H5N1 Avian Flu Virus Therapy
Conventional and Herbal Options:

by Jonathan R. Byron
jrb at med-owl dot com
Version 2,  February, 2006.

The H5N1 virus is spreading rapidly in bird populations across Eurasia.  As virus activity in birds increases, so does the possibility that this virus will again make the jump to the human species.  Left untreated, the disease it causes can be fatal in 30% or more of human cases.  This article is an attempt to outline the basics of how H5N1 kills, and how humans might take action to minimize the course of an infection after exposure. I will not attempt to deal with the public health measures - these are very important in reducing the spread of the disease, but dealt with elsewhere, like the Curevents message board or fluwiki.com.

The first section of this article deals with the concept of a cytokine storm in general.  In the second section, the particular characteristics of the H5N1 cytokine storm are discussed.  Then the neuramidase system is discussed.  Finally, a discussion of possible conventional and herbal therapies is presented.  This material is intended as a biology discussion and is not meant to provide specific medical advice. 


How the Virus Causes Disease and Death

Viruses can disrupt the body in many ways.  They take over cells, using our energy and biochemicals to reproduce themselves.  This is enough to result in some cell death, and is not a good thing.  But usually, virus become lethal when they produce a toxin or disrupt the regulation of one of the bodies systems.  Often, they weaken the body and invite secondary infections, which may also contribute to the lethality of a virus infection.

Fortunately, secondary bacterial infections are not the norm in avian flu. They can occur, but a persistent bacterial infection is not responsible for for most deaths. In a way, this makes treating avian flu easier. 

Most of the research into the H5N1 virus suggests that this virus actually overstimulates the immune system, and that the body kills itself while trying to eliminate the avian flu infection.

Cytokine Storms and Inflammatory Cascades - General Concepts

In many diseases (including H5N1 in humans), a "cytokine storm" is triggered by the infection. Cytokines are hormones that regulate the immune sytem. When released at the right time in the proper amounts, cytokines can help fight infections and regulate processes through out the body.  But many cytokines are inflammatory and are damaging to the body if present in too high levels, or for too long.

The term cytokine storm is a common designation for the technical term hypercytokinemia (sometimes spelled hypercytokinaemia). Some people object to the use of the term cytokine storm, as it carries weather related images that may not apply to hypercytokinemia.  But whatever it is called, this phenomenon is a type of inflammatory cascade.

One type of inflammatory cascade familiar to many people is hay fever.  In hay fever, the proteins in pollen enter the body through the sinuses, lungs, or eyes.  The immune system recognizes that these proteins are not part of the self, and it turns on the defense mechanisms.  Histamine is released, nitric oxide is produced, and antibodies are produced.  The inflammation and collateral damage to the body are far greater than the threat posed by a bit of pollen.  But the immune system does not always recognize the real magnitude of the danger, and can over-react.

Inflammatory cascades involve positive feedback - the initial change tends to magnify itself.  Like a small disturbance in a snow field that turns into an avalanche, the release of histamine or cytokines tends to trigger the release of more histamine or cytokines. Rubbing your eyes when you have allergies is another example of postive feedback in an inflammatory cascade - the initial irritation is made worse by rubbing, which leads to more release of histamine and other inflammatory compounds, more redness, and possible physical damage to sensitive tissues as the process spirals.

Many inflammatory cascades have self limiting components - the release of an inflammatory agent often leads to the production of both anti-inflammatory and inflammatory compounds.  But as microbes evolve, they sometimes begin producing a mix of toxins that interfere with the control mechanisms of the immune system.  This seems to be the case for the deadly strains of bird flu. The H5N1 virus is not only partially resistant to the cytokines that are involved in fighting viruses, but it also reduces the production of anti-inflammatory cytokines - in essence, it enhances the accelerator while impairing the brakes, and the immune system goes out of control and crashes.

The Cytokine Storm in H5N1 Infection

The cytokine that is most widely recognized by the public is Interferon (there are actually several interferons, but they are lumped together by most people).  When interferon was first discovered and synthesized using biotechnology, many thought it would be the cure for cancer and many viral infections.  Interferon has proved useful in treating some types of these diseases, but it is not a panacea.  One reason that interferon is not a magical cure is that is only one messenger in an immune system that is incredibly complex.  While a strong agent can be helpful,  a full and balanced immune response requires the coordinated efforts of many cytokines with bizzare names and abbreviations (IL-1beta, IL-2, RANTES, IL-4, IL-6, IL-10, TGF, TNF, etc).

In H5N1 infection, many of the inflammatory cytokines are increased, and each of these tends to increase the production of the others. The cytokines also increase production of reactive oxygen compounds (free radicals) that further the inflammation. 

But recent research suggests that one cytokine is more important than the others in humans infected with H5N! avian flu: Tumor Necrosis Factor Alpha (TNF-a, referred to as TNF for the rest of this article).

 TNF

Not surprisingly, TNF got its name from the increased levels of this compound that were first seen in cancer patients.  TNF can be useful in fighting some cancers, but it is also secreted to fight foreign invaders like bacteria and viruses.  TNF is one of the compounds responsible for the weight loss and wasting that is seen in people with advanced stage cancers.

TNF is elevated in autoimmune diseases like rheumatoid arthritis, psoriasis, ankylosing spondylitis, and crohns disease. Excessive TNF can also lead to damage of the liver, kidneys, and other organs.

While Type A influenza strains like H1N1 or H3N2 lead to small or modest increases in cytokines, the H5N1 strain has been shown to lead to extreme elevation of inflammatory cytokines, particularly TNF. PMID: 16051807  Also important is the way that TNF is elevated by the avian flu virus; while all Type A viruses stimulate NF-KappaB (which can raise TNF), the H5N1 virus appears to be unusual by acting to strongly stimulate the MAPK pathway.  The MAPK (mitogen activated protein kinase) system, (in this case, particularly the MAPK p38 system) has been shown to be responsible for the cytokine storm in bird flu infections, while compounds that inhibit MAPK p38 lead to marked reduction in TNF release in infected cells.

Anti-TNF Therapies

 Enbrel, Remicade, & Humira

A number of pharmaceutical compounds have been developed for rheumatoid arthritis, psoriasis, ankylosing spondylitis, crohns disease, and other diseases associated with increased TNF production. Etanercept (trade name: Enbrel) is a receptor compound that binds TNF and makes it innactive.  Adalimumab (trade name: Humira) is an antibody that binds to and inactivates TNF.  Infliximab (trade name: Remicade) is also an antibody that specifically binds to TNF.

These 3 drugs hold promise in mitigating the damage caused by H5N1 infection.  Unfortunately, they are expensive (costing around $18,000 per year when adminstered for chronic inflammatory disease).  They are large molecules that must be injected, and are heat sensitive, making it difficult to rush them to remote less-developed areas where H5N1 outbreaks may first occur.

There is concern that the use of the pharmaceutical Anti-TNF drugs may increase the risks of certain cancers, although this is not completely understood yet.  While certain lymphomas seem to appear after psoriasis patients use these drugs, it is also true that psoriasis patients that never use them are at increased risk of those cancers.  I believe that the immune supression that results from the nearly complete supression of TNF may allow the tendency towards developing lymphoma to express itself, but this is an area requiring further study.  And if H5N1 was spreading in my community and I showed symptoms, I think the risk from the avian flu would be far greater than the risk of possible lymphoma. 

 Curcumin

Curcumin is the compound that gives turmeric spice its bright yellow appearance. It has been used in herbal medicine for a variety of inflammatory conditions, including fever, arthritis, and psoriasis.  Curcumin not only blocks TNF, but it is an inhibitor of the MAPK p38 system. At present, the Pubmed research database identifies 110 citations when searching for "MAPK curcumin" while the search phrase "TNF curcumin" returns 82 results.  Review of these articles makes it clear that curcumin holds great promise as an agent that may reduce the lethal effects of the avian flu cytokine storm.

Curcumin is quite inexpensive. At Vitacost (where I buy most of my supplements), 60 capsules of  NSI Turmeric (standardized 95% curcumin) 900 mg  cost just under $14 when I last checked - less than the typical co-pay for a prescription. 

Absorption of curcumin is modest to poor, but can be increased when co-administered with piperine (a compound found in various species of pepper, including the black pepper found in most kitchens).  PMID: 9619120   Several commercial formulations of curcumin include piperine (sometimes called bioperine). Piperine itself inhibits TNF, IL-1, IL-6 and other inflammatory cytokines. PMID: 15531295

 While it is best to store it at room temperature, it will not be completely inactivated under the un-refrigerated conditions that would destroy the potency of some expensive pharmaceutical TNF blockers.  Unlike the pharmaceutical TNF blockers, curcumin is associated with a reduced risk of many types of cancer.  In particular, lab studies have shown that curcumin induces apoptosis (programmed cell death) in several types of lymphoma.  ( citation 1, citation 2, citation 3,  citation 4 ). 

 Corticosteroids

Corticosteroids like prednisone lower TNF, but they also lower resistance to many diseases. Corticosteroids are a prime weapon against the SARS virus (another disease where over-reaction of the immune system seems to do as much damage as the virus itself). The amount of corticosteroids administered is important. Following the recent SARS outbreak, many people in China were given excessive doses of corticosteroids and later developed serious complications.  There has been little discussion on the use of these steroids to blunt the cytokine storm seen in avian flu.

Anti-Viral Infectives: Neuraminidase Inhibitors

There has been much talk about Tamiflu and the possibility that it can curb the reproduction of the H5N1 virus.  Tamiflu works by inhibiting an enzyme called neuraminidase (aka sialidase).  This enzyme is used by many virus particles to attach to cells and invade them.  When a neuraminidase inhibitor like Tamiflu is administered, it can reduce the spread of Type A influenza in the population.  It can also shorten the duration and intensity of Type A influenza if administered in the first 48 hours after symptoms appear (it typically reduces a 5-7 day influenza episode by 1 to 2 days).

The strategic use of neuraminidase inhibitors can probably help keep a lid on small outbreaks of the virus.  But if a larger epidemic occurs, supplies will probably run short.  Viruses have demonstrated the ability to mutate and become resistant to Tamiflu, which could be a problem over time.

There are natural neuramidase inhibitors found in plants: the most widely studied is a compound called 5,7,4'-trihydroxy-8-methoxyflavone, which is found in the herb Scutellaria (commonly called scullcap or skullcap).  In a study on mice cells, bathing the cell cultures in Scutellaria tea inhibited both Type A (H3N2 type) and Type B (Ibaraki/2/85 type) influenza when the flavone was administered 18 hours before the virus challenge.  It was not effective when administered five minutes before the virus.  (citation)

Many herbalists have suggested that only the Baikal variety of skullcap would be effective, but these  beliefs are not based on evidence.  Common scullcap (S. lateriflora) contains baicalin (40 mg/g) and baicalein (33 mg/g):  PMID:14692724  Baicalin and baicalein inhibit the neuraminidase/sialidase enzymes: PMID:2717686

I generally use loose skullcap herb to make tea, although there are extracts and capsules available, like these from Nature's Way.

Other hydroxy-flavones are found in plants like Passiflora incarnata (passionflower herb - but not passionflower fruit, Passiflora edulis).   It is not clear whether these flavones also inhibit neuraminidases or influenza viruses  (or the H5N1 virus in particular).  However, both scutellaria and passionflower are also mild tranquilizers (the methoxy-flavone compounds also have a gentle GABAinergic effect and are used by herbalists for anxiety).  These teas have a long history of safe use (on par with chamomile and hibiscus), so it seems logical to first prepare for a possible avian flu epidemic, and stay home and consume relaxing herbs if the epidemic does arrive.

Emodin

Emodin and related compounds are also found in the Aloe vera plant. Unfortunately, emodin is an anthraquinone laxative; taking it orally has significant side effects. Emodin is a cathartic known to stimulate muscle contraction in the intestines, and a large dose can result in painful cramping. It is not clear how much is absorbed into the blood where it can fight a virus.  The studies done on the anti-viral properties of emodin were done in cells in a test tube, not in live animals. Many Aloe vera juices on the market are made using only the gel of the plant; they contain very little emodin. The outer part of an aloe leaf contains most of the emodin - it is in the milky sap portion close to the surface. 

The aloe vera juices on the market do contain polysaccharides like acemannan that stimulate the immune system to produce IL-1 and TNF, but those inflammatory cytokines are not in short supply in people infected by H5N1 avian flu. Most of the research conducted on acemannan have involved HIV/AIDS, or related animal viruses like feline leukemia virus.  It is not clear that aloe polysaccharides protect against influenza viruses in general, or the H5N1 virus in particular.

Resveratrol

Resveratrol is a compound found in large amounts in red wine, grape seeds, and Japanese knotweed. Resveratrol is known to be absorbed into the blood, and it is believed to be part of the "French Paradox" where many people in France eat a high fat diet, yet have low rates of heart disease. 

The root of Japanese knotweed (Polygonum multiflorum aka "He Sho Wu") is the richest known source of resveratrol. It has long been used in a variety of herbal medicines in China and Japan, where it is considered a tonic and life prolonging plant.  This plant has spread to many other countries and is naturalized in the US and parts of Europe.

The effects of alcohol on a person infected with avian flu raises obvious concerns - drinking red wine might help prevent an infection, but once an infection does occur, the alcoholic component of wine is probably not desirable. And resveratrol in wine is not stable: After opening a bottle of red wine, the resveratrol begins to oxidize and much of it is degraded within 24-48 hours. 

In addition to inhibiting neuraminidase, resveratrol also sends a message to cells to stop manufacturing viruses. This was described in terms of blocking the "nuclear-cytoplasmic translocation of viral ribonucleoproteins" and reducing the "expression of late viral proteins seemingly related to the inhibition of protein kinase C activity and its dependent pathway."  PMID:15838800  This study found no toxic effects of resveratrol at levels that significantly inhibited influenza virus.

Resveratrol Supplements are relatively innexpensive, more stable than wine, and lack the alcohol content that might be harmful while fighting a serious infection.

Other Approaches

  Cranberry NDM

Some research has shown that the high molecular weight components of cranberry juice can inhibit influenza viruses in a number of ways. This Non-Dialysable Material (NDM) seems to affect the influenza virus in a number of ways, blocking its adhesion to cells, making it less able to invade and multiply. PMID:15781126

This research is exciting, but some caveats deserve consideration.  The study was done on isolated cells in a petri dish, not in living animals. It is not clear how much  (if any) of the cranberry NDM would be absorbed into the blood, or how long it would circulate in the blood before being metabolized or excreted. Most of the anti-bacterial research on cranberry juice has focused on low molecular weight compounds that block bacteria from adhering to cells in the urinary tract - these clearly are absorbed. Most of the research on the NDM material in cranberry juice focused on the mouth, where absorption was never an issue.

   N-Acetyl-Cysteine

N-Acetyl-Cysteine (or NAC) is a particular activated form of the amino acid cysteine. It has been shown to reduce lethality of influenza A in a number of animal studies PMID: 12657201,

NAC led to a modest reduction in the cytokine RANTES (18%), probably by reducing reactive oxygen species that were generated by the inflammatory cascade. PMID:10706714  NAC also reduced macrophage death due to influenza infection. PMID: 9260892  It does not appear to directly inhibit TNF.

NAC is a hygroscopic material - it soaks up water from the air. Like aspirin, it can break down and release acetic acid, resulting in a vinegary smell. It should be stored in a cool, dry area in a well sealed container.

Elderberry / Sambucol

Elderberry is a controversial herb with respect to H5N1. There is evidence that black elderberry extract (trade name: Sambucol) can reduce the risk of contracting ordinary influenza strains, or shorten the course of disease in those who contract the typical flu.  It does so (at least partially) by increasing the production of inflammatory cytokines like IL-1, IL-6, and TNF! (citation)  While black elderberry extract be appropriate for ordinary Type A influenza, there is a concern it could make avian flu more lethal.  Ordinary strains of flu do not trigger massive production of TNF, and ordinary flu viruses are generally susceptible to the action of TNF.  Avian flu, by contrast, does trigger massive production of TNF, while the virus is relatively resistant to the anti-viral effects of TNF.  If TNF is a significant cause of the illness and mortality in avian flu, anything that increases TNF would be undesirable.

It has been pointed out that black elderberry does not just increase TNF and other cytokines. It also may reduce the spread of the virus through inactivation, or exert anti-inflammatory effects as well as contributing to the cytokine storm.  It may be that combining elberberry with other anti-inflammatories may allow it to check the infection without producing tissue destroying levels of cytokines. But there is insufficient evidence to make a solid conclusion, while there are significant red flags that should be raised about the mode of action of elderberry.

Chocolate

Sorry. While most recent research on has suggested that chocolate has health benefits, the TNF stimulating effects of the cocoa flavonoids does not look like it would be healthy for people infected with avian flu virus. PMID:12885154,PMID:10917928  The flavonoid compounds in chocolate can be compared to beads and short chains of beads; although the individual beads had a slight cooling effect on the immune system, the more numerous chains of 5 to 10 flavonoid groups dramatically increased the production of inflammatory cytokines. While the researchers suggested that this may be beneficial for stimulating circulation or fighting bacterial infection, I believe it may not be good for someone in a severe cytokine storm.

(Side note to migraine researchers: If migraine headaches are associated with elevated cytokines like IL-1, IL-6 and TNF, and cocoa flavonoids can dramatically elevate these cytokines, maybe there is a basis for claims that chocolate can trigger migraines.  PMID: 15985111)

There are many other compounds that modulate the immune system and which may be of benefit in treating avian flu: a few include melatonin, garlic, green tea, and ginger.  This paper will be expanded to include discussion of these over the next weeks.

Conclusions

If the H5N1 avian flu was spreading in my community and my doctor offered me a pharmaceutical TNF blocker and a neuramidase inhibitor, I would take them.  But it is doubtful that everyone will have that choice if an epidemic does occur.  Although the pharmaceutical agents have not been well tested, and the potential herbal treatments I discussed are based on theory, I think that it is likely that they would reduce mortality ...  taking them would be better than doing nothing.  So I have a bottle of curcumin (which I occasionally take to keep my psoriasis in remission) and a container of scutellaria tea (which I sip at work to keep my nerves from frazzling when there are too many deadlines).  And I am ordering some resveratrol.

Further discussion of these topics at www.med-owl.com/herbal-antivirals/

  Med-Owl Health Notes   Med-Owl Home

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ITEM HISTORY
v. 1:  August, 2005.
v. 2: February, 2006.

This article was written to discuss the biology of the H5N1 Avian Flu, and is not intended to provide specific medical advice.