TCS Daily

Figuring Out the Flu

By Henry I. Miller - January 20, 2006 12:00 AM

The current outbreak of H5N1 avian flu in Turkey -- birds infected in more than 20 localities, about two dozen confirmed human cases and four deaths within about a month -- may be a kind of dress rehearsal for what an actual pandemic would look like in its earliest stages if the virus were to mutate and become transmissible from person to person.

Some background is necessary to understand the threat of a flu pandemic, as well as the possible public health, economic and political consequences.

The exterior of the flu virus consists of a lipid envelope from which project two surface proteins, hemagglutinin (H) and neuraminidase (N). The virus constantly mutates, which may cause significant alterations in either or both of these, enabling the virus to elude detection and neutralization by humans' immune system. A minor change is called genetic drift; a major one, genetic shift. The former is the reason that flu vaccines need to be updated from year to year; an example of the latter was the change in subtype from H1N1 to H2N2 that gave rise to the 1957 pandemic. This new variant was sufficiently distinct that people had little immunity to it: The rate of infection with symptomatic flu that year exceeded 50 percent in urban populations -- and 70,000 died from it in the United States alone.

During the past several years, an especially virulent strain of avian flu, designated H5N1, has ravaged flocks of domesticated poultry in Asia and spread to migratory birds and (rarely) to humans. It has been detected in much of East and Southeast Asia, as well as in Russia, Turkey, and parts of Eastern Europe. And it continues to spread. Since 2003, more than 80 human deaths have been attributed to H5N1. Public health experts and virologists are concerned about the potential of this strain because it already possesses two of the three characteristics needed to cause a pandemic: It can jump from birds to human and can produce a severe and often fatal illness. If additional genetic evolution makes H5N1 highly transmissible among humans -- the third characteristic of a pandemic strain -- a devastating world-wide outbreak could become a reality.

Ordinary seasonal flu -- marked by high fever, muscle aches, malaise, cough and sore throat -- is a bad disease, killing 30,000-40,000 annually in the United States, but the pandemic strains are both qualitatively and quantitatively worse. They infect the lower as well as upper respiratory tract -- that is, deep down in the smaller airways -- and may elicit hemorrhage and "cytokine storm," an outpouring of hormone-like chemicals that causes huge amounts of fluid to accumulate in the lungs. In this way, these pandemic strains of flu can kill within 24 to 48 hours of the onset of symptoms. By contrast, seasonal flu most often kills not directly but via secondary bacterial infections that follow the initial viral infection.

A subtle but important point is that although it is not possible to predict the timing of that last evolutionary step, because mutations occur each time the virus replicates, the more H5N1 viruses that are produced the more likely it is that the event will occur -- and as avian flu spreads and more birds are infected, there are trillions more virus particles in existence every day. Flu can also evolve toward human to human transmission when both human and animal strains of flu infect a person or animal (often a pig) simultaneously, offering an opportunity for swapping genes. That process is also favored by the presence of more viral particles.

If the current outbreak in Turkey had been the beginning of the pandemic -- which appears not to be the case -- we would expect to see illness spreading through families and among both healthcare workers and patients in hospitals where the victims were treated. The rapidity of such spread would depend on the infectiousness of the pandemic strain, another variable that we cannot predict. Before long, infected persons (perhaps even carriers who aren't ill) would introduce it to Ankara, Istanbul, Tbilisi, Damascus, Baghdad, and then beyond.

In reality, with no effective vaccine available, little could be done to attenuate significantly the first wave of infections. If we're able to rush the pandemic strain into a crash program to manufacture vaccine, we could possibly blunt the second wave, however.

Much has been made of whether we can significantly ramp up production of two anti-flu drugs, Tamiflu and Relenza, but they are far from a panacea under the best of circumstances, and their usefulness is becoming more problematic as we learn more about their interactions with H5N1. Unlike vaccines, which confer long-term immunity after one or two doses, drugs need to be taken for long periods. The only drug that has been shown to prevent the flu is Tamiflu, the usual prophylactic dose of which is one tablet a day, the effect lasting only as long as one takes the drug. (The other major anti-flu medicine, Relenza, has only been shown to be effective to treat, but not prevent, flu.)

Historically, flu pandemics have come in two or three waves, lasting a total of 13-23 months. In other words, the need to take Tamiflu -- by first responders, health care workers and ordinary citizens -- could go on for months and months, or even years. U.S. public health officials have said they plan to buy 20 million doses of Tamiflu, but that would be enough to treat only 200,000 people for 100 days at the dosage approved by FDA for prophylaxis. And the retail price per pill is around $8, so the expense to treat that small number of people for that amount of time would be $160 million. According to various models, in the absence of sufficient amounts of an effective vaccine -- which is not yet within reach -- to blunt the first wave of the pandemic, we would need to treat perhaps half of the population with Tamiflu. Do the math: 150 million people for 100 days equals 15 billion doses, at a retail cost of $120 billion.

And that seems to be the best-case scenario, because there are now credible reports that H5N1 is less sensitive to Tamiflu (generic name, oseltamivir) than other strains of flu and that some mutants of H5N1 are resistant to Tamiflu. In an elegant paper in the New England Journal of Medicine, Anne Moscona, M.D., observes: "H5N1 virus infections may require higher doses of oseltamivir for longer periods than do other types of influenza. Indeed, it is becoming clear that more medication than the currently recommended doses may be required for adequate treatment. If so, treatment with the current doses could not only fail but also select for resistant influenza A (H5N1) viruses." Dr. Moscona's point about resistance is a critical one: Treatment or prophylaxis of viral or bacterial diseases with sub-optimal dosages of drugs actually promotes the appearance of resistant strains; therefore, although it will put further pressure on our supply of Tamiflu, federal officials should consider sending a "Dear Doctor" letter that advises of the need for higher doses of the drug when H5N1 is suspected or documented. Dr. Moscona's paper includes an animated diagram (here) that illustrates the molecular mechanisms that permit mutant strains of H5N1 to become resistant to Tamiflu, but not to Relenza.

In spite of all this, there has been some skepticism -- mostly from non-scientists -- about the imminence and possible impact of an H5N1 pandemic. Laura Kelley, an associate of the National Intelligence Council (writing in her private capacity), wrote recently, "Remarkable though it may seem, all of this spending and activity is based on the deaths of fewer than seventy-five people, caused by a viral strain that has little or no person-to-person transmissibility." That is rather like saying that because it hasn't caused any damage yet, we don't need to worry about a Category 5 hurricane on a track to hit New Orleans. Columnist Tom Bethell calls the threat "grossly exaggerated," and ascribes the attention paid to avian flu to "a shared interest" between public health agencies and the press: "One wants a bigger slice of the budget and the other wants greater circulation."

We do need good surveillance of H5N1 in Europe, Asia and Africa, in order to obtain the earliest possible warning that a strain of H5N1 flu transmissible from human to human has been detected, so that nations around the world can rapidly initiate a variety of public health measures -- not the least of which would be to begin an emergency program to produce large amounts of vaccine against that strain.

The U.N.'s World Health Organization is probably best equipped to perform worldwide surveillance, but its role must be limited. Dr. David Nabarro, the U.N. coordinator on avian and human influenza, who has wide experience as a public health bureaucrat but none in the highly specialized field of influenza, is busily raising money from countries around the world to finance efforts to combat the disease. However, we cannot ignore the dismal record of the scientifically challenged, politically correct, unaccountable U.N., and the reality that any component of it is inherently incapable of keeping politics out of scientific and medical decisions.

A flu pandemic will require triage and hard-headed decisions on many levels -- including not only judgments about which patients are likely to benefit from scarce commodities such as drugs, vaccines and ventilators -- but also broader public policy choices about where and how to expend resources. To prepare for a possible catastrophe, we need to be aggressive, innovative and, above all, resilient. In society, as in biology, survival requires nothing less.

Henry I. Miller, a physician and fellow at the Hoover Institution, headed the FDA's Office of Biotechnology from 1989 to 1993. Barron's selected his most recent book, The Frankenfood Myth, one of the 25 Best Books of 2004.


Figuring out the flu
If I understand Dr Miller's article, the probability of a genetic shift is proportional to the number of people who become infected with H5N1 and thus provide proportionate opportunities for gene swapping and a possibly devastating mutation.
Not to minimize the importance of Dr Miller's warning that we urgently need efficient apolitical early detection and response systems to an outbreak of a deadly human to human transmissible form of this flu, but in my naivete I think something could be usefully done now.
Why couldn't we vaccinate poultry workers world wide against type H5N1. True, this would be ineffective against a future variant, but by lowering the number of human infections it would seem that you would significantly reduce the probability of a bad mutation.

Stoopid Bird Flu question
I am seeing constant images of workers rounding up poultry which I assume are then destroyed.
If the virus reservoir is the local wild birds then as soon as the poultry stocks are replaced will they then not be re-infected by the wild birds again?
Or does this mean all poultry are forever removed from these locations?

Can someone please help me to understand how killing the infected birds protects anyone?
I can see how this would work temporarily but in the long haul what good is this supposed to do?
Well unless are we going to round up the wild birds too?

Things should be as simple as possible but no simpler

bird question
Fewer infected birds in close proximity to humans results in fewer chances of humans becoming infected.
Just because we can't eliminate every vector does not mean we shouldn't eliminate those we can.

I thought what was needed was a human infected with H5N1 that was also infected with another virus that had the ability to easily infect humans. Since viruses have the ability to swap genes amongst each other.

Stoopid Bird Flu question
But this means that this is a only temporary fix right?
As soon as the poultry are returned they will be re-infected from the wild again.
Seems to me it would follow logically that poultry production will have to be stopped forever in the affected areas at least till an effective vaccine is found and implemented.
Is this the plan?

close but no....
One way for the pandemic to start is for the virus to mutate from a avian ready form to human ready.

The more common method is for avian flu to morph into a swine form due to closer body systems and and greater proximity to each other in many countries.

While this is unfortunate for the pigs etc. it is also not a good thing for humans as swine body sytems are much closer to human morphology. Typically, avian flu shape shifts sufficiently to infect nearby swine which provide a platform for the flu virus to adjust and make the jump to humans.

Most previous flu epidemics emanate from Northern China where chickens, pigs and humans live in extremely close contact by the hundreds of millions. Hence the Hong Kong flu of 1957, various _asian_ flus etc.

The notorious Spanish flu appears to be an example of a leap directly from avian to human form. The human immune system confronted with an alien life form over reacted producing the cytokine storm the author referred to which exacerbated an already very serious condition. It is worth noting that as a consequence it was those with the strongest immune systems that succumbed to the Spanish flu.

At the time the high proportion of 20 to 50 year old fatality rate was attributed to the vector for infection which was the troops returning from the first world war. Now we know that while that was the vector, it is the aforementioned immune response that did in so many healthy adults leaving the moderately young and moderately old with a higher survival rate. Of course, the very young and the very old died at the rate one would expect.

Finally, spending a hundred and fifty billion dollars on a treatment program that won't work and can't be delivered in time to enough people even if it did help seems futile at best. Better to spend a significant portion of that sum on finding and developing a whole new approach.

Yes, I know, it's betting the farm without much guarantee of success.

Anyway, if the next big flu scare comes out of Northern China don't be too alarmed. But if it's deadly and comes from somewhere else, especially a region without swine then get ready to bend over and kiss your ass goodbye.

close but no
Thank you for your informative posting.

I had thought that a vaccine developed for the current flu form given to large numbers of exposed poultry workers would lower the probability of a direct mutation to human ready form. I still believe it could, but recognize now that there are other pathways including a swine flu intermediary adaptation which could more easily become human ready.

Turkish mystery
Talk about politics. It seems clear that WHO is either incompetent or covering things up in Turkey. How do we really know what's going on in Turkey? Most of the recent press statements saying everything is under control are coming out of the Turkish Press or quotes from Turkish officials. A huge amount of Turkish GDP comes from tourism.

According to Dr. Henry Niman of Recombinomics, there are still individuals being hospitalized for symptoms in the two large Turkish families that make up more than 75% of the 21-22 cases. These families are Ozcan and Kocyigit. From the onset dates, it seems likely that these families are passing the flu amongst themselves at family gatherings and funerals.

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