A cautionary tale about cytokine storm

Here's a cautionary tale. Many readers know that H5N1 infection is capable of causing a sudden over activity of the immune system, manifested in a so-called cytokine storm. Over active immune systems have been implicated in many other diseases, as well, although the type of "over activity" isn't the same. Autoimmune diseases, like rheumatoid arthritis or lupus erythematosus are caused by the body making antibodies to its own tissues. As in cytokine storm, an immune system that normally functions to protect us, makes us sick. To damp down the inappropriate activity, drugs like steroids are used to modulate the immune reaction. Steroids have also been used to treat cytokine storm, to varying but usually modest or no success. Still, many readers here equate "over active immune system" with cytokine storm. It is a dangerous way to think.

In August we posted here about a case series in The New England Journal of Medicine describing a drug trial that went suddenly and terribly wrong. Six patients were infused with an experimental drug to treat the over active immune system that produces rheumatoid arthritis. The drug, TGN1412, worked by stimulating a receptor, CD28, on the surface of a key cell in the immune system, a T helper cell (Th cell). Th cells are master signalling cells, releasing chemicals that tell one or another type of immune cell to do things, that affect the tightness of blood vessel walls to allow inflammation fighting cells from the blood to get into the tissue and attack invaders, or to reverse some process that another signal has started. The many different chemical signals involved in this back and forth in the immune system are called cytokines and chemokines.

Th cells are induced to do these things by a fail-safe double key mechanism. Th cells first must recognize a foreign protein that is presented to them by another type of immune cell, called an Antigen Presenting Cell (APC). Th cells are very fussy. They must have a proper introduction to the foreign protein by the APC. They recognize the protein by a lock and key arrangement with a specialized receptor on their surfaces, called a T cell receptor (Tcr). Tcr's are specific for particular proteins in the same way that antibodies are specific for foreign materials (Tcr's only recognize proteins, though; antibodies can recognize other kinds of molecules as well). Thus Th cells are part of the adaptive immune system. They are not part of the generic, innate immune response. They are trained or adapted to recognize specific proteins, by virtue of previous exposure.

But recognizing the foreign protein via presentation by an APC is not sufficient. Ordinarily there is a second requirement, a non-specific one that is given by a molecule on the surface of the APC. That molecule (B7) must make contact with the CD28 receptor on the surface of the Th cell. When both of these buttons are pushed (the Tcr and CD28) the Th cell becomes activated. It starts giving off signals. Two signals are required because activated Th cells are very powerful weapons, only to be used under the right circumstances. In addition, you don't want them to keep signalling for help. So there is some kind of negative feedback system where some signals given by the Th cell activate other T regulatory cells whose job it is to damp down the immune response after a suitable lag.

Now to the drug, TGN1412. It was noticed that in many immune diseases there seemed to be a deficiency in the T regulatory cells. Therefore the immune response wasn't damped down in general and immune disease resulted. It was also found that if you could stimulate the CD28 receptors with a "superagonist" you could preferentially expanded the T regulatory cells. A superagonist is a molecule capable of turning on the Th cell by hitting CD28 without needing to have the Tcr stimulated. The generic key alone is sufficient if that key is a superagonist instead of B7. TGN1412 is a CD28 Th superagonist.

Tests in animals showed it did just what they hoped. In 2005 the scientists developing the drug for a biotech company reported their results in the scientific literature:

We have recently shown that superagonistic monoclonal antibodies with specificity for CD28 (CD28 superagonists) are capable of activating and preferentially expanding Treg cells over conventional T cells in vitro and, importantly, also in vivo. Moreover, therapeutic application of CD28 superagonists elicited profound therapeutic effects in various animal models of autoimmunity, including experimental autoimmune encephalomyelitis (EAE) and adjuvant arthritis (AA) of the Lewis rat. Adoptive transfer experiments with Treg cells from CD28 superagonist-treated rats proved that protection from EAE is, indeed, mediated by CD28 superagonist-activated Treg cells.

Therefore, effective targeting of CD4+CD25+ regulatory T cells makes CD28 superagonists a promising novel tool for the treatment of human autoimmune diseases. (From the abstract)

In other words, it worked to dramatically reduce the effects of autoimmune disease in two animal models. The autoimmune process in these diseases is not the same as cytokine storm, except that it is the result of an over active immune system. The objective was to calm the activity of the immune system, and that seemed to work in animals.

In the spring of this year the drug was tested on humans. Six subjects received doses of the drug lower than given the animals because this was a safety trial. This is what happened:

Around 60 to 90 minutes after the men received their injections, their bodies were flooded by a surge of inflammatory chemicals called cytokines, which combat severe infections like those seen in patients with blood poisoning. The cytokines caused severe inflammation.

1 hour - simultaneously, the six men begin suffering excruciating headaches, shivering, back pain, gut pain, diarrhoea, swelling and nausea

4 hrs - all have fevers, are flushed, their blood pressure drops dangerously low and their hearts start to race. Blood tests show their lymphocytes and monocytes are fast vanishing.

5 hrs - one patient begins fighting for his breath. All suffer lung pain. They are all given steroids and other medications to ease inflammation.

12 hrs - the patient fighting for his breath is so bad that he has to be taken into intensive care and put on a ventilator to keep him alive.

Suntharalingam [physician supervising the trial] decides to take all the volunteers into intensive care as a precaution.

24 hrs - two people are on ventilators, and the four others need support with breathing.

48 hrs - the four least affected men start to recover, but all six begin to suffer multi-organ failure, and have to be attached to kidney machines, one of them for a fortnight.

Thereafter, the men began to recover and their lymphocyte and monocyte counts began to creep up again. (New Scientist)

Thus the immune calming turned into a cytokine storm.

. . . scientists note that the trial illustrates how incredibly potent some immune-altering agents can be. "The immune system is capable of extraordinary power and we must be very careful when we tinker with it," says Louis Weiner who studies immunotherapy at Fox Chase Cancer Center in Philadelphia, Pennsylvania. (Nature)

It might be that H5N1 somehow produces a CD28 superagonist like TGN1412. Or maybe not. The immune system is complicated. We do not understand most of it. It is not as simple as calming an over active immune system.

As I said, a cautionary tale.

More like this

So, perhaps we laypersons should say, H5N1 causes "cytokine disregulation" when they don't really understand how the complicated immune system works in the first place, so, that's why we don't have good treatments yet?

By crfullmoon (not verified) on 11 Oct 2006 #permalink

crfullmoon: Not just laypeople. Scientists, when they are speaking precisely, refer to cytokine storm as cytokine dysregulation, too. There are different ways for dysregulation to appear, some of which show extreme forms called cytokine storms. Probably there are different kinds of storms and there are some dysregulations that don't appear stormlike. The term "cytokine storm" is an imprecise metaphor, not a real technical term. Dysregulation is still vague, because it doesn't specify the nature of the dysregulation, but it is more precise because it locates the problem in a failure of the signals and countersignals to function normally.

One immunology book likens the task of the immunologist to trying to figure out a football team's playbook by intense observation of just one player (e.g., the tight end) on play after play. It is hard to figure out what is going on unless you know what all the other players are doing and why.

crfullmoon: we scientists should also be using that term, too. I also use the term cytokine imbalance. Hypercytokinemia is probably an overused term, and should be reserved for those situations in which massive upregulation of pro-inflammatory genes occurs.

Great post, Revere. I think what H5N1 does best is destroy the delicate feedback loops. When we use steroids in too high a quantity, it swings the loop in the other direction, with too much supression. In other words, and treatment must be positioned so as to maintain the feedback loops.

Revere, here's your chance to clarify any further misunderstanding re: immune system disregulation and cytokine storms.

I am more familiar with the frightening effects of inflammation in the airways due to asthma attacks, a histamine response, (right?) that small, metered doses of inhaled steroids can minimize without affecting the whole blood stream.

And I had thought that such meds would be useful in treating H5N1.

You, however, are describing a whole body response, which makes an asthma attack, dangerous as it can be, pale by comparison.

Is this treatment for asthma also comparing apples to oranges, a misunderstanding of the biochemistry involved, not to mention the vast difference in scale?

I suppose I was hoping that similiar meds could at least help more modest manifestations of the disease.

Thanks again for your incisive attention to the issues involved.

By limestone (not verified) on 11 Oct 2006 #permalink

Is a cytokine storm similar to an anaphylactic reaction?

By Gaudeamus (not verified) on 11 Oct 2006 #permalink

limestone: They are very different responses. That doesn't mean you would treat them differently but the mechanisms are very dissimilar. Steroids have had very uneven success in treating gram negative sepsis, the commonest version of a cytokine storm. Sepsis still carries about a 50% mortality in an intensive care unit. We just don't understand this whole thing well enough to know what to do. People are trying to dissect the whole mechanism to find a good hand hold for therapy. Steroids have quite a blunt instrument, with lots of side effects and uncertain outcome. We already know that many H5N1 patients could not be saved with the usual treatments. You wouldn't want to use steroids for anything but the more dire effects anyway. So there is not much to be optimistic about at the moment. But it's being worked on.

Gaudeamus: No. Anaphylaxis (in the classic form) is an allergic reaction that occurs within minutes or hours of exposure to some antigen the person is already sensitized to. There is constriction of the airways, swelling, secretion from mucuous membranes, vascular collapse and often skin symptoms like intense itching (hives). There is a similarity in the sense that anaphylaxis is caused by the sudden release of various chemical mediators like histamine and leukotriene C4, but other than that they are not the same thing.

Off topic, but the Reveres have shown an interest in 'open' science / research. The Royal Society in UK have contributed to this cause by making their archives back to 1665 freely downloadable for 2 months. Here's the URL

http://www.pubs.royalsoc.ac.uk/index.cfm?page=1373

My favourite: Philosophical Transactions (1683-1775)
Account of a very remarkable young musician (Mozart) In a Letter from the Honourable Daines Barrington, F. R. S. to Mathew Maty, M. D. Sec. R. S. (1770) (PDF downloadable)

By DavidK NZ (not verified) on 11 Oct 2006 #permalink

Would a cytokine storm or dysregulation easily go undetected (or undiagnosed) in a patient suffering from say a "gram negative" sepsis? Might a patient die from a heart attack or another organ failure and the cause of death be attributed to that alone without mention of a sepsis or the overactive immune response that it caused?

By Marcie Hascall Clark (not verified) on 11 Oct 2006 #permalink

There could be more than just a cytokine storm
==================================
From
http://www.nzherald.co.nz/section/story.cfm?c_id=1&objectid=10405467

Bird-flu laws must be clear and set out early, says Palmer

Thursday October 12, 2006
By Mike Houlahan

Parliament should set out what laws and regulations will be suspended or enforced during a bird flu pandemic before the disease hits, the Law Commission says.

The Epidemic Preparedness Bill, being considered by the Government administration select committee, allows ministers to relax statutory restrictions or requirements to deal with the flu.

However, Law Commissioner Sir Geoffrey Palmer told it yesterday the term "relaxation" seemed to be new and, while it appeared to amount to a suspension of the law, it lacked clear definition.

"The power is wide and the way it will be used is difficult to predict."

While acknowledging that it would be virtually impossible to identify every statute which might need to be modified if a pandemic struck the country, Sir Geoffrey said it would be simpler and more transparent to set out some regulations before the event.

"The actions that need to be taken should be clear to the health authorities from their operational plan for such events. The bulk of what is required should be capable of being dealt with in advance of the epidemic if planning for it is well advanced," the commission's submission said.

Sir Geoffrey said a pandemic would see politicians and officials able to assume draconian powers over people's individual rights. Those rights could not be suspended without real justification, so those powers should be scrutinised by Parliament before the event so that everyone knew what they were and officials knew what was expected of them.

Regulations being set out in advance of any pandemic would also help after the event, during any review of whether officials had exceeded their powers or not.

"It is better in our view to make as many plans in advance as can usefully be made. The powers that are needed should be defined and drafted, the regulations scrutinised and only those matters that have not been properly anticipated dealt with by emergency regulations."

By DavidK NZ (not verified) on 11 Oct 2006 #permalink

Would a cytokine storm or dysregulation easily go undetected (or undiagnosed) in a patient suffering from say a "gram negative" sepsis? Might a patient die from a heart attack or another organ failure and the cause of death be attributed to that alone without mention of a sepsis or the overactive immune response that it caused?

By Marcie Hascall Clark (not verified) on 11 Oct 2006 #permalink

Marcie: Gram negative sepsis is a dire emergency and not likely to be overlooked, IMO, although diagnostic workups vary and may not be done correctly. I'm sure people who are very sick may have undiagnosed gram negative sepsis, although there is usually a lot of co-morbidity so they are going downhill for a variety of reasons. Sepsis is one of the most lifethreatening things you can have.

Contrary to what some believe, humans are just another animal.

H5N1, SARS, Strept. suis, West Nile, Nipah virus etc. are all zoonoses...in fact most if not all emerging threats to our species of animal, are viruses and bacteria and parasites that have gained the ability to cross the species barrier.

While human doctors treat one species, veterinarians treat the rest of the thousands of animal species in the world and have been treating these diseases in animals for an extended period...to a veterinarian, these diseases are everyday occurences...localized epidemics are our stock and trade.

Most viral diseases that I have mentioned in animals produce 'cytokine storms'...and gram negative sepsis is also very common.

As in animal treatment protocols, when faced with viral induced toxemia-shock-fever complexes or septic shock from bacterial infections...treatment alternatives are limited.

Targeted prednisolone in moderate dosages for short periods of time, supported with concurrent treatments with anti-fever drugs like acetominophen work very effectively in several animal species...I see no reason whatsoever why they will not work with the human species.

I believe SARS treatments failed on two levels...1)prednisolone dosages of 1000-2000 mg. per day were too high and would cause immediate unexpected physiological consequences and 2) the treatments were carried on for too many days...in some cases up to a month.

Contrary to some opinions, the cytokine storm or viral toxic shock lasts for a short period of time...less than forty-eight hours...the period in which prednisolone can be effective is also short...if the treatments are extended, the law of diminishing returns comes into play and patients will be lost as a result of both immuno-suppresion and delayed wound healing etc.

The concurrent anti-fever medications are there to potentiate the prednisolone and support the patient when the prednisolone is removed on day 3-4...continuing beyond day 5 is counterproductive introducing many other complications.

The fact is that in a pandemic we will have no healthcare system and therefore no intensive care. Prednisolone is, if nothing else, and effective intensive care drug even in the oral formation, and is highly effective at secondary shock including hypovolumic shock which occurs with viral toxic storms.

We may not have harnessed prednisolone's pharmacologic potential at the moment in the human species...but we have no effective alternative and at the moment, no effective alternative on the horizon...and until there is an alternative, we should figure out why it has failed and in what combination it should be used...a lot of patients would benefit from the result...in my opinion.

I would respectfully suggest that human doctors get to know their counter-parts, particularly those involved in farm animal medicine who deal with these issues routinely on a daily basis.

Tom: I don't think the lack of success in sepsis is related to lack of trying. Just about everything has been tried. It is very difficult to treat and the window for success is narrow. Having seen sepsis up close I don't think there is a magic bullet or even a beebee for this one, veterinary experience aside.

Revere. I agree that there aren't many magic pills but I also believe there is nothing special under the sun about humans...except in our own minds.

If sepsis and cytokine storms in a broad array of animal species can be consistently treated successfully with prednisolone balanced with other supportive treatments...then there is no reason that the same can't be done with humans.

Prednisolone (not prednisone) was one of those few magic pills that came my way both professionally and personally.

"It(sepsis)is very difficult to treat and the window for success is narrow."...I agree.

Please explain the difference between Prednisolone and Prednisone.

Cytokine storm...I am confused.My husband had a heart transplant 13 years ago.He is well,taking the usual drugs yada yada..Question.Is he now in a better position to survive bird-flu or not?;given the immune response question that is ongoing?

If I understand this right, autoimmune diseases are caused by an insufficient number of Treg cells compared to the number of Th cells...either the Th cells are not sending enough of the proper signals to "activate other T regulatory cells whose job it is to damp down the immune response after a suitable lag", or the Treg cells themselves are lacking. The test you describe was an attempt to activate a higher ratio of Treg cells to other T cells by overstimulating the Th cells; however instead it just caused essentially a complete breakdown of the regulatory effect, leading to a cytokine storm. Comparing this to the disregulation effect of H5N1, it seems the virus might either deactivate the Treg cells, interfere with the chemical signal from Th cells that is supposed to activate the Treg cells, overstimulate the Th cells like a 'superagonist' beyond the ability of the Treg cells to control, or use some combination of factors. However since a virus is just a nucleic acid surrounded by a protein coat, whose primary function is to protect the nucleic acid and help it get into another host cell, how is it able to cause this disregulation? It seems like the only way it could work this disregulation function is if either it attacks the Th or Treg cell directly, or one of the proteins it codes for is not a part of its own protein coat but is a separate protein that acts to interfere with this immune regulatory response.

One thing that needs to be considered is that this "cytokine disregulation effect" in H5N1 - as in the 1918 Spanish Flu - is primarily seen in young healthy adults. Regardless of which mechanism H5N1 uses to create the cytokine effect, it is not consistent to everyone. Why would it have a greater effect on those with the most healthy and active immune responses? And can we really compare the tests run on these men (with, I presume, autoimmune disease)with the effects of the virus on young healthy adults?

By mary in hawaii (not verified) on 11 Oct 2006 #permalink

MiH: You need to be careful reasoning this way. Cytokine dysregulation may be caused by the imbalance or cause the imbalance or they may not have anything to do with each other. Just because you see imbalance in autoimmune diseases doesn't mean it has anything to do with cytokine storm or doesn't mean if it does we know what the meaning is. It was just this kind of thinking that got these 6 people in trouble. This is a dynamical system and they can behave in ways that are completely counterintuitive. It's like saying that because the tight end caught a touchdown pass, tight ends are the cause of touchdowns. You need to understand the rules of the game and the playbook. We don't understand either.

mara: the same remarks apply. No one has any idea if your husband is more or less susceptible to cytokine storm. Since he has a preexisting disease that affects his body's ability to fight infections (because of the treatment) I would think he would be extra careful. It may turn out that there is a silver lining to this, too, but we don't know that.

There is no easy way to reason about this, which is what I was trying to say in the post.

LEG,

Prednisolone is the active metabolite of prednisone, once it is processed in the liver.

By gaudeamus (not verified) on 12 Oct 2006 #permalink

Most here will know I'm not a medical specialist, just a behaviour observer in my own profession. But I am interested in this field.
From the posts here I get the impression the cytokine system is a very complex one with a lot of agents interacting and the only way to discover how it works is to trace the processes at work.
Now in my view medicine started observing the dead body by obduction, where the life processes had ended for some time, and in that way only the final results were traceable. By inventing all modern techniques (x-rays, contrast fluids, MRI and CT scans, visible colourful bodily temperature changes, measuring electricity in some regions, enlargement of minuscule cell parts) we are able more and more to observe the bodily functions in action. We now have pictures of the H5N1 virus in action.
There is also the cytokines pathfinder encyclopedia.

Cytokines Online Pathfinder Encyclopaedia
(the url doesn't work here, but it's easily found on Google).

And now, as I have been following the posts of the Reveres for some time, it has been concluded in several posts the more we know about avian influenza, the more we realize we don't know much about this all.

But still I am impressed by the techniques that are used to get this massive body of knowledge already.

My question is: how advanced is science in observing a cytokine system in action in the blood, is it possible to see it in vitro (less risky, considered the experiment revisited by Revere) and is it possible to control the variables in a process like that to a certain degree?
Maybe my question is a bit too generally formulated, but more to the point: can we really observe live cell action or is it just some inferences we make and from there we put it in some animation film as a best guess about what is happening?

tan06: Yes, we observe the action of live cells, even cells of different kinds interacting. We have a very large body of observations and we "know" quite a lot. But we still don't have the Big Picture of how this system works. The system itself may follow very complicated rules. Or, the rules may be very simple but they look complicated because we don't know what they are. There are many very simple systems (e.g., the finite difference logistic equation in one dimension) with very complicated dynamics. So nothing is obvious, here.

How complicated are the factors that lead to cytokine dysregulation? Imagine about 100 different cytokines that can be turned off and on to varying degrees, each with slightly overlapping effects. If you tinker with one or two, you are going to affect several others.

Tom, I agree with your comments on steroids with one exception. Courses of steroid treatment should run at least 10-15 days or until the virus is cleared by the body. There have been two mechanisms postulated whereby H5N1 depresses ACTH secretion. This is the one I favor: [taken from my paper under review]

"In reviewing acute respiratory distress syndrome cases that fail to resolve, Meduri and Yates [33] suggest an alternative mechanism based on excess activation of NF-κB compared to the anti-inflammatory transcription factor glucocorticoid receptor alpha. This imbalance causes an inability to downregulate the transcription of inflammatory cytokines despite elevated cortisol levels, which the authors term 'systemic inflammation-induced acquired GC resistance'. However, the imbalance can be alleviated via prolonged glucocorticoid administration [33]. Other explanations for this condition, which also appears to be the peripheral glucocorticoid resistance encountered in the sepsis/shock literature [26, 27], include dysfunctional transcription of the GR gene and dysregulation of the mineralocorticoid receptor enzyme, 11-beta-HSD [34].

While the glucocorticoid resistance mechanism appears to provide a better rationale for the use of supraphysiological 'low-dose' steroid levels, there are caveats. For example, repeated cycles of restraint stress, an exogenous stressor used in mice and rat models, can produce high enough corticosterone levels that compromise the overall immune response to an influenza infection, perhaps by over-suppressing cytokine production [23]. Further, differential suppression of cytokines can also occur, as was witnessed in murine influenza A/PR8 infection following restraint stress that suppressed IL-1α, but not IL-6 [35]. This is interesting, because both IL-1 and IL-6 can stimulate adrenal glucocorticoid production.

If stress-mediated responses are present in the early stages of influenza-infected patients, and the doses of corticosteroids are employed are too high, the result might be oversuppression of the immune response and a further cytokine imbalance, essentially a forward feedback that leads to fatality. Such scenarios might explain apparent steroid treatment failure in some severe cases of severe acute respiratory syndrome and avian influenza. Conversely, in the absence of an a priori stress-mediated response and no exogenous steroids, a virulent influenza strain can prevent corticosteroid production with the result of uncontrolled hypercytokinemia and poor prognosis."

A followup to Tan06's line of reasoning: have there been in vitro tests of the H5N1 virus, re its ability to survive the digestive process and its route into the body via ingestion, to see what pH it can withstand and for how long? Or is the evidence largely anecdotal. (I read the article revere referred me to saying that the virus had been proven to withstand the low pH of the digestive system, but that article didn't say in vitro tests had been run to verify this.)

By mary in hawaii (not verified) on 12 Oct 2006 #permalink

Marissa.

I just used the treatment protocol because it worked and did not ever consider using the 'massive dosages' used in the SARS outbreak.

My experience was that the cyotkine storm was short and sharp (less than 36 hours)...and if you could get the edge on it then the prednisolone could be removed and symptoms could be controlled with aspirin (of course aspirin would not be avaliable to be used in young people because of Reye's syndrome).

In a sense it is like taking the headache pill before the headache really gets going.

If you don't get a hold on it in the first 24 hrs of treatment, it is unlikely that you will later.

I also found a significant diminishing rate of return after four-five days. I couldn't put my finger on the exact reason for it but it happened consistently...the concurrent management with non-steroidal anti-fever etc. drugs was essential.

I am having a hard time understanding your last three paragraphs. If you could summarize then in laymen's terms, I would appreciate it...Thanks.

Let me try another angle at this question of mine. I recall a couple of weeks back a similar discussion, where it was explained that this cytokine "storm" was related to the release by mitochondria of cytochrome c. I think it was Marissa who pointed out that it was probably the rapid replication of the virus (2 to 3 hours) and resultant massive cell death that lead to the release of so many cell by-products - including the cytochrome c - that it caused an imbalance which led to the cytokine disregulation effect. Correct me if I have remembered wrong.
Now, my question is, why would there be so much higher an incidence of this "cytokine storm" in young healthy adults? If it is the result of the scenario above, one would expect that less immune proficient humans - the usual suspects of very young or very old - would be more likely to have the rapid progression of infection and cell death that purportedly leads to the cytokine storm, wouldn't one? On the other hand, if this cytokine effect is the result of an immune system dysfunction (failure to activate Treg cells or an over-production of Th cell products) not related to the massive die off of cells, what is the virus doing to cause this? I thought all a virus could do was insert its nucleic acid into a host cell, copy its nucleic acid and proteins to make a slew of new virus particles, and then break out of the cell to infect more cells. Also, what kinds of cells does it infect besides respiratory system cells? Could any of these send out the chemical signals that lead to this dysregulation?

By mary in hawaii (not verified) on 12 Oct 2006 #permalink

Mary. The way I see it may be too simplified but basically, the young person has a faster and more efficient and effective immune system than an older person.

In the older person even though the cells are infected, they are destroyed by the immune system at a slower rate = less junk and chemical byproducts of cellular death circulating in the blood stream = no cytokine storm.

In younger persons, the infected cells are efficiently destroyed all at the same time and the body ends up overwhelmed with the related junk and molecules = shock.

The thing is that this is a short term effect and if we can get a hold on it before it happens, the end result will be much better, in my opinion.

MiH (and Tom): I think we should try to avoid simplified schemes of how this all "happens." There are too many possibilities. Just one example (not meant to be "the" explanation) is that the virus makes a protein which is a superagonist, like TNG1412. Viruses make non-structural proteins that help them replicate but don't wind up in the final virion. But that's just one possibility, There are many others. We don't know why the age distribution shift sto the left in a pandemic. This has been puzzled over for decades. It remains a mystery. the mortality in 1918 was W shaped, with the hump young adults. Why the "valleys" on either side? We don't know.

There is a tendency to try to fix an explanation for all this when there are too many possibilties. We will eventually understand this, but with the data at hand, speculating is just a parlor game, one that can lead you to do dangerous things (like TNG1412).

Tom, what I am saying basically is that H5N1 sets up an imbalance in the regulation of the production of steroid production in our bodies by making the steroid receptors insensitive to the hormone. In order to correct the imbalance, a supraphysiological dosage of steroids has to be used. However, if external stressors are already present in the body when the infection gets underway, too much steroid dosage, innate immune functions can be supressed. (This is very much like an equilibrium reaction.) However, much of this is conjecture; a theory of what happens.

I agree with Revere. In the 1918 pandemic it was the 20-40 age group that got whacked, presumably because their immune systems were the most active. In H5N1, we have more younger victims. This could be the result of something different, or the fact that younger individuals have been more in close proximity to viral sources. We just don't know.

When H5N1 infects the type II pneumocyte, the subsequent destruction of the cell somehow causes this cascade to begin. Even if you successfully attenuated the immune response, you now have no surfactant production, subsequent atelectasis, alveolar hypoxemia, (which kills more cells) and the beginning of ARDS, even without cytokine "deregulation"

By respiratorythe… (not verified) on 13 Oct 2006 #permalink

Marissa Thanks for the explanation.

I have a fundamental belief that one should never let a problem get in the way of a solution. What I mean by that is that you don't always have to know every nuance of the multitude of molecular interactions to come up with a solution.

It seems to me that there is always a solution and in hindsight the solution and the problem are usually simple and straightforward...sometimes getting there is the problem.

There is a straightforward explanation why the young die in pandemics and it is explained in the replication rates of pandemic viruses.

The virus replicates in the young and the old at probably the same rate...but it is the young immune system that shoots all the viruses at the same time...the cells are collateral damage in this battle...this leaves a lot of viral debris to circulate on top of the viral debris that is already circulating as a result of the rapid replication rate...some of these segments could be interfering directly in the immune response, altering it. Then, there is the cellular breakdown products-junk that also are circulating. Then there are the holes punched in blood vessels etc. by the immune system that results in the flooding of interstitial spaces with plasma and/or blood affecting air exchange.

I have used prednisolone to offset these effects very successfuly in the past...cutting mortality and chronic sequelae by more than 50%...

...What is the physiology behind the treatment protocol. First, the prednisolone plugs the holes in the blood vessels and assists in removing the fluid from the interstital spaces etc. that is interfering in Oxygen exchange. It indirectly increases blood volume improving O2 delivery to the tissues and brain. It modulates the effects of the cellular immune response. How exactly it does it, I don't know but I remember from Pharmacology class that it somehow coats inflammatory cells lowering their effectiveness. Prednisolone also lowers body temperature and improves the general feeling of well-being allowing the patient to drink more fluids restoring electrolyte balance. I believe it also assists in the utilization of fat stores to again improve blood sugar etc.

Effective protocols require a short duration treatment with concurrent nonsteroidal anti-fever drugs that will continue as the prednisolone is withdrawn by day four five.

The approx. treatment in humans would be approx. 50 mg per day orally...a dosage that is currently dispensed by physicians without the requirement for monitoring of any kind.

Thanks to all for the interesting discussion.