Figuring Out The Flu
 

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.