is equally impossible to prove that a specific human infection was due to transmission from a bird. Given that, all three possible modes of transmission should be evaluated according to the same criteria. There is no reason that bird-to-human transmission should be the default explanation.
Implications. Human-to-human spread by close contact may be much more frequent than is currently advertised. There is the potential for large outbreaks if an infected person is in close contact with many others (daycare or school) or handles food for many others (cruise ships, restaurants) [suggested by Medical Maven]. Also, the funeral practices of some Africans involve close contact with the body of the deceased and their bodily fluids. Marburg and Ebola have been spread this way [suggested by Chrazer]. H5N1 might also cause large outbreaks in Africa through this mechanism. Manure from chickens and livestock may be infectious [suggested by European].
The prescence of a mammalian reservoir for H5N1 in Indonesia and possibly elsewhere would result in selective pressure for H5N1 to adapt to mammals. We discussed whether it was possible for H5N1 to be evolving towards a pandemic strain on other threads here and here. Some had argued this would be impossible because the virus would have to start over again every time it jumped from bird to human. But if it starts out in a mammal, it’s got a head start when it infects a human.
Action steps
Excellent points, well-defined and highly plausible theory.
Question re H2H + resultant reduced virulence: If birds are the historically predominant host of the virus, is virulence NECESSARILY reduced as a corollary to SEH2H? Or, if humans are a, say, sideline dalliance, could it retain its virulence, retreating to birds in the event of burn-through in an isolated village?
Sorry if this is the wrong place; I didn’t see another likely spot to ask.
2beans-
All solid insights.
There is no reason to expect an SEH2H HP H5N1 to reduce virulence just because of the increase in transmissibility. This virus doesn’t require a host to live in order for the virus to reproduce and spread.
Viral particles are shed in extreme counts prior to symptom onset.
The bug may move back and forth between multiple reservoirs which may not all be vectors at the same time.
Thanks NS1.
I agree with your statement 19:12.
Monotreme-
In your action steps or elsewhere, have you covered the very, very important aspect of risk communication to native villagers that they must be notified and trustworthy of full and immediate compensation for any culled animals?
Monotreme
Wow!
Your post has triggered a flood of questions about the ability of the H5N1 virus to cross “the species barrier”in mammals. Do other viruses infect so many different mammals? What studies have been done regarding transmision in mammals? Thanks in advance and please keep posting on this subject.
Hi Monotreme NS1, 2beans et al.
As a practising veterinarian, this particular situation is common place. You have a localized epidemic to deal with and you thought you had it figured out but it is just not doing what it is supposed to do…the pit of your stomach tells you something just isn’t right with your previous conclusion.
First, the Chinese Governments factory farm for migratory birds in the vicinity of Q. lake, has answered the question about whether H5N1 is man-made or developed as a mutation in migratory birds. H5N1 was a harmless wild bird strain that was weaponized in the factory farms in China and was then spread around Asia until 2005 as a result of primarilly movements of poultry or products. The farm at Q. lake, in effect, injected the weaponized virus into migratory birds that then spread it across Asia along with poultry and poultry products…so that’s one question answered.
A second issue is why has eradication efforts through culling failed to control the linear spread of the disease.
The point is…does it really matter the source of the contact at this point. This virus is now everywhere in Asia…the question is probably not which animal species are harbouring the virus but at this point which ones are not carriers.
We know that the WHO has run around finding poultry or poultry product contact for every case but I could do the same in North America for each seasonal flu last year…in otherwords it doesn’t mean much. This diseased has probably been spreading without poultry as the cause for some time and maybe years.
At this point, H5N1 is in so many species to make the question of source of infection irrelevant…and now it seems that testing is made to fit whatever is least damaging…if presence in pigs is a problem then just provide some results that says it isn’t in the pigs, like occured today…the WHO is making the source of contact irrelevant by their ‘Keystone Cops’ routine.
Monotreme, as I have said before the other thread was truly ground-breaking as recent events have again demonstrated. H5N1 is continuing the pattern of more efficient H-H then B-H that you identified.
The interesting point at this time is whether genetics is playing a role in susceptibility within these clusters…and my answer is not a chance. Genetics is not quite so black and white…there is always a lot of gray in the picture. It is a little simplistic to say that the mother is carrying a genetic factor for susceptibility and has passed it on to all relatives…not going to happen.
Genetic susceptibility might be passed to a few but the fact is that siblings in a family are the only ones who are really close genetically. Mothers and Fathers are genetically quite distinct from offspring.
There are other issues that will come up in this discussion but in conclusion I said a while ago that if it got into pigs and especially if it got into pigs asymptomatically, we were screwed…
…It appears we are screwed…there may be no stopping it now.
Sorry, something else that doesn’t make sense is their conclusion that if it wasn’t the birds then it had to be faeces or feathers. This again, doesn’t make sense either. There are farm workers who work under conditions, working with feathers and faeces every day, that would contact it as an aerosol. It these workers neither show symptoms of disease or serology demonstrating immunity then the two vector arguments can’t and won’t work.
As far as the pigs in Indonesia, the only way to tell the source of infection is with PAIRED SEROLOGY…BLOOD SAMPLES THREE WEEKS APART…if you have a rising titre then the animal was infected, if the titre doesn’t change then it is possible the pathogen wasn’t active at the time…
…if you notice in Indonesia instead of paired blood samples they decided to take nasal swabs…HAVE YOU EVER TRIED TO WORK WITH A PIGS NOSE OR TAKE NASAL SWABS…ISN’T GOING TO HAPPEN!!!!
Needless to say, you have given us another thread and opportunity to answer all of the remaining questions about avian influenza…and there is always, in retrospect, a perfectly reasonable straightforward answer to all questions in nature.
NS1, you’re absolutely right about risk communication to villagers. I think those of us in the First World ought to be willing to help poor countries compensate farmers for their losses due to culling.
slow reader, influenza viruses are better able to cross the species barrier than most. Something that makes them particularly dangerous. However, even among flu viruses H5N1 is a champion species-crosser. Here’s a partial list of H5N1′s victims.
Tom DVM, I think the factor farms helped H5N1 evolve into a killer, but not directly. Keeping animals at high density and under stress makes them more vulnerable to disease. Flu is one of these diseases. In order to protect their investment, the owners of factory farms in China wanted a vaccine to H5N1. Unfortunately, the vaccine they got was bad. It may have protected their chickens from immediate death but did not prevent the virus from infecting them. As a result, the virus was put under selection to evade the chickens immune system. I think this is what made an ordinary flu virus a monster.
I agree that it is too late to stop H5N1. All we can do now is to try to delay the pandemic as long as possible and brace for impact, ie, prepare.
Tom at 23:30…”It appears we are screwed…there may be no stopping it now.”
With the limited time that I have available to me I have tried to understand H5N1. Without a science background it is often a challenge to understand the science behind the problem. From reading the wiki I understand that (1) pigs can act as a mixing bowl for the flu to pass to humans (2) that pigs in Indonesia and other parts of the world are showing antibodies for H5N1.
Would you or others please explain (1) why if the pigs have antibodies for H5N1 it is not now going H2H? (2) What will be the process that will allow it to go H2H due to pigs?
Monotreme. I think before H5N1 was a threat, before the factory farms would have needed a vaccine…the wild harmless virus entered the factory farms and mutated to become what we know of today as H5N1.
Think of it in terms of numbers and probabilities. These factory farms are now so large as to supersede nature and take it completely out of the equation when it comes to mutation. Once it was weaponized, it was a short hop back into the wild bird population.
The next thing that happened was the Chinese Government kept it a secret (same time as SARS) and tried to stop it with antivirals to poultry and later vaccine.
Where did H5N1 show up years later…on the borders of China.
Vietnam currently has a Foot and Mouth outbreak affecting over half the country…it just so happens that China has had an uncontrolled Foot and Mouth outbreak for more than seven years…another disease simmering for years and then showing up in a border country.
This horse was out of the barn a long time ago, it just took a while for the ‘pot to boil’. H5N1 is following a classical animal pattern of development especially in terms of China.
Kathy in Or. I am not quite as literate as my friend Monotreme. He will do a wonderful job at explaining the issue for you…and if he doesn’t have time then I will.
Kathy in OR,infections in pigs are bad for a couple of reasons. Pigs can harbor both avian and human flu viruses which can permit re-assortment between the two such that a new chimeric virus can emerge to infect humans. Flu viruses can also change by random mutation or recombination (another way for viruses can exchange genetic information). Pigs are mammals, like us. A virus that infects and adapts to a mammal is much more likely to be able to infect and adapt to humans than a virus that is restricted to birds.
Tom DVM, I agree H5N1 probably started as a relatively benign virus transmitted by waterfowl and that it’s lethality was enabled by factory farms. But I suspect bad vaccine helped select for nasty variants.
Tom DVM, you’re too modest. And I screwed up the link above. Here’s the correct link:
Thanks for your answer Monotreme.
Would I be correct to assume that because there are antibodies to H5N1 in the pigs that it does not necessarily mean that there has been re-assortment?
Hi, all. If pigs are infected with H5N1 at this time of year, shouldn’t H5N1 be part of next seasons flu vaccine?
Tom what do you mean by weaponized ?
Kathy in OR – at 23:53
Antibodies only reflect an infection. Now, let’s follow the chain of clues:
If H5N1 infects a swine and we hold as a given that swine are seasonal influenza reservoirs, then you may have two or more strains of influenza in the same proximity and probably in direct contact in that individual swine.
Proximity = Opportunity for Genetic Acquisition
Regardless of your politics on shift, drift or rules-based recombination, Influenza is promiscuous and will update its code if given the opportunity.
Raising the matter to a higher concern is the fact that swine are mammalian and as such provide a better bridge for the virus to become acclimated to other mammals, like us.
I think, as TomDVM, has stated that all of this source chasing and source debasing is supplying a drudgery of misinformation and tailchasing.
We need basic science here. Give us the sequences of the strains from animals of all species and people of all contacts (family, medical, workplace, et al) around the foci.
Matching the sequences to the sources is simpler, more accurate, more timely and very actionable.
Wasp – at 00:53
The medical establishments primary weapon is the vaccine and most of the resources are going toward that development very unsuccessfully at the moment.
We do not have the SEH2H HP H5N1 strain yet, so a vaccine at this time is mistargeted.
Kathy in OR, the presence of antibodies in the pigs doesn’t tell us anything about the variant of H5N1 that infected it. As NS1 indicates, we need the virus itself and it’s sequence to know whether it’s any closer to infecting humans. However, the mere fact that it’s infected pigs is disturbing. Even more disturbing would be pig-to-human transmission.
Wasp, the decision on when to make an H5N1 vaccine is a tricky one. As NS1 points out, if the virus changes too much between when the vaccine is made and when the virus becomes a pandemic strain, then the vaccine will be worthless. On the other hand, if you wait until the virus is a pandemic strain to make a vaccine, you will have no protection against the first wave of a pandemic - it takes at least 6 months to make a vaccine using conventional approaches. Some vaccines are being made now to H5N1 in the hope’s that they might do some good. Even if not a perfect match there is a possibility that they would decrease mortality. There is some evidence that vaccines administered intranasally, (FluMist) are better able to stimulate the immune system even if the vaccine is not a perfect match. The truth is, we won’t know how well any vaccine works until the pandemic starts.
Kathy in OR, if you’re still around or anyone else, the pigs have both a2,3 and a2,6 cell receptors in their higher passages which allow both bird and human viruses to infect them. The fact that H5N1 is in pigs does not alone tell us how well it has adapted without sequences showing the mutations. We would really like to see what the Indonesian swine samples have. The longer the virus is passed along in swine, the more chance it have to switch to the human cell receptors. Here is an example of the time it took, 6 years for one strain-
“Scientists have actually made a kind of time-lapse recording of this process. In 1979, pigs in Europe became infected with an avian H1N1 virus, a strain quite different from any previous H1 strain that had ever infected humans. By 1984 that virus could latch onto both human and avian receptors, but after 1985, the virus recognized only human receptors. In other words, while multiplying in pigs, the bird virus acquired a preference for human receptors in the pig’s respiratory system.”
This is from the book- “Secret Agents - The Menace of Emerging Infections”. I’m am giving a link of the book which puts you on the page 173 of the above quote, but you can read the whole book online, which is very worthwhile.
Tom DVM, Montreme, NS1 and others, thank you very much for this discussion and your efforts.
Mstrbubbie at 1:25 asked “Tom what do you mean by weaponized ?” I feel this is an important question and here is why.
Quite a number of the alternative health discussion groups are circulating communications that (at best) this virus is a “hoax”, or (at worst) the virus has been created by evil people in a lab and released so as to either decrease the human population and/or sell more drugs and vaccines. One of the terms commonly used in the second scenario is “weaponized”. Tom, it is obvious to me from your posts that you are not referring to lab creation, but perhaps it might be helpful to find a different word, so as not to confuse newcomers that might be reading those thoughts.
Unfortunately, it is obvious that the writers of the communications in the alternative health community have *not* informed themselves of how influenza A virus behaves in nature; nor are they informing themselves of relevant scientific studies or recent events, before posting inflammatory information.
About H5N1 and commercial farms - another prominent scientific group, the London-based Institute of Science in Society (ISIS), has just released two review articles on H5N1. They are well-written, and while not everyone may agree with every detail, they are also coming to the conclusion that commercial poultry farms are playing a much larger role in the spread of H5N1 than is being acknowledged. These articles are available online but the references in the articles cannot be accessed without a membership to ISIS. http://www.i-sis.org.uk/Fowl-Play-in-Bird-Flu.php http://www.i-sis.org.uk/WCYBABF.php
The scientists from ISIS are by the way, well-informed about reassortment and recombination issues in nucleic acids, as they have been warning for years about crossover transmission of the viral promoters and antibiotic resistance genes used in the creation and production of genetically engineered products.
Once this general phenomenon is more widely acknowledged to be occuring, perhaps more people will understand why there is concern about nucleic acid transfer from outside agents in medicines, including vaccines. While the overall intent of vaccines may be noble, there are problematic issues that lurk in the shadows. As an example, the abstract at J Med Virol. 1990 May;31(1):5–12 (PubMed accession number 2198327) states:
“The use of cell substrates to propagate viruses or recombinant plasmids for vaccine productions has been the subject of long evolutionary conflict, primarily from the standpoint of product safety, and especially from the viewpoint of cancer induction. The present concern is for safety of vaccines made using transformed or neoplastic mammalian cells that may contain endogenous contaminating viruses or integrated gene sequences from oncogenic viruses. There is also concern for use of plasmid vectors employing promoter elements from oncogenic viruses. The principal concern for safety lies with retention of residual DNA in the vaccine, especially since induction of cancer is a single-cell phenomenon, and a single functional unit of foreign DNA integrated into the host cell genome might serve to induce cell transformation as a single event or part of a series of multifactorial events. Current proposed standards for vaccines would permit contamination with up to 100 pg of heterologous DNA per dose. This is equivalent to about 10(8) “functional lengths” of DNA. Total safety would seem to require complete absence of DNA from the product. While preparation of biologicals used to treat serious disease might demand the use of mammalian cells, this is not the situation with vaccines that are given prophylactically to persons who might be given equally efficacious vaccines produced in bacterial cells or in yeast that have attributes for greater safety. Careful assessment of safety and risk vs. benefit of continuous mammalian cell-produced vaccines should be made by technically expert scientists in the relevant disciplines and a consensus needs to be evolved in the scientific community at large.”
Somehow, the possibility of 100,000,000 functional lengths of contaminant DNA in any one vaccine dose, is rather discomforting and can create understandable reluctance to take any vaccine that would not be absolutely necessary. A well-referenced review article of various types of vaccine contaminants is available at http://tinyurl.com/hdfz7.
I apologize that the subject matter of this reply has wandered off a bit! The issues are all so closely related…
Beehiver and Mstrbubbie. I have heard and considered the experiment escaped lab argument, in fact I believe that someone listed an bioterrorism lab in the area of Guandong where the virus first surfaced…
…but the truth is, as anyone who has been following this story would know, that we don’t know enough about influenza to manipulate it in a laboratory setting to increase virulence.
My use of the word weaponize was to indicate only that 1) it did not occur naturally, man has inadvertentlly created evironments that favour mutations. and 2) to indicate that H5N1 in the wild was harmless and in addition,no high virulence strain had ever jumped the species barrier let alone several species barriers at the same time until 1997.
Beehiver. I agree the word ‘weaponize’ might be misinterpreted. If you think of another word I could use instead please let me know. I haven’t been able to find a word that describes it as completely.
Tom at 13:11, I have been looking at various words and definitions, and actually think that the word “weaponize” may be closer to your intention than any other word.
Problem - this word is a verb and I am having trouble finding any other single word that is a verb to fit your meaning. One might consider “lethalize” but that word implies mortality. Your phrase “increase virulence” may be the closest (or, “increases virulence”). Maybe someone else can suggest another possibility.
My concern was with the association - for instance, “weaponized anthrax” that has been in front of everyone’s eyes the last few years, implying intentional bioterrorism.
May I take this opportunity to again thank you for your invaluable input and experience into these disussions!
Beehiver.
At some point Monotreme et al are going to have a truly great scientific discussion on this thread…it is just going to take a while to get going because as you have said, this topic is complex.
I have said it before but the last thread represented for me a paradigm shift. The end result for me was that H5N1 had progressed in its adaption to humans a lot farther than I would have previously suspected (greater than 80% adapted).
Maybe we should not think of humans as the end-host but as a key central component in H5N1’s ultimate goal to fully adapt to bird populations.
I think we are now set up to answer he rest of the remaining questions and problems. This end result may not only be of scienific interest at the moment…but who knows in the future.
You have made a contribution to this and I hope you help us as we sort these final questions out…Thanks.
There have been a lot of ‘red herrings’ thrown in the way over the last 4 months and the end result has been a clouding of the issue…while pure science’s goal is to clarify issues.
The most recent of these is that there must be a genetic component producing these clusters. In most cases including the last cluster in Indonesia, I don’t think genetics is playing a role at all, and I would ask our research team to for the moment ignore the genetics argument and come up with alternative scientific explanations for clusters which as Monotreme pointed out indicate that human to human spread is more efficient to bird to human spread.
The second key question then is if the transmission within the cluster is inefficient then why is transmission outside the cluster for the moment at least inefficient.
To answer this question is to unlock the virulence of H5N1 and tell us how long we have until a pandemic…because a virus that is endemic and entrenched asymptomatically in birds and a wide variety of mammals is not going to ever disappear.
Sorry, that should have read ‘The second key question then is if the transmission within the cluster is efficient…’
Another factor that has clouded the issue has been the analytic tools used (testing procedures).
First there is the epidemiologists…we had someone going around Vietnam with a questionare asking people if they felt sick…on the basis of the peer-reviewed results, it was concluded that there were widespread asymptomatic infections. This would have been good news in a sense because it would mean that the potential pandemic mortality rate would be much lower. As it stands now, we could concievably have a pandemic at 30–50% mortallity rates.
Second is the issue of nasal swabs. There is a background level of wild strains in migratory birds. Britain and China reported results of swabs with great fanfare that they had no avian influenza in wild bird populations (a little humorous for China to come to this conclusion). The problem was that it is an impossibility to get such low test results indicating that there was a problem with test procedure. This test procedure has such a high error rate as to make it’s usefulness questionable…
…Now in Indonesia we have had it stated that the disease is not in pigs despite positive serology (comment on serology in a minute). My point would be has anyone ever tried to tie a pig up in someone’s backyard and shove a probe up their rather long noses…NOT GOING TO HAPPEN. One bite from a pig can mean certain death in humans so I would expect that the technician would try to make it look good and then walk away…another example of the limitation of this test method.
A third test method is a single blood sample for serology. It has been stated that this is proof of infection but that is not necessarily the case. It proves that the pathogen contacted the animals immune system in a way that produced a response at some time. This pathogen could be totally not adaptable or capable of producing any infection in the animal and that is why it did not produce clinical disease…
…Again, this test method has fewer limitation then those mentioned above but would seriously affect the accuracy of conclusions based solely on them.
Test method # 4 is the only true measure for infections….that is paired serology taken two to three weeks apart. Lets say you have positive serology for birds and pigs. The bird titres do not change between the acute and convalescent sample but the pig’s test results do by several multiplication factors…then you would know that the avian results were a ‘red herring’ and the pigs were the source of the infection…
…the limitation on this test is in the accuracy of the antigen used in the test reagent…we would assume that this would be known beforehand.
As before, this is not rocket science. Every WHO or other scientist who is reporting results knows of these inaccuracies and if they don’t appropriately qualify their remarks…?
So next time you here conflicting test results from Indonesia you will know exactly why they are occuring.
Maybe we should not think of humans as the end-host but as a key central component in H5N1′s ultimate goal to fully adapt to bird populations.Tom DVM – at 14:15
I just read this thread and picked out a bit that got my mind working. Very interesting and challenging thread!
“When you look at the relationship between bugs and humans, the more important thing to look at is the bug,” says NIAID medical epidemiologist David Morens. “When an enterovirus like polio goes through the human gastrointestinal tract in three days, its genome mutates about two percent. That level of mutation—two percent of the genome—has taken the human species eight million years to accomplish. So who’s going to adapt to whom?” Pitted against such nimble competition, the human capacity to evolve “may be dismissed as almost totally inconsequential,” adds Joshua Lederberg, professor emeritus at Rockefeller University, whose discoveries about genetic recombination in bacteria earned him the Nobel Prize in 1958.
http://darwin.nap.edu/books/0309076382/html/8.html
This is a quote from the book that NJ Preppie pointeed us to. “Secret agents…
Tom DVM, this thread and its predecessor evolved out of desire to explain how H5N1 could be apparently adapting to a human host and how it could spread more easily from human-to-human than bird-to-human. My basic hypothesis here is that it has been adapting to mammals for some time now, we just didn’t pay attention. If we had been testing pigs, cats and other mammals for H5N1 and published the sequences, we would have seen the intermediate adaptations. But we were so focused on the bird-to-human dogma that we missed something very ominous that was occuring right under our nose. There were a few who tried to warn the world of the significance of the mammalian infections (a researcher at China’s Harbin Vet Res Institute in 2004, a researcher in Indonesia in 2005, and Dr. Jeremijenko in 2006). Sadly, no-one listened.
I agree with your assessment that H5N1 is much closer to a pandemic strain than is advertised.
References Avian influenza: H5N1 detected in pigs in China Indonesian pigs have avian flu virus Indonesia and questions about its virus
Monotreme-
I agree wholeheartedly that we, mankind, are truly in the pathogen development business.
Everytime we us a gene promotor (in any organism), we are making the gene pool more fluid. With an already promiscuous virus like Influenza, the potential is astounding.
I’ve mentioned the CaMV 35S promotor in previous posts as a firm example of how we are commonly causing inadvertent and unplanned gene sequences to appear in unrelated species. When 70+% of the corn grown in the US is genetically modified, we are setting the stage for some odd recombinations in the habitats bordering the fields.
The SV40 retrovirus found in the African Green Monkey kidney cell lines used for polio vaccine manufacture for many years is also implicated in our current cancer epidemic.
All this hope that the community has for the cell-based vaccine development should be tempered by the fact that we will not in the near future create methods to purify the end product and remove the DNA. The potential cancers and other retroviral activity are topics of high concern on my list.
I personally don’t enjoy the idea of some retroviral sequence from a vaccine crawling into my chromosomes?
At the WA Flu Summit on 4/14, I asked the Fed appointee from US AG, who was talking about their plans for the Alaska surveillance, what else they were going to sample besides birds? He said nothing but birds, and when I mentioned that German cat and the ferret that died around that week (causing a quite a stir), he just shrugged and said …”we’re only sampling birds.”
Missed opportunities.
Dr. C-
Though you report unfortunate news, at the very least, we’ve found one official who is willing to tell the full truth.
NS1 - this goes back to Laurie Garrett’s book “The new plague” (I forget the title). The concept is “emerging diseases” and how what we do increases the chances of them appearing. Those causes should be tackled as “primary prevention” but of course no-one believes we have time for that. But we’ll have to keep them in mind if we want to build Civilization 2.0, right?
Hi everyone.
I agree with most of what’s been said.
I think the excessive efforts to convince us of a link to poultry in all cases represented the least line of resistance…to do otherwise would require additional efforts may experience has been that this is not the way, internally, regulatory agencies work although you would never know it by their public posturing.
After reading Monotremes’s links it appears that we have had some attempts at suppression and not supporting investigations into pigs and H5N1 since at least 2004…
…and there appears to have been concerns about other mammals and H5N1, as far back as 1997, in the book listed by Clark and NJ Preppie.
When the direct poultry contacts could not maintain the status quo, as often happens when nature doesn’t agree with the spin, then feathers and faeces as vector were brought into the mix…and once again, the lack of supporting serological data and other data to indicate that workers who work in environments with aerosolized particles from feathers and faeces would seem to destroy this latest version of events as well.
I bring this up to discuss the role of genetic predisposition in relation to clusters (the textbook…Clark and NJPreppie…links to clusters in Hong Kong in 1997 as well…this is not new).
Once again genetic predisposition represents the least line of resistance. I do not think genetics is playing a role because genetic predispositions are never this consistent. Genetics overall is never this consistent…and therefore I do not believe genetics is playing any role at all.
If genetics does not provide the answer to clustering then what other factors would?.
We have three potential routes of infection 1) intra-occular 2) oral and 3) respiratory.
It is interesting to note that washing ones hands frequently is listed as the primary way to avoid influenza infections. What this says to me is that the respiratory route is not the primary mode of infection. Intra-occular infections can occur through children rubbing their eyes but for the purposes of this post, I am most interested in the oral route which tends to mimic that in animals.
We have read discussions about the oral route being unlikely due to stomach acid etc. but I believe that conclusion may be a result of tunnel vision. In most cases the virus enters the oral cavity where it has the opportunity to take three routes …to the lung…to the stomach…or directly absorbed in the mouth or throat. I think this localized absorption of the virus is the primary route of infection after respiratory aerosols. When discussing the gastro-intestinal routes we should never forget that the oral cavity as a primary route of infection.
A number of infected vectors have been mentioned…respiratory aerosols, feathers, faeces, bodily fluids from infected humans, virus in water etc.
It seems that bodily fluids were not considered as a primary source of infection which surprises me a little bit. I have always considered that this would probably be a main source of infection within family members. In the case of H5N1, it seems that respiratory vectors have always outweighed oral ones which may be too simplistic for nature.
So if genetics is not the reason for the clusters then what is…and why has the infection not to this point been identified outside the initial cluster (I said not identified because it will have to have jumped outside the clusters…it just hasn’t been identified yet).
I don’t think this can be explained by faeces or feathers or contaminated food because if that was the case then all clinical cases would occur at approx the same time (continually stretching out incubation periods to fit with flawed hypotheses - 17 day incubation periods for H5N1- don’t make common sense and never work in the end).
Therefore, the index case is infecting other family members but not a large number of members in the community. This could be explained by oral spread through respiratory aerosols or bodily fluids entering through intr-occular or oral routes.
Dr. C, your anecdote supports my point nicely. The bird-to-human dogma is so entrenched that otherwise reasonable people completely ignore the possibility of mammals as a vector to the extent that they refuse to even test them.
lugon, maybe we should start another Wiki called Civilization 2.0 Wiki. Pair it with a “Civilization Re-Building for Dummies” book. I am only half-joking.
Tom DVM, I agree with everthing you said at 14:25.
Sorry, the first paragraph should have read…
…to do otherwise would require additional effort…my experience has been that this is not the way, internally, that regulatory agencies work, although you would never know it by their public posturing.
Monotreme. Thanks.
I am convinced that we are going to answer all of the remaining questions about H5N1 in this thread.
As I said before, the issues you raised on the previous thread were a two by four to the side of my head…really!!!
Let us assume that this hypothesized oral spread beccomes more efficient, and that it results in stage 4 clusters, (more than 25). But it stops short of a true pandemic. Could there be a sliver lining to this development? Might it not concetrate the minds of organizations and indiviudals as to the necessity of preparedness? And so I assuming here that if H5N1 evolves by this route that the time between Stage 4 and Stage 6 would be considerably lengthened.
But that also the final Stage 6 may result from a totally different H5N1 variant, say from Africa (or even North America eventually). And that this variant could be mainly respiratory in its spread.
And I offbase here?
I made this comment on the Indonesia cluster thread.
One thing that has gone un-noticed (regarding recent events in Indonesia) is the silence coming form the experts. We haven’t heard a comment from Dr’s. Osterhaus, Osterholm, Webster, Nabarro, etc. etc….the ‘silence is deafening’.
It seems that things are happening in waves at the moment, similar in my mind to the lead up to a war. However, I don’t think this event would indicate the beginning of a pandemic. I think it will be more likely that a large number of persons will be diagnosed with another circulating disease (ex. dengue fever) and by the time they realize it is behaving clinically in an atypical manner, it will already be in several countries.
What I mean to say is when it occurs we will not be following the progression of suspected bird flu cases, but rather cases clinically suspected of another disease…and the numbers will be in the hundred’s of cases rather than ten’s.
Medical Maven…thoughtful comments as always. I think we have to keep in mind, as you have pointed out, that all of these recent changes to other mammals, migratory birds, and clusters represent the slow steady adaption process of H5N1…we know it’s origin and its intermediate stages but we do not as yet know what its end game is…is its goal to acclimatize only to birds, mammmals and humans as well as birds…or to mammals onlly and not birds.
We know what we have at this intermediate adaptive stage…mortality rates greater than 50 %, lack of asymptomatic infections in humans, and restricted and limited transmissibility…
…this may bear little resemblance to the final pandemic strain.
Although oral spread would explain the existing clusters, if H5N1 is going pandemic, its transmissibility coefficient will have to be in aeorosols or respiratory as well as oral and intra-occular spread…I think this is key…without respiratory we will never have a pandemic.
The scary thing in my mind, is that we don’t need to know all the factors…this movie we have seen before…in 1918…H5N1’s behavior is virtually identical.
Tom DVM: You hit a home run with that answer! Excellent summation.
Thanks MM.
NSI at 6:06, Monotrome at 8:56 and NJ Preppie at 9:26, please accept my delayed but heartfelt thanks for taking the time to answer my queries. It is very helpful in understanding more of what you are saying. I appreciate the dialogue here and find it helpful in getting a better understanding of this current situation with H5N1. Now I can return to observing with a clearer understanding.
I am not a geneticist and so do not know the mechanics involved. However, I do know something about statistics and there are facts that are simply being ignored or shunted to the side as in some way irrelevant. First, if genetics is not involved then it could be expected that in 50% of the cases the virus would cross blood lines. That is 50% of the time the mother and father should be infected. To put it another way, biologically unrelated people should be infected in a cluster about 50% of the time.
By my calculations (including the recent Indosnesian case) in 27 of 28 clusters the virus manifested in only one side of a family blood line. That is in 27/28 or 96% of the clusters only one side of the family appears to be infected. That is the .04 level of significance in any science and merits publication as a potentially significant finding. It certainly merits discussion not dismissal.
In the most recent cluster, after infecting something like eight people the virus crossed the blood line and appears to have infected the father. So in 8/9 cases (88%) in this cluster the virus manifested in one side of the family.
This may not be genetics but there is sure as hell is some sort of differential biological susceptibility. Why do you all put it down and speculate in areas where there is far, far less “evidence”???
I have no idea what this differential susceptibility could be but some of you with more biological training should not be ignoring this clear finding.
Could it have something to do with certain household dependent tasks? If we assume that the primary infection is either B2H or M2H via a household task, then that task could explain this “anomoly” or genetic difference. If such a task is normally only performed inside a family group, and usually by one of the main providers (husband or wife), it gets even clearer. Then you have a primary infection and a number of secondary infections caused by the primary, but only withing a family type group. What type of task this could be is things like preparing and cooking meals, cleaning clothes, cleaning the household, sanitary cleaning, etc.
and once it becomes oral, who are the primary caregivers in the family? and as one falls another steps in and so on
Question that has been on my mind? This virus has been found in the blood of victims, can it be spread thru contact of needles, cuts, open wounds?
JoeW, I don’t discount that there are genetic factors that can influence susceptibility to infectious disease or that mothers and their children are usually the ones who are infected. But there is more than one way to explain this pattern. It could be that the children are initially infected by an animal and that caregivers, a mother or sister, get infected while taking care of the first victim. If the pattern we see were due strictly to genetics it would have to be a single-gene, dominant trait. Possible, but it would be surprising.
Monotreme at 17.32 and Joe
I think that Monotreme may have a partial explanation on the statistics considering the traditional caregiver role of the females. Let’s watch for the sequence of infection in future clusters. If the father is infected first, will the same ordering occur as if the mother was first infected. If so, then perhaps no genetic link exists. If the father is infected last, then the test is inconclusive.
Thank you addressing the issue. I too have wondered how often it is the child mother pair that initializes a cluster and it seems “often,” thus supporting Monotreme’s comment. I agree with NS1, there is a need to more carefully review the data to determine who is infected by whom.
The issue of behavior, based on caregiver, is also suggestive and has several implications. In this case, close contact is involved and I wonder at the closeness of the contact in so many cases. Perhaps it is the universal nature of mother - child relationships.
Whether this will hold true when the virus is aerosolized is perhaps another matter. However, what if it is something about others behaviors such as food consumed, shared water facilities, use of similar objects. What if similar consumption of some types of food leave the person more vulnerable? The list is lengthy but there could be many issues that are not being considered.
In many (?) of the cases it seems to me that it goes from child – mother – brother, cousins or sister –sister, cousin, brother, then neighbor (Azerbaijan). When you begin to think in terms of extended members of a cluster there are times when the assumed nature of intimate contact apparently breaks down. Although I suspect that this is often not the case and it is apparently more likely that there is some form of intimate contact involved. Intimate contact alone may not explain the contagion.
None-the-less, it could also be expected that intimate caregiver contact is practiced with other members of the family and these people do not get the virus. Again more data about the relationships, the composition of the family group and available contacts are needed.
My primary concern here is that this virus may currently need and or use some vehicle for transmission that could be determined. If it was known what the vehicle is there are obvious implications for avoiding the virus. Later, when it aerosolizes the same mechanism may be an alternate route for contagiousness.
Whatever the mechanism of transmission the sheer number of people in one blood line seems to imply something worthy of further study.
For instance consider the idea that a mother who is giving intimate care to the index case (a child) becomes infected. During the initial phase, she probably kisses and otherwise engages in intimate care with other members of the family who do not become infected. I think that we need to look into the nature of those who do not become infected as well as those who are infected. Perhaps some people already have some form of immunity based on other behaviors (past type of cold), food, exercise, age etc, etc, etc. It would be good to know what these characteristics could be.
JoeW-
I still think we are seeing proximity = opportunity for spread with perhaps some mild tranmissibility modifier.
I agree that if their is a modifier (genetics, roles, et al) that it should be considered and studied, but I think that the modifier will not be found to be a significant contributor.
I say all of this with the same small amount of info that we all have and with no eyes-on-the-problem, boots-on-the-ground intelligence, so its purely conjecture without data.
We wait and watch.
I suspect that you are right NS1 but (there is always a but)we will all be watching and looking for any other opportunities the virus may be exploiting. Hopefully, others who direct those in the field also read here on occassion and perhaps their consciousness will be raised (another of those terms - - I wonder if anyone has ever felt their consciousness rise?). :-)
I have decided, given the current statistics, that for the forseeable future, I will not be a mother.
LOL
Joe-
Aren’t you a little too ancient to be a mother anyway?
Well, yeah I am a little old for gener changing. I won’t take that estrogen either.
Good show, Joe!
Let’s keep chasing this thing until we catch it!
I have been following the discussion in this thread and its predecessor, though I haven’t had time to respond. I really don’t have time now, but I just gotta jump in here somewhere.
I don’t think it is at all reasonable to make statements to the effect that “genetics plays no role” in clusters. Genetics plays a role in pretty much everything biological. It may turn out that inherited susceptibility is not the best explanation for clusters, but at this point, I see no basis for much confidence in that conclusion. We certainly don’t know everything there is to know about susceptibility.
It is always a mistake to look at a virus as an independent entity; viral infection is not the result of the action of the virus alone, but of the complex interaction between virus and host. Say (as a thought experiment) that you took a quantity of a specific isolate of virus and determined, by exposing the host to the virus, that that initial host was not susceptible to that virus. Given enough time, you could periodically innoculate successive offspring of that host with the same isolate. It is entirely possible that eventually, one of the subjects would develop infection due to genetic changes in the host, rather than the virus. As clark pointed out, human evolution is essentially nonexistent, temporally, by comparison with viral evolution — but humans have been evolving for enough time that it is easily possible that there presently is enough pre-existing variation in the human genome to account for differing degrees of susceptibility to a particular virus.
So, for now, I continue to favor the genetic susceptibility explanation for clusters. Maybe I’m just in denial.
JoeW,
The following is pure speculation. (that’s for you DemFromCT and Melanie :-)
One of the symptoms of H5N1, unlike other influenzas, is diarrhea. Imagine a frantic mom taking care of a very sick kid with very bad diarrhea. How often is she going to wash her hands in that situation? Especially in a rural area in 3rd world country. Fecal-oral spread in this circumstance is not hard to imagine. I hypothesize that small clusters that were observed until recently spread child-to-mother and sibling-to-sibling while the care-giver was cleaning up the first victim. By the time the caregiver gets sick, people realize that it’s something contagious and they are taken to a hospital where sanitary standards are higher.
One reason I keep coming back to the Turkey cluster(s) is that I think that there was something different there. Perhaps the virus became more easily transmitted fecal-oral for some reason. This pattern was seen again in Azerbaijan and now in Indonesia. Norovirus can be transmitted fecal-orally quite efficiently. As others have pointed out, there are large outbreaks of this virus on cruise ships, in daycares and in schools. The difference is that Norovirus doesn’t kill you, usually.
Racter, Joe, Monotreme and Tom-
Let’s also consider the more real possibility that we may be looking at this variability to infect due to the expression of certain genetic sequences that may typically go unexpressed.
2 billion base pairs and we only have very small correlative clues about 40,000 of them.
Even within a single family with almost exact homology, different nutrition, environmental, even stress standards may cause varying expression of significant sequences.
Monotreme-
Are you considering recombination between H5N1 and norovirus due to worldwide coverage of the two and emergent properties that have become similar?
Racter,
I would never argue that there is no role for genetics in explaining susceptibility to any infectious disease. However, I don’t think this can explain the clusters. Here’s why. In many clusters, a mother and one or more children are infected. What does that mean if genetics is the explanation? It would imply that susceptibility to infection of H5N1 is a dominant Mendelian trait. This would imply only one gene is involved. I’m not an expert on infectious diseases, but I think most of the work in this area is focused on multiple genes which each contribute a small amount to susceptibility. This is true of most genetic traits, btw. Mendelian traits are the exception not the rule. Also, the animal studies suggest do not give any hint of a single gene being involved in susceptibility to infection.
NS1, no I’m just using Norovirus as an example of a virus that spreads fecal-oral and causes large outbreaks. H5N1 has plenty of flu partners to have sex with.
Monotreme at 20:52
I figured that you were just looking at the ORF route, but wanted to think more about it if you were going in the other direction.
Monotreme – at 20:49
I think you’re right. Typically, we are looking at a multi-factorial basis in the gene bases for susceptability . . . primaries combined with modifiers.
Racter-
What’s keeping you so busy? We miss your keen contributions.
Monotreme: “In many clusters, a mother and one or more children are infected. What does that mean if genetics is the explanation? It would imply that susceptibility to infection of H5N1 is a dominant Mendelian trait.”
I don’t see why it has to mean that. It could be that in some genetic group — in which it is common for individuals to possess N-1 out of N genes which (in addition to whatever other, presumably more beneficial functions they serve) taken as a whole produce a higher genetic susceptibility to H5N1 — some mother could pass on to her children the last gene required to complete the package.
As for what’s been keeping me busy, I wouldn’t know where to begin, but some of it involves being on the phone for a number of hours each day, as well as a lot of research into some areas not directly related to “bird flu” (I say “not directly” because I regard every aspect of living to be subject to being impacted by a pandemic, which is why I always visit here numerous times a day even if I don’t have time to contribute). I’ve actually found the distraction to have something of a cleansing effect; one can get too close to this bird flu thing.
Racter, I think I’m missing your point. Unless you assume that all of the susceptibility genes are tightly linked (in close physical proximity on the same chromosome), they are unlikely to be inherited en masse by more than 50% of a parents offspring. Also, I don’t understand N-1 genes. We all have the same number of genes, more or less. We differ in specific sequences of these genes. Am I missing something?
By N-1 genes, I was simply proposing that when considering the possibility that susceptibility is increased by possession of certain sets of genes, we let “N” represent the number of genes in a “set” (actually, I wasn’t proposing that, I was just implementing it without bothering to consult you first; sorry about the confusion). (And, calling them “alleles” might help to avoid the confusion about the total number; I’m not suggesting that some individuals carry extra genes or anything).
Especially in small, relatively isolated populations (such as those found, say, on an island), it would not be such a stretch to suppose that several siblings might inherit an incomplete “set” from both parents, as well as inheriting an additional gene (the one needed to complete the “set”), from only one of the parents.
Monotreme-
Racter may be indicating that within a sequence of 10 (N) nucleotides that sometimes 9 (N minus 1) may be distributed and other times all 10 may be distributed. When all 10 are present, the expected outcome occurs of susceptability?
Great. As if I hadn’t caused enough confusion already, now here comes a guy called “NS1″. If I had written it out: “N minus one”, probably would have been clearer.
Anyway.
Close, NS1. I’m referring not to individual nucleotides, but to nucleotide sequences (genes, or for better clarity, alleles). The possibility-space of factors that may affect susceptibility is enormous; it goes way beyond receptor binding; some obscure and thus far unconsidered aspect of cellular function could be critical — and such a function could be (in fact, almost certainly is) influenced by a large number of genes. A group of (say) ten genes might, when found together, result in a certain property at the level of phenotype which would be entirely absent if only nine of the genes (alleles) were present.
The moment we start talking about a “gene” for this or that (musical ability, susceptibility to H5N1 infection, whatever), we incur a risk of error by atempting to impose our ideas on a world that has no obligation to accept them. But if susceptibility to H5N1 is favored by certain combinations of alleles, one result is that we would expect to see certain patterns in the clusters, and those patterns are somewhat different from the patterns we would expect to see if the virus was being transmitted from one person to another. Though the sample size is still too small to support strong conclusions, I believe that the patterns so far indicate genetic susceptibility rather than H2H transmission. (And, for once, I don’t hope I’m wrong).
After musing about this possible oral-fecal or some type of fluid route, I started wondering about pH factors on the virus and/or its components and did some poking around at PubMed. Because it’s late I am going to just throw out these rather interesting abstracts and we can munch on them later as time permits. I am still trying to sort out the possible implications myself. By the way, the Japanese group seems to be quite far along on some aspects of the research. ____
J Biochem (Tokyo). 2001 Aug;130(2):279–83. Duck and human pandemic influenza A viruses retain sialidase activity under low pH conditions.
Takahashi T, Suzuki Y, Nishinaka D, Kawase N, Kobayashi Y, Hidari KI, Miyamoto D, Guo CT, Shortridge KF, Suzuki T. Department of Biochemistry, University of Shizuoka, School of Pharmaceutical Sciences, Shizuoka 422–8526, Japan.
The majority of influenza A viruses isolated from wild birds, but not humans, can replicate in the duck intestinal tract. Here we demonstrate that all duck isolates tested universally retain sialidase activities under low pH conditions independent of their neuraminidase (NA) subtypes. In contrast, the sialidase activities of most isolates from humans and pigs practically disappear below pH 4.5, with the exception of four human pandemic viruses isolated in 1957 and 1968. Sequence comparisons among duck, human, and swine N2 NA subtypes indicate that amino acids at positions 153, 253, 307, 329, 344, 347, 356, 368, 390, and 431 may be associated with the low pH stability of duck and human pandemic N2 NAs. This finding suggests that the low pH stability of duck influenza A virus NA may be a critical factor for replication in the intestinal tract through the digestive tract of ducks, and that the properties of NAs are important for understanding the epidemiology of the influenza virus. PMID: 11481046 __________________
Arch Virol. 1985;85(1–2):1–11. Stability of infectious influenza A viruses to treatment at low pH and heating.
Scholtissek C.
We have measured the infectivity of influenza A virus strains grown either in embryonated eggs or in chick embryo cells in culture after treatment at low pH. At pH values at which hemolysis occurs there was an irreversible loss of infectivity. The threshold pH, at which the infectivity was lost, depended on the hemagglutinin subtype of the virus strain. All H5 and H7 strains tested were extremely labile at low pH. In contrast, all H3 strains were relatively stable, independent of the species from which the viruses were isolated. With several H1 viruses the hemagglutination (HA) activity was irreversibly lost at intermediate pH values causing inactivation of infectivity. Strains with noncleaved hemagglutinins were much more stable. These observations might explain why duck influenza viruses can easily survive in lake water and wet faeces, and multiply in the intestinal tract, where trypsin is present. There are also significant differences in heat stability exhibited by influenza A strains. In contrast to pH stability this is not a specific trait of the hemagglutinin, since it can be influenced by reassortment. There is no correlation between the stability of infectivity at low pH and heat.
PMID: 4015405 __________________
Res Virol. 1989 Sep-Oct;140(5):395–404.
Comparison of biological and physical properties of human and animal A(H1N1) influenza viruses.
Fiszon B, Hannoun C, Garcia-Sastre A, Villar E, Cabezas JA.
Unite d’Ecologie Virale, Institut Pasteur, Paris.
The study of biological properties of influenza virus strains belonging to the same subtype A(H1N1) and closely antigenically related, but isolated from different animal species (man, pig and duck), demonstrated that avian strains were more resistant than those isolated from mammals to high temperature and low pH, as shown by titration of residual infectivity in cell cultures (MDCK) and by sialidase assay. The difference in behaviour could be correlated to biological adaptation of the virus to its host. Avian body temperature is 40 degrees C and influenza virus, in ducks, is enterotropic and therefore capable of passing through the low pH values in the upper digestive tract of the animal. These results do not contradict the hypothesis of a possible filiation between avian and mammalian orthomyxoviruses.
PMID: 2587848 ____________________
FEBS Lett. 2004 Jan 16;557(1–3):228–32. Evolutional analysis of human influenza A virus N2 neuraminidase genes based on the transition of the low-pH stability of sialidase activity.
Suzuki T, Takahashi T, Saito T, Guo CT, Hidari KI, Miyamoto D, Suzuki Y. Department of Biochemistry, University of Shizuoka, School of Pharmaceutical Sciences, CREST, JST, and COE Program in the 21st century, Shizuoka 422–8526, Japan. suzukit@u-shizuoka-ken.ac.jp
The 1957 and 1968 human pandemic influenza A virus strains as well as duck viruses possess sialidase activity under low-pH conditions, but human H3N2 strains isolated after 1968 do not possess such activity. We investigated the transition of avian (duck)-like low-pH stability of sialidase activities with the evolution of N2 neuraminidase (NA) genes in human influenza A virus strains. We found that the NA genes of H3N2 viruses isolated from 1971 to 1982 had evolved from the side branches of NA genes of H2N2 epidemic strains isolated in 1968 that were characterized by the low-pH-unstable sialidase activities, though the NA genes of the 1968 pandemic strains preserved the low-pH-stable sialidase. These findings suggest that the prototype of the H3N2 epidemic influenza strains isolated after 1968 probably acquired the NA gene from the H2N2 low-pH-unstable sialidase strain by second genetic reassortment in humans. PMID: 14741372
Racter, I think your hypothesis is theoretically possible, but statistically very unikely. But it would take more statistics than I have to demonstrate this. So, we will just have to agree to disagree on this one.
Monotreme, you’re the cluster specialist around here, so check me on this. I don’t think it will require much stats. What I see most often in the cluster information which you have so diligently maintained are instances in which siblings are infected. Sometimes a parent is infected as well, but hardly ever both parents.
To the extent that we have enough information to identify patterns, SiblingsAndMaybeOneParent is the pattern that seens to be emerging — though it would be more compelling if there were documented instances of siblings who did not live together fell ill while others around them all remained unaffected. I cannot dismiss the possibility that horizontal transmission is the cause, but that would be more compelling if there were more documented instances of non-relatives who did live together (or care providers, etc) becoming infected.
Maybe some of the fathers just thought they were the fathers. That probably happens a lot more often than a lot of people think.
Beehiver. When you consider pH in relation to oral-faecal spread of influenza, remember that for many diseases the disease gains entry in the oral cavity before reaching acids in the stomach. I believe that hands to eyes - intraocular and hands to mouth - oral infection or naso-pharyngeal spread.
Racter JoeW. It seems obvious that genetics would play a role in the spread within clusters but my experience with genetics indicates that when it seems this obvious…it never is. Genetics is rarely as simple as one dominant gene…most diseases as you may no have multiple gene components…and I think you would agree that there are too many people infected for it to be as a result of a multiple alleles.
Proximity could just as easily be the main factor in disease spread among family members. The important question to be considered now is …where is the disconnect between family members and community contacts and how can this be explained by an infectious model.
The goal in answering this question is…does this represent a improved adaption of H5N1…what will it take for community spread and therefore how far are we realistically from a pandemic.
Racter, I don’t dispute the members of the clusters. It just the pattern of inheritance that bothers me. The pattern of infected people implies a single-gene effect. Doesn’t matter who the fathers are.
Are there human specific insects that tend to stay put in the same household rather than moving out into the community with the host (e.g. scabies) to school, to market etc. I mention human specific because they wouldn’t seem to travel about with rats for instance or else H5N1 should appear outide the infected household. I’m wondering about bedding and such.
Reviewing Monotreme’s clusters I find the following relationships:
27 cluster were reviewed: Parent child relationship n=11
(mother / child relationship n=5)
Sibling to sibling n=15 Uncle or Aunt to or from a nephew or niece n = 4
Some cases had to be listed in more than one place because of the number of people and complex relationships in the cluster. These numbers are not definitive and might come out slightly different with a more careful review.
Mother child relationships account for 5/27 clusters (19%) Parent child relationships account for 11/27 (41%)
If it is assumed that aunts and uncle were the caretakers the caretaker variable accounts for 15/27 (56%) of the contagion.
The problem here is with the sheer number of brother sister relationships 15/27 (56%). Now we would have to assume that parents, aunts or uncles were not present and or if present were not caretakers.
Proximity is certainly a variable but “caretaker” role is not supported as a driving force in these infections. Note too that if we assume one or more caretakers the “other” people in the household were not infected by the index case or by the caretaker. Of course we do not know how many other people may have been in the home.
Given the overwhelming “one side of the family” finding discussed previously I suggest that it may be some variable the leads some people to be more susceptible. Some thing like green eyes (to be facetious). In families where the virus is found one side of the family apparently has some sort of predisposition to be infected. Whatever the predisposition is, it must be some thing that is uncommon. One - - there are not many clusters, and two, the other side of the family doesn’t have it.
With the current later infection of the father in the most recent Indosnesian cluster I believe there are are only 2 clusters in which both mother and father were infected. Thus, it would appear that in 26/28 clusters (93%) of the clusters only one side of the family is infected based on the limited availability of family relationships information which are tenuous.
Another way of viewing the number of sibling to sibling infections that excludes the caretaking parent’s infection is that the caretaker was not susceptible in about 50% of the cases. This too sugests some sort of personal susceptability in compliance with the “one side of the family” variable.
JoeW, several things to consider
Here’s a website you might find interesting.
Monotreme et al. I was wondering a couple of things about these clusters. Maybe Joe W can tell us how many individual cases we see per incident of a cluster.
First of all, Has H5N1 specifically mutated in the cluster cases and not in the individual cases (I realize this is a broad generalization). If this was the case, then the mutation would be an intermediate stage increasing transmissibility without going pandemic.
This could be explained by a specific mutation that favoured either intra-occular or oral infectivity without respiratory effects. This would explain the limited infectivity to family who would have close personal contact to the patient.
The fact that both parents do not seem to get the infection at the same time could be explained by the fact that adults are less susceptible to infection and would be far less likely for both to get it.
The only mutation that would allow a true pandemic, in my opinion, would be one to increase the risk of infection through respiratory means. It hasn’t happened yet…it could happen anytime…when it does we have instant pandemic conditions.
I’m suggesting that we may be seeing single-gene effects acting upon multiple-gene effects. Does that make sense?
Wdon’t know everything about susceptibility, but one thing that is pretty much a slam dunk is that it is a result of multiple alleles. I mean, never mind obscure cellular mechanisms, the shape and size of an airway, a nostril, a finger — all of these surely have at least some affect on the likelihood of a virus finding its way into a host and successfully conducting its business.
All humans are closely related genetically; it has been said that there are populations of chimpanzees with more genetic variation than exists in the entire global population of humans — but we aren’t identical at the level of the genome, or the cell, any more than we are identical in other ways. Not all of us have a normal temperature of 98.6, we can’t all digest dairy products, we don’t all like country music, etc. Even in a pandemic form, no flu virus would be expected to infect every single person exposed to it, just as not every person who contracts the illness would be expected to die from it. If the seemingly obvious conclusion regarding genetics often turns out to be wrong, it is often because we hope things will be neat and tidy, whereas in reality, biology is as sloppy as it gets. Looking for a gene that determines susceptibility may not be quite as absurd as looking for a gene that determines whether a person likes country music, but it’s not likely to be nearly as crisp as we would like.
If we assume that susceptibility is a continuum, with the most susceptible individuals on one end of the scale and the least susceptible on the other, and if we further assume that these differences are due at least in part to genetically determined factors, we would expect to see a discontinuous distribution of this variablity. Some populations would be more susceptible as a whole, and others less so. The attack rate, the R-nought (in a pandemic strain), and the CFR would all be higher in some populations than in others. It may be that some populations (or genetic groups) are more likely to become infected with the virus in its current form(s), but still not likely enough that many are becoming infected. It may be that there is a single allele which, when added to such pre-existing susceptibility, is enough to move almost able to catch the virus across the line to able to catch the virus. It might appear to us that such a single allele determines “susceptibility”, where in reality, it is actually a multiple-allele combination which does so.
From our perspective as lovers of discrete categories, susceptibility might appear to be an all-or-nothing affair, but (as is the case with so many other things) the best understanding may be gained by approaching it from a probabilistic perspective.
I suppose we need to start collecting and analyzing the sequences of the patients as well as the offending influenza?
Who’s game to ask the WHO for that info?
Here is another way to look at Monotreme’s clusters. I counted all cases where there was a possible caretaker (adult sibling or other relative) as one group n=19. The second group consists of clusters composed of underage children and or siblings who died n=15. Arranged in this way there are 34 cases and in 15/34 (44%) of the cases a caregiver was present (or should have been) and the caregiver was not listed as being among the infected people. It can be concluded, can it not, that less than half the time when a caregiver is (or should be) present that person is not infected.
JoeW,
Care to extrapolate from the statistics about what this means for R-0 right now?
Monotreme: thanks for the URL. That much about genetics I follow quite well. What is inherited is another matter.
I am by no means attached to the idea that it is genetics per se that need to be identified. For instance we “know” that a predisposition to schizophrenia, alocoholism, and behavior disorders in general are inherited. However, whether these diagnostic entities are expressed depends upon the interaction between person and environment. One can inherit a predisposition and never express the trait.
For instance, if we can identify a tendency towards schizophrenia early on and we can adjust the stressors in a person’s life they may never have a psychotic break. On the other hand if the trait is too predominent little can be done to offset a chronic schizophrenics course. In some rare cases even drugs do not help. I tend to agree with a dimensional consideration rater than all or none.
I have in the back of my mind that some people may have a predispostion to susceptability and that some environmental trigger may enhance this prior disposition. I suspect that the traces of this susceptability must be fairly rare given the low frequency. However, the environmental triggers may be important as they may be triggers that can enhance any individual’s susceptability.
I think the real “find” might be in what triggers could increase anyone’s susceptability.
I fully realizze that as a behaviorist I am not very knowleable about the biology and tend to listen when the biologically trained are talking.
JoeW,
I’m hoping that you don’t have a model to study all too soon.
BTW, I am not looking for any alternative medicine solutions. From my experience most of them are placebos. I suspect that perhaps something in exercise, diet, breathing patterns, psychological stress or any of a host of variables may be at work. It sure seems that something is triggering something else and that there is some sort of differential susceptability. I have no idea what it might be.
Racter JoeW. I agree with the genetic predisposition to infection with H5N1…and I believe that the reason for the effect is increased metabolism leading to increased normal body temperature.
However, although this could explain one person being infected, it cannot explain a whole family with a genetic predisposition. It cannot be a single gene effect, nature doesn’t work that way. A multiple gene effect could not infect families in the way that appears to be happening…but I will acknowledge that we have not had complete information since I became seriously involved 2.5 years ago.
Genetic predispositions with multiple alleles would result, in my opinion, with much lower numbers of family members infected.
You also must allow for age differences affecting those infected as well.
For what it’s worth…we have to come up with another explanation that fits and explains the infectivity pattern.
Melanie from what I read, like most others here, it is certainly increasing and it doesn’t look good does it.
Tom: I was impressed by the idea that the children in Turkey were laughing and playing with chicken heads and that the young girls in Azerbaijan were probably on an enjoyable excursion collecting feathers. It seems there also were some similar indications of increased levels of exercise and perhaps deeper levels of respiration. However, those thoughts were discounted by the biologically trained. None-the-less, I wonder ???
Something just popped into my head…what about super-shedders (index cases) as a contributing factor.
JoeW. It is only my opinion, but I think we have to forget all the bird contact stories…I mean listen to the latest…some kid makes birds for badminton…
…the problem with these stories is…why are the poultry and slaughter house and workers who collect these feathers not getting sick in large numbers or at least showing serology (even though I am not a believer that any conclusions can be reached from one blood sample).
The fact is the results aren’t there to back up any claim that birds are involved…at all.
That doesn’t mean birds aren’t involved and there is another explanation.
This is my life…welcome to ‘seat of your pants’ medicine!!!
By the way Joe, you and Racter are making an important contribution through your questioning and I hope you don’t stop until we get the answers we are searching for.
Thanks to all for continuing and contributing to this discussion.
Super shedders would explain the family clusters but would not explain why the super shedder would not also spread the infection into other close contacts outside the family unit and healthcare workers.
It seems the best explanation is body fluids. In that case community contacts would not be expected to contact body fluids…and healthcare workers are trained to avoid them…
…Secondly, more virus might be shed in early stages, before these patients enter hospital resulting in a decreased chance of affecting healthcare workers.
Could it be that at some point the index case becomes more infectious given the course of the infection. Perhaps at some point the index case develops into a “super shedder” and not before. From a behavioral standpoint I could understand the caregiver leaving the room so to speak and others taking over.
As a general comment to the susceptibility comments, the idea of susceptibility alleles in human disorders is gaining further credence, and may explain some of the “genetic basis” for the recent familial chain of transmission seen in the clusters.
For example, epilepsy is a complex polygenic disorder and it appears that there are susceptibility alleles that make an individual more likely to suffer from that condition. The susceptibility alleles are simply mutations (polymorphisms) that exist in a number of genes in the general population at differing frequencies. Different combinations of these alleles change the threshold to susceptibility.
In any one family it would be expected that there would be different patterns of inheritance of these alleles. Nevertheless, you may still see an increased susceptibility in some families, due to the way the different mutations are inherited and function. For this reason you could expect to see some families with an increased risk of contracting bird flu without the genetics following what appears to be a strict Mendelian inheritance pattern. The upshot of all this of course that it may be a long time before we understand what makes some individuals susceptible to bird flu and others not so.
I agree with Prepper Australis, JoeW, Racter and TomDVM, that it is possible that there is a genetic susceptibility ot H5N1 infection. The issue is: how much of what we see is due to genetics and how much to environment? This is a common problem in understanding complex dieseases. Some people can smoke every day from the time they are 12 and never get lung cancer. OTOH, there are non-smokers who get lung cancer. Still, we know that on a popluation basis, smokers have an increased risk of cancer. Until we know what the genetic basis is of lung cancer susceptibility, it’s prudent not to smoke. It may be that some of us have built-in protection against H5N1. But I’m not going to bet my preps that I’m one of them.
The genetic’s story is just hand waving with no data. In fact the available data heavily discounts genetics. “No transmission to husband and wife” has been cited, but that statemnt is false. The Haiphong family of 5 was H5N1 confirmed and both husband and wife (and 3 daughters) were H5N1 positive. About the same time there was the transmission chain or brother to sister [http://www.recombinomics.com/News/04230501/H5N1_P2HCW.html| to nurse]]. The brother’s nurse was not related to the brother. Then there were the 147 Bengal tigers in the Thailand zoo. The infected chicken only infected one or two and then the transmission was tiger to tiger and they were not all related. About the same time there was an H5N1 positive dog with almost an identical H5N1, but the dog wasn’t related to the tigers or the people in Thailand who were H5N1 infected at about the same time.
A sufficient level of virulence and everyone and everything becomes infected. Some particular set of conditions leads to mass infection. Preceding that, as in the current clusters, only some people are infected and the infection dies out.
It seems quite obvious to me that these people did not die in a vacuum. There were several caregivers and many opportunities for infection preceding their deaths. None-the-less an epidemic did not start and so there must be something to the differential susceptibility hypothesis else the clusters would be much larger.
Currently it is reasonably well known that the virus has a preference (I use that word reservedly) for one side of the family in 26 of 28 clusters. If such numbers are referred to a Chi Square goodness of fit test the significance is extraordinary. There may be other explanations but none can be found that are in agreement with the finding. At this point I think that I have shown, from limited data, that caregiver can be discounted because in less than 50% of the cases the ostensible caregiver is infected.
Perhaps it is simply the proximity of patients or some other easily identified variable. At this point the high percentage of what appears to be one side of a family needs explaining. That is not hand waving - - that is scientific thinking at an early phase.
JoeW I came to the same conclusion that you state in your post at 00:58 when I should have been going to sleep last night…and I think you have hit on it…the virus is only partially adapted and the infectivity (shedding pattern) may also be different than standard influenza. Also with this model, super-shedders do cause the spread within these clusters and therefore there could be a significant difference between the index case and the index case in these clusters…I am with Dr. Niman…although it looks like there is a genetic predisposition involved, l think it is in fact an illusion, turning us away from other alternatives to explain the hypotheses.
Here’s a pattern to think about.
The index case was clinically ill two days before the barbeque…which means she should have been infective while she was in the community purchasing products for the barbeque…however, with H5N1 there is not a period of viral shedding in the incubation period and the inital stages of infection (as in seasonal influenza)…in this way it acts more like SARS.
This woman did become a super-shedder and the point of maximum viral shedding coincided with the barbeque. This would explain several things about the cases (if we forget genetic predisposition). The virus would always be shed by body fluids but this would not explain family members which would have no contact with vomit or faeces…we would assume this was not occuring at the barbeque. Therefore, the only explanation that works is 1) that respiratory spread is occuring and 2) she was a super-shedder and was shedding high amounts of virus during the barbeque. This would result in a much wider variety of family members infected and I would assume that if the broader community was at this barbeque, then a much bigger outbreak would occur (ex. if kissing every townsperson was part of the culture…religous rites…etc)
Healthcare workers and the wide community are not affected later because the virus has a narrow period, at this time, of being shed in respiratory forms and then shedding decreases by the time the patient is sick enough to enter hospital…if we assume only body fluid spread at this time and lower concentration in body fluids…this would explain the low cases in the community while high cases in family members.
Therefore, different infectious viral shedding patterns explains the behavior of the outbreaks and the clusters…the bottom line…this virus is very close to becoming a pandemic…imminent.
Sorry, I should have said that at this intermediate stage of adaption, H5N1 is acting like SARS did. If we can talk the virus into acting more like a coronavirus and less like an avian influenza virus then we have a chance of avoiding a pandemic…
…but H5N1 has been telling us for 16 months that it is not willing to listen and is driving the bus…we are only passengers.
Niman:
It is an attempt at interpreting sparce data. We’re all doing that.
Do you feel that the SiblingAndMaybeOneParent pattern is entirely refuted by these two counterexamples?
That the virus affects different species differently is trivially obvious: it causes nearly 100% mortality in some species of birds while others remain asymptomatic. This illustrates that the way the virus moves depends, as much anything, on the genetic landscape it’s moving over. I don’t know how much genetic variation there is in Bengal Tigers as a whole, but inbreeding is common in both wild and captive populations, and, according to this, Sri Racha is anything but the exception:
The tigers at Sri Racha came from a founder stock of two male and two female so-called “Bengal” tigers in 1987. In August 2002 there were over 350 tigers. Only four more tigers have been introduced to the original stock in that time.
The Thailand zoo example might as easily be cited in support of the genetic susceptibility hypothesis.
I think genetic susceptibility may play a role in some cases but it would only play a role in the inital index infection and not the secondary infections within family units. This is explained by proximity, supershedders and intermediate stage infectivity patterns of H5N1. As it continues to adapt this pattern will change or when a supershedder comes in close contact with community (cutural factors) we are going to get a cluster in the range of 50–100 persons.
The number of “examples” supporting genetics is VANISHINGLY small. Most H5N1 familial clusters involve only 2 or 3 family members and most index cases are children/teenagers. Thus, those with a child as an index case cannot have two parents infected because there is only one more member in the cluster. Clusters of 3 are also unlikely, because that would require infection of both parents and no siblings.
The “data” for genetic predispositions are just more “hopes and dreams”, with no real basis.
Once you’re done prepping, hopes and dreams are all you’ve got.
I’m thinking of Occum’s Razor (going for the simplest explanation) and thinking about behavior patterns. One of my kids has allergies and is constantly rubbing his eyes and nose. I think he is most susceptible to picking up a flu because of his hand/face interactions. One of my kids “gets” handwashing and does a good job — he also has allergies but is better about taking his antihistimine as well (less itchy eyes, less runny nose).
Families tend to share behavioral patterns (including other mammals). Some families will think nothing of sharing a wine glass and others never do. Same with eating utensils. (“Here, honey, try a bite of this”). It’s a thought.
Racter and JoeW. Please, put your skeptic’s hat on and take a run at my hypothesis. Thanks.
I assume, they did some tests with ferrets at St.Jude’s
Tom I can understand how there may be some critical stage for passing the virus on to another who is in close proximity and that it is more likely to be a blood relative who is present. This is a good possibility in the admittedly small data set. This suggests looking for some critical stage in the development of the disease.
I think Racter made a good point re the tigers, seems that he turned that argument on its head !
I do not understand Nieman’s comment “Most H5N1 familial clusters involve only 2 or 3 family members and most index cases are children/teenagers. Thus, those with a child as an index case cannot have two parents infected because there is only one more member in the cluster.”
The cluster is not limited by the size of the cluster it is limited by it ability to infect. If a child is infected there is no inherent reason why another child and both parents could not be infected. I must be missing something here.
I do agree that we are working with a very small number of cases and that the attempt is to tease out some possible relationship. However, as we all know it is the errors and or anomalies in the data set that often lead to insight. In this small data set the blood line consistency is too consistent. The recent cluster in Indonesia fits this bloodline hypothesis too well for it to be another coincidence. Many people apparently in the same bloodline are infected and then the father is found to have it. It took an inordinately long time for him to develop symptoms given the “usual” progression in prior clusters.
I guess that from my perspective I am used to working with small data sets and attempting to ferret out some possibility that can be fruitfully pursued. Not all of us have the luxury of working with large data sets.
anonymous, yes, a number of experiments have been done with ferrets.
The severity of clinical disease caused by H5N1 viruses isolated during the 2003 and 2004 outbreak was evaluated in four to six naïve ferrets inoculated i.n. with 107 EID50 of each virus. Two or three ferrets were monitored up to 14 days p.i. for clinical signs of disease, while two or three ferrets were euthanatized on day 3 p.i. to assess pathological and virologic parameters. All viruses caused fever, with the peak mean change in body temperature ranging from 1.2 to 2.9°C over baseline (range, 37.1 to 38.7°C). Four viruses isolated from humans, VN1203, VN1204, Thai16, and Kan353, caused severe lethargy in all infected ferrets that was accompanied by anorexia, rhinorrhea, dyspnea, diarrhea, and a mean maximal weight loss of 16 to 23% (Fig. 3 and Table 3). Furthermore, at least two-thirds of the animals died by day 9 p.i., indicating that these viruses are highly virulent for ferrets. Three additional ferrets were inoculated with either 105 or 105.5 EID50 of the VN1203 isolate; none of these ferrets survived beyond day 7 p.i. (data not shown), confirming the virulence of this virus, even at lower infectious doses.
The animal studies are one reason why I don’t think the clusters are primarily due to genetics, although note that there was some variation in outcome with some of the strains of virus.
JoeW. Thanks for the comments. Medical History has shown that the gifted do pull unseen patterns from small data sets…but you would know that already.
Racter makes an excellent point. I do believe genetics plays a role but only in a small number of cases and especially in the index cases. All of the index cases have had family members looking after them so there has to be a difference in the clusters. You and Racter and others may feel genetics is the difference. My experience with genetics indicates that you couldn’t have that many in family with the same genetic anomaly leading to predisposition.
I think my hypothesis outlines a way for the current situation to happen without genetic predisposition playing a role.
In your comment about the father, remember that adults have a much lower inherent susceptibility to H5N1 so I would assume it would be unusual for two parents to have it at the same time. Only in the case of extremely high viral shedding would a second parent be expected to get it…I don’t think this would be explained by genetics.
Monotreme. What do you think?
Tom DVM, basically agree with you. Genetics likely plays a role but probably does not account for the clusters. I think close exposure to diarrhea or vomitus is required to get infected (at least until recently). I also agree children are more susceptible. Very few grandparents are getting sick with H5N1. Very different from “regular” flu. But it’s hard to prove the pro-genetics people wrong. Guess we’ll find out once the pandemic starts.
With my limited knowledge, I think that it is unlikely that one whole side of a bloodline could be genetically susceptible. Monotreme’s point re a dominant gene and the unlikelihood of this possibility is striking. I too doubt that it is some single characteristic. But it may be a combination of genetics and environment and behaviors that leads to this anomaly.
JoeW – at 10:41 …it may be a combination of genetics and environment and behaviors that leads to this anomaly.
No disagreement there.
Tom:
Again, I think that would be more compelling if there were more cases of infected caregivers.
There are some hidden assumptions in the use of the word “adapt” here. As I’ve said before, until the virus achieves H2H transmissibility, there is no selective pressure to adapt to humans. On the other hand, a strain which did achieve that — even if very inefficiently — would suddenly be subjected to strong selective pressure to further adapt. It has often been proposed that for a virus crossing a species barrier, such a “percolation” period may be typical. What makes sense to me is repeated “attempts” (to indulge a bit of teleology) by successive mutant strains to establish a beachhead, the locations of the landing zones being determined partly opportunistically, and partly by vulnerability due to pre-existing genetic susceptibility. Small, infrequent clusters, perhaps gradually increasing in frequency and size (and perhaps not) is just what would be expected, and this also appears consistent with the cluster patterns so far.
Afraid I’m going to have to drop out of the discussion again for a while, but I’ll be following along.
Everytime we go through this process, I become more and more convinced that the this virus has evolved a lot further than many experts and regulators probably have noticed.
Racter, one of my points is that the virus may be infecting more mammals than has been reported. Perhaps its under selection to adapt to pigs or some other mammalian species. Making the final adaptation to humans may thus require less of a leap.
Lay person question: Is age a factor here? Bird flu seems to disproportionably affect people under the age of 40 or so…do you think this could have an effect on familial cluster patterns? (aka, one parent may be older than the other.) We haven’t heard of a grandparent - grandchild pattern yet.
(Is it possible that there may been a virus prevalent 40 odd years ago that could provide some immunity to older people?)
There is NO ANOMALY. Only hocus pocus. It is VERY hard for a human to get infected by a bird, and although it is much easier to get infected by a family member (because there is more contact, especially if the family member is treated at home initially, or misdiagnosed with dengue fever and has contact with the patient without protection in the hospital.
The genetics argument cites the lack of infection in BOTH husband and wife, but because the H2H transmission is so poor, there are not enough opportunities to proof any significance. There would be proof if a child is infected, and then several siblings are infected and only one parent is infected instead of both (only one would indicated the infected was predisposed but the other was not).
Since most clusters have only 2 or 3 members, the numbers are stacked against both parents being infected, because the number of family contacts infected is so low.
Proof of no role of genetics would be both parents infected or someone unrelated being infected.
For clusters of 2, where a child is the index case, it is not possible for both parents to be infected.
For clusters of 3, there are anly two slots available for the index case to fill. One sibling infected eliminates the the chance of both parenst gettibng infected because only one slot is left.
Thus, the best proof would be in larger clusters, where the failure to infect both parents would have some significance.
The number of larger clusters is limited, but they fail to generate any convincing examples.
The cluster of five in Haiphong in 2005 involved both parents (no genetics)
The cluster of four in Vietnam in 2004 only involved siblings and cousins (no data)
The cluster in Vietnam in 2005 involved two siblings, a grandfather with antibodies, and an unrelated nurse (no genetics)
The cluster in Turkey only involved cousins (no data)
The cluster in Azerbaijan included a neighbor/friend (no genetics)
The cluster in Sumatra (possibly if all members of the family were from index case’s side)
Score:
Genetics: maybe 1
No genetics: 3
No data: 2
Hocus Pocus: no contest, a clear winner
I have one question for those of you that understand this. There is one thing I do can’t see that you have touched at all.
What if the current version of the virus is not all that well-adapted to initial human attack, and that a “successful” infection is related to “volume” or “mass” (excuse the use of these terms, as I don’t know the proper ones) of infective agent? The infected person needs to “build up” the volume before it becomes lethal (or highly dangerous). That could take time, even in a familial setting.
I know it is assumed the body can handle a certain amount of infective agent before it is no longer capable of responding in a productive manner (lots of assumptions there and my very limited knowledge is based on cancer treatment). That would, to me explain a few things, like time lags, different CFR rates, infections of primarely closely grouped people, but not outsiders.
All pure speculation on my part, but without asking there wont be any answer either :-)
amt- can’t figure the source after reading so many things, but some book mentioned that because H1N1 was the regular flu type before giving way to the “57 flu type, people born before “57, may be helped by the N1 antigen recognition. That wouldn’t be an immunity, as there would be no working antibody already made, but would get the immune system aware of an invader sooner than no recognition.
Thank you - that could be a good news if true.
Glancing back at the postings, I saw one poster mentioned scabies. Noone addressed it, could a burrowing creature which does pass one to another and tunnels its way during its life cycle pass on a virus? A few years ago a hospital in our area had a big problem with scabies.I have been thinking it genetic in spite of Nimans analysis of the data. I can recall once getting a flu visiting in-laws. My sister in law, ill, didn’t want to miss the party. My only contact was opening her gift. out of all there, her genetic family, I unrelated came down with the virus. Perhaps they had antibodies. It bothers me that it is so capricious in infecting. All those thousands of unprotected workers culling millions of birds without protective gear? And no infection? There have to be multiple causative reasons. Like a jackpot on a slot machine, the peices have to fall into a proper order for the virus to be a winner. That is how I look at it. A genetic variation, that the Japanese researcher is investigating, and then some other things. A jigsaw puzzle. Might be someone reading this who doesn’t understand it as you do could spot it, simply because they aren’t cognisant, so look at it with fresh eyes.I can’t express this in your terms. While I wasn’t impressed with Da Vinci Code, isn’t this a problem that can be solved by one of you because you have the background, and will see that something, really quite dumb, could possibly be the missing piece of the puzzle. The Avian Flu Code.Perhaps there is a great deal that must factor into becoming one of the doomed. Immediate and full medical response will be impossible for most who come down with it. Now we have to figure out why they out of all others have fallen ill with the virus. I hesitate, you know what I have said yourselves, and I have said it before. So I’ll say it again.Its something obvious.
niman:
Respectfully, I think you have grasped the wrong end of the stick here; the “slot” is an artifact of the way you have chosen to frame the problem. Your initial premise is that because the cluster size was what it was, it could not have been larger. It seems more reasonable to me to assume that if the second parent is not infected (and the cluster therefore larger) it can only be due to lack of exposure, or lack of susceptibility (which is another way of saying that the virus is not well-adapted to the host). It cannot be to preserve an artificial limit to the size of the cluster.
There are always anomalies. We are not created equal, that’s a legal assumption, not biological. Take for example the mutation called delta 32, which was found to give immunity to AIDS if carried on both sides. One copy of the gene gave 50% immunity, greatly slowing down the progression of the disease.
Several drug companies began exploring the possibility of developing pharmaceuticals that would mimic delta 32 by binding to CCR5 and blocking the attachment of HIV. The non-mutated form is what’s called a chemokine receptor. This is the receptor the AIDS virus uses. The mutation doesn’t cause any other problem except it blocks the portal for the AIDS virus. If you inherit both copies, all portals are blocked, if you inherit only one copy, 50% of the white cell portals are blocked. This new class of HIV treatment, called fusion-inhibitor, seek to prevent the virus from ever attaching at all.
People with the delta 32 mutation apparently descend from the European plaque survivors. Tracing family records of villagers in England back to survivors of the 1665 Black Death plaque, they found a rate of 14% of the living descendants had this delta 32 gene mutation. This mutation is almost zero in native Africans, Indian, and Asians. The Black Plaque also attacked the white blood cells.
There are stories of the grave diggers handling hundreds of corpses, never getting ill. Even in the 1918 pandemic, some nurses spent hundreds of days in rooms of dying patients without ever getting ill. Perhaps these supersurvivors from 1918 have a counterpart mutation for influenza. There could be traits inherited from the supersurvivors of past flu pandemics. Such a factor could give us the artificial means to block the cytokine receptors from influenza, just as pharmeacutical companies are developing for AIDS. They recently had a blood sample taken from a 98 year old survivor of the 1918 pandemic, but she was a five year old, and not a supersurvivor nurse. The descendants of such people should be screened and cross compared to look for repeating mutations.
niman @ 11:22 - “For clusters of 2, where a child is the index case, it is not possible for both parents to be infected.”
This statement doesn’t make sense to me. How can it not be possible for both parents to be infected? Then you would have a cluster of 3.
Anyway, I do tend to agree with niman that genetics is not involved. If it is, I think it is in a minor way, although for me that is based more on intuition than science. What data there is doesn’t seem to prove anything one way or another. A lot of assumptions are being made (unless I have missed something, which is entirely possible): that the index case (Indonesia) purchased the food for the BBQ, that mothers are the caregivers, that both parents in a family would interact equally closely with a child, or as closely as other children and so on.
I don’t think we have enough detailed information on the clusters (although maybe the WHO does) to come to a conclusion re genetic links. And the fact that there have been cases where husband and wife, or neighbor or nurse HAVE gotten infected would seem to undermine the hypothesis.
This thread is good but getting really long. New thread opened here.
Using something similar to Nieman’s way of thinking it would appear that when there is a cluster of cases, the distribution of cases should cross bloodlines approximately 50% of the time. It could be expected that in a cluster of four or more people about one half of the cases should be on either side of the blood line.
I selected all clusters with at least four cases from Monotreme’s data and found 10 clusters with at least four cases. I reviewed the cases to determine how often a case occurred that was not related by blood. The numerator is the number of people who are or are likely to be related by blood. The denominator is the total number of cases.
4/5, ¾, 4/4, ¾, 4/5, 4/4, 4/5, 3/6, 2/4, 7/8 (the last is the current case in Indonesia and I am not sure of the denominator.
In 8 of 10 clusters the virus was apparently located on one side of the bloodline.
I also noted that with the addition of Indonesia there are not two but three cases in which the mother and father were both infected.
The use of percentages would not be appropriate in this type of review because of the small numbers in each cluster. It would appear based on all ten clusters, that the virus is found (on average) about 75% of the time in one side of the family. In only two large clusters was the virus found to cross the bloodline 50% of the time.
I have assumed that aunts, uncles (and their children) as well as grandfathers are related by blood. This may or may not be true.
It would appear that using reasoning similar to Niman’s there is a case for the virus having more of an impact on one side of a family.