A Journey Through The World of Pandemic Influenza

A Lesson from our Last Influenza Pandemic

One of the most frustrating things I find as a "blogger" is that I tend to ramble, and for what is supposed to be a "tightly focused" blog that is a bad thing. Another bad thing in this medium is the long entry. As I attempted to write up everything I wanted to say in my last entry it was too long and too winding and just plain too. So I am "chunking" the stuff I want to ramble on about in the hopes that y'all out there won't notice.

 

My last post, Informed Seats and My Favorite Chair, dealt mainly with introducing R₀ (Reproduction number) of infectious disease, and specifically, pandemic influenza. How pandemic planners are working with the assumption of a 1.x – 2.x for the R₀.

 

My favorite theory to explain the epidemiology of the influenza pandemic of 1918 has been prior exposure/circulation of H1N1 or a close relative. Now I have to consider heterosubtypic immunity (immunity across subtypes) as at least as likely an explanation, if not more so.

 

 

 

Fig. 1.

All-cause and P&I monthly mortality rates for all ages (A and B) and all-cause mortality rates by age group (C-H) are calculated per 10,000 population. Observed rates are days-per-month adjusted. Expected model baselines (solid lines) are derived from each series of nonepidemic months. Epidemic thresholds (dashed lines) are the upper 95% confidence limit above each baseline. The major epidemic influenza season months are indicated (shaded). Two 1917/1918 influenza season peaks (arrowheads) show excess mortality primarily confined to the ≥65-years age group in January (C), and to the groups <45 years old in March 1918 (E-H). Other severe mortality events are evident: summer diarrheal disease epidemics were confined to young children (H), the 1916 polio epidemic to all children (G and H), and the summer 1917 heat wave and diarrheal disease epidemic among the youngest and oldest age groups (C and H).

Proc Natl Acad Sci U S A. 2005 August 2; 102(31): 11059–11063.

Published online 2005 July 26. doi: 10.1073/pnas.0408290102.

Graph and legend from Epidemiological evidence of an early wave of the 1918 influenza pandemic in New York City Donald R. Olson, et al.

Of particular interest is section B of the above graphic showing the monthly mortality rates due to P&I (Pneumonia & Influenza) for all ages. The above paper also happens to be one of the major supports for my "prior exposure/circulation" belief.

 

But what if…

 

What if we only saw a ~30% CAR (Clinical Attack Rate) and ~2.5% CFR (Case Fatality Ratio) because many people benefited from heterosubtypic immunity from a not too long past bout of seasonal influenza A?

 

Drawing on A Biological Model for Influenza Transmission: Pandemic Planning Implications of asymptomatic Infection and Immunity John D. Mathews et al.

Reports of past influenza pandemics show marked variation in clinical attack rates between populations. In the 1918–19 H1N1 pandemic, rates of clinical illness were less than 20% in some urbanised communities, but more than 60% in isolated communities such as Western Samoa [1]–[4]. During the 1968 H3N2 pandemic, attack rates in US households were limited to 30–40% [5], whereas almost the whole population fell ill when the virus reached the isolated island of Tristan da Cunha (TdC) in 1971 [6]. Biologically-based models for pandemic influenza [1] that incorporate effects of host immunity can help to explain such differences in observed attack rates.

The paper draws a correlation to urban settings and the likelihood of a higher, more consistent rate of seasonal influenza infection than those likely experienced in relatively geographically isolated areas. The island of Tristan Da Cunha is both geographically isolated and remote thus serving as a perfect example.

[snip]

 

The population of Tristan da Cunha, a remote island in the South Atlantic, had been free of influenza for 8–9 years when H3N2 was introduced by ship from South Africa in 1971[6]. The resulting epidemic curve over 50 days was based on reports of cases by day of symptom-onset. In two waves, 96% of the population of 284 fell ill; there were 365 recorded attacks, of which 312 could be identified with a precise day of onset. 273/284 islanders experienced a first attack of influenza, and 92/284 experienced a second attack. Most second attacks coincided with the second population wave; a minority of individuals experienced a first (and only) clinical attack during the second wave, possibly following asymptomatic infection during the first wave. Second attacks were generally less severe.

 

What might this imply for a future influenza pandemic?

 

This paper's findings suggest someone suffering a bout of influenza A in their recent past may have a degree of immunity, even if the previous influenza is not the same sub-strain (homogeneous). Immunity could range from total, to asymptomatic infection or lessened severity. Conversely, someone who has not suffered a recent bout of influenza A could be as naked and vulnerable to a novel influenza strain as a newborn babe is to the world they arrive into.

 

Taking this possibility three steps further into supposition territory:

 

We are currently seeing a frightfully high mortality rate with human infections of H5N1, ~60% cumulative and ~80% in Indonesia. The infections have been in countries and in populations that do not have annual influenza vaccination programs to protect them from the seasonal influenza that arrives yearly. Is it reasonable to postulate that those infected had also suffered a human seasonal A variety sometime within three years previous? I would assume that it is a reasonable assumption that many had. Heterosubtypic immunity did not play a great role here, or if it did, perhaps it allowed for only a severe infection as opposed to a fatal one. A severe infection, that with Tamiflu and medical support ended up being survivable.

 

In my previous post I made mention that the R₀ was not the only staggering gem the recent paper on A Biological Model for Influenza Transmission: Pandemic Planning Implications of asymptomatic Infection and Immunity held.

Unfortunately, heterosubtypic immunity, which can be short-lived, is likely induced more effectively by recent infection with a live influenza virus than by conventional sub-unit vaccines [14], [24]. This raises the possibility that inter-pandemic sub-unit vaccine, by preventing infection with live inter-pandemic virus, could even make people more susceptible to a novel pandemic virus. The bottom line is that we need much more information about heterosubtypic immunity in humans, and about the potential value of live-attenuated influenza vaccines against H1N1 and H3N2 in protecting populations against H5N1 or any other novel pandemic virus. We await the results of relevant research with great interest.

 

I will share with you the closing thoughts of the person who pointed out a logical end-point to these findings and assumptions; they say it far better than I could:

"I don't think that it is enough to have had the experience of just not having access to vaccines, and getting seasonal influenza's that would protect a person, else the mortality rate in Indonesia wouldn't be what it is. The problem is not that people do well if not vaccinated yearly, rather that they may do worse if they have been dutifully getting their influenza vaccine." [emphasis added]

 

 

SZ

Adenoviridae

Today's news has been heavy with the internet publication of information on yet another emerging human pathogen, a variant of Ad14.

Ad14 is an adenovirus, of which there are somewhere between 40 and 50 human serotypes, depending on which resource one reads. There are also adenoviruses that infect other mammals, birds, and even amphibians.

From today's CDC MMWR:

Acute Respiratory Disease Associated with Adenovirus Serotype 14 --- Four States, 2006--2007

Adenovirus serotype 14 (Ad14) is a rarely reported but emerging serotype of adenovirus that can cause severe and sometimes fatal respiratory illness in patients of all ages, including healthy young adults. In May 2006, an infant in New York aged 12 days died from respiratory illness caused by Ad14. During March--June 2007, a total of 140 additional cases of confirmed Ad14 respiratory illness were identified in clusters of patients in Oregon, Washington, and Texas. Fifty-three (38%) of these patients were hospitalized, including 24 (17%) who were admitted to intensive care units (ICUs); nine (5%) patients died. Ad14 isolates from all four states were identical by sequence data from the full hexon and fiber genes. However, the isolates were distinct from the Ad14 reference strain from 1955, suggesting the emergence and spread of a new Ad14 variant in the United States. No epidemiologic evidence of direct transmission linking the New York case or any of the clusters was identified. This report summarizes the investigation of these Ad14 cases by state and city health authorities, the U.S. Air Force, and CDC. State and local public health departments should be alert to the possibility of outbreaks caused by Ad14.

 

As with most infectious diseases, it is difficult to know the true extent and severity of a pathogen based solely on the cases that result in medical consultations and/or hospitalizations. There is no way of knowing how many cases occurred, and probably continue to occur, that were not severe enough to require medical treatment. Were we to have access to that data the alarming statistics in all likelihood wouldn't be so alarming, but without the full data set we are left with what we the data we do have. And that data is rather alarming.

This from MSNBC:

New cold bug kills 10, scores sickened

Scores sickened as mutated virus becoming more common, CDC says

The Associated Press

updated 1:55 p.m. ET, Thurs., Nov. 15, 2007

ATLANTA - A mutated version of a common cold virus has caused 10 deaths in the last 18 months, U.S. health officials said Thursday.

Adenoviruses usually cause respiratory infections that aren't considered lethal. But a new variant has caused at least 140 illnesses in New York, Oregon, Washington and Texas, according to a report issued Thursday by the U.S. Centers for Disease Control and Prevention.

That is incorrect based on the MMRW report:

[snip]

Cases reported postinvestigation. Since the investigation, new cases of febrile respiratory illness have continued to occur at LAFB, but the weekly incidence has declined from a peak of 74 cases with onset during the week of May 27--June 2, to 55 cases with onset during the week of September 23--29 (the most recent period for which data were available). In addition, during March--September 2007, three other military bases in Texas that received trainees from LAFB reported a total of 220 cases of Ad14 illness (Air Force Institute for Operational Health, personal communication, 2007). However, whether Ad14 spread from LAFB to these three bases has not been determined. Ad14 also was detected in April in an eye culture from an outpatient in the surrounding community who had respiratory symptoms and conjunctivitis. No link between this case and the LAFB cases was identified.

 

The Associated Press article from MSNBC closes with this paragraph:

More common
It's not clear how the changes made it more lethal, said Linda Gooding, an Emory University researcher who specializes in adenoviruses.

Earlier this year, hundreds of trainees at Lackland became ill with respiratory infections. Tests showed a variety of adenoviruses in the trainees, but at least 106 — and probably more — had the mutated form of Ad14, including five who ended up in an intensive care unit.

 

So while the reporting is alarming, the story that they attempt to report on is not clearly delineated, nor can it be; we just don't possess all of the facts on all of the (likely) cases.

We do, however, know that adenovirus is long-lived outside a host. Door handles/knobs, counter surfaces, toilet and bathroom sink handles, shopping cart handles, and the myriad other surfaces we touch on a regular basis throughout our normal day. Washing our hands regularly and keeping our hands away from our face will go a long way in helping to guard against infection. In today's "viral jungle" we must learn to adapt our behaviors as rapidly and efficiently as the pathogens we face.

 

 

Tamiflu and Pandemic H5N1

Tamiflu (Oseltamivir ) stockpiling for use during an influenza pandemic, I assume for convenience and brevity to be H5N1, is controversial—at best. Not even the very knowledgeable among the Cyber Flu Community fully agree on the issue, but it is an issue that evolves so periodically we dust it off and reconsider it afresh.

A brief rundown of some of the operative issues that reside within the Tamiflu issue may be warranted.

• Obtaining the end product (Tamiflu) is a difficult and time consuming process.
• Tamiflu is expensive.
• Tamiflu has a finite shelf life, thus the earliest acquired (expensive) stock is already expiring, unused.
• There will never be enough for everyone who would likely benefit from receiving it.
• It produces resistant strains of influenza virus, thus it will render useless the expensive stockpiles.
• WHO Clinical Management:

  Modified regimens of oseltamivir [Tamiflu] treatment, including two-fold higher dosage 1 , longer duration and possibly combination therapy with amantadine or rimantadine (in countries where A(H5N1) viruses are likely to be susceptible to adamantanes) may be considered on a case by case basis, especially in patients with pneumonia or progressive disease.

  That's double the dose for up to double the standard length of time, requiring 40 capsules instead of 10, potentially slashing our stockpiles to a quarter of their standard treatment courses. A standard treatment course consists of 10 capsules, 2 a day for five days.

Some or all of the above, but by no means a full listing of all the relevant issues, have weighed on whether or not private and governmental entities stockpile Tamilfu against the future threat of an influenza pandemic.

For those interested in exploring the issues of Tamiflu from a scientific perspective I recommend EffectMeasure's latest offering on Tamiflu, which in turn will link to an entire series on modeling antiviral resistance.

Here is the opening bit to (hopefully) whet your appetite:

Genetically fit oseltamivir resistant H5N1 mutants 

Posted on: November 8, 2007 7:23 AM, by revere

Via the Clinician's Biosecurity Network Report we learn of a new study from the Webster St. Jude laboratory in Memphis showing that H5N1 can mutate to oseltamivir (Tamiflu) resistance without any loss in genetic fitness. Tamiflu resistance has been seen but infrequent and there was considerable evidence that the resistant strains were handicapped in some way, thus making them either less virulent or less transmissible. The hope was this was a built-in limitation. Now we know it isn't…

And here is the piece that inspired the Revere post…

CBN Report: Drug-Resistant H5N1 Influenza Viruses May Retain Fitness
By Eric Toner, M.D., November 1, 2007

Should widespread resistance to antiviral drugs occur in a pandemic influenza strain, the chance of limiting the disease outbreak, either locally or globally, or treating the sick with antiviral medications would be greatly diminished. This has been of particular concern because many isolates of H5N1, the virus currently considered to have the greatest pandemic potential, are known to be resistant to one class of antivirals, the M2 inhibitors, and a few isolates have evidenced resistance to the only other class of influenza antivirals, the neuraminidase inhibitors (NAI). It has been posited, however, that the risk of NAI resistance becoming widespread might be relatively low because it was thought that as influenza viruses acquire NAI resistance, they become less fit and as a result, cannot be transmitted efficiently.

Continues at Clinician's Biosecurity Network.

As is usual with things relating to pandemic influenza issues aren't clearly understood, clearly defined, or easily made so, but there are people out there, in the trenches, trying to remedy that, and the Reveres at EffectMeasure are longstanding exemplars. My humble thanks for all they do in that endeavor.

SZ

Human Disease and Our Pets

It has been demonstrated, both clinically and in natural settings, that dogs and cats are susceptible to H5N1. Different animals have actively shed virus to one degree or another; in the case of one lab experiment on dogs it was quite significant.

I raise Chesapeake Bay Retrievers, I call them my four legged children, when I'm not calling them The Four Horsemen of the Apocalypse, but whatever I am calling them, I love them dearly. I have studied the disease implications for them in regards to H5N1, and I have formulated a course of action, as well as stocked an emergency supply of their "stuff".

There are things we can do to protect our beloved pets from H5N1, it all starts with educating ourselves, and that I have certainly done. But today I found a very disturbing piece of information, although I will stress that the information has not been scientifically scrutinized, it is deeply concerning none the less. It doesn't have to do with PanFlu or H5N1, but another deadly disease….

Pets Might Pack Deadly Human Bacteria

By Robert Roy Britt, LiveScience Managing Editor posted: 31 July 2007 04:24 pm ET

(Excerpt)

Deadly bacterial infections have been on the rise in recent years as some microbes are gaining resistance to existing antibiotics. These superbugs, as researchers call them, once were seen as a problem mostly in hospitals, but lately the resistant infections also are cropping up more and more outside hospitals.

Now, scientists have begun to suspect that pets could be at least partly to blame.

Methicillin-resistant Staphylococcus aureus (MRSA) can be fatal in humans and has proven particularly virulent. The superbug can live on the skin or nose of a person or pet and not produce symptoms, researchers say. But when it enters a wound, any wound, it can create serious infection that often resists multiple types of antibiotics.

In 1974, MRSA infections accounted for 2 percent of the total number of staphylococcal infections. By 2004, that figure was 63 percent, according to the Centers for Disease Control.

"We used to think of these antibiotic-resistant infections as a healthcare issue that appeared in post-operative or long-term patients," said Stephanie Kottler, a veterinarian at the University of Missouri-Columbia Veterinary Medical Teaching Hospital. "However, we have been seeing more of these infections that have been acquired throughout the general population, or 'community acquired' infections. It's important to know what environmental factors might be encouraging or prolonging these infections."

'Multiple cases' 

While evidence that points to pets helping to infect humans is so far slim, Kottler and University of Missouri-Columbia colleagues Leah Cohn and John Middleton announced today they will study the issue, which is hinted at in some previous research.

"There are multiple case reports of humans with infection with MRSA when the household pet was also found to have MRSA," Cohn told LiveScience. "Sometimes, the human infection could not be successfully eradicated until the animal was also treated."

Studies have been relatively small and somewhat inconclusive, however.

For instance, a small 2005 British study of a vet facility, detailed in the journal Emerging Infectious Diseases, "suggests that dogs can act as reservoirs of MRSA, which can pose a public health risk to owners and veterinary staff."

A 2003 report in the journal Clinical Infectious Diseases found that two dog owners who suffered persistent MRSA infections relapsed every time they returned home from the hospital. The dog was found to carry the same strain of MSRA, but the researchers could not determine whether the dog initially acquired the infection from the humans or the other way around.

Continues…

 

I had a young cousin die from MRSA, it was so rapid that the doctors didn't even have a chance to test for it. While I am not considering getting rid of "my children" I will be even more careful of their interactions with other dogs, something that I am already very careful after the "Dog Flu" surfaced.

 

As bad as an H5N1 infection is, it is more treatable than some of the MRSA infections.

 

SZ

Egypt 3 April 07

Egypt is causing a bit of a stir in the Flubiehood today. The story of a young sister and brother becoming infected with H5N1 four days apart has been buzzing around, because of the timing of onset of symptoms between the girl, first to become ill and the younger brother it is suspected that the boy caught the virus from his sister, H2H (human-to-human) transmission. H2H transmission is The Thing that Flubies incessantly watch for.

 

REUTERS AlertNet

No human transmission in Egypt bird flu case-WHO
03 Apr 2007 16:43:16 GMT
More (Updates with human transmission ruled out)
GENEVA, Apr 3 (Reuters) - Egyptian health authorities excluded the possibility of human to human transmission in the case of a brother and sister with bird flu, the World Health Organisation (WHO) said on Tuesday.

A four-year-old boy, from Qena province around 670 km (400 miles) south of Cairo, was among three human cases announced by the health ministry at the weekend. His six-year-old sister was one of two children diagnosed with the virus late last week.

"We have heard from the Ministry of Health that human to human transmission has been ruled out," WHO spokesman Greg Hartl told Reuters.

Both of the children had been exposed to poultry infected with the H5N1 virus, the most common way in which bird flu has been spreading.

In all, five Egyptian children have been reported as being in hospital in stable condition. "Egypt has an extremely good record of child survival of H5N1," Hartl added.

The highly pathogenic H5N1 virus is not easily transmissible between people, although there has been evidence of several clusters involving human to human transmission over the past three years, according to the WHO.

Experts fear that the virus will mutate or combine with the highly contagious seasonal influenza virus and spark a deadly pandemic which could circle the globe and kill millions.

Egypt has the highest number of confirmed human bird flu cases outside Asia. Of the 32 confirmed cases in the country to date, 13 have been fatal.

While the article states WHO made the announcement, the information seems to have come from Egyptian health authorities.  It seems to be just too early for such a definitive announcement, although with NAMRU-3 there, perhaps it isn't outside the realm of possibility.

Siblings with a spread of symptom on-set dates leave only two possibilities: A common environmental contaminate or the sister infected the brother.

 

If the sister infected the brother we still may not be seeing a humanly transmissible virus.  Avian Influenza preferentially binds to alpha 2,3 sialic acids because birds have the 2,3 receptors, while human influenza preferentially binds to alpha 2,6 sialic acids.  Humans, adults anyway, have both receptors in their respiratory tracts, however almost exclusively the 2,6 receptors in the URT, the 2,3 being mostly restricted to the the lower tract, LRT. 

There is a strange happenstance though, young children it seems have almost exclusively 2,3 binding receptors which slowly change to the 2,6 receptors as they age. So, our young victims would have the same types of cells H5N1 would use to infect ducks and chickens, but adults would have far, far fewer, and in a much harder place to reach.

This means that it is logically possible to have had an occurrence of H2H with H5N1 without having a human adapted virus.  Is it factual?  Who knows... we simply do not have enough information in the hands of Flubies who are capable of puzzling the pieces at this time.  Until we do, the Flubiehood will be buzzing, and my PPF (Personal Pucker Factor) won't be going down any.

 

SZ

Stretching Our Supply of Tamiflu

Tamiflu is our first line of defense in preventing and treating H5N1 human infections.  It is utilized as a prophylactic, HCWs and poultry flock cullers often take it to prevent infection in a known high risk environment, it has also been used on occasion to give close contacts of confirmed or highly suspected cases.  When a Tamiflu Blanket is mentioned, this is what they are referring to.

Of course, it is also the primary treatment for human infection, and while not perfect, it is, currently, the best available treatment, affording the highest chance of survival.  Its success is the reason that governments around the world have or are building a Pre-Pandemic supply. 

Private businesses, of all sizes have either stocked, or are trying to stock Tamiflu for their critical personnel.  This would theoretically entice those workers to report to the job, keep them alive to perform it should they become infected, thus ensuring, theoretically, the continuity of the business.

While Tamiflu is currently our best defense, until we get a functional vaccine in place, ready to deploy, it is expensive, difficult to manufacture, under a patent held by one company, Roche Pharmaceuticals, and demand is far outstripping supply.

The final stressor on the limited supply is the suspected need of doubling the dosage over a longer period of time, a study spearheaded by WHO of this theory is currently getting under way.  So, anything that would effectively stretch the on hand stocks, both public and private would be a monumentally good thing, or you would think so anyway. 

Probenecid burst onto the Cyber Flu scene the end of October 2005 with Declan Butler's piece in Nature Wartime tactic doubles power of scarce bird-flu drug: Use of common drug could stretch world stocks of Tamiflu.

Doctors think they have hit on a way to effectively double supplies of a drug that fights bird flu. Administering Tamiflu alongside a second drug that stops it being excreted in urine means that only half doses of the treatment would be needed.

Tamiflu (oseltamivir phosphate) is the main antiflu medicine recommended by the World Health Organization (WHO). The WHO suggests that, in anticipation of a flu pandemic, countries should stockpile enough for at least a quarter of their population. But although Swiss drugmaker Roche, the sole supplier, has quadrupled its production capacity over the past two years, the current supply is thought to cover just 2% of the world population.

Last week, Joe Howton, medical director at the Adventist Medical Center in Portland, Oregon, suggested a way to double supplies, after browsing basic safety data from Roche for a talk on avian flu.

The technique was invented during the Second World War to extend precious penicillin supplies. Scientists found that a simple benzoic acid derivative called probenecid stops many drugs, including antibiotics, being removed from the blood by the kidneys. Probenecid is readily available and is still widely used alongside antibiotics to treat gonorrhoea and syphilis, and in emergency rooms, where doctors need their patients to have high, sustained levels of antibiotics in their blood.

. . . [And the article closes:]
Like many scientists, Fedson is stumped by the apparent lack of interest from Roche, and the relevant authorities. "It's stupefying," he says.

This information broke 17 months ago, beyond its repeated mention amongst the Flubies it gets no play or mention.  Several physicians who are active in Flublogia (the cyber pandemic flu community) have endorsed the idea of using Probenecid in combination with Tamiflu, although it would be an "off-label" usage.  Dr Grattan Woodson, perhaps one of the most well known Physician Flubies posted his comments about the concept at the original Fluwiki, the entire piece by him on Tamiflu found at the link is worth a read but I will just include the Probenecid portion here.

Using oseltamivir in combination with probenecid

While preparing a presentation on Bird Flu for his colleagues at Portland Adventist Medical Center in Oregon, Joe Howton, MD, Medical Director, Emergency Services at the hospital, ran across an obscure comment in the product information on the antiviral drug Tamiflu® used for treatment of influenza. The comment was in the section on safety and drug interactions and referred to the results of safety studies that were completed before the drug was approved for use. The finding was that when Tamiflu was given at the same time as another commonly used drug, probenecid which is used to treat gout, the blood level of Tamiflu doubled and the time it remained at effective levels in the body increased from about 8 hours to more than 20 hours.

This finding astounded Joe. He immediately realized its importance given our concerns about Bird Flu and the present severe shortage of Tamiflu. He understood that this means that if it were safe to give Tamiflu in combination with probenecid, it would increase the clinical effects of each Tamiflu tablet significantly and this would starch the available supply.

When Joe called me about this to see what I thought, at first I was a bit skeptical. Why hadn’t someone else figured this out before now? Besides gout, probenecid has been indicated for increasing penicillin blood levels and the length of time it stays in the body for years. So, it was not much of a stretch to think of it for use with Tamiflu especially since we are facing such a shortfall of this drug. So, I spent the night and much of the next on the National Library of Medicine’s web site and reading my trusty Goodman and Gilman Pharmacology Text and sure enough, Joe was right. Tamiflu levels could be increased as can the length of time it stays in the body fighting the virus by combining it with probenecid. I had used probenecid for as long as I had practiced, over 25 years now, and regarded it as a reliable old standby in my pharmaceutical armamentarium. What made this discovery all the sweeter, it is generic and relatively inexpensive at a cost of about $20 for a 10-day treatment course.

During my investigations, I discovered that infectious disease doctors worldwide were already using probenecid to increase the levels of drugs used to fight tuberculosis and HIV-AIDS, but did not find any references to using it intentionally with Tamiflu for this purpose. The way probenecid increased the effects of these drugs, including Tamiflu, is exactly the same way it increases the level and effective blood levels of penicillin. This was very reassuring. I was not too concerned that the combination of probenecid with Tamiflu was not formally approved by the any regulatory agency like the US FDA since every day, as a doctor who takes care of people, I find myself using approved drugs for “off label” indications. This is a perfectly acceptable and established practice as long as the doctor has good reason to believe that it will be of benefit to his or her patient.

In my opinion this is an important finding. We all owe Dr. Howton a debt of gratitude. While this novel combination does not solve our Bird Flu problem by any stretch of the imagination, it does mean that suddenly the world has the equivalent of two-and-a-half times more Tamiflu in the world’s stockpile now than we thought. What’s more, the Tamiflu produced from this point forward will also go two-and-a-half times further than we originally thought. Of course, this all depends on our ability to ramp up probenecid manufacture, which I believe can be accomplished rather quickly and inexpensively. On the whole, this is one of the few pieces of really good news concerning the Bird Flu pandemic that I have heard since becoming concerned about it in 2004.

 

Since this information hit 17 months ago it is hard for me to understand why it hasn't been "officially" looked at, but more importantly, why it isn't being loudly trumpeted.  In fairness, perhaps it is being whispered about in the official circles that need the information but where does that leave the individual that is trying to prepare for themselves and their family?  It leaves them out in the cold unless they just happen to stumble upon the information.

 

As always, I am not recommending Probenecid to anyone, I am providing a simple summary of what information is available on a promising option.  What I have personally planned I did so only after researching the issues.  Nothing is risk free and that includes using Probenecid.  Should you decide that Probenecid holds potential benefit to your personal pandemic preparations I strongly suggest you research the issue on your own, weigh it against your individual needs and potential risk vs. benefit scale, as it does have potentially dangerous side effects.  A listing of advisements and cautions can be found here.

 

We, as average citizens, are not helpless, even in the face of something as difficult and horrific as a severe pandemic.  There are things that we can and should do for ourselves to strengthen our possibility of survival, ours and those we love and care about.  But in order to take those actions we need information, good information, or what I like to term Best Available Information.  This post is dedicated to the practice of that concept.

 

SZ

Statins and H5N1 Infection Mitigation

My husband takes prescription cholesterol lowering medication and when the news started circulating around the Cyber Flu Community back in the fall of 2005 I sat up and took note.  Statins are ubiquitous in the US since doctors seem to like to prescribe them at the first hint of cholesterol elevation.

As this piece from one of the Reveres at EffectMeasure states, the research is intriguing and logically indicates that statins may be beneficial should those taking them become infected.  Please be aware that it is presumed that you must be on them for at least (guess) a month prior to infection to see the positive (if any) effects, but the benefits may mean the difference between living and dying.

From EffectMeasure (old site) [They have since moved: New Site]

Thursday, September 29, 2005

Bird flu and statins 

In an extremely interesting article in the Clinicians Biosecurity Network Weekly Bulletin (issue of 9/27/05) Borio and Bartlett review a suggestion of David Fedson, an expert on vaccines (and former Director of Medical Affairs at Aventis Pasteur), that statins (tradenames Zocor or Lipitor) might be helpful in preventing serious complications of influenza, perhaps by dampening the cytokine response.

The statins are widely used and available drugs used to lower cholesterol. They also have anti-inflammatory activities, perhaps by preventing activation of the transcription factor NF-kappaB. One mechanism thought to underlie the virulence of the H5N1 virus is production of a "cytokine storm," an unregulated systemic inflammatory response that results in a rapidly developing generalized clotting disorder, hemorrhage, kidney failure and fluid-filled lungs. The phenomenon is similar to or the same as what is called gram-negative sepsis or septic shock, a serious complication of bacterial infections that claims 400,000 to 500,000 lives each year in the US and has 50% to 70% mortality. Treatment for sepsis is a high priority independently of any role for the same or similar mechanism in influenza.

The idea that statins might be helpful for sepsis or influenza is based on more than speculation about mechanism. In 2004 Almog et al. (Circulation, Aug 17 2004;110(7):880-885) reported that patients admitted to the hospital with acute bacterial infections and who were on statins for more than a month for other reasons had a dramatically reduced incidence of severe sepsis (19% versus 2.2%) and reduced admission to the Intensive Care Unit (12.2% vs. 3.7%). An interesting point is that patients on statins might be expected to be at greater risk because they are taking a medication for a pre-existing medical condition.

Another study (.pdf available free on line here) looked back at the experience of over 700 patients that were admitted to a hospital for pneumonia. About 100 of them were also taking statins. Using 30-day mortality as a measure of outcome, the statin group had about two thirds fewer deaths than the non-statin group (odds ratio .36, 95% confidence interval .14 - .92).

Borio and Bartlett also report on an article from The Netherlands by Enserink to appear shortly in Science (hence not available to me other than through their summary). Enserink examined influenza seasons between 1996 to 2003, and using a database of 60,000 primary care patients compared those with at least two statin prescriptions in the previous year to those without. There was a 26% lower risk of pneumonia in the statin group. Because of the imprecision of the measure of statin use, I would expect the statin effect to be even greater than reported here.

Borio and Bartlett conclude:

These studies suggest that statin therapy may ameliorate the course and/or prevent complications of influenza. In these studies, it appears that all of the people were already receiving statins when they got infected. Whether statins would be beneficial after the onset of symptoms is still unknown. However, further investigation is merited. This is particularly important given the likelihood that vaccines and antiviral agents will be in short supply during an influenza pandemic, and statins are widely available and may be produced relatively inexpensively.

This is extremely interesting work. It is too early to say that prophylactic statin use in a pandemic is a reasonable strategy, but it is worth considering.

There is also an OTC product, Red Yeast Rice (the base ingredient in many statins) that is cheap and easily obtained.

The entry on Red Yeast Rice from the Mayo Clinic's site:

[snip]

Red yeast rice is the product of yeast ( Monascus purpureus ) grown on rice, and is served as a dietary staple in some Asian countries. It contains several compounds collectively known as Monacolins, substances known to inhibit cholesterol synthesis. One of these, "Monacolin K" is a potent inhibitor of HMG-CoA reductase, and is also known as Mevinolin or Lovastatin (Mevacor®, a drug produced by Merck & Co., Inc).

Red yeast rice extract has been sold as a natural cholesterol-lowering agent in over the counter supplements, such as Cholestin ^TM (Pharmanex, Inc). However, there has been legal and industrial dispute as to whether red yeast rice is a drug or dietary supplement, involving this manufacturer, the U.S. Food and Drug Administration (FDA) and the pharmaceutical industry (particularly producers of HMG-CoA reductase inhibitor prescription drugs or "statins").

[snip]

Uses based on scientific evidence

High cholesterol

Since the 1970s, human studies have reported that red yeast lowers blood levels of total cholesterol, low-density lipoprotein/LDL ("bad cholesterol"), and triglyceride levels. Other products containing red yeast rice extract can still be purchased, mostly over the Internet. However, these products may not be standardized, and effects are not predictable. For lowering cholesterol, there is better evidence for using prescription drugs such as lovastatin.

[snip]

Dosing

The below doses are based on scientific research, publications, traditional use, or expert opinion. Many herbs and supplements have not been thoroughly tested, and safety and effectiveness may not be proven. Brands may be made differently, with variable ingredients, even within the same brand. The below doses may not apply to all products. You should read product labels, and discuss doses with a qualified healthcare provider before starting therapy.

Adults (18 years and older):

1,200 milligrams of concentrated red yeast powder capsules have been taken two times per day by mouth with food.

The average consumption of naturally occurring red yeast rice in Asia has been reported as 14-55 grams per day.

Children (younger than 18 years):

There is not enough scientific evidence to recommend red yeast for children.

Safety

The U.S. Food and Drug Administration does not strictly regulate herbs and supplements. There is no guarantee of strength, purity or safety of products, and effects may vary. You should always read product labels. If you have a medical condition, or are taking other drugs, herbs, or supplements, you should speak with a qualified healthcare provider before starting a new therapy. Consult a healthcare provider immediately if you experience side effects.

Allergies

There is one report of anaphylaxis (a severe allergic reaction) in a butcher who touched meat containing red yeast.

Side Effects and Warnings

There is limited evidence about the side effects of red yeast. Mild headache and abdominal discomfort can occur. Side effects may be similar to those for the prescription drug lovastatin (Mevacor®). Heartburn, gas, bloating, muscle pain or damage, dizziness, asthma, and kidney problems are possible. People with liver disease should not use red yeast products.

In theory, red yeast may increase the risk of bleeding. Caution is advised in patients with bleeding disorders or taking drugs that may increase the risk of bleeding. Dosing adjustments may be necessary. A metabolite of Monascus called mycotoxin citrinin (CTN) in fermentation may be harmful.

While no one knows if Statins or Red Yeast Rice will have any beneficial effects on an infection of H5N1 I will be utilizing them as prophylactic countermeasures for my family, but most especially for my son who is smack in the middle of the most-at-risk age group for dying from it.  I am fully cognizant of the risks and downsides.  I have done my homework and read all of the available information (scant though it is) and made a conscious and informed decision that the potential benefits outweigh any of the potential risks.  Should you consider these as options for yourself I suggest you do the same.  Nothing in life is entirely risk free, and everything generally comes at some price, the key is knowing enough to make informed and intelligent decisions.

My plan of attack is to utilize the supplement Red Yeast Rice once a Pandemic Influenza strain manifests and switch to the prescription Statin once the virus is in my area.  As can be appreciated, I have a lot more of the OTC supplement than I have of the prescription medication.  Timing will be all important.  My thanks to Bannor at PlanForPandemic for the idea of best use of the resources.

SZ

Influenza Pandemic Vaccines

As has been widely reported, Indonesia reached an agreement with WHO to resume the sharing of H5N1 samples for analysis and research.  They did not, however, agree to any usage in vaccine development, as that part of the agreement still needs to be worked out.  While I was surfing around for the latest tidbits I checked NewScientist.com for their latest and came across an after issue publication story on the Indonesian agreement.

[snip]

It could take some doing. Virtually all flu vaccine is made in rich countries, which have laws prohibiting its export in an emergency. So poor countries hit hard by H5N1 are effectively sending virus samples to develop pandemic vaccines that they may never have access to.

There is not much more to the story than what is publicly available, but it does restate the problem of getting vaccines out of the countries where they are manufactured during a time of crisis.  A pandemic is a time of emergency, even a relatively mild pandemic.

 

I have been operating on the assumption that the vaccine that the US has contracted for will not likely make it to us should the pandemic happen because a country, any country, would likely insist that their citizens are vaccinated prior to any vaccine leaving their borders.  For some reason the "assumption" and "likely" withholding is conceptually different to me than finding out that there are laws enforcing this.  That it's not really assumption or likely but more of a certainty, something that should be written into the response plans of our governments and essential services providers.  In case you didn't know, it's not, it it were, they wouldn't be contracting for the purchase(s) in the event of a pandemic.

We need to start understanding the fact that the only chance we have of protecting HCW's, Police, EMS, Firefighters, and Essential Services and Infrastructure workers is to start bringing in a Pre-Pandemic vaccine NOW.  While the US does have a small strategic supply of Pre-Pandemic Influenza vaccine, some of it is loosing potency due to aging, and this is the vaccine that proved to only be about 40% effective to begin with, and some of it requires massive doses of antigen to gain the presumptive levels of presumed immunity to H5N1. Plus, most of it is in the hands of DOD (Dept of Defense), who will be in desperate need of it since everyone will be looking to the military to provide all manner of services when the private sector falls flat on its face.

Even as slow as vaccine development is, there have been major strides made in the last year.  Baxter has released news of its candidate vaccine that looks very promising, but it is a Press Release, so of course the slant is on the positive side, but I tend to smile and welcome any positive news on the vaccine front...slant or not.

Baxter International, Inc. (NYSE: BAX) has officially announced the completion of phase I/II testing for its adjuvant-free investigational pandemic H5N1 influenza vaccine. Having finished Phases I and II, they are ready to begin Phase III, which entails testing their vaccine on the general public to insure the safety and efficacy of this vaccine.

Baxter’s Bird Flu vaccine has proven very effective in Phase I and II studies already, and it shows promise as the only vaccine that fights multiple strains of influenza, as opposed to the seasonal flu vaccines we are used to. This means that the vaccine can be used as a preventative agent rather than a treatment.

Baxter’s new influenza vaccine is one of the only vaccines to use the Vero cell-based system. This means that the vaccine will not be using an adjuvant to stimulate the body’s immune system. Instead, the vaccine is effective enough on its own, even in small doses, to prevent influenza without additional stimulants. So far the vaccine tested with a 76.2 success rate of neutralizing antibodies by day 42, and this is without an adjuvant.

According to Dr. Hartmut Ehrlich, vice president of Global Research and Development for Baxter's BioScience business, “These preliminary results suggest that the vaccine produces a highly immunogenic vaccine with a favorable safety profile without the need for an adjuvant to boost the immune response. Adjuvant can add considerable cost and may have a negative effect on tolerability.” 

Continues here.

 

Incredibly, sadly, criminally, insanely, the US does not have the vaccine manufacturing capacity to address the needs of its citizens.  We purchase most of our vaccines from manufacturers based in other countries.  Those countries will not be overly anxious to send vaccine our way if, and when, a pandemic happens, and as pointed out in the opening of this post, they may not be able to by law.  This is the very reason that I have become such a supporter of the Pre-Pandemic vaccine.  While not perfect, it will be leagues better than a whole bunch of nothing.

A post from FuturePundit almost a year ago...

2006 June 18 Sunday

Support Builds For Pre-Pandemic Vaccination

One of the problems with use of vaccines to stop a flu pandemic is that it takes many months to develop and manufacture vaccines against a new flu strain. Even worse, the manufacturing capacity for making vaccines is woefully inadequate for the case of a global pandemic. In a pandemic the need for vaccine would go up over an order of magnitude and the current process for making flu vaccine is hard to scale up. One way to partially solve this problem would be to manufacture vaccines in advance using flu strains that are not exact matches for an eventual pandemic strain. Support for pre-pandemic vaccine production is building.

"People are taking pre-pandemic vaccination seriously," says Derek Smith at the University of Cambridge. In May, a meeting of scientists and manufacturers at the World Health Organization in Geneva, Switzerland, recommended the development of vaccines that could be used to inoculate people before a pandemic takes hold. These, they said, must have long-lasting effects, and be "broad-spectrum" enough to work against whatever pandemic virus emerges. Several novel vaccines that do both are now close to testing in humans. They include the addition of immunity-stimulating chemicals called adjuvants, vaccines made of DNA instead of the virus itself, and perhaps the ultimate - a vaccine that protects against every kind of flu.

While there is no way of knowing before a pandemic starts exactly how well the vaccine will work, the risks of doing nothing could be far greater. "Stockpiling pre-pandemic vaccines is more valuable than people realise," Robert Webster of St Jude Children's Research Hospital in Memphis, Tennessee, told a flu conference in Singapore last month. "It may not necessarily protect you from infection, but it will probably stop you dying."

I've been in favor of this idea for years and continue to think that movement in the direction of developing pre-pandemic vaccines is too slow. The problem with pre-pandemic vaccines is that they won't be an exact match for whatever strain of influenza eventually becomes pandemic. But if an H5N1 avian flu strain mutates into a human pandemic strain then even a vaccine made from a different H5N1 strain will provide partial immunity to the pandemic strain. That partial immunity might some day save millions of lives.

The article reports on promising advances in DNA-based vaccines and in adjuvants (which amplify immune system response to vaccines). Production of DNA vaccines could be scaled up much more rapidly than the current chicken egg-based vaccine manufacturing process.

By Randall Parker    2006 June 18 10:29 PM

 

I'm sorry to report that we are not much better off today than we were when Mr Parker wrote the above piece.  Perhaps the Pandemic after next will see us better prepared and more capable of thinking outside the box, because this (potential) pandemic not only finds us not able to think outside the box, we can't even seem to see over the top, a box officialdom is so comfortable in they don't even know that's where they are residing.

 

SZ (Still as vaccineless as the average Indonesian)

Tweaking Tamiflu Dosage

Today it was announced that a new human trial of Tamiflu dosage was going to be conducted.  The participants in the test will be human victims of H5N1 as well as severe seasonal flu.

Doctors test double Tamiflu dose to cut H5N1 deaths

Wed Mar 28, 2007 1:52PM BST

HONG KONG (Reuters) - Doctors in Asia and the United States will give double doses of Tamiflu to patients suffering bird flu and severe seasonal human flu from May in a trial aimed at cutting high death rates from avian flu.

People infected with the H5N1 bird flu virus are now prescribed the standard dose of Tamiflu, which is one capsule twice daily for five days.

But less than half the patients survive.

"In animal studies, higher doses of Tamiflu have resulted in higher cure rates for H5N1. The death rate from H5N1 is 60 percent, we want to see if we can solve this problem," said Tawee Chotpitayasunondh, senior medical officer at Thailand's Ministry of Public Health.

The Cyber Flu Community has been discussing the Tamiflu dosage regimen since the middle of 2005 when information on a mouse study came to our attention.  The published findings of this study may be found here, and a more "user friendly explanation of the study's findings may be found here, from the National Institute of Allergy and Infectious Diseases.

While we are not privy to treatment protocols, I do wonder if there are primary treatment doctors in areas experiencing human H5N1 infection that have already "tweaked" the Tamiflu dosage and that may be why we are seeing a reduction in CFR (Case Fatality Ratio).  Helen Branswell did an excellent piece on the recent meeting in Turkey of over 100 physicians with experience treating human H5N1 infections.

Doctors who have treated bird flu cases meet to share treatment info

HELEN BRANSWELL

Doctors who have treated H5N1 avian flu patients are meeting in a Turkish seaside town to try to find answers to the myriad mysteries that remain about what the brutal virus does to its human victims and how dismal survival rates might be improved.

The World Health Organization hopes that by pooling patient data, the meeting will answer critical questions such as whether all lineages of the H5N1 virus cause the same severity of disease and how best to treat pregnant women who become infected.

Based on what it learns at this meeting, the WHO will update H5N1 treatment guidelines, so that doctors who face cases in the future can benefit from the successes - and missteps - of those who have treated patients in the past.

"There's a real deficit there," says Dr. Frederick Hayden, a WHO influenza expert and a key organizer of the meeting.

"We don't have basic information at hand to try to give the best advice. We're going to address that gap."

The meeting will also seek buy-in from doctors for a new patient data collection system the WHO hopes to get up and running.

Doctors treating H5N1 patients - past, present and future - would be asked to submit a couple of pages of standardized clinical and treatment information so that the global health body can track patterns of disease and treatment efficacy on an ongoing basis.

"This will give us, I think, the best available opportunity under the current circumstances to make sense out of what's happening," Hayden said.

The 100 or so doctors and other experts are meeting in Antalya, in southern Turkey. The meeting, which is being held Monday through Wednesday, is being hosted by the Turkish government.

It is a follow-up to a conference that was held in Hanoi in May 2005. At that point three countries - Thailand, Vietnam and Cambodia - had reported human cases of H5N1; there were 89 confirmed cases and 52 deaths.

Since then nine more countries - Azerbaijan, Iraq, Indonesia, Laos, Egypt, Nigeria, Djibouti, Turkey and China - have reported human cases. As of Sunday, the WHO had confirmed 279 cases since November 2003; 169 of those people died.

In the intervening months, small collections of case data have been published in medical journals. An account of the treatment of eight patients in Turkey. A paper describing a similar number in Indonesia. A report that revealed how patients responded - or didn't - to treatment with the antiviral drug oseltamivir (Tamiflu) in southern Vietnam.

But in the main, the details of the symptoms and disease progression of the vast majority of H5N1 patients, the steps their doctors took to try to save them and the outcome of those treatment choices remain locked up in the files of doctors who cared for them.

"There is a huge number of unanswered questions about human infections with highly pathogenic H5N1 viruses," says Dr. Tim Uyeki, an influenza expert from the U.S. Centers for Disease Control in Atlanta, who is attending the meeting.

"I think it's so important to share information so others can benefit from the experiences of those who have dealt with this."

Pooling data should allow patterns to come into focus in a way that is impossible when two or three doctors are looking at a handful of cases.

The meeting is taking place behind closed doors to encourage doctors who may be working on scientific articles to share their findings before publication. Hayden says he's been told some large, unpublished sets of patient data will be presented in Antalya.

This bit is continually railed against in the Cyber Flu Community.  Instead of the free exchange of information that can be used to save people's lives it is being hoarded all in the name of being able to publish a paper.  Selfish and ego driven concerns outweigh the potential life saving addition to the general knowledge base.

"They'll tell us what's been done and what's happened. That may allow one to say: 'This does not work and we shouldn't be doing this.' That's sometimes just as important as saying: 'This does work,"' Hayden notes.

In addition to learning about past cases, gathering together the physicians who have treated H5N1 cases in 12 countries should enhance research collaborations - including planned clinical trials of intravenous forms of two antiviral drugs - zanamivir (sold as Relenza) and peramivir, a drug still in development.

(GlaxoSmithKline, which makes Relenza, has shelved plans to test an intravenous form of the drug in the United States, but is in discussions with a WHO-organized treatment network in Southeast Asia to test the new formulation there.)

Dr. Menno de Jong believes opportunities for additional research are inevitable when some many clinicians from so many countries are brought together.

"If we can make a list - What are the questions of highest priority and what needs to be done to answers those questions? - I think that already will be a big gain for a meeting like this," says de Jong, a virologist at the Tropical Medicine Hospital in Ho Chi Minh City, Vietnam, where some of the first H5N1 patients were treated.

Still, some mysteries won't be solved until more autopsies are done on H5N1 cases, de Jong insists.

It's believed there have only been about a handful of autopsies on people who succumbed to the assault of this vicious virus. To date cases have occurred in countries where, for cultural or religious reasons, autopsies are not done.

De Jong says pleas for more autopsies are made at every scientific meeting on H5N1, but they haven't produced results. He suggests a way around the autopsy barrier would be to encourage hospitals treating H5N1 cases to do post-mortem biopsies - using special biopsy needles to take bits of key organs for study.

Since the Cyber Flu Community has been aware of higher dose Tamiflu treatment for almost two years now, and many plan to utilize the increased dosage levels, why is it only now that the experts are getting their heads together and planning to put this protocol to the test?

It is widely believed that an H5N1 infection treated with Tamiflu runs the risk of creating Tamiflu resistant strain(s), and we have already seen a few instances of this.  If the current recommendations of 2 capsules a day for 5 days is inadequate to kill the virus, but only to blunt it, the danger of resistance is magnitudes greater.  This doesn't address the issue of life saving dosage, a separate issue, and one of no less importance. 

As Tamiflu is in such limited supply it would be much more efficacious if the supplies we did have were used to the maximum benefit, even though that means treating 2/3 fewer.  Whether that is for treatment of the ill or as a prophylactic for HCWs and other Essential Service persons can be argued separately, but if it is used as treatment we owe it to all those that will not receive any, to use what we have to gain the best possible outcome.  Of course, that means reducing our "courses of treatment" stockpile by two-thirds, assuming 32 capsules vs 10 for an effective course.

But this points out how far ahead of the curve the knowledgeable and dedicated Flubies are.... we had this information twenty-one months ago.  It also points out how important information is, if we have it, we can act upon it, if not, it could have dire consequences.

H5N1 and Prophylactic Elderberry

First things first:

I am not a doctor, nor affiliated in anyway with the medical profession.  I am not recommending that anyone do what I have planned for myself and my family should a moderate to severe pandemic come to pass.  I am simply sharing what I, as a layman, have reasonably deduced to be prudent and *hopefully* effective to some measure.

I will be posting various and sundry items of potential medical mitigation strategies that any average person can stock and utilize.  These are items that I have decided on after two years of watching, reading, researching, and analyzing.  Many of the items I have decided on were thoroughly "vetted" on the various flu forums, most specifically and thoroughly on CurEvents.com's Flu Clinic.  A lot of work and untold hours were put in by Flubies far more knowledgeable and medically astute than myself.  After reading their finding and weighing them against my own understanding I made my decisions.  I did not blindly accept anyone's recommendations, even if I knew the person to be knowledgeable and trustworthy, I did independent follow-on research and *studied* the issues.  I ask that if you are interested in non-pharmaceutical influenza interventions you do the exact same thing.  Our lives, and the lives of our loved ones are worth the effort.

 

Second things second:

This entry deals with Black Elderberry, Sambucus Nigra, and its use in regard to treatment of H5N1 is not without controversy.  The controversy swirls around Elderberry's increase of cytokines as part of its effectiveness in treating influenza, this entry deals with the prophylactic usage of Elderberry extract, and although the increase in cytokines is still an issue should infection occur, it is not as great an issue, in my layman's estimation, and therefor the benefits, again in my estimation, outweigh the (potential) risks.

Should you decide that you are interested in utilizing elderberry extract I stridently encourage you to do your own research into the pros and cons as they are too extensive and randomly flung around the Cyber Flu Community for me to address in this entry.

 

My personal plan for my family, and more importantly, for my son who is a patrol officer for a small city police department and will be at high risk for infection, is to take Elderberry extract prophylactically in hopes of preventing infection with H5N1 should the pandemic manifest. Secondarily, should infection occur, Elderberry may slow viral replication down at the beginning of the disease to (hopefully) prevent the cytokine storm so often mentioned with H5N1 human infection.  Since my son is in his mid-twenties he is smack in the middle of the cohort most at risk for the deadly immune response.

I have been using Elderberry extract as a preventive for the last two flu seasons, as has my husband.  We have both found it to be very effective at preventing seasonal flu, now whether that will translate as effectively to H5N1 is anyone's guess at this time.  My hope is that at minimum it will not hurt, and at best, it may help, and may help a great deal.

 

Here is a major piece I used for making my decision on Elderberry as a prophylactic during a pandemic influenza outbreak. 

 

J Int Med Res 2004;32(2):132-140

Randomized Study of the Efficacy and Safety of Oral Elderberry Extract in the Treatment of Influenza A and B Virus Infections

Z Zakay-Rones¹, E Thom², T Wollan³, J Wadstein^4
1Department of Virology, Hebrew University-Hadassah Medical School, Jerusalem, Israel; ²Parexel Norway AS, PO Box 210, N-2001 Lillestrøm, Norway; ³Jernbanealléen 30, N-3210 Sandefjord, Norway; ⁴Østra Rønneholmsv 6B, 21147 Malmö, Sweden

 

Elderberry has been used in folk medicine for centuries to treat influenza, colds and sinusitis, and has been reported to have antiviral activity against influenza and herpes simplex. We investigated the efficacy and safety of oral elderberry syrup for treating influenza A and B infections. Sixty patients (aged 18 – 54 years) suffering from influenza-like symptoms for 48 h or less were enrolled in this randomized, double-blind, placebo-controlled study during the influenza season of 1999 – 2000 in Norway. Patients received 15 ml of elderberry or placebo syrup four times a day for 5 days, and recorded their symptoms using a visual analogue scale. Symptoms were relieved on average 4 days earlier and use of rescue medication was significantly less in those receiving elderberry extract compared with placebo. Elderberry extract seems to offer an efficient, safe and cost-effective treatment for influenza. These findings need to be confirmed in a larger study.

KEY WORDS: BLACK ELDERBERRY; SAMBUCOL®; INFLUENZA A AND B; CLINICAL EFFICACY; TOLERABILITY; CONTROLLED STUDY

The black elder (Sambucus nigra L.) has been used in folk medicine for centuries to treat influenza, colds and sinusitis.³ Antiviral activity of three plants, including the elder, has been reported against influenza and herpes.⁴ The berries of black elder contain high levels of flavonoids,⁵ which are naturally occurring plant substances. Several plant extracts containing flavonoids or purified flavonoids have been shown to have antiviral activity against herpes simplex virus type 1, respiratory syncytial virus, and the parainfluenza and influenza viruses.^{6 – 9} The main flavonoids found in elderberries are the anthocyanins cyanidin 3-glucoside and cyanidin 3-sambubioside.^10,11 It has recently been shown that these substances are detectable in plasma after oral intake of elderberry extract.¹²

Elderberry extracts are commercially available as nutritional supplements for humans, and are used extensively in many countries. Standardized elderberry extract has been shown to reduce haemagglutination and inhibit replication of influenza A and B viruses in vitro,¹³ and be effective in treating influenza B/Panama.¹³ The prophylactic and symptom-dependent treatment of influenza-like symptoms using a commercial elderberry extract was also demonstrated in a colony of chimpanzees in the Jerusalem Zoo, Israel.¹⁴

We aimed to investigate the efficacy and tolerability of a standardized elderberry extract for treating influenza A and B infections in humans.

[snip]

Discussion

The efficacy of elderberry syrup has previously been investigated in a placebo-controlled, double-blind clinical study during an outbreak of influenza B/Panama.¹³ A complete cure was achieved within 2 – 3 days in nearly 90% of the elderberry-treated group compared with at least 6 days in the placebo group (P < 0.001). The results of our study show that elderberry syrup is also effective against influenza A virus infections. Both studies show that the duration of the illness can be reduced by 3 – 4 days with elderberry syrup compared with placebo. The prophylactic and curative effects of this syrup have been demonstrated in a study performed in a chimpanzee colony,¹⁴ in which the appearance of symptoms was reduced by two-thirds. To our knowledge, no placebo-controlled, double-blind studies have been done with other natural remedies against the influenza viruses.

The main flavonoids present in elderberries are the anthocyanins cyanidin 3-glucoside and cyanidin 3-sambubioside,^10,11 and are detectable in plasma after oral intake of elderberry extract.¹² A possible mechanism of action of elderberry extract in the treatment of influenza is that the flavonoids stimulate the immune system by enhancing production of cytokines by monocytes.¹⁸ In addition, elderberry has been shown to inhibit the haemagglutination of the influenza virus and thus prevent the adhesion of the virus to the cell receptors.¹³ Anthocyanins also have an anti-inflammatory effect comparable to that of acetylsalicylic acid;¹⁹ this could explain the pronounced effect on aches, pain and fever seen in the group treated with elderberry syrup.

Vaccination is effective for prophylaxis and in reducing the impact of influenza, but only about 60% of people aged 65 years and above, and less than 30% of people aged less than 65 years, are vaccinated annually (worldwide figures). Some elderly individuals and immunocompromised people do not respond optimally to the vaccine, and the vaccine may not always include the strain of virus circulating within a given community.¹

It is not known whether amantadine and rimantadine prevent the complications of type A influenza infections among people at high risk. Use of these drugs is limited due to their side-effects and the frequent incidence (approximately 30%) of drug resistance. No data are available to determine the efficacy of rimantadine among children, so it is currently approved for prophylaxis but not treatment of influenza in children.

Zanamivir has been shown to reduce the duration of influenza A and B infections by 1 – 2.5 days. The route of administration is by inhalation via a Diskhaler^® (GlaxoSmithKline, Middlesex, UK) and the drug is designed for patients aged 12 years and above.^20,21 Oseltamivir may reduce the duration of illness by 1.5 days.²²

In contrast to these antiviral drugs, elderberries can be administered to the whole population, including infants and children. It should, however, be stressed that a wide number of elderberry preparations are available on the market, in the form of both syrups and capsules. The extract tested in this study was standardized with respect to the content of flavonoids and was produced in accordance with good manufacturing practice. A number of the other preparations available lack or have a very low flavonoid content. We believe that adequate amounts, as well as the composition, of flavonoids present in the extract are essential for the therapeutic effect of elderberry syrup as reported in our study.

In view of its in vitro and in vivo efficacy on influenza A and B viruses, elderberry extract offers an efficient, safe and cost-effective supplement to the present armamentarium of medications for the prophylaxis and treatment of influenza. It should be stressed that our study involved only adult influenza patients who were otherwise healthy, and did not include any high-risk patients. Further studies are required to confirm these results in larger numbers of patients and to investigate the effect of elderberry syrup in other patient groups.

Acknowledgement

The study was sponsored by Razei Bar, Jerusalem, Israel.

• Received for publication 12 September 2003 • Accepted subject to revision 23 September 2003

• Revised accepted 3 November 2003