Series on Cytokinic Dysregulation
I’ve had something running through the back of my mind again that I posited early this year. Please feel free to take a look and add.
My thinking may appear to be counter-intuitive to some and at the moment I don’t have the opportunity to post a point by point reference.
Monotreme, TomDVM, ManyCats, Racter and our other esteemed guests interested in the genetic factors and microbiology are encouraged to engage, especially one Dr. A22 please.
Gather and Solve
Posted this comment earlier on Effect Measure: De Jong’s Vietnam Paper
I am convinced that these strains of H5N1 with the residue 92 polymorph on the NS1 gene segment are rapid replicants due to the Interferon pathway interference. The in vivo interference, likely a stultification of NF-kappaB, allows the early viral particles a headstart on the immune system, a temporary invisibility.
I surmise that the Cytokinic Dysregulation is closely mediated by the late start of the immune response due to this early stage failure to detect and respond. By the time the H5N1 infection is fully detected, numerous polymerase activities are already completed. The CD is a fail-safe, even a limited self-destruct, because the virus evaded the early sentinals.
I’ve additionally conjectured early this year that this particular glutamic acid polymorphism on the NS1 gene segment may also mediate higher mortality rates in pregnant women and the young due to the involvement again with NF-kappaB, which is also required in a number of phases of cell differentiation.
I can’t seem to get to the bottom of the actual mechanism / tropism as yet.
Perhaps the bulk of a particular cell’s NF-kappaB population is consistently engaged for cell differentiation in the pregnant and the young leaving the H5N1-infected cell short of resources when NF-kappaB is needed to unbind and translocate to spur the Interferon pathways?
Perhaps we are all short of NF-kappaB (or the two kinase units for unbinding) from the start . . . or some other important mediative factor?
The topic should be easily researchable . . . many viral strains outside of influenza employee an NS1 segment to evade the interferon response.
How exactly does it apply in H5N1 as we see it expressed today?
“The topic should be easily researchable.”
Firm conclusions, however, remain somewhat elusive.
Thanks for the invite. It was you who initially got me looking at this, and while I’m still interested, I don’t feel like I’m up to speed at all, and I’ll probably limit my participation to that of observer for now. I’m glad to see you back, and want to say that I’m not feeling so hot about how some of our most recent discussions have gone. I’d like to thank you for your suggestions regarding possible areas for improvement in my posting style, and to let you know that these have been taken to heart, and to apologize to you and to anyone else who may be bearing scar tissue as a result of my not having addressed this need for improvement sooner. It’s not easy being a cranky old misfit who thinks he knows everything, but it’s gotta be a cake walk compared to being around one.
The obvious first place to start looking at this virus is with hemagglutinin, and the drawback is that the only thing this approach ignores is everything else. If tossing “conjecture” around is what it takes to get out of that rut, then it’s important work, and it needs to be done. If I obtain any insights into this matter which I consider particularly penetrating, I’ll let you know, but I wouldn’t recommend holding your breath; I’ll probably be doing good to keep your dust cloud on the horizon in view.
Racter, my friend-
I still recall our first joust with cheer. We’re both better informed now because of those early engagements. And we are all coming to know each other and this H5N1. Daunting tasks, indeed, aren’t they?
I look forward to your insights on my NF-kappaB conjecture. As you know I have a deepening respect for your particular hueristics, depth of logic and mostly your openness to malleable content (fuzzy logic against fuzzy inputs). I’ve specifically asked for your help because you bring a distinct talent for reconverging divergencies and I’ve not yet seen you shrink from the hard questions.
Gather and solve.
Let’s try that again.
Some background, loosely correlated info on the work of NF-kappaB:
Thanks A22, you’re a pal.
We still need to chase some basics. Please post links on this thread relating to:
I understand that I’m driving in a very counter-Conventional Wisdom direction.
Most of the research that I’ve cited for background relates to suppressing NF-kB. But it makes excellent background reading because we only know what we know. Many of the researchers relate causality to NF-kB due to its presence in disease situations. Some are correct; others wait to be corrected.
I’m postulating that proper release timing of proper amounts of functioning NF-kB may be one of the answers to the Cytokinic Dysregulation seen in current instantiations of H5N1 because proper release timing of proper amounts of functioning NF-kB may create the proper response from the immune system.
This pursuit is tied to the fact that the NS1 gene segment situated as it is in many viral strains acts to inhibit cell-mediated response of the immune system. If we investigate how and why, we’ll have a much better opportunity of creating proper immune response.
We really have no excuse with all the available research available to miss an opportunity to explain and stop the ARDS type responses to H5N1.
I truly now believe the virulence and high CFR is due to viral cloaking giving it a headstart that is too much for the body to ever retake. The body can’t retake the lane because H5N1 is also a massively efficient replicator, an order of magnitude more capable than seasonal influenza.
It’s like trying to ‘herd feral rats that are reproducing as they are moving into better hiding places.
If you don’t contain them in the sewer main on day 1, you’ll have to bunker-bomb the city to be rid of them later.
Let’s find a way to spay H5N1.
Carefully consider TABLE 3: Host defense response genes induced by reovirus.
What are the ways that H5N1 evades NF-kB and how can we manage it positively?
I know this isn’t an Influenza virus, but it is a mammalian test that is driven by NF-kB.
More homework, I know.
How many ninja H5N1 particles will we allow to pass our untrained NF-kB sentinels?
Are we doing these three things with H5N1? Or are we just concentrating all our efforts on the Neuraminidase?
Well, I haven’t done the homework yet, but here’s one thought.
Any consideration of changes to the NS1 gene as explicit design features serving to thwart early immune response in humans seems to immediately encounter a logical difficulty: H5N1 is not yet well adapted to infect humans. Even if it could be established that cytokine disregulation was a common feature in infection of avian hosts, it would still be hard to say whether it would work the same way in humans, or if it would be a benefit to the virus in terms of replication rate even if it did. See what I mean?
I have been wondering something for a while. It may be simplistic but before antibiotics in some ways made us lazy to explore other solutions, scientists were very good at producing antitoxins and antivenoms without having a through knowledge of every aspect of what they were treating…
…could we produce an antitoxin to the active ingredient messengers or effect toxins of the cytokine storm?
TomDVM,
You’re tracking with me now.
I’m naturally not interested in a pharmaceutical solution, but in finding a non-toxic means of causing the body to respond properly and invoke the normal innate immune response genetically.
I’m convinced that if a virus can find a gene flip in nature to evade our Innate Immune response (in this discussion NF-kB activation of our ISG’s, Interferon Stimulated Genes), then we should be able to find a plant or group of plants that create an opposing paracrine or autocrine host cell effect or a blocking effect of the NS1 gene expression.
Let’s not forget the possibility of phytochemical-mediated host DNA repair if we find that some people have defective NF-kB or some other important signaller?
Maybe we’re looking for a natural NS1-inhibitor? Then I would just go away.
Perhaps we build a more effective NF-kB or a more effective IkB kinase set to release the NF-kB via proper inputs, proper nourishment?
Summary
But we need to know exactly what the beginning is of the cytokinic dysregulation and exactly what else those signallers control, thus our thread here.
You stand gazing at a buffet of possibilities, so take a small sample of each until you find one that interests you or go ahead and fill your plate high now with one that looks the best.
Let’s prove that the wiki model works!
Racter – at 10:37
I see exactly what you mean.
Would you mind exploring avian host cell immunity for NF-kB expression profiles? I haven’t begun to look at that particular aspect.
At any rate, we know that many of the H5N1 strains carry the amino at residue 92 that cloaks the viral infection in humans. How it got there is important if we consider a method of moving it away from glutamic acid. How to fight it if we can’t change it is still open to suggestion regardless of origins.
ns1:
i dont understand 90% (or more) of what you say, but i still read it anyway. thanks for your clear-sighted can-do-ism, open-mindedness and persistence.
chivito,
We don’t need explicit microbiology or genetics knowledge for all of this thinking, just a willingness to use our minds to find patterns and outliers.
Look for the bit that doesn’t make sense and then chase it. Sometimes that’s the part that nobody understands yet or has cared enough to investigate.
Join the GBI.
The Gene Bureau of Investigation.
And then recruit your friends to come here . . . we need more eyes on the problem.
Hi NS1. I am a phenotype kind of guy. I am interested in the gene expression…not in exactly how the gene is configured that is doing the expressing.
To be honest, if chivito is understanding 10% then he/she is doing better than me…a lot of this is beyond the average mortal…and I don’t know how to get around it.
I know only three or maybe four persons that could articulate these hypotheses with you: Monotreme, Racter and maybe anon 22…and of course DR. NIMAN.
Anyway, I wanted to raise something with you that I have believed all along…I’m not sure the immune system is totally out of control but may just be doing what it is trained to do…this may have consequences when considering mediating the effects of the immune system.
My belief has been that the virus invades probably a majority of lung cells. The immune system then just does what it is trained to do..a normal expression…but the targeted cells are so large that it in effect kills too many cells for the particular organ (lung) to continue to function.
The only way around this in my opinion would be to create pharmaceuticals or natural (plant based) treatments that would mediate the kill factor for the immune system…in other words…spread the killing out over a longer time period or make the kill factor less efficient.
Anyway, the bottom line is that I don’t think it is an abnormal reaction…the F-16 in the trunk of the volkswagon bug…is just doing exactly what it is trained to do.
My experience in the animal world is that most deaths are not due to secondary bacterial pneumonia but due to primary viral pneumonia…direct viral toxicity for lung cells…this process is predictable and basically untreatable…it happens too fast.
I agree totally with not coming up with pharmaceutical solutions because in a pandemic there will be no pharmaceuticals or anyone to administer them…the third way…I’m not sure how it would work.
TomDVM,
So many cells become infected because the body fails to see the infection early in the cycle. If we catch it early, the body will be in a better position to stop the rapid replicator.
If we try to reduce the kill rate from the virus, then those cells not killed remain as cozy condominiums for reproduction, enhancing the problem.
TomDVM,
That’s exactly what I think.
NS1.
Is it that “So many cells become infected because the body fails to see the infection early in the cycle.”…
…or is it that this virus replicates so fast that it…in effect…hits all these cells at the same time so there is no chance or time for immune recognition?
Then when the immune system reacts…it just reacts normally but unfortunately it doesn’t realize that too many respiratory cells are infected and if it destroys them all, it will win the battle…but lose the war…compromised lung function and death.
TomDVM,
At the end of day one, H5N1 has made 50,000 times the number of copies that seasonal flu does. So you have to correct the problem at the first cells that are infected. After that, CD ensues and so many cells are lysed that the body’s elimination systems can’t bear the burden.
The key is to cause the body to respond to the first wave of infection.
NS1. I agree but would the body in seasonal influenza normally pick up those first few cells.
I think they have answered the question why at this point vaccines and particularly tamiflu won’t work…the virus will out replicate these things before they presence of the virus is even picked up.
In my opinion, there is only one compound that I have seen or heard of with the potential to have an effect on this ‘virial asteroid slamming into the body from far away’…and that is prednisolone in moderate doses…50–100mg/day for 3–5 days…it is the only thing that worked on the animals with ARDS and the cytokine storm that I was treating…also it is cheap, avaliable and enter the blood stream from pill form the exact same way it enters the bloodstream in an intensive care room with the nurse giving it IV…just takes a little more time to reach therapeutic concentration…
…or maybe we can come up with a natural way to slow the immune system or create a temporary antitoxin against the immune system. They used to talk about dexamethazone and prednisone coating the inflammatory cells so they won’t work…maybe another compound could do the same without the side effects of dexamethazone and prednisone.
TomDVM at 19:45-
With seasonal flu, the body has a longer cycle of opportunity prior to complete implosion due to the lower rate of replication. I don’t know if the seasonal strains invoke NS1 92 glutamic acid either to slow the Interferon response.
I understand the unique possibility of your prednisolone practice. Your experience with this pharmaceutical places you in a special position.
I don’t believe that we should be focusing on slowing the immune system; we need to cause it to have perfect reflex at the start of infection.
Ergo, preparation should involve more than a perfectly prepared pantry. Preparation should involve properly nourishing and training the immune system.
We just need to get a better light and peek into the corners until we find the answer.
Initial paper on knockout residue at H5N1.NS1.92
Lethal H5N1 influenza viruses escape host anti-viral cytokine responses Sang Heui Seo, Erich Hoffmann & Robert G. Webster
NS1. I think that part of the problem is that they (not us) profess that they have conquered the immune system…that they know everything about the immune system…like those comments a few years back insinuating that they knew everything about influenza…
…well…I don’t think they know much about infuenza viruses in general and I don’t think they know very much about the immune system.
I think the first step in the path is to admit what we don’t know…I know nature is a lot more intricate then my five senses can figure out…if they had tried to be a farm animal veterinarian for a few months they would know it to.
So given our meager knowledge…do you think that we can modulate that normal and natural (in my opinion) reaction of the immune system that is forced to take out all of the infected cells at once.
Also, I we laymen don’t quite understand the nuances between the eight genes and particularly the NS1 gene…could you explain it in layman’s terms Thanks.
What you people are failing to see is that the problem is greatest in the most naive immune systems, those that haven’t met a virus anything like this. Note that older, experienced immune systems do better. So how do you quickly train up a naive immune system? With seasonal flu vaccine. Vaccinate anyone who moves. Ambush them at the mall, give ‘em an ice cream afterward. Do anything to get at least one flu shot into everyone under 35 who can tolerate it. H1N1 is better than nothing, it gets the ball rolling. And if this bug has been talking with H3N2, a little of that won’t hurt, either.
disgruntled. I like the handle. What does it mean?
As far as seasonal vaccine goes…as long as it does not harm than why not?
I remember reading an article about a Dr. in Hong Kong that treated some of the first H5N1 patients several years ago. He said what was striking was that his patients “never had a chance”. He said that it was clear after the first couple patients he treated that the virus replication was so intense and lightning fast, that their bodies were never in the position to overcome it from the start.
I think that has sort of been established. But here is the mystery to me personally: What is it doing during that approx. 2–5 day lag time between initial infection and commencement of symptoms? Is it replicating like crazy on the first day or the fourth day? Is there a chance to nail it at exposure or during the pre-sypmtom phase?
Now I realize that there are educated experts out there that believe that cytokinic dysregulation is a proper contributor for the dire state of illness that many patients succumb to, but if you have an overwhelming amount of virus inside of you, is it possible that’s initially where the answer lies? In the period before the immune system goes haywire? Before the virus can replicate to disastrous amounts?
It seems like even if your immune system was at peak performance, even enhanced by drugs limiting the negative effects of some of the cytokine response, that in spite of all that going for you, your still at a serious disadvantage simply due to the overwhelming amount of virus in the body.
So here I am back at square one, where you discussed somehow encouraging the body through some artificial or natural means to recognize the virus right away so it can be nailed before it goes into its replicating rampage. O.K. My mind keeps reverting back to what I read about Sambucol (Elderberry extract). (By the way, I am in no way associated with the product) But the clinical studies that the manufacturer has published has shown that it reduces the length of seasonal flus by SEVERAL DAYS, which is more than can be said for Tamiflu (one day, maybe two if your lucky). In addition, it has been shown to KILL H5N1 in a petri dish (in vivo?) Well, I realize in vitro is a totally different environment than a petri dish, but the idea of it actually KILLING virus is right on.
It seems that the immune system is so complicated, and mysterious, to boot, that rather than trying to find the magic key to unlocking it right now, would it be less difficult to find the magic bullet to nailing the virus before IT HAS A CHANCE?
It seems that one of the advantages of this avenue is being able to take something prophylactically at the slightest hint of exposure, rather than when symptoms begin, which is what poeple with seasonal flu usually do, and what has mostly been happening with H5N1 infections. It is clearly already at a very late stage ONCE THE SYMPTOMS begin.
Tamiflu is a nice thought, but hasn’t been proven to kill anything that I’m aware of. Maybe there is still something out there that can seriously inhibit the actual virus from the get-go.
Please forgive me for the lengthiness, but I admit it has been a little therapeutic for me to express my thoughts on this, despite the fact that you all are probably light years beyond my naieve theories on the subject. :-)
P.S. I very much enjoy reading threads such as these, and everyone’s intelligent thoughts and info. Thanks for allowing me to take part. :-)
I am not sure where to ask this. But the 5 new cases in S Korea : about this- “South Korea’s disease control agency confirmed Friday that five people have developed antibodies to the lethal H5N1 strain of bird flu after taking part in the slaughtering and disposal of infected chickens and ducks.
The five people tested positive for bird flu antibodies, but none of them have shown symptoms of the disease as defined by the World Health Organization (WHO), the Korea Center for Disease Control and Prevention (KCDC) said.” see news thread,
Does that mean that they have a strain with a low CFR, or that they did something to decrease the “storm” or what?
“Would you mind exploring avian host cell immunity for NF-kB expression profiles? I haven’t begun to look at that particular aspect.”
You’ve got me buttered up so good I don’t see how I could refuse. I’m a little jammed up IRL right now though, so I don’t want to make any wild promises about how fast I’ll be. For now, just another quick drive-by:
Both Tom and disgruntled (and niah) have just made excellent points. Anyone who thinks he has conquered the immune system has to be a loon. If smacking down the innate response with steroids is tempting, it’s probably because it eliminates the necessity of continuing to wrestle the complexity. Extrapolating from that, it’s hard to see H5N1 as being likely to have its fingers on the right buttons at this point either. Has the NS1 gene in the H1N1 virus been closely examined? (Was this covered in the material assigned as homework? If so, my asking gives me up as not having done it yet).
Disgruntled’s suggestion regarding a coercive approach to vaccination seems a little heavy-handed (hey, maybe we could just modify some tranquilizer dart guns; ever think of that?), but the suggestion that immunological naivete may be the decisive factor is worth considering. I suddenly realize I’ve been locked in on robustness. The fact that the age distribution curve for Spanish Flu mortalities was a “W” rather than a “J” doesn’t strongly support the idea, but it doesn’t eliminate it altogether.
I remain pessimistic about the prospects for developing any practical means of maintaining (let alone restoring) cytokine regulation without risking crippling the adaptive response altogether. We’ll probably be lucky to be able to do it a hundred years from now. Nanobots or something maybe. “We’d better get started then” — did I hear you say?
FluWiki happy thought for the day: If H5N1 comes to dine on humanity, maybe it will pay for its meal by teaching us things about our own immune systems we would have had a hard time learning on our own.
NS1:
I believe your thinking is on target. For some reason the immune system doesn’t see the threat before the virus has multiplied into a gazillion hungry viri. It could be something as simple as we stun our immune systems daily with a sugar load. Consider the amount of sugar a child takes in before going to school. Ceral, juice, jam, pop tarts etc, Koolaid and cookies for snacks. I know some parents do much better, but the majority don’t. I’ve also wondered if some common medications may have the same effect as well. But it’s a different story when the ARDS situation develops. That cascade is very involved and it’s not simple, or easy to stop or even influence.
What is your take on the Sambucol—it blocks virus from invading a cell, versus Tamiflu blocking the virus from within a cell. From my reading on the cytokine stimulation of Sambucol I think it’s a good effect—while I know many warn against it. If I had a kid that would be one dose they got everyday until this flu in question is settled.
Allow me to check my understanding here. niah asks what the virus is doing during the incubation period. Could it be this is the time that the virus is using its NS1 adaptation to dodge interferon? Combined with steeply exponential rates of replication, what appears to be a sudden onset is really just the tipping point at which the number of infected host cells is really high and the ‘fail-safe’ defense of apoptosis or lysing of infected cells kicks in that NS1 mentions?
Leo:
“For some reason the immune system doesn’t see the threat before the virus has multiplied into a gazillion hungry viri.”
Immunological naivete alone can go a long way toward explaining early success of the virus. A strong inflammatory response indicates that the immune system has at least noticed that the body is under attack. The simple explanation I’ve sort of been defaulting to as far as cytokine disregulation goes is that it’s just sort of where the whole business tends to end up if the innate response is strong and the adaptive response takes too long.
Sarge:
“Combined with steeply exponential rates of replication, what appears to be a sudden onset is really just the tipping point at which the number of infected host cells is really high and the ‘fail-safe’ defense of apoptosis or lysing of infected cells kicks in that NS1 mentions?”
But sudden onset is typical of seasonal influenza as well, yet seasonal influenza lacks the “adaptation” we’re hypothesizing here, and does not typically lead to cytokine disregulation.
Just a thought. The storage of immunologic memory in a highly intricate and efficient system…and may be the most intricate system in the human body…
…it is designed to react very quickly to disease challenge. Part of the difference in response between seasonal influenza’s and H5N1, would be the rapid reaction force that is envoked with the seasonal flu and is unavaliable with H5N1 because the force was not created in the first place…because the immune system has not encountered this specific threat before.
Vaccination and well as previous disease challenge provides and arms this ‘rapid reaction force’. Maybe in the lack of response to the vaccine is the reason for the lack of the immune system to respond soon enough.
Racter. My opinion about HIV/Aids has always been the same as your opinion of H5N1 with respect to advancing the science of immunology. I have always believed that if they solved HIV, they would not only have to answer many questions about the immune system in the process…but they would also answer the immunologic questions regarding cancers. I think the fact that they have not succeeded as yet indicates the significant challenge the immune system presents.
Another implication of the immunological naivete argument is that _any_ H5N1 vaccine is better than nothing. Mingus, on another site, has explained numerically how ‘the better the match, the better the response’ works using gene sequence similarity to predict the effictiveness of the vaccine. The closer to 100% the match is, the better the vaccine defends. But I note that even at 90% effeciveness, you save a whole lot of lives. Surely ‘close’ ought to count for something (besides horseshoes, grenade throwing, and thermonuclear war).
disgruntled:
I agree, but my contacts inform me that manufacturers are having a lot of trouble making H5N1 pre-pan vaccine. The yields from the egg-based process are very disappointing and stocks are well below the targeted levels. Unless something changes, we may be without a vaccine through the period when it is really needed. Even if the vaccine doesn’t completely protect from the virus, a vaccine-moderated clinical course is almost certain to be prefereable to a head-on strike on a naive immune system.
“ Surely ‘close’ ought to count for something (besides horseshoes, grenade throwing, and thermonuclear war.”
There is the old saying ‘do no harm’…and if the vaccine does no harm then I would agree with you…close counts for something or at least can’t hurt.
However, with vaccines…in a sense every reaction produces an equal and opposite reaction.
1) there are vaccine reactions…I should know…I have suffered from them twice in my life including one that ended up to be life-threatening.
2) vaccines could immuno-suppress the recepient at precisely the wrong point in time…when they are about to encounter the real thing.
3) vaccines could give a ‘false sense of security’ in say healthcare workers such that they would not take the need for other precautions seriously…leading to infections and further spread amongst the general public.
4) vaccines injecting live virus intentionally or inadvertently could induce the disease we are trying to prevent and because of it setting off a pandemic.
Just a few things, with respect to colateral damage,to keep in mind.
Have you seen the article posted last night by AnnieB on the news and vitamin D threads (thanks again, Annie!), about vitamin D use against influenza. I’ve not had time to do research followup on possible mechanism of action at the molecular level.
Here are some snips that might be of interest to this group regarding immune system(also posted at vit D thread). The entire article is good.
“Hope-Simpson had no way of knowing that vitamin D has profound effects on human immunity, no way of knowing that it increases production of broad-spectrum antimicrobial peptides, peptides that quickly destroy the influenza virus. We have only recently learned how vitamin D increases production of antimicrobial peptides while simultaneously preventing the immune system from releasing too many inflammatory cells, called chemokines and cytokines, into infected lung tissue.
In 1918, when medical scientists did autopsies on some of the fifty million people who died during the 1918 flu pandemic, they were amazed to find destroyed respiratory tracts; sometimes these inflammatory cytokines had triggered the complete destruction of the normal epithelial cells lining the respiratory tract. It was as if the flu victims had been attacked and killed by their own immune systems. This is the severe inflammatory reaction that vitamin D has recently been found to prevent.
I subsequently did what physicians have done for centuries. I experimented, first on myself and then on my family, trying different doses of vitamin D to see if it has any effects on viral respiratory infections. After that, as the word spread, several of my medical colleagues experimented on themselves by taking three-day courses of pharmacological doses (2,000 units per kilogram per day) of vitamin D at the first sign of the flu. I also asked numerous colleagues and friends who were taking physiological doses of vitamin D (5,000 units per day in the winter and less, or none, in the summer) if they ever got colds or the flu, and, if so, how severe the infections were. I became convinced that physiological doses of vitamin D reduce the incidence of viral respiratory infections and that pharmacological doses significantly ameliorate the symptoms of some viral respiratory infections if taken early in the course of the illness. However, such observations are so personal, so likely to be biased, that they are worthless science.”
Tom DVM – at 12:10 Let’s infect 10,000 naive people. We can expect perhaps 1/3 to die. That’s our baseline. That’s 3,333 deaths. Let’s use a 90% match vaccine with 60% effectiveness, that’s about half protected, 5,000, ,and of the remaining 5,000, maybe 25% die, because cases are less severe. That’s 1250 deaths. Add to that .01% severe adverse reactions, and of that 1% lethal, so 1 more death from vax itself.
The false sense of security argument I would counter with the observation that most severely ill have ARDS, and are not particularly infectious. Recall how many HCW got SARS, and how none have been getting H5N1. HCW are more likely to be infected by nonsymptomatic relatives, and in fact, relatives ought to be kept away for this reason.
disgruntled. These are complex issues as I am sure that you know…so any answer by definition will be incomplete.
The way I see the pandemic developing, the Case Fatality Rate will be approx. 10% and the attack rate during the active pandemic period will be approx. 70%.
Approx. 80% of those affected will survive with no chronic after-effects…chronic sequelae.
So the vaccine is designed to try and limit the damage in the 20% of the 70% infected with H5N1.
Regarding the vaccine, the first question is whether or not this vaccine is to be fully tested before the pandemic starts…or will this be an experimental vaccine…
…vaccines are dangerous for if you get a vaccine reaction, the odds for adverse effects are 100%…vaccines are inherently dangerous…in degrees…
…therefore, the vaccine should not be given until the pandemic is confirmed and the risk from the vaccine can be balanced off against the risk from the pandemic.
Secondly, I think you are being a little too optimistic with a sixty percent efficacy…I have seen reports indicating a six percent efficacy with seasonal influenza vaccines…
…the vaccine has to work and often they don’t…and I’m pretty sure they never will (under present antiquated technologies) because the virus drifts away faster than the vaccine lag period for production 6–8 months.
With respect to the false sense of security…you are right…it could extend into the community such that the HCW would not protect themselves or the community.
On the relative infectiveness of SARS vs. H5N1. SARS hit its peak infectivity at exactly the time the person was symptomatic and seeking care from healthcare providers…therefore the high transmissibility to healthcare providers.
Karo indicated to me that the peak infectivity for H5N1 is before the person is symptomatic and therefore by time the person seeks healthcare…they are relatively less likely to pass it on in comparison to SARS…which may be something good that we can harness to our advantage.
So if you have a 5% success rate vs a 1% serious adverse reaction rate, then things look a little different.
Checking the CDC website, I find that yeah, a lot of people get a sore arm after the shot for a coupla days, but severe, lifethreatening reactions are RARE. Like, 1 in a million for GBS.
As for how well it takes, it’s like 65% in kids, 40% in seniors, and 30%−70% in between. As for how protective it actually is, it depends on the match to the circulating strain. According to Mingus, this is linear with the percent matching sequences, so a 90% similar strain has a 90% effectiveness compared with a 99% match.
I don’t think it’s fair to use the adverse effects rate for rabies/smallpox/whatever vaccine to predict the rate for influenza vaccine. It’s just not good science. It’s likely that the rate would be similar to the known rates. We have rates for this type of vaccine, so how about giving it the benefit of the doubt?
My take is still, get young people vaccinated with seasonal flu vaccine ASAP. Us geezers can wait.
disgruntled.
Well…I certainly respect your opinion.
“I don’t think it’s fair to use the adverse effects rate for rabies/smallpox/whatever vaccine to predict the rate for influenza vaccine.”
I agree with your statement. rabies/smallpox/whatever vaccines actually work and I believe that influenza vaccines don’t…and in this respect, they are unique…as influenza vaccines are unique in many other characteristics as well.
The number of life-threatening vaccine reactions is inversly porportional to the care and time taken in preparing and purifying the vaccine…I will withhold judgement on all pandemic vaccines.
And last but not least…if all current capacity is taken over for H5N1 vaccine production including all avaliable seasonal vaccine production…at best…the total possible number of doses per year would be 200 million for a world population of 6.5 billion.
What do you think your odds are of ever getting a shot in the first place…I will sacrifice myself and give you my vaccination. /:0)
They don’t have the vaccines and they don’t have the anti-virals…okay, is there another intervention that will save lives here and what is it?
…their collective paralysis is well exhibited for all to see…they hang themselves and us and our families on their ‘magic pill’…
…and ignore the boring stuff at their peril.
Sorry should have said …I agree with your statement. rabies/smallpox/whatever vaccines actually work and I believe that influenza vaccines don’t…and in this respect, they are unique…as influenza is unique in many other characteristics as well.
quoting: Tom DVM – at 16:03
“…I agree with your statement. rabies/smallpox/whatever vaccines actually work and I believe that influenza vaccines don’t…and in this respect, they are unique…as influenza vaccines are unique in many other characteristics as well. “
If what you mean is, that we wouldn’t have such big problems with seasonal influenza if they _did_ work, then I could potentially agree, but plead that it isn’t the vaccine’s fault. They give most of the vaccine to the weak and elderly, who have the poorest responses, and are in a population where spread is limited, so the overall vaccine effeciveness is low. If the vaccine was distributed so as to minimize spread, then it would go to preschoolers, who mount the highest response and are superspreaders. Giving it to adults means some is wasted on people who are already immune. But that’s a distribution problem, not a vaccine problem per se.
disgruntled. I agree with much of what you have said and there are certainly more scientists in your camp then mine…in fact, I may be the only one in my camp…but that’s okay…I just call them as I see them.
I will plant the seed of doubt and my fellow colleagues on flu wiki will be skeptical and will question regulatory authorities on these things…
… it is for them to produce irrefutable, peer reviewed scientific data to convince you and me…and not the spin they have been distributing for several years. If they do that then everyone wins.
Lets agree to disagree on this, then, because it seems you want to raise the proof bar over what the CDC has to say about the seasonal flu vaccine, and you can’t provide any evidence to back your claim.
However, I am interested in your idea about using prednisOLone (emphasis added to differentiate from prednisone) as a treatment. I notice you are very vague when it comes to your treatment protocol in cattle. Yet it seems you do have some idea what dosage pattern worked best. Did you use something like a predburst?
“Lets agree to disagree on this, then, because it seems you want to raise the proof bar over what the CDC has to say about the seasonal flu vaccine, and you can’t provide any evidence to back your claim.”
disgruntled. There have been three studies that have said the same thing that I am saying in the past 20 months. One that I remember most clearly was a senior independent researcher who did a long term 20–30 yr. comparison between years when the influenza vaccine was a perfect match to years when the vaccine was not a perfect match. She found no difference between those years…coming to the conclusion that the vaccine doesn’t work.
In the second study, it was determined that death rates in the very young and the very old did not change in years when the vaccine matched and the vaccine didn’t match…in my opinion, if your vaccine doesn’t prevent the disease or prevent deaths in the target group, then it doesn’t work…seems pretty straightforward to me.
The third longterm study was from my home province of Ontario Canada. Ontario began a plan of free vaccinations about five years ago. The study determined I believe that there was no difference in hospitalization visits before the free vaccine vs after the same vaccine.
I can’t produce these studies because I didn’t bother to save them after I read them…I’m sure they are still on the internet…I’m just not that good in this medium.
Anyway, I haven’t seen any peer reviewed references from the CDC…so their information is on the same level as mine. If you have some maybe you could provide them as well.
To me, it is quite clear that the archaic technologies for influenza vaccines don’t work and its clear that the archaic design of antivirals also don’t work.
That is my conclusion. I am convinced. If you want to put your faith in these technologies and believe that you will recieve them in a timely manner, then good for you…I do hope they work for you.
I have enjoyed our conversation but it is a little off topic for the purpose intended for this thread.
On the prednisolone, the medical practioners should talk to a few farm animal veterinarians…because we have way more experience with the cytokine storm and ARDS and viral pneumonia then they do.
The theory behind the prednisolone treatment is moderate dosages for short periods of time…if you give too low a dose or too high a dose for too short or too long a period of time…they it makes things worse rather than better…and that is exactly what happened with SARS.
Thanks again.
NS1 and Monotreme. I’m not sure about others but I am still not quite clear on the finer points of the individual genes on H5N1.
NS1, I know that you believe the NS1 gene is essential to the virulence and potential future behavior of this virus but I don’t so am rather limited in the discussion which is alright with me…really.
If you could give some basic information in really low laymens terms then maybe I could achieve some sort of starting point to the discussion. Thanks.
Disgruntled:
While I’m not arguing against any of your posts let me tell you what I find interesting. The CDC says just about every year without fail that around 30,000 deaths occurred due to the flu. This number rarely changes, even if vaccination rates drop or increase, or even if vaccines are grossly late or on time. It makes me think they don’t really know the effectiveness, and are just guessing like the rest of us. Death rates remain unchanged even when we take the shots in high numbers, so was the vaccine efffective?
Second: I’m really not on board that there is actually a yearly influenza going around the world in every country every single year. Yes, they make a yearly vaccine, based on guesstimates of three strains which may or may not arrive. But most of us when we’re sick aren’t getting a test that confirms influenza, we’re just told that based on symptoms after we’re asked if we got a flu shot. Unlike a lot of people I’ve worked in research which had me digging through death certificates in my state for respiratory deaths. I never once saw a cause of death listed as influenza, but saw plenty for pneumonia. You can argue with me that pneumonia is a final gift of influenza but exactly how do they tease that info out? Not all pneumonia is a result of flu. Do they go through charts reading case histories and checking x-rays?
And finally I guess I just don’t believe that doctors whose patients they think died of flu actually pick up the phone and reported it to CDC. With H5N1 or pandemic flu they might, otherwise no. If the numbers varied more dramatically I might believe the official estimate—but they stay right on, even in an admitted low flu season.
“NS1, I know that you believe the NS1 gene is essential to the virulence and potential future behavior of this virus but I don’t so am rather limited in the discussion which is alright with me…really.”
What I really meant to say, was that you know about the significance of the NS1 gene and I don’t understand the background physiology and genetics of these genes…not that I don’t agree with your conclusions because I don’t know enough to agree or disagree.
Anyway, if someone could give a background for dummies on the genes and what they do…I as the dummy will soak it up…Thanks.
Leo 7. There is alot about seasonal influenza that just does not make scientific sense…let alone H5N1.
I continue to be amazed every day about how little we actually know in 2006…and how little we know that they didn’t already know in 1918…
…and how often the experts have expounded on a topic…only later to be completely and absolutely wrong…this has happened time after time after time. It is a repeating pattern over several years now.
What is wrong with saying we don’t know and then bearing down to find the answers…like some good serological surveys in Indonesia or China?
Leo7. I doubt they are exactly guessing, but I also doubt they have very good numbers, for the reasons you cite: doctors don’t routinely test for influenza A until someone hits the hospital. Therefore, we don’t know the true incidence of any one strain, particularly in the ordinary sick population. Studies I’ve seen put it at 3–10% of seasonal respiratory illness. They have a network of sentinel doctors who do more testing, but it’s still pretty inadequate for calculating real numbers. I think all they have is a sort of consensus opinion and a bunch of testing of hospitalized patients. There isn’t any reason to change the number because they don’t even collect the kind of data needed to change it.
Likewise, it’s hard to measure the true efficacy of the seasonal vaccine because there is so much background respiratory illness. And from a practical standpoint, HMOs would howl if they had to pay for testing of everyone who came in with a miserable case. And someone would have to track it. I get the sense that it just isn’t worth the effort. Not for seasonal flu.
So what happens is that the vaccine is used defensively, not offensively. The flu vaccine is mainly offered to those who are likely to get a bad case, not to the superspreaders. The way it is deployed, it just isn’t going to reduce the overall incidence of flu, only mitigate its severity in some people. And as you and Tom point out, it’s hard to decide by numbers how well they are doing.
I’m in agreement. Let’s do the studies! With the freak of nature heading our way ordinary folks like us are investigating all things flu. Hopefully people in charge will see our confusion and move to make changes for the good of the Public Health.
TomDVM and Disgruntled-
I personally coincide with TomDVM here and realise that the vaccine issue is a non-issue for PF51. As such, I am no longer highly interested in the discussion.
I am highly interested in the discussion of how H5N1 and potentially PF51 will do its work. Ergo, we are discussing the role of cytokines, chemokines and gene expression (host/viral) on this thread.
Please let us stay on topic. Do your homework by studying the papers presented here and others like them to establish background. Present your ideas for discussion.
niah – at 23:32
Excellent post and directly on topic. I wish that I had time to answer point by point. The time factor is why I am asking for help here.
While I don’t have time to study all of the papers in depth, I do believe that my original topic from early this year and at the beginning of this thread is very relevant to reducing the CFR. Because of the weight that I place on the topic personally, I’ve undertaken a discipline to understand what everyone says is not understandable.
We are just scratching the surface on the observational science, so firm conclusions cannot be drawn . . . but that’s all science, isn’t it. We theorise, test, correct and retheorise.
However, we have substantially more information available than many would have you believe, especially if we undertake a directed study on cytokinic dysregulation and its mediators.
I firmly believe as Tom and others have agreed over the past several months that if you wait until the time of infection, then you are doing yourself a dis-service. Most of the allopathic treatment modalities do not appear to be highly beneficial.
I’m not here to debate that last statement . . . I’m just showing each of you why I search for a better answer.
Here is a good explanation of what’s going on with the eight segments and whatnot.
And here is a pretty readable rundown on the NS1 gene (comparatively speaking).
Racter at 0915-
The simple explanation is just that on this item, overly simple.
You see, we know that the H5N1.NS1.92.glutamic-acid slows the Innate Interferon response of the host cell with the viral particle in it. If the Innate Immune System responded properly in a timely fashion then the virus in that cell would be suppressed from replicating. And no Cytokinic Dysregulation would occur.
Please have a look at the very clear paper by Dr. Webster at my link on post, NS1 - at 20:25. Dr. Webster convinced me to take a closer look.
The adaptive immunity will not likely play a major role in early phases of a pandemic strain of H5N1 in my estimation. It just takes too long. The vaccines are below efficacy, will be the wrong strain, will be dangerous due to reduced testing requirements and will only stimulate temporary memory cell activity.
The key is to have each infected cell react in 2 hours instead of 10 hours using the innate anti-viral and anti-replicative immune response.
How do we understand the signal transducers from NS1 that halt our interferon response (part of the innate immunity)?
By the time a person can make antibodies to H5N1, they’ve already experienced a flood of H5N1 particles likely in multiple organ systems. In my best estimation, adaptive response on first infection isn’t where we want to hang our hats.
‘Adaptive immunity is a linear response.
The virus continues to replicate during this adaptive response without the early innate interferon response.
So we are not necessarily looking at a too strong innate response, we may be looking at a too late innate response.
Where do you want to hang your hat?
Racter Thanks
…so NS stands for non-structural…NS1, I think you were right to go with the short form./:0)
Racter at 20:44
That’s exactly what we are doing here. Thanks for adding to the library.
Now, did you read any of the studies on the total NS1 segment knockout or the NS1.92 knockout to aspartic acid?
The results are pretty clear. Interferon-mediation . . . now let’s find how it does it?
TomDVM,
I know that you’ve inquired twice now about why I think the NS1 is important. I’m hoping to guide others to take a look at the studies and then see if they come to similar ideas?
This all just conjecture, mind you, but I believe that we need to be pursuing something that is beneficial. Consider this wiki thread to be the Basic Research that doesn’t seem to get funded very broadly in today’s economies. Study the generalities, synergise and then collaborate if you can.
I need your intuition guided by some of the content in the papers that I’ve presented here. You certainly have a talent for cutting past the skin and into the organ. I want that organ opened for viewing and fully annotated by experienced instructors.
Bring your friends and teach me.
I’m ready to learn.
TomDVM,
As you and I have agreed and noted in previous posts here and on other threads, we really need to admit to what we don’t know in the science community.
MSM is always looking for sound bites, so we give them sound bites. Those sound bites, Cytokine Storm, for example, then drive enquiry in the wrong direction by forcing images into peoples’ minds of a chaotic and singular event, vast oversimplification. The least common denominator then rules because once the public has hold of that sound bite, they know what is happening and can explain it by intoning the sound bite.
And further conversation is blunted. The emperor has new clothes . . . and very nice ones, don’t you see? That cloud looks very much like a whale, don’t you think?
Back in the real world, Cytokinic Dysregulation is anything but chaotic and singular.
A complex dance takes place across the bloodstream, the glands, the cell wall, the cell cytoplasm, the cell nucleus and even the intercellular spaces. Signals cause certain genes to be expressed. Those genes may, in turn, inhibit or activate additional steps on the chain of cell-to-cell signalling, paracrine protection or autocrine protection.
To be more specific on some typical steps, you may have signals causing induction of transcription factors, signal transduction, kinase activation, phosphorylation and ubiquitination and then back to activation of more transcription factors.
Now it is very complex and we truly don’t know how it all works.
We do have hundreds of papers that describe small parts of the puzzle with enough overlapping to at least build a corner of the whole picture.
Let’s work on the corner with what we have instead of shaking the box randomly hoping for a finished construction.
Then maybe we’ll be ready when more information arises.
NS1:
“The simple explanation is just that on this item, overly simple.”
My wording was carefully chosen to implicitly acknowledge that. The Webster piece looks familiar; think it was covered in some earlier incarnation of this discussion.
But escaping early host response isn’t necessarily a trick unique to H5N1. (Dang it, lost the link; I was just looking at that earlier; if I’m interpreting and remembering correctly what I was reading, other influenzas can do the same. I’ll try to fetch it back. So many details, so little time). Also, escaping early host response and triggering full-blown cytokine disregulation aren’t necessarily the same thing. Just because H1N1 did this (we think), I don’t think we should be too quick to assume that a pandemic strain of H5N1 will do it. I think the possibility should be considered that it may have been a fluke; just a peculiarity of the way the viral evasive maneuvers happened to act upon the human immune response — all of which is certainly deserving of as much attention as time and resources permit.
The Sarge – at 08:51
I believe that the infectious minimum for H5N1 is a very low viral particle count.
So initially, it is possible to have only a hundred or so of the host cells invaded. You don’t have to ingest or breath a huge number of H5N1 particles to begin an infection. I don’t think that initial pathogen load is always extremely high. In fact, it may be better for the virus to initially invade with a lower count . . . part of the cloaking, maybe? But if you leave H5N1 for a few days without the innate response, you’ll have millions of actively infected host cells.
If the body only recognises the infection at this millions level, then we have a problem that may become what everyone calls the Cytokine Storm.
I know this is out of context for this discussion…but we should keep in mind the practical possibilities coming out of a discussion like this…my practical possibility that has worked over twenty years of practise…is prednisolone, when used strategically to blunt the immune response yes but also to heal the damage already caused by the immune response (fixs leaks in blood vessels)
But the point of this post is the most likely other possibility would be a synthesized anti-toxin that may be cheaper to make then the ****** antitioxins.
Only, a targeted anti-toxin might actually work and if we could synthesize it…it might be cheap as well.
Just a thought to keep in mind while we discuss the theoretical.
Racter – at 21:45
My premise is that H5N1 is more unique than other viral strains that use NS1 to evade innate immunity because H5N1 is also a rapid replicator.
Two key H5N1 Abilities
This combination along with the other 12,000 nucleotides make it formidable.
“I don’t think that initial pathogen load is always extremely high.”
“H5N1 is also a rapid replicator.”
It depends on what your definition of the word “IS” is.
We won’t be able to make any kind of guess as to what the minimum infecting dose of a pandemic strain will be until we see the pandemic strain. (The “minimum infecting dose”, is usually expressed as the amount of innoculum required to produce infection in 50% of susceptible hosts exposed, and abbreviated to “ID50”).
Not saying your premise is unreasonable, just pointing out that it’s easy to slip into talking as if the crossing of the human species boundary was not only a forgone conclusion, but an event that’s already occurred.
“just pointing out that it’s easy to slip into talking as if the crossing of the human species boundary was not only a forgone conclusion, but an event that’s already occurred.”
…but it has already occurred. /:0)
LL: You are not the only one confused by cytokine storm. This is just a shorthand way to designate a dysregulated signalling system that leads (in this case) the signals to send inflammatory cells to the lung to be stuck in the “on” position.
We don’t know what causes this to happen. It might be the virus itself that does this or some consequence of the infection. In my view, getting your immune system “ready” won’t affect that at all. The better your immune system works the better off you will be since it is your immune system, in its various parts that is your primary protection. For some reason it can also operate terribly wrongly, just as a car can go out of control when its accelerator is stuck down. But that’s not an argument for not keeping your car well maintained and in top operating condition.
Posted by: revere | September 15, 2006 08:54 PM
NS1:
I’m confused about the discussion. I understand that you feel NS1 contains a key to help us. Knowing that you’re into natural medications, the purpose is hopefully to find something natural that will block the NS1 response or something to trigger off the natural killer cells? I’ve studied this dance but I expect it’s even more three dimensional. So if a human is under stress at the time of a vaccination and as a result receives a better immune response than someone more relaxed at the same time, maybe the key to jumpstarting the immune system is emotions? I will provide the stress link if someone wants it but I can’t make it tiny url. Sorry. Also the natural killer cells of the immune system are in the throat, perhaps H5N1 blocks their signal.
Posted to Reveres Blog on SARS as an invitation.
Revere wrote: “We don’t know what causes this to happen. It might be the virus itself that does this or some consequence of the infection. In my view, getting your immune system “ready” won’t affect that at all.”
I am beginning to study the components of Cytokinic Dysregulation and have found that, though, we don’t conclusively know anything about it, we do have a substantial body of data available. In reviewing the data, I’ve found references to incompetent NF-kB potentially being an open door to early and rapid viral replication.
Some of my thoughts on this matter are counter-intuitive to others, I know.
Incompetent NF-kB, a substance found in your cytoplasm, may be implicated by its failure to translocate and/or to activate the necessary genes (dozens potentially) for viral clearance. If we are able to devise a method of causing the body to make fully functional NF-kB or to reform the incompetent NF-kB, then are we creating proper immune response by building the essential components of the immune system? True or not True?
I’m not asking anyone to try this at home. I’m inviting study on the matter. We are discussing these ideas on the FluWiki at http://www.fluwikie2.com/pmwiki.php?n=Forum.CytokinicDysregulation4 if you’d like to comment?
Immune boosting can have just as bad an effect as immune suppressing. Deep nourishment is very different from immune boosting or immune stimulating.
Please know that deeply nourishing the immune system is essential if we are to build these fully functional components. What are the odds that the average person gets all that’s required to build these components?
Posted by: NS1 | September 15, 2006 11:32 PM
Leo7 – at 23:19
Please post your info on emotional mediation of Cytokine and Immune Regulation here. Instead of tinyurl, you can use the format that is show on the bottom of every screen in the grey box.
Stress generates various chemicals in the body including adrenaline and cortisol. Depending on the quantity and other host factors, seroconversion and / or immune response to a vaccination may be up-regulated or down-regulated.
Racter – at 22:33
You are correct that we haven’t seen the PF51 strain yet.
We can only go on what we have seen.
I think NS1 and Tom DVM have hit some key issues about the speed of the immune response.
Example for Tom DVM:
If I sleep in and I am late for an important meeting, I might drive way to fast and be a danger to myself and others. This is the “Cytokine Storm”. Tom DVM recognizes that I should slow down so he asks a cop to follow me to where I am going. This is Prednisolone.
On the other hand NS1 is never late for anything. She can’t fiqure out why I didn’t leave for my important meeting earlier. To prevent me from sleeping in, she’s trying to find me an alarm clock. This is the interferon response.
So the question is:
Do we need the cop or the alarm clock or both? I’ve heard some people say that Sambucol is the alarm clock?
And of course it’s more complicated because no one really knows me. Sometimes I sleep through alarms, earthquakes, loud noises, etc. And I’ve been known to try and out run cops which tends to makes things worse. If I’m in jail how can I make it to my meeting?
Keep up the great work, I’ll keep following :)
Pretty entertaining spok!
Forget the alarm clock, I want my immune system to be banging 4 foot metal gongs and shining a 5 million candle power spotlight on the invaders.
The alarm clock may be what’s getting us in trouble because H5N1.NS1.92.Glutamic_acid knows how to hit the snooze as soon as the first note sounds.
NS1 – at 03:53
“H5N1.NS1.92.Glutamic_acid knows how to hit the snooze as soon as the first note sounds.”
I never thought of it that way. I pictured the alarm clock not going off because it was never set. Meaning the body doesn’t recognize it should be “alarmed”.
I think you are saying that we have the alarm clock and it is set but H5N1 could be hitting the snooze button?
On another note, do you know where I can get some 4′ metal gongs? :)
Just a non-medical lay person here, but I have a question. If someone has an immune system disease, for example, Lupus or Rhuematoid Arthritis, how do you think that person’s immune system would react to H5N1?
Saylor,
Most immune disorders have yet to pinpoint causality according to conventional medicine. Due to that little problem, we can’t begin to speculate on H5N1 benefits or disadvantages.
I can easily say that the problems are multi-factorial and that there are no single-point solutions.
spok,
I’m up to the 3 foot gongs now and working on hammering it into a longer radius with just the perfect curvature. The 4 foot gong depends on the outcome of this thread.
Hi NS1. I was just scanning the papers you referenced to see where I should start reading and they look really scary…like if I read too many, I will have nightmares about being back in university./:0)
Something popped into my mind. I know that you believe there may be a nauturopathic solution to this and there very well might be…
…but history is full of antitoxin and similar developments without understanding very much of the biology behind it (Banting and Best-Canadians-insulin)…maybe some of these chemicals are in the bloodstream of those newly recovered from H5N1.
My question is…if I came to you and asked you to pick something to target an experimental anti-toxin against…could you come up with likely suspects.
Is anyone aware of, or have any thoughts about the role of the CCR5 gene — called “delta 32″ and its role in modulating cytokine response?
”The non-mutated form is what’s called a chemokine receptor. Chemokines are protein distress calls released by an injured region of your body. “The normal function of the CCR5 gene is to act as a retriever of the chemokine distress signal from these bruises, which will then be alleviated by the chemokines.”
“It’s highly unusual,” says Dr. Stephen J. O’Brien of the National Institutes of Health in Washington D.C. “Most genes, if you knock them out, cause serious diseases like cystic fibrosis or sickle cell anemia or diabetes. But CCR5-delta32 is rather innocuous to its carriers. The reason seems to be that the normal function of CCR5 is redundant in our genes; that several other genes can perform the same function.”
This may not sound exciting, but delta 32 is a powerful mistake. HIV, the virus that causes AIDS, attacks the human immune system, infecting the white blood cells sent to destroy it. The delta 32 mutation, however, effectively blocks the crucial gateway into human cells the virus needs. In the case of Steve Crohn, whose partner was the fifth person to die from AIDS, possessing the CCR5 mutation has prevented him from contracting the virus.
The results of the Eyam study suggest that delta 32 may have helped save Europe from the bubonic plague pandemic. It seems logical, then, that this could be confirmed by an experiment in which the plague bacterium is injected into the cells of someone possessing the delta 32 mutation. “We have attempted to design experiments that allow us to expose the plague to the lymphocytes of different people, including Steve Crohn,” O’Brien says. “But so far we haven’t been able to design that kind of experiment ..
The stress factors in this article have been applied to Hepatitis, Pneumonia, and meningitis vaccines too. http://tinyurl.com/l2ryk
Klatu,
CCR5 is a very interesting direction, but its just one gene in a mix of thousands that may be mobilised for our topic. I haven’t seen it yet on the lists within any of the referenced papers on this particular topic.
I’m not so much looking for a solution at this point, but I am hoping to understand the problem better.
So I guess I better do some more homework.
Thanks for mentioning it.
Tom,
I am not equipped for BSL3/3+ and I’m not so sure that handling H5N1 as it stands now would do us much good for the future.
We’re still looking at the basics so we can understand the problem and now you are already solving the thing?
I’m glad you’re with us!
I believe that when the time comes that we need to have labs and technicians ready to conduct your studies.
Any volunteers?
Leo,
I look at your study tomorrow. From the title, I’d say it may be limited in wide application. I’ve seen numerous studies, including using a cohort of medical students, that showed stress dramatically reducing immune response.
We’ll have to study some more because this paper you’ve cited seems to have exact application, but I’m not so sure about the purported facts in the paper at this point.
The Reveres replied yesterday to my request at Effect Measure Learning and Not Learning from SARS.
Marissa also replied on the same thread at Effect Measure
I posted a quick response asking for additional study.
Why shouldn’t we solve this. Fredrick Banting took a part-time teaching job because he hadn’t been very successful as a practising physician…and during his teaching of the pancreas he came up with an idea concerning the possible identification and collection of insulin. He teamed up with another bright young researcher Best and despite the fact they had no funding…together they solved a problem in i8 months that well funded scientists had grappled with for decades.
Why can’t we develop an antitoxin to combat the cytokine storm…I’ll bet you someone who has been snakebit would feel like they were a victim of a cyokine storm as well…it is solvable…pretty much everything is solvable if the stars align as they did when Dr’s Banting and Best got together in that run down laboratory.
bump
Tom,
First we must find the toxin.
Sorry to butt in, most of this discussion goes over my head, I can’t absorb all the scientific links for lack of the basics, but would you translate a little of this discussion for my simple mind please, with respect to the following (only)? To make my thoughts clearer, may I ask these questions that have been bugging me for a while? Thanks.
With reference to: NS1 – at 19:38 - TomDVM, - At the end of day one, H5N1 has made 50,000 times the number of copies that seasonal flu does. So you have to correct the problem at the first cells that are infected. After that, CD ensues and so many cells are lysed that the body’s elimination systems can’t bear the burden.
Is it a question of:
Which of the two (a) or (b) is the most deadly?
Should we discuss of slowing or stopping the cytokinic storm?
If either is impossible by today’s science, would there be a useful track in trying to improve the elimination system’s capacity to get rid of the lysed cells?
Thank you again
(b)
Maybe I should expand on that a little. The problem is that the detritus from all the cell death ends up in the lungs (since cells in the respiratory tract are the ones most affected by influenza). At that point, the “elimination system” isn’t anything complex or subtle; it’s a question of whether the patient can cough the junk out faster than it builds up, and how long he can continue to do so without becoming exhausted. The gas exchange can’t take place if the critical structures are submerged in fluid. There’s only so much you can do to help such a person.
Since much of the cell death typically results from the immune system’s efforts to contain the virus by targeting infected cells for destruction, it’s tempting to look at ways to damp that response down, but even if that works, it’s only a temporary fix. If the virus is allowed to have its way with the cells, its numbers will go astronomical, and the number of infected cells will increase at a frightening rate — and those cells which become infected will die soon enough anyway, because they won’t be able to properly see to their own functions if they’re dedicating their resources to making copies of the virus.
Racter at 9:46-Excellent teaching moment there. A great bit of writing, clarity to the horizon.
Much obliged. Thank you very much Racter.
Racter – at 09:46
“it’s tempting to look at ways to damp that response down, but even if that works, it’s only a temporary fix.”
Then at this point, would it come down to a race between the immune systems coming back on line and how fast H5N1 could replicate?
If you damp the response down to lose this 1st battle, how does the body come back to win the war?
How about an antitoxin to the virus?
Racter at 09:46 - it’s a question of whether the patient can cough the junk out faster than it builds up, and how long he can continue to do so without becoming exhausted.
If the viral load is confined to the lungs yes? What if there is significant viral loads in the digestive system?
Mechanics: do we have (at least in hospitals) the utmost mechanical gear to help clear the junk, in the lungs, in the gut? I realize trying to go and clean up the thousands of little alveolas where oxygen/blood exchanges happen may be very complicated, but would there be a way to do just that - so many things are miniaturized now? What about gut load, anyway of rinsing the whole system without otherwise provoking more damage?
What other ways do we have of eliminating: kidneys, liver/gallbladder, sweat. Anything we can do there to help these functions?
Ideas still foggy on the following, but maybe someone can join the dots: At another level, would there be a way of provoking a temporary graft-versus-host-disease - xenograft/human graft?
I’m sorry if I annoy with my stupid questions, but maybe, somewhere, someone with such questions, may provoke the light in an otherwise unexplored avenue. That’s why I ask.
OOops that was me FrenchieGirl
spok:
“Then at this point, would it come down to a race between the immune systems coming back on line and how fast H5N1 could replicate?”
“If you damp the response down to lose this 1st battle, how does the body come back to win the war?”
At the same time that the cytotoxic T-cells and NK cells are targeting infected cells for destruction, helper T-cells and B-cells are involved in a complicated process which, if successful, will lead to secretion of massive quantities of antibodies well structured to effective neutralization of the viral antigens (the “adaptive” response). Once that point is reached, the immune system will invoke its own methods for damping the inflammatory cytokine response. If we knew more about these regulatory methods, we might be able to initiate them ourselves. But the term “cytokine” refers to a broad class of proteins used as messengers within the system, and the overall response involves many interdependent factors; we don’t know everything there is to know about the interplay between the innate response and the adaptive response, so any attempt to damp the former runs the risk of adversely impacting the latter. The crude methods we have at our disposal now should be regarded as the last resort of a healer who is convinced that he has nothing left to lose.
“If the viral load is confined to the lungs yes? What if there is significant viral loads in the digestive system?” Then elimination is out the other end, and if things get plugged up, you can basically just sort of hose it out. But I wouldn’t expect a pandemic strain to feature receptor binding preferences both for cells in the digestive tract or blood or whatever AND for those found in the respiratory tract (which are the ones it most needs in order to achieve efficient H2H transmissibility).
FrenchieGirl:
“I realize trying to go and clean up the thousands of little alveolas where oxygen/blood exchanges happen may be very complicated, but would there be a way to do just that - so many things are miniaturized now?”
Nanobots. Also on my wish list are an anti-gravity belt, and a full-length VR body suit. May we all live long enough to see such wonders.
Racter. Excellent descripton Thanks!!
Racter – at 13:53 - Thank you.
Wonderful interchange of thoughts and theory here, thank you all for your contributions. Even find myself understanding much of the discussion, at least until it gets too detailed. One comment by Tom DVM made me take notice, that most of his experience in his vet practice shows death from primary viral rather than secondary bacterial pneumonia. I was under the impression from Barry’s book and other sources, that it was the reverse. If true, so much for getting the Pneumovax shot with it’s protection against 20 something bacterial types!
Has there been information published from samples taken from many of the 240 or so victims of H5N1 that would show whether they have died from either and if so, which type shows up more often in victims? If it is viral, then my understanding is that we have not made much progress against viral, as we have made so little progress against the so called cytokine “storm”. Not very encouraging. Let’s hope that some of the discussions here on other avenues may bear some fruit.
Henry Niman, would like to see you back commenting here. Miss your contributions.
Wow. Reading these posts I really realize that I am out of my league on this thread, but I throw this out there anyhow.
This came from the result of postings on the thread: IHadMyFirstPandemicDreamII
Question: Where do the cytokines go when released as a result of bee venom? To the lungs or to the sting? Could this be a way to divert to cytokines to a less vulnerable part of the body?
Thanx.
Beehiver - This is the severe inflammatory reaction that vitamin D has recently been found to prevent.
Tom DVM - prednisolone
NS1
How about (natural) COX-II inhibitors?
JWB – at 15:35:
The short answer is, “It depends.”
“Cytokine” is a rather generic term for small proteins that are secreted (mostly by cells in the blood called lymphocytes and monocytes). Their function is to regulate immunity and inflammation. Some of them operate on the very cells that secrete them, some operate on nearby cells, and some operate on distant cells. If I remember correctly, a cytokine called “Interluekin 1-alpha” is one of the cytokines released in large quantities during a cytokine storm; it is responsible for generating an immune response and fever in many different cells thoughout the body.
Based on that, I don’t think it would be possible to “divert” cytokines to another part of the body … but I am not a immunologist, nor do I play one on TV.
Certain chemicals that occur naturally in bee venom, seem to have anti-inflammatory effects in the body. In fact, bee venom apparently helps to produce cortisoles in the body that act as a pain reliever. The antioxidant property of bee venom also naturally supports the immune system.
In 1973 the Kennedy Institute of Rheumatology published a study about a certain compound that occurs naturally in bee venom, Peptide-401. The study proves that Peptide-401 to be 100 times stronger than hydro cortisone in its anti-inflammatory properties.
The other substance that occurs naturally in bee venom is Melittin. Melittin helps stop the production of harmful free radicals in the body. Free radicals can have negative effects on the joints. Another benefit of Melittin is that it causes the pituitary gland in the body to release ACTH, which in turn stimulates the adrenal gland to help produce the body’s own cortisol.
Bee Venom positively affects the immune system through the hypothalamus, pituitary and adrenal glands. Therefore, when compared to most other medications, bee venom therapy supports the immune system and does not weaken it.
Further compounds that can be found in bee venom are apamin, dopamine and adolapin. Apamin helps the synaptic transmissions in the body, while dopamine is known to stimulate motor activity. Adolapin seems to have a pain relieving, analgesic effect.
And
In a controlled study from Allegheny University of the Health Sciences in Philadelphia, bee venom was found to have no positive effects at any dosage in mice with EAE, the animal model for multiple sclerosis. Additionally many of the animals expressed worse symptoms from the placebo groups. [1]
Phase I of a study at Georgetown University Medical Center in Washington, DC, funded by the Multiple Sclerosis Association of America (MSAA) was geared towards safety in administering bee venom treatments to humans with multiple sclerosis
Dennis in Colorado, TomDVM and other likeminded scientific people, Does this snippet about bee sting venom anti-inflam. action have any relation to h5n1 cytokine activity (or suppresion of?)?
http://tinyurl.com/qbjey Next, the team investigated the mechanism of the antiarthritic effect in a murine macrophage cell line and in synoviocytes obtained from RA patients. They showed that bee venom inhibited the generation of inflammation mediators, reducing lipopolysaccharide (LPS)-induced prostaglandin E2 and nitric oxide (NO) production, and they speculate that this is a result of COX-2 inhibition. This inhibitory effect of bee venom is consistent with that shown previously for indomethacin, they comment. Bee venom also exhibited important inhibitory effects on the generation of inflammation mediators, including tumor necrosis factor- (TNF-), and their enzyme expression and on LPS-induced reactive oxygen species generation as well as calcium release. In addition, the researchers showed that bee venom and 1 of the purified proteins, melittin, inhibit the transcriptional activity of NF-B, 1 of the most important regulators of expression of proinflammatory genes such COX-2, cytosolic phospholipase A2 (cPLA2), inducible NO synthase (iNOS), and TNF-. The result is a reduction in inflammatory gene expression. Surface plasmon resonance (SPR) analysis showed that bee venom and melittin interact at a specific p50 binding site.
I belive Tom is better equipped to answer Lisa’s question than I, but I’ll provide some background info while waiting for him to reply. There is a tutorial on cytokines at
http://microvet.arizona.edu/Courses/MIC419/Tutorials/cytokines.html
There, they list 20 “selected” cytokines and their properties. Of those listed, TNF is the only one from your article above.
There is an article in Widipedia on cytokine storms, athttp://en.wikipedia.org/wiki/Cytokine_storm
There, they list three pro-inflammatory cytokines that are usually elevated in a cytokine storm: TNF, IL-1 and IL-6 (note that there are also some anti-inflammatory cytokines which are elevated during a cytonkine storm, namely IL-1 Receptor Antagonist, and IL-10.
If, in fact, bee venom only works to inhibit TNF (among the cytokine storm villians), then I question whether or not it could be of great benefit to prevent or treat a cytokine storm. The IL-1 and IL-6 cytokines might still be elevated enough to cause problems.
Tom (or others) what thinkest thou?
Dennis in Colorado – at 20:10
“If, in fact, bee venom only works to inhibit TNF (among the cytokine storm villians), then I question whether or not it could be of great benefit to prevent or treat a cytokine storm.”
Maybe, bee venom is more important as a “stress factor” from
Leo7 – at 01:32 The stress factors in this article have been applied to Hepatitis, Pneumonia, and meningitis vaccines too. http://tinyurl.com/l2ryk
Maybe it is the alarm clock or the snooze button de-activator that NS1 has been looking for?
Dennis in Colorado - thank you for putting the bee venom article into clear, understandable context for me. I’m deathly allergic to bees, so even if this were lifesaving for many it would be an off-limits treatment for me. I was fascinated though, and needed some help clarifying the article content which your reponse provided.
spok - are you thinking that the venom could possibly/theoretically be used to increase antibody production with a vaccine?
Lisa in Southern Maine – at 21:38
Yeah, my interest in bee venom is purely hypothetical, too. I am also allergic to bee venom and have no personal interest in using it <grin>
I’ll have to use other methods to avoid a cytokine storm.
Lisa in Southern Maine – at 21:38 “spok - are you thinking that the venom could possibly/theoretically be used to increase antibody production with a vaccine?”
I wasn’t thinking about a vaccine. I was thinking about trying to get an immune response with H5N1 based on what NS1 said below:
From NS1 – at 20:49 “You see, we know that the H5N1.NS1.92.glutamic-acid slows the Innate Interferon response of the host cell with the viral particle in it. If the Innate Immune System responded properly in a timely fashion then the virus in that cell would be suppressed from replicating. And no Cytokinic Dysregulation would occur.
The key is to have each infected cell react in 2 hours instead of 10 hours using the innate anti-viral and anti-replicative immune response.”
And also, based on: Leo7 – at 01:32 The stress factors in this article have been applied to Hepatitis, Pneumonia, and meningitis vaccines too. http://tinyurl.com/l2ryk
I was wondering if a bee venom supplement could artificialy speed up the immune response to H5N1
Hi everyone. You are doing a wonderful job with this thread…it may not be going exactly the way NS1 envisioned…but it is darn interesting to read.
Dennis and Racter have done a wonderful job of simplifying things.
I am way out of my league on this thread.
“I belive Tom is better equipped to answer Lisa’s question”
Dennis the fact is that I am a boots on the ground phenotype kind of guy. The genotype is the specific genetic makeup of something…I don’t deal in this but the phenotype which is the expression of that genetic make-up in nature. I really don’t care much about genotype I want to diagnose the problem and then fix the problem…and I rarely understand everything about the problems I fix…I just take what I do know and just fix them anyway. Therefore, I could not have provide such a clear and concise explantion as you just did.
Which brings me to the reason for this post. I will try any angle to solve a problem…if one approach doesn’t work I will just change approaches until I find one I can understand and make work.
I would like to discuss this from a little different angle in the hopes that we come up with a solution…because in my world, theoretical solutions without a translation to practical solutions don’t mean much.
It is my opinion that we will have a ten percent mortality rate in this pandemic… so that means in my mind…10% mortality…10% life-limiting chronic sequelae…10% mortality from collateral damage…that means 10% of the attack rate of course and not necessarily 10% of the population. The attack rate in my opinion will come in around 70 % and I believe eventually only approx. 5% will have some form of natural immunity and escape infection (over a decade).
This means that if we line up 100 sick people, 80 % will be very sick but have no cytokine storm and recover with no after effects…
…and here lies the major problem with our concept. We can’t afford nor would we have the avaliability to treat 100 of 100 patients with a preventative for the cytokine storm…secondly…most of the deaths and chronic aftereffects are not due to secondary infections but due to direct viral infection….antivirals role (efficacy) in these infections are very much up in the air at the moment.
So we need an anti-toxin or an anti-cytokinin that will inactivate cytokinin activity for a short period of time to allow us to insulate our patient with other pharmaceuticals…in my mind prednisolone.
The advantage of an antitoxin or sorts would be that it would work instantaneously and could be targeted to only patients who needed the treatment rather than blanket treatments with limited resources.
Unfortunately, we have stopped the production of antitoxins after antibiotics became common at the end of the second world war…
…but the pathway has been lit for us by our predecessors who I have great personal respect for…we need to go back in history, learn from them and apply their technologies to provide us with a solution to this problem…we could save a lot of young and beautiful people this way…like JWB said on another thread…maybe our next Einstein who may save the world in the future.
I don’t need to know every nuance of this process to solve the problem…I just need to start making anti-cytokinins for all the known cytokinins in these hundred papers that may be related.
As always the answers and the solutions are straightforward after the fact…and there are many ways to get ‘purchase’ on the problem.
Just thought I would throw my two cents in and see what you thought Thanks.
As a practising veterinarian, I ran into a new type of pneumonia in the late 1980′s that was the animal equivalent of SARS in every minute detail…so I spent a lot of time first failing miserably and then designing a treatment that worked in Cattle.
Now I am not saying that H5N1 is remotely similar to what I treated in the past because H5N1 is a ‘monster’…let no one make the mistake of underestimated the vehemence, viscousness physiologically of this pathogen.
However, I have found that slowing the immune system a bit does not result in the virus over-running the body. I think the reason for this is that the cytokinins or whatever do two rather serious things from a treatment point of view…ie in the first 24 hours…
…the immune system punches holes in the blood vessels. This results in decreased blood volume and basically sludging of blood (decreased oxygen to the tissues) and plasma leaks into interstitial spaces and then directly into the lungs as edema etc. (decreased transfer of oxygen from air to blood).
The second thing that happens whether from the immune system or the virus (I think maybe the immune system) is that holes are punched in the lungs themselves resulting in gas pockets under the skin…this doesn’t help oxygen exchange either.
I found that the targeting of moderate doses of prednisolone for short periods of time would limit this damage and give my antibiotics time to build up blood concentrations. I would maintain the prednisolone form one day…or sometimes two days but rarely longer than that…and then with concurrent anti-fever drugs tried to get the body working without steroids quite quickly..temperatures would spike but the animal would usually improve at a steady state although still being quite sick over the next 5–7 days.
This modulation of the immune system limits the damage to only direct viral injury…the antibiotics ensure there will be no secondary bacterial infections and by removing the immune system over-reaction for a short period of time…my success rate improved by many multiples without chronic after-effects too.
If we could develop the additional anticytokinin to use with prednisolone…I think we would stand a pretty good chance of saving a whole lot of children. /:0)
Is it possible that the immune reaction to a bee venom suppliment could speed up the Innate Immune System’s response to H5N1?
NS1 said that if we could get the Innate Immune System to respond faster then the virus in that cell would be suppressed from replicating. And no Cytokinic Dysregulation would occur.
If bee a bee benom suppliment can’t get a faster Innate Immune System response to H5N1 then what are the other options to speed up this process up?
NauticalMan – at 15:32
Niman has been permanently banned by the moderators.
Thank you NS1, did not realize that. Thought it was just a two week suspension. Too bad, but it is their site and they seem to know what they are doing.
I was also under the impression that it was just a suspension, and that Niman simply chose not to return. Still am, in fact.
Racter. NS1 is right…the ban was permanent.
The way I remember it:
Niman was banned for one week and then he came back. Then when he came back he was banned permanently.
Hence the name
Regarding Niman at fluwiki-a “cytokine storm” under the bridge.
Medical Maven – at 21:59 Regarding Niman at fluwiki-a “cytokine storm” under the bridge.
Now if we can find a way to ban H5N1 :)
MM - ??
A special thanks to all the great postings regarding the bee venom question! :-)
I don’t have any experience with bee venom suppliments and it seems like no else does either. I entered bee venom on PubMed and there were over 200 results. When I make it through the reading, I’ll post anything that pertains to immune response or the cytokine storm.
This is cross posted from the vitamin D thread.
The recently published article “Epidemic influenza and vitamin D” has free full text available online here.
Page 4 has a section titled “Mechanism of action of vitamin D”. It says in the third paragraph (references are in brackets):
“Perhaps most importantly, three independent research groups have recently shown that 1,25(OH)2D dramatically stimulates genetic expression of antimicrobial peptides (AMP) in human monocytes, neutrophils, and other human cell lines [43–45]. These endogenous antibiotics, such as defensins and cathelicidins, directly destroy invading microorganisms [46]. AMP display broad-spectrum antimicrobial activity, including antiviral activity, and have been shown to inactivate the influenza virus [47–49]. Not only do neutrophils, macrophages, and natural killer cells secrete AMP, but epithelial cells lining the upper and lower respiratory tract secrete them as well, where they play a major role in pulmonary defense [50,51].”
Please note that 1,25(OH)2D is vitamin D3.
Friends, I made a slight mistake in my post above. Vitamin D3 is not 1,25(OH)2D. Not quite, anyway. Vitamin D3 (cholecalciferol), a common supplement, is converted to 1,25(OH)2D in the body after it is ingested.
This link has a slide show demonstrating the cytokine production. Just click on “view figure”. Cytokine Storm- Interactive Figure. Proposed Mechanism of the Cytokine Storm Evoked by Influenzavirus.
In the image, you will see cytokines being produced by three sources: the epithedial cells, the T-cells, and the macrophanges. There are many different types of cytokine proteins, which deliver various messages to other cells. We are still unraveling what the differences are in cytokines.So it’s a lot more complicated than just talking about cytokine as a single problem causing entity.
It’s not just that too many damaged cells are lying around clogging up oxygen exchange, but the inflammation triggered by certain overproduced cytokines, cause a blowtorch effect internally, causing the lung tissue and capillaries to dissolve. This causes the blue “cyanosis” and haemorraging symptoms.
H5N1 seems to trigger far more of the cytokine storm factors than the H1N1 virus. This is why the next pandemic could be far worse than the 1918 pandemic. The New England Journal of Medicine “According to Michael Chan and colleagues from the University of Hong Kong and collaborators in Vietnam, the H5N1 is a much more potent inducer of pro-inflammatory proteins than H1N1. Twenty-four hours after infection with H5N1/04, the levels of the chemokine IP-10 in bronchial epithelial cells reach 2200 pg/ml, whereas in cells infected with H1N1 they only reach 200pg/ml. In H5N1/97-infected cells, IP-10 levels reach 1750 pg/ml. Similar results were found for other chemokines and cytokines.”
This birdfluriddle site is promoting a Dr.Moskovitz’s treatment hypothesis.
“Because, just like SARS, the H5N1 virus targets the lungs. In West Nile Virus patients the targeted organ is the brain, so that is where the cytokine storm will occur, because the West Nile virus is also immune to these cytokines.
Let us take a look at the solution offered by Dr. David Moskowitz. Although other researchers also arrived at the same conclusions, he is the only one with a track record of successful clinical trials. What medication did he use? He used FDA approved and widely used blood pressure drugs. His answer to the cytokine storm is to take an ACE inhibitor, or an ARB. How do ACE inhibitors interfere with the over-production of cytokines? For a detailed description, go to the links provided in Chapter 2, in the ACE inhibitors and ARBs section. The important thing is that they inhibit the white blood cells from releasing TNF and IL-6 cytokines, preventing or stopping the cytokine cascade, thus saving the life of the patient. Angiotensin II receptor blockers (ARBs) are medications that lower blood pressure like ACE inhibitors, but by a different mechanism. Both medications work by affecting a substance in the body that signals blood vessels to constrict or narrow, called angiotensin II. Why should you trust this method to prevent or stop the acute respiratory distress syndrome (ARDS), caused by the cytokine storm? After all, it has never been tried against a single bird flu patient. Dr. Moskowitz applied it to a group of West Nile Virus patients, and Dr. Penninger to SARS-infected mice. Both trials were successful, but do they prove efficacy for bird flu patients?”
Another hypothesis from the Lancet, March 11, 2006, titled “Cytoxic therapy for severe avian influenza A (H5N1) infection” (Huenter, Chow, Leung, Lou) This compares H5N1 to another disease, HLH, and suggests that the same treatment might work. (Sorry for no online link)
snips…”Patients with H5N1 infection have symptoms similiar to those found in HLH, an often rapidly fatal disease for which survival rates recently have improved greatly. Investigators from Hong Kong have reported that two patients with fatal H5N1 disease in 1997 had a reactive haemophagocytic syndrome as the most prominent feature. Moreover, these patients had high amounts of soluble interleukin 6, and interferon y. Similiarly, HLH is associated with a massive hypercytokinaemia, and the earliest reference to this term in PubMed is actually to HLH. reactive haemophagocytosis has also been reported in H5N1-infected patients from Hong Kong in 2003 and from Thailand in 2004.
…HLH-94 has been used successfully in human beings affected by severe virus infections for more than 10 years, thus, we thought well-controlled use of the treatment inpeople with severe H5N1 infection would be reasonable and relevant. The first 8 weeks of HLH-94 treatment include etoposide and dexamethasone, and intrathecal methotrexate..” (refer to article for the doses of treatment)
“…it would be unfortunate if this therapy was effective but never attempted… we welcome WHO to consider a platform for undertaking clinical trials based on a modified HLH protocal (including corticosteriods and etoposide) in addition to supportive and antiviral therapy.”
There is also an interesting article out in the Oct. Scientific American, but not online yet, titled “Peacekeepers of the Immune System”. Regulatory T cells have only recently been discovered to exist and that keep the body’s defenses from attacking itself, and suppress the immune system. Obviously they sometimes do go wrong, in autoimmune diseases- MS, diabetes, rhumatoid arthritis, psoraisis, allergies, etc. Knowledge of the immunosuppressive T-reg cells will be key in recruiting them for use against a host of debilitating and even fatal disorders.
NJ. Preppie – at 14:43
Keep in mind that Dr. Osterholm’s article is over a year old and that the graphics are designed to have “sound bite” level specificity. They depict a vastly simplified and generalised sequence of events. The diagram presented in the previous post bears little to no alignment to the reality of dozens of chemicals and hundreds to thousands of individual interactions in each few mL of infected tissue volume.
NJ. Preppie – at 14:43
The effect described here as blowtorch may be more precisely and less dratically described as a chokepoint effect. Inflammation increases tissue volume and partially or completely closes the area from ingress and egress. Again, a natural protection mechanism of the body to concentrate beneficial biological resolvements and reduce pathogenic spread.
The highly lytic nature of H5N1 also produces vast amounts of dead cell detritus that, in turn, decreases gas exchange.
Let’s talk some more about things like these comments:
Oscillations in NF-B Signaling Control the Dynamics of Gene Expression
Now you can see that we need to dig deeply because even using the most current tools and methods and probing one particular mediator, many questions arise in the investigation.
Phenotype speculation is important as a framework and as a final actionable solution; however, that final actionable solution will be built on a foundation of solid data if we do our homework here.
Please read the papers referenced and provide comments.
Anyone willing to review and comment on this recent article in the September issue of Pediatric Neurology?
Role of Viral Infections in the Etiology of Febrile Seizures.
More info on genetic information exchange and a look at the concept of quasispecies. A basis for my discussion on the relative promiscuity of the viral gene pool.
RNA virus quasispecies and Virus Receptor Diseases
The previous paper asserts another key point in gauging identification of dominant genotypes in the lab and by our immune system.
NS1. I will never know the entire biochemcial nuance of reactions caused during the cytokine sotrm…so all I can do is use what experience and knowledge that I do have to comment where possible.
I think your statement above may be the key to the cytokine storm…the immune system, no matter how efficient it is, and it is highly effective like a F-15 fighter jet…has a lag period while it is prepped for take-off and appropriately armed.
If the statement above is correct, the immune system will not only be ineffective in response but will also be diverted to fighting a multitude of harmless background scatter ‘defective and non-infectious particles’ circulating around the body.
An immune response to a vaccine is designed to repond to live virus and not to particles so it may be inappropriate especially if the particles are a main contributor to the cytokine storm…
…for instance if a virus could break in to a thousand fragments circulated to various tissues but primarily captured in brain, liver, lung and kidney…than the monocellular response (non-antibody response) would remove every one of these particles…punching holes in organs, cells and blood vessels.
Therefore, we may need a process that inactivates these particles so they will not be identified by inflammatory cells…
…again I think the solution is in the form of an anti-toxin and not a vaccine…and I am not talking about the infection in general where a vaccine works best…but a response to the cytokine storm that we know will kill at least ten percent of all young people who get it.
What do you think?
Tom:”An immune response to a vaccine is designed to repond to live virus and not to particles so it may be inappropriate especially if the particles are a main contributor to the cytokine storm.”
Well… hold on.
I hope this isn’t too much of a quibble. An immune system is designed by millions of years of evolution. A vaccine is designed by humans in that it exploits a certain degree of predictibility in the pre-existing biological design. An immune response to a vaccine is what happens when the two meet. You can poke a stick at a tiger and make some reasonable predictions as to the general character of the response, and maybe exploit that predictibility to get him to move around a circus ring in a certain way, but you’re not exactly going to get him dancing the macarena as if he were a marionette in the hands of a skilled puppeteer.
And, technically, many vaccines do not involve live virus, or even whole virus. Neither does naturally aquired immunity necessarily depend entirely on whole virus. The response is triggered by antigens, defined rather loosely and almost tautologically as “something an antibody binds to”. Even fragments of viral protein may trigger a response.
“for instance if a virus could break in to a thousand fragments circulated to various tissues but primarily captured in brain, liver, lung and kidney… than the monocellular response (non-antibody response) would remove every one of these particles… punching holes in organs, cells and blood vessels.”
Part of what the inflammatory response is designed to do is to make it harder for a pathogen to travel around. That would apply to fragments too — and much of the cell death is part of the immune response, but the targets are infected cells; fragments aren’t going to do that.
Hi Racter. “I hope this isn’t too much of a quibble.” Nope!! /:0)
fragments can be used to produce an immune response…but the target is the intact virus.
Pieces of virus would not be affected by the immune system but would be recognized and removed by the cellular response.
Viral debris could contribute significantly to the cytokine storm and the monocellular response would be tied up for significant periods of time.
If the fragments attach to blood vessels then a hole will very likely end up being punched in the blood vessel and then you get leakage, interference with gas exchange etc. and a functional decrease in circulating blood volume also lowering gas exchange with the tissues…prednisolone is looking better and better all the time./;0)
I have had the personal and professional experience backed up by some studies to indicate that vaccines don’t work for influenza.
But lets ignore reality and say that vaccines are 100% effective…we are only going to have 200 million doses…
…only about 20% of all those infected will require the vaccine to prevent the cytokine storm etc…there is no way that anyone can pick out who is going to need the vaccine beforehand…meaning most of the vaccine will not change the end result one bit…even if it works 1005 of the time…
…However, if we develop an antitoxin that can be used concurrently with prednisolone and other drugs only when the patient has the cytokine storm or is appearing to develop the cytokine storm…these treatments can be targeted to only those who need it raising effectiveness and efficiency significantly.
This finding listed by NS1 has answered a lot of my questions about the cytokine storm and why the immune system wins the battle (removes the virus) but loses the war (the patient dies)…the viral space junk is the answer.
thanks.
Some of that several billion dollar investment given to the private sector for vaccines should instead to be used to fund public sector (university etc) research into anti-toxins…most of the ground work has been done by our predecessors before antibiotics were developed.
Patents produced in the development phase should be retained in the public trust and liscensed if necessary to public/private partnerships which is exactly how the polio epidemic problem was handled by Connaught Laboratories in Toronto, Ontario, Canada.
Why could this approach not work to save many more young lives…that is after all what we are after.
Have any of the people here considered using a parasite to blunt the replication of H5N1? The example of using bacteriophages to control antibiotic-resistant bacterial infection suggests that this might be a viable strategy. With this in mind, check out: Quantitative Analysis of a Parasitic Antiviral Strategy Authors: Hwijin Kim and John Yin* Appears in Antimicrob Agents Chemother. 2004 March; 48(3): 1017–1020
Their model system was a bacteriophage (qbeta) that targets E coli bacteria. The measure of the efficacy of their treatment was E coli survival. They protected E coli by adding parasitic RNA to the mix, derived from Qbeta. This parasitic RNA competed for viral replicase, thereby blunting Qbeta’s ability to replicate. The parasitic RNA lacks ribosome and coat protein binding sites, and thus is (relatively) benign. Because of its shorter chain length it could replicate faster than Qbeta, and hog the replicase.
Anyway, that’s as much violence as I’m willing to do to someone else’s work. This might be a way to stunt the explosive replication rates of H5N1
“Viral debris could contribute significantly to the cytokine storm and the monocellular response would be tied up for significant periods of time.”
That does seem to make sense, though I don’t see why H5N1 (or H1N1) would be a special case, unless it had to do with the greater extent of cell death due to the prolonged time for the adaptive response to build against a novel virus — which is where I always end up coming back around to with the cytokine storm thing.
“‘’If the fragments attach to blood vessels’”“
I’m not sure I understand why you think they would do that.
“prednisolone is looking better and better all the time.”
Not to me it isn’t. Just had a bone scan. TODAY, as a matter of fact. Just inside the yellow zone. Could have been worse. I’m probably feeling a little extra biased against corticosteroids in general right now.
How do we always seem to end up talking about vaccines?
Dont laugh!!! After all this time - I am wondering what the proper pronunciation of ‘cytokine’ is?? Is it - sight-oh-keeen??
Long term use of corticosteroids is very different than a two to four day blast of prednisolone.
gharris – at 13:17
SIGHT-ah-kyne (long i for the last syllable, not a long e)
Only my second post, please excuse me for mentioning something that has been in my mind a while
“South Korea’s disease control agency confirmed Friday that five people have developed antibodies to the lethal H5N1 strain of bird flu after taking part in the slaughtering and disposal of infected chickens and ducks.
I’m curious to know if very much attention is being paid to why Ducks are carriers but show no symptoms. What is it that is different about their immune response and would it be conceivable that something in their blood could be isolated to induce antibodies?
ducksoup – at 18:37
The idea is beautiful!
Until we have a deeper understanding of the bridging relationships between those viral strains that we deem bacteriophages and the ones we only call viral strains, I’m reluctant to place my faith in any more anti-biotic experiments that may go awry or contribute resistence genetics to the very promiscuous gene pool. You’re just taling about another antibiotic . . . you know that right? Just because it also competes for resources with another infecting virus does little to assuage my concerns.
Think longer term.
Remember that our manipulation of the little fellas may have caused them to build stronger versions of themselves. Do we want to continue to drive them under pressure to search for new inputs (genetic material) in their build toward dominance.
Tom and Racter,
At the moment, with very little time, I’m leaning away from the ideas that Tom is presenting and holding a closer line to Racter’s ideas. I’m sorry that I can’t write more at this instant.
Each of you is driving this conversation toward a solution and I’ve very grateful for your individual devotion.
“Long term use of corticosteroids is very different than a two to four day blast of prednisolone.”
Having learned it the hard way, it’s a lesson I’m not likely to forget.
NS1, I haven’t had much time lately either, and it looks like it’s going to get worse before it gets better. As ashamed as I am to admit it, I still haven’t even finished the homework.
Racter,
I was hoping that you and Tom specifically could act a first or second reviewers on each text of the homework, because I haven’t been able to fully concentrate on 100% of the presented texts (90% read and 70% studied).
Please email me at the address in my profile here . . . yellow zone?
I’ll be back much later tonight and have a load of questions for you.
The Series on Cytokinic Dysregulation is continued on
Please forgive the formatting of the first post that was done in haste.
oops -my error
Something wrong with the post above this one, I think.