November 12, 2005
H5N1 Avian Flu Causes Dangerous Cytokine Storm

The H5N1 avian flu strains of today have something deadly in common with the 1918 killer pandemic flu strain: over-stimulation of cytokine production.

Scientists might have identified one of the reasons why the bird flu virus H5N1 is so deadly to humans. A study published today in the open access journal Respiratory Research reveals that, in human cells, the virus can trigger levels of inflammatory proteins more than 10 times higher than the common human flu virus H1N1. This might contribute to the unusual severity of the disease caused by H5N1 in humans, which can escalate into life-threatening pneumonia and acute respiratory distress.

Michael Chan and colleagues from the University of Hong Kong and collaborators in Vietnam, studied the levels of a subset of the pro-inflammatory proteins called 'cytokines' and 'chemokines', induced by the virus H5N1 in human lung cells, in vitro. The authors compared protein levels induced by strains of the H5N1 virus that had appeared in Hong Kong in 1997 (H5N1/97) and Vietnam in 2004 (H5N1/04), with levels induced by the human flu virus H1N1.

Their results show that 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.

High levels of cytokines cause excessive levels of inflammation and that can help to kill you.

Chemokines and cytokines are the "messengers of the immune system" and are critical in coordinating and regulating the immune response. Altering this balance is likely to lead to an uncontrolled inflammatory response in the lung and probably explains, at least in part, the severe lung inflammation associated with avian flu virus H5N1.

Michael Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota, says cytokine storm caused excessive immune response in 1918 pandemic victims and this caused organ damage and high fatality rates.

Today we are very concerned that the H5N1 virus circulating in wild and domesticated birds in Asia is moving genetically towards a human-to-human transmitted agent and could result in a 1918-like pandemic. If this happens, we expect that the illnesses that we see among those infected with H5N1 virus will be similar to those individuals who were infected in 1918 and the limited number of humans who have been infected with H5N1 to date. Many of the deaths that occurred in these populations resulted from the explosive growth of the virus in humans and a subsequent cytokine storm. A cytokine storm is the release of a chemical in the body that stimulates the human immune system to respond to the virus infection. In these serious illnesses and deaths, it's actually been an over vigorous immune response elicited by this infection that result in the organ damage and ultimately the death of the individual. Ironically this means that those with the strongest immune systems may be at highest risk for a serious outcome if infected with the H5N1 virus.

Also see the Flu Wikie Cytokine Storm entry for more discussion on how a cytokine storm can kill you. Adults between the ages 18 and 40 suffered most of the deaths from the 1918 strain probably because their immune systems were stronger than those of older people. Hence their immune systems were better able to overreact to the cytokines which the 1918 flu caused to be made.

As Mr. Mackey might say, "Cytokine storms are bad, mmmmkay?" and so we need ways to stop cytokine storms, mmmmkay? Well, back in 2003 an Imperial College London team showed that a molecule named OX40:Ig that blocks the effect of OX40

Until now, treatments to eliminate the cytokine storm have focused on inhibiting all T cells. But this leaves the patient unable to clear the virus and susceptible to other infections. Dr Hussell's team have developed a way of down regulating a molecule known as OX40 that only targets T cells that have recently been alerted to the presence of the flu virus.

"OX40 sends out a 'survival signal' instructing activated T cells to remain in the lungs for longer to help fight the infection. However, because new cells are arriving all the time this prolonged presence is not needed," explains lead researcher Ian Humphreys of Imperial's Centre for Molecular Microbiology and Infection.

"Inhibiting this signal therefore allows T cells to vacate the lungs earlier whilst leaving behind a sufficient immune presence."

Using a fusion protein OX40:Ig supplied by the pharmaceutical company Xenova Research, the scientists were able to demonstrate that OX40:Ig blocks active T cells.

Results show six days after infection with flu, mice treated with OX40:Ig were indistinguishable from uninfected control mice. But infected mice that had not been treated lost 25 per cent of their body weight, appeared hunched, withdrawn and lost their appetite - all characteristic symptoms of flu.

When treatment with OX40:Ig was delayed for several days after infection, until the mice had lost 20 per cent of their body weight and OX40:Ig was administered, symptoms were reversed.

Re-infection also indicated that the ability of mice to respond to a second infection was not affected by the reduced T cell immunity during the initial infection.

Parenthetically, OX40 is also known as CD134.

Sounds hopeful, right? That was 2003. Xenova was supposed to begin human testing in 2004.

Hussell believes the drug could potentially treat any illness with an excessive inflammatory response, including asthma and possibly SARS. The researchers are testing the fusion protein as an asthma treatment in mice. They hope to test OX40:Ig in adult humans in a phase one trial in 2004.

Near as I can tell no such human trial took place in 2004. Poking around Xenova's web site I found indications that Xenova probably has not moved on to human trials.

OX40 is a platform technology capable of producing multiple drug candidates targeting cancer, autoimmune and other diseases where the immune system is involved. Xenova is developing the OX40 technology for the up-regulation of the immune system, for the development of novel treatments for cancer and infectious diseases. Xenova's rights to down-regulate the immune system have been the subject of development and licence agreements entered into with Celltech and Genentech (April 2002).

What's the hold up? Sounds like maybe either CellTech or Genentech have the right to develop OX40-related treatments to down regulate the immune system.

Xenova’s rights to the OX40 technology include rights relating to the up-regulation of the immune system which may be used for the development of novel treatments for cancer and infectious disease. Xenova’s rights to down-regulate the immune system have been the subject of development and licence agreements entered into with Celltech and Genentech.

Here's an August 2004 press release which states more clearly that Xenova has sold the rights for OX40 development to down-regulate against, for example, a cytokine storm caused by an influenza infection.

Xenova retains all rights for the use of OX40 in up-regulation whilst Genentech Inc and Celltech Group plc have the rights for down-regulation.

While neuraminidase inhibitors like Tamiflu can be used against all manner of flu types and hence have a market even when there is no pandemic the OX40 blockers probably do not have much utility against influenza under normal conditions. So OX40 blocker development probably isn't going to get much funding against flu unless governments step in (and my guess is governments are probably not smart enough and prudent enough to do that).

I haven't been able to find indications that Celltech and Genentech are pursuing OX40 development for flu treatment. Rapid development and production of OX40:Ig during an H5N1 pandemic might save millions of lives. Would any governments show sufficient regulatory flexibility to allow rapid introduction of a prototype drug during a pandemic?

So what to do about the cytokine storm threat come a pandemic? Statin drugs such as Lipitor and Crestor (widely used to lower cholesterol) probably will lower the risk of death of those infected by an influenza strain that causes a cytokine storm. If you have high cholesterol and haven't done anything about it go get a statin drug prescription and it might just save your life two different ways: Avoid a heart attack and avoid death in an influenza pandemic.

Share |      Randall Parker, 2005 November 12 04:43 PM  Pandemic Signs


Comments
Lou Pagnucco said at November 12, 2005 9:57 PM:

In addition to statin drugs, the following may also attenuate a "cytokine storm":

- tetracycline-derived antibiotics, e.g., doxycycline, minocycline

- high dose omega-3 fish oil, coupled with decreased omega-6 consumption

- NSAIDS

- leukotriene blockers

- and, possibly some of the bisphosphonates

Brainpik said at November 12, 2005 11:52 PM:

Oh for Pete's sake:

If a cytokine storm is the problem, then squashing the cytokine storm is the solution.

There are NO drug cocktails that will do that.

Solution:
Take two large catheters, run the blood to an extracorporal circuit, run through plasma seperator, run plasma through an absorbent matrix, recombine, return blood to patient, abide by a strict heparin protocol.

It was what used to be done with septic and encephalophathic liver patients. Worked really well.

Carl Shulman said at November 13, 2005 11:50 AM:

This confirms the idiocy of HHS' rationing plan. Ordinarily, when rationing life-saving medical supplies the elderly are more vulnerable, but have fewer expected years of life to be lost. For whatever reasons we prioritize reducing the number of casualties as opposed to lost years of life. But in this case the elderly are less vulnerable than the young, healthy adults with the most to lose and who are more likely to be significantly contributing to the economy. Will the administration change "Group 2" in its vaccine rationing plan to be 18-40 year olds rather than seniors? Or would this require too much education of the population and confrontation with the AARP for them to bother?

From the Draft Pandemic Influenza Preparedness Plan:

http://www.usnews.com/usnews/health/briefs/infectiousdiseases/hb050720a.htm

# Froup 1. The highest-priority group includes 9 million healthcare workers involved in direct patient care; 40,000 people who are making the vaccine and antiflu medicines; and some 37 million people who are at greatest risk if they get the flu, namely those over age 64 with a medical illness, younger people with two serious underlying medical conditions, pregnant women, and all household contacts of children under 6 months of age. Also in this top group are key government officials and specialized pandemic flu responders.
# Group 2. In the next tier are healthy seniors; younger people with one risky health condition; young children between 6 to 23 months old (the vaccine is not recommended for infants under 6 months); and workers in critical fields like public safety, utilities, emergency response, transportation, and telecommunication. This group is 68 million strong.
# Group 3. The third priority is 500,000 people, including key government healthcare decision makers and those working in mortuary services.
# Group 4.At the bottom are the remaining 179 million healthy people, 2 to 64 years old, not included in any other category.

Marvin said at November 13, 2005 3:42 PM:

It is likely that statins and leukotriene modifiers will only work if started weeks ahead of the actual viral insult triggering the positive feedback reaction. As for extracorporal filtration of blood, the resources are quite limited in terms of machines and trained personnel. In a large scale pandemic only a relative few could be treated that way. As for OX40 modifiers, it costs almost a billion dollars to move a new drug to market. With the trial lawyer vultures salivating over any potential complication that can be blamed on the drug, bringing them millions of dollars in contingency fees, sometimes much more. Sometimes a new drug might save millions of people, but end of costing the drug company its very existence from free wheeling liability. Everybody hates the drug companies until their lives need saving. Then they love the company just long enough to get out of danger, and start hating it again.

Want to help society prepare for emerging infections and health threats? Eliminate a few thousand trial lawyers. Do the world a favor.

MJ said at November 13, 2005 10:28 PM:

Smoking reduce cytokines in the airways and lungs. Usually that's a bad thing, but in this case the immunosuppresive effect might be beneficial. Any stats on smokers/non-smoker deaths in the 1918 pandemic?

Michele Hinz said at November 14, 2005 2:43 PM:

Why reduce Omega-6 (GLA - right?) intake. Doesn't GLA curb cytokine production?

Doug said at November 17, 2005 2:53 AM:

Randall and interested readers should please have a look at http://www.cholecalciferol-council.com and especially the newsletter archived at http://www.cholecalciferol-council.com/pascal.pdf for interesting discussion of a possible role for vitamin D3 in control of the cytokine storm. If I understand correctly, there's some evidence, by no means conclusive, that circulating 25-OH-vitamin-D3 (calcidiol) is converted by pulmonary alveolar macrophages to 1{alpha},25-OH(2)-vitamin-D3 (calcitriol) and that in this context calcitriol serves as a paracrine hormone that reduces the inflammatory activity of these macrophages. On these hypotheses, macrophages' sensitivity to paracrine calcitriol may restrain them from producing the "cytokine storm." Thus, proper immune response to an influenzal infection may require vitamin-D3 sufficiency so that there will be enough circulating calcidiol to allow its uptake and conversion to calcitriol by macrophages at the infection site. John Cannell, M.D., author of the newsletter and of the website, suggests targeting 50 ng/ml as a healthy level of circulating 25-OH-vitamin-D3 (calcidiol). He recommends moderate exposure to ultraviolet B from sunlight or sunlamps, or consumption of vitamin D3 in food or supplements sufficient to raise circulating calcidiol to the target.

Cannell's analysis is crying out for attention under our present circumstances. As he explains, most people living in industrialized societies outside the tropics are deficient in vitamin D3, and becoming vitamin-D3 replete appears to confer numerous benefits, whether or not protection from cytokine storm induced by macrophagic overactivity is one of them. I'm not a medical or nutritional specialist, and I don't want anyone to treat anything I say as prescriptive, but I don't mind saying that I've become vitamin-D3-replete by taking a few thousand I.U. (international units) of vitamin D3 per day and that I plan to be careful to remain vitamin-D3-sufficient for the rest of my life, for numerous reasons that are suggested in the literature. See the very numerous links at http://www.cholecalciferol-council.com for more information.

Randall Parker said at November 17, 2005 5:19 PM:

Doug,

Thanks for chiming in about vitamin D and cytokine storm. I also already take vitamin D in order to reduce cancer risk.

Curiously, vitamin D is also linked to the lower incidence of multiple sclerosis in the southern US versus the northern parts. It is theorized that vitamin D reduces the odds of auto-immune response. That makes the idea of vtamin D reducing cytokines sound even more plausible.

DugS. said at November 21, 2005 11:06 AM:

Being a very health conscious person who reads research on and takes supplements because he is diabetic, I'm now wondering if there is any benefit to taking supplements that have been shown in clinical studies to enhance and strengthen the immunes system as it relates to SARS and H5N1 avian flu?? (Astragalus, Medicinal Mushrooms i.e. maitake-reishi-shiitake, elderberry extract-Sambucol, etc.) Is one more at risk potentially because they are strengthening their immune response through supplementation? Are some supplements better than others because they don't enhance cytokine production?

Doug said at November 26, 2005 8:34 PM:

Randall,

Since you take vitamin D, it may interest you to know that I've had no detectable problem with daily supplementation with 10,000 I.U. for a few months at a time. I had test results showing I was deficient according to the standard John Cannell, M.D., of http://www.cholecalciferol-council.com has adopted and promoted, so I took the large dose for the sake of repletion. After two or three months, I dropped back to 4,000 - 5,000 I.U. per day and have usually taken that amount daily, ever since. Since I have a life, but not a laboratory (nor a twin to use as an experimental control!), it's impossible to tease apart factors and effects reliably, but I can report that since starting vitamin D3 supplementation, I've had increased interest in and tolerance for exercise. My exercise and appetite control have been sufficient to allow me to lose an inch or two in the waist--an indication that vitamin D3 does help control or avoid the "metabolic syndrome" or "syndrome X." I've largely overcome the low mood and low energy that prompted my endocrinological investigations in the first place.

I also can't recall having had a cold or influenza-like illness in the last twelve months or so, for whatever that's worth.

If it's all right, I'll just mention that the Life Extension Foundation sells vitamin D3 in 1000 I.U. capsules.

Randall Parker said at November 26, 2005 9:37 PM:

Doug,

You might be interested to know that Carlson sells 2000 IU vitamin D capsules. That's the only brand I've found that sells a dose higher than 1000 IU. I don't want to take so many capsules and so look for higher doses.

You can also get vitamin D in powder form from Vitamin Research Products. Though I haven't purchased it that way in a few years and so can't be sure they still sell it that way.

Lester Edenborough said at December 10, 2005 9:07 AM:

I understand that glyconutrients and phytonutrients have the effect of MODULATING the immune system. Although I am only a lay person, I would think that their presence may inhibit a cytokine storm and hence help prevent this phenomenon in H5N1 flu. Could this be correct? The only way I know of getting sufficient of these nutrients in the Western world is to supplement the diet. I am supplementing these nutrients (along with others missing from my diet)in an attempt to control an undiagnosed leg problem which did also have RSD. The nutrients have banished the RSD (Reflex Sympathetioc Dystrophy) and I am hoping they will reduce my chances of succumbing to H5N1 flu should it arrive in the UK.
If anyone can comment on this, please don't blind me with science!

John Richards said at January 8, 2006 12:02 PM:

Responding merely to the macrophage modulation matter, don't forget the effect of Beta 1,3-D Glucan in this arena. If one is short of macrophage, the Beta 1,3-D Glucan builds it up. If one has too much macrophage (as in a cytokine storm maybe?), it modulates it down. That's what I understood from an A.J. Lanigan lecture years ago. You can read more about Beta 1,3-D Glucan at http://www.transferpoint.com/index.html.

Note: I do not have a financial interest in Transfer Point.

Deborah said at January 25, 2006 6:51 AM:

New reader--Just a thank you to all participants in this discussion of how we might reduce the chance of experiencing cytokine storm. Just want to encourage anyone with ideas/hypotheses to go ahead and offer them. I personally think this line of thinking may prove fruitful in devising preventive measures individuals can take.

Kathie, RN said at April 4, 2006 9:46 AM:

Dear Readers/co-colaborators, I appreciate all of the above comments and ideas. I am still doing internet research trying to formulate as complete a list as possible of interventions and or therapies that might possibly help (and not harm) a person to live through the apparent "cytokine storm" induced by the H5H1 Avian Flu. I am specifically concentrating on interventions that can be done at HOME--as hospitals will be completely over run and will be vessels of viral and co-bacterial infection themselves, should the pandemic materialize.

Assuming that antiviral extracorporeal treatments (some form of blood dialysis), ventilators and other high tech therapeutics will be unavailable for homes, what can be done to survive at home?

My Thoughts (PLEASE comment,correct or add):

1. Social distancing immeadiately at known onset of pandemic. Avoid crowds and close
exposure to others when not absolutely necessary.

2. Excellent infection control: Strict/frequent/vigorous handwashing, use of alcohol
based hand gels, use/disposal of tissues, no sharing of towels/linens, wash linens
frequently, isolate family tooth brushes and replace frequently, frequent cleaning at
home with antiviral/antibacterial cleaning agents, possible use of vinyl or latex (if
not allergic) gloves and N95 masks, good general hygiene, timely replacement of furnace
filters.

3. A good home supply of non-perishable food/beverages/water. Oral Electrolyte
Replacements (Pedialyte, low sugar sports drinks).

4. Tamiflu within 24 hour onset of symptoms after known pandemic onset (Prescription).

4. Home IV fluids (Assuming your MD will prescribe and you know an RN who can administer).

5. Home Oxygen Therapy (again, assuming MD prescription and O2 tank availibility).

6. NSAIDs (non-steroidal anti-inflamitory drugs) Ibuprophen, Naproxen Sodium, etc.
(Any ideas on which NSAIDs would be best--also would IV Toradol be any increasd benefit
and at what doses?)

5. Anti-Diarhea drugs (Immodium).

6. Use of the above stated vitamin D3 (caution-vitamin D is a fat soluable vitamin (A, D,
E and K) and can be taken in toxic doses).

7. Possible use of foods/herbs/beverages that have anti-viral properties (ex. a glass of
red wine per day--providing that you are not an alcoholic).

8. Use of Omega-3 fatty acids as stated above.

Please reply to the above, with addendums, or other ideas that can be employed at home for Americans or other people to empower themselves to be part of the solution and not the problem.

Randall Parker said at April 4, 2006 6:43 PM:

Kathie, RN,

I think more focus needs to be placed on ways to avoid spread of infection in the first place. See my post "Economic Collapse Avoidable During An Influenza Pandemic" for my discussion of the concept of "workplace cocooning" to decrease the risk of infection while simultaneously allowing the economy to continue to function.

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