A new paper in the Annals of Internal Medicine underlines a point we have tried to make multiple times (e.g., see here, here and here). Naive and unthought out therapeutic responses to the idea that bird flu kills via a "cytokine storm" is a bad idea. Cytokine storm is also a common feature of sepsis, which accompanies some pneumonia and other infections and has a high case fatality ratio. I haven't read the original paper because I am at the beach where the Annals of Internal Medicine isn't carried at the local convenience store and my internet connection is barely adequate for email, but I do have this Bloomberg News report, which is enough to allow a few general observations:
With funding from the National Institutes of Health, [Derek Angus, department of critical care medicine at the University of Pittsburgh School of Medicine] and his colleagues examined what happened to every patient who came in to emergency rooms at 28 hospitals around the country with pneumonia, an infection that often leads to sepsis. They followed more than 1,800 patients, and 30 percent of them developed the condition. About a quarter of the patients who got sepsis died, the study found.The researchers didn't just track the patient's overt symptoms, they tried to get a handle on the biological activity going on under the surface, Angus said.
During the first week a patient was in the hospital, the study team took daily measurements of levels of three different cytokines, proteins that are involved in the inflammatory response the body unleashes when there's an infection.
They found that while most patients had elevated cytokine levels, those levels varied widely, even among patients with similar clinical symptoms. In some cases, patients with elevated cytokine levels fared well, suggesting that the inflammatory response was playing a helpful role, Angus said.
The researchers also found that these high levels lasted far longer than had been assumed previously, and Angus suspects that they may play a role in chronic conditions such as heart disease. (Rob Waters, Bloomberg News)
So there are cytokine storms and cytokine storms, and unless you understand what you are dealing with you can easily do more harm than good. As Angus point out, drugs to deal with sepsis, a major medical problem, are "a biotech graveyard":
"There have been 30 or 40 large-scale trials of fancy new biologic agents trying to modify the course of sepsis and all have failed."
There is no evidence so far anyone has found an effective therapy for the immune dysregulation we call a cytokine storm and that we see in H5N1 infections. Naive ideas that a cytokine storm is "an overactive immune system" is even more likely to result in desperate and dangerous measures.
Many drugs being used to alter the immune system are often very powerful and non-specific. Until we understand the pathophysiology of the cytokine storm that accompanies some cases of H5N1 infection, we are spraying a machine gun into the dark, hoping it will hit our targets and not our friends. Bad idea.
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Right on, Revere. For some people the hypercytokinemia is a good thing as it shows that their immune system is responding. The only way to get a handle on whether a patient's cytokine levels are out of control is to look at the hpa axis response. Low cortisol levels or poor ACTH response is indicative of a problem. If we treat all patients as the same, we are going to suppress immune functions in 40-50% of cases, which will be detrimental to outcome.
Marissa.
I could very well be totally wrong...but I believe, with the help of a couple of esteemed colleagues, that the only unique difference for avian influenza and the odd time with seasonal influenza...
...is that the virus specifically knocks out the adrenals production of natural steroids-glucocorticoids...
...and this natural system is a back-up control system to control and direct and modulate the immune response that has the potential to kill a normal person in a few minutes (ex. acute allergies-peanut etc.)
What is doing the killing is an unregulated immune system...and our only hope for control is preventative-proactive moderate prednisolone before the reaction gets going...because once it does...there is no stopping it.
That is in effect, what my field experience demonstrated. Once I was on the farm, I could head it off if I caught it soon enough.
We will write a further analysis later.
Thanks for your article...it was really interesting.
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I must have missed something. What evidence is there for adrenal insufficiency in H5N1 infection?
I suspect there are many roads to sepsis and until we know enough to separate the various routes then we will remain unsuccessful in preventing it.
Hi Lisa. There are a number of references when taken together give the result...unfortunately, I am not highly organized with filing...even though I remind myself I should be everytime I go searching for stuff...
...anyway, here is 'one' of the references.
http://www.jimmunol.org/cgi/reprint/162/6/3527
Endogenous Glucocorticoids Protect Against Cytokine-Mediated Lethality During Viral Infection
"In conclusion, these studies have definitively established a protective role of endogenous glucocorticoid responses during a viral infection and identified the mechanism for mortality resulting in the absence of these responses. Thus, they show that glucocorticoids are key factors in regulating the delicate balance between protective and detrimental consequences resulting from immune responses to infections. By dissecting the individual components of the regulatory interactions between endocrine and immune systems, they further our understanding of pathways for defense against both infection and infection-induced cytokine disease."
Lisa. Here is another one:
Prolonged methylprednisolone treatment suppresses systemic inflammation in patients with unresolving acute respiratory distress syndrome: evidence for inadequate endogenous glucocorticoid secretion and inflammation-induced immune cell resistance to glucocorticoids.
Meduri GU, Tolley EA, Chrousos GP, Stentz F.
Memphis Lung Research Program, Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Tennessee, Memphis, Tennessee, USA. umeduri@utmem.edu
Nuclear factor-kappaB (NF-kappaB) and glucocorticoid receptor-alpha (GR-alpha) have diametrically opposed functions in regulating inflammation...
...We investigated whether unresolving acute respiratory distress syndrome (ARDS) is associated with systemic inflammation- induced glucocorticoid resistance and whether prolonged methylprednisolone administration accelerates the suppression of systemic inflammatory indices and normalizes the sensitivity of the immune system to glucocorticoids. Patients enrolled into a randomized trial evaluating prolonged methylprednisolone administration in unresolving ARDS had serial plasma samples collected before and after randomization. In the plasma, we measured the concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukins (IL) IL-1beta and IL-6, adrenocorticotropic hormone (ACTH), and cortisol. The ability of patient plasma to influence the NF-kappaB and GR-signal transduction systems of normal peripheral blood leukocytes (PBL) was examined. Patients treated with methylprednisolone had progressive and sustained reductions of TNF-alpha, IL-1beta, IL-6, ACTH, and cortisol concentrations over time. Normal PBL exposed to plasma samples collected during methylprednisolone exhibited significant progressive increases in all aspects of GR-mediated activity and significant reductions in NF-kappaB DNA-binding and transcription of TNF-alpha and IL-1beta.
...These findings provide support for the presence of endogenous glucocorticoid inadequacy in the control of inflammation and systemic inflammation-induced peripheral glucocorticoid resistance in ARDS....
Prolonged methylprednisolone administration accelerated the resolution of both systemic inflammation and peripheral acquired glucocorticoid resistance in ARDS.
PMID: 11934726
I have a reference somewhere that I think says that H5N1 specifically turns off the glucocorticoid response in the adrenals...
...I can't find it at the moment.
If one of my colleagues happens along...they might be able to find and post it.
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...anyway, for me it all comes down to timing...in a the middle of a pandemic when there will be little doubt what infection our children have...proactive prednisolone in low-moderate doses and proactive antibiotics should do the trick.
By the way, the turned off glucocorticoids could also explain the rare cases of death in seasonal influenza as well...I think.
oops...sorry for all the posts Revere.
These types of double feedback systems...positive in some areas-negative in others is very common in animal physiology.
Glucocorticoids can no be all negative or they would have evolved out of our systems by now...and it only makes sense in retrospect that they have a modulating effect on the immune systems and that without the specific coordination of such a system...immunological havoc results.
In my opinion, once the damage is done in the first 24-48 of 'clinical' infection...the damage is done...and largely irreversible...
...which is why the mortality rate is remaining over fifty percent despite every advanced technology we have to throw at it.
In my opinion, we had better find 'an edge' soon because it now looks like H5N1 is going to hit with a high CFR and a high attack rate.
Thanks again!!
From the above (although I do not understand all the medical stuff) I think I must have had a cytokine storm going on when I was diagnosed with Meningococcal Septicaemia and Meningitis with Adrenal Insufficiency when I was 14, nearly 40 years ago. I was given 2 million units of Penicillin, 2 grams of Sulphadimidine and 100mgms of Hydrocortisone every six hours by intravenous infusion.
Considering I was virtually DOA at the time, I was very lucky and it did the trick.
I have the results of the investigations done at the time concerning white cells, platelets etc but it's all double dutch to me.
As a non-scientist, I look at the immune system and I see a Complex Adaptvie System par excellence. Complex Systems are characterized by self-organization and emergent properties that cannot be explained or predicted in advance by looking at the individual components of the system. The organization and emergent properties of the system are the result of the interaction between the components of the system rather than the components themselves. Complex Adaptive Systems are able to scan the data stream, formulate a schema that explains the data, and adapt to it; at which point they continue to examine the data and respond through endless iterations.
These systems may also display sensitive dependence to initial conditions where tiny differences in the intial conditions may lead, through multiple iterations in time, to widely varying outcomes. This simple, inherently unpredictable characteristic could explain why cytokines can be helpful in one case, and kill you in another.
The only way to fully understand complex systems is with a "sytems" view. Reductionist scientific methods will reveal valuable information, but will not provide answers.
Tom, I thought WHO or someone like that fairly recently published specific advice based on reasonable evidence that prednisolone was likely to do more harm than good in the case of H5N1? I wouldn't use it blind - even though we have some since last year it (probably) saved my husband's life.
I remember the hesitation and concern over giving it, even in a situation where every test result was available. It's a blunt instrument.
In any case, I don't know about giving it in "low to moderate doses" - what happened to my husband, which I think is standard, is that it was given initially in high doses, and then tapered. I have the impression that giving it in low doses initially in the case of flu would be pointless, even if a high dose might have helped. Would be interested in more information, though.
Hi Mathematician.
First...I am not a frustrated medical doctor...it's harder to get into veterinary school /:0)...I do not work in the pharmaceutical industry or have shares in any particular company that may produce prednisolone...I am not a researcher or professor seeking fame, fortune or research funds...as best as I know I do not have a conflict of interest but I guess you never know.
What I am is a veterinarian with a good deal of field experience with similar diseases. I believe that for many reasons, existing vaccine technology is useless...I believe Tamiflu is going to be useless...I don't believe that statins will make a difference and I don't believe that human researchers understand the 'cytokine storm'...at all...I think they have 'missed the boat' so to speak.
I believe that the adrenals are essential to an immune system that is incredibly powerful and can kill you in minutes without any pathogen being present when it 'misfires'....
...I have been given prednisone and believe it saved my life. I have seen prednisolone repeatedly dispensed by human practioners without any monitoring or follow up...AT ALL!!...
...I believe that aspirin has more side-effects and contraindications then for moderate doses of prednisolone for five days...
...I believe that H5N1 is a monster...a one in two thousand year virus...that is 'naturally weaponized' far beyond anything that we have ever encountered previously...and though I hope and believe the CFR will end up being much lower at 10%, I have nothing to base it on.
I should just learn to keep my mouth shut...but anyway, this is my opinion for what it is worth...
...I am really not here to convince anyone to use it...I believe in fully informed choices however...
...I am here, hopefully with a great deal of respect, to tell my human colleagues that they have an inflated view of their knowledge of the immune system and the cytokine storm...they often have 'god' complexes and will not listen to reason...
...I believe they believe that this pandemic is never going to happen which I believe and have believed for several years to be very wrong based on my observations of ANIMAL DISEASES IN NATURE.
So I am simply asking the medical community to get the real danger-usefullness of prednisolone in perspective and give the general public the straight goods.
Finally, I believe that giving gms. of thousands of milligrams of prednisolone intravenously for days and weeks and months on end will definitely kill you...which has been the experience with SARS and ARDS etc.
The whole basis of my treatment is that in the middle of a pandemic...when the early clinical signs are discovered and identified...we use proactive-preventative low dosages of oral prednisolone to head off the cytokine storm before it happens...
We must also use antibiotics proactively to prevent the secondary bacterial infections before they happen...and I would remind everyone that in a pandemic, which is what I am talking about, everything changes...if you think about it.
Veterinarians treat epidemics every week of their lives...human doctors might see one in a lifetime...
...my best advice to them would be to talk to as many farm animal veterinarians as possible as soon as possible...and get the research sorted out because we are running out of time...in my opinion of course.
I am off to Ottawa for a few days...sorry, I can't continue this interesting conversation.
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...and by the way...when we have an allergic reaction...which is an immune dysfunction that can kill you in minutes, hours or days...
...do we wait until you are in hospital on a ventillator to begin to treat the disease that put you there.
I have a member of my family with multiple lifelong obvious serious ailments. She was dispensed in an emergency room, 50 mg of prednisolone for five days for a bee sting...without any requirement for follow-up visit or monitoring etc.
If prednisolone is so dangerous...why was this the case...malpractice...I don't think so.
You have to treat viscous diseases proactively. The damage that occurs in the first day or two is irreversible...and the dosage to prevent it is much less than the dosage to treat it...this is the same strategy now used with pain control...stop it before it starts.
...and heck, while I am at it...antibiotic resistance has nothing to do with the number of prescriptions given but in the fact that people do not take the full course of antibiotics...they stop them too soon and that is the base reason for resistant bacteria...that and the fact that hospitals have very very very cleaning and disenfection and bug control procedures.
...I believe and spoken out for years that farmers should only use antibiotics for acute disease and if you want to eat meat in the future...you had better allow them to continue using it.
However, antibiotics for farmers are very expensive and other than the misinformed use in animal feeds, they are rarely used because they are almost unaffordable.
Once the bacterial infection comes in over top of H5N1, you can kiss your *** goodbye...which by the way is there experience...losing more than 50% of their patients.
I have made the case repeatedly...the protocol works in animals...for those medical practioners and researchers who believe that the world was created for humans and that humans are not animals...God help you in a pandemic.
Thanks. I will do my best to hold my tongue in the future.
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Thanks
Mathematician: that was me. See article.
Tom: this is a tough subject that needs more investigation. The problem is that virtually no studies have researched influenza and hpa axis failure, especially with regard to my pet theory, glucocorticoid receptor changes. I'be happy to set up a design if I could find some folks interested in doing the clinical part.
I've been reading this blog for months now, biting my tongue. I did my thesis on medicinal plants that support the HPA axis. Look at the traditional use of herbs for SARS and for influenza, including the herbs used during the Spanish flu by the Eclectic Physicians. Check out the antiviral properties of licorice root (Glycyrrhiza). This plant mimics cortisol.
Enough said.
The problem with trying to intervene during a cytokine storm is that there is so much going on, much of which cannot be measured and certainly is not understood if it should be made higher or lower.
Take blood sugar. What level should it be controlled to?
I think the main problem in sepsis is not enough glucose and not enough capacity to clear lactate. That is why cachexia turns the muscles into glucose and yet body fat goes up.
The high NO level from inducible nitric oxide synthase shuts down the mitochondria by inhibiting cytochrome oxidase. That is ok, if "enough" ATP can be made via glycolysis. If "enough" ATP can't be made via glycolysis, then ATP falls, the mitochondria turn on, and in a high NO environment must produce high superoxide levels to pull down NO to disinhibit cytochrome oxidase so that O2 can be consumed. Too much superoxide in a high NO environment makes peroxynitrite which inhibits MnSOD (in the mitochondria matrix), superoxide goes up, peroxynitrite goes up, the respiration chain gets nitrated, the mitochondria turn off. If "enough" turn off, you get multiple organ failure and death.