Traditional "social distancing" measures, such as banning public gatherings or shutting down mass transit, will have to be guided by what epidemiologists find once the pandemic is under way. If children are especially susceptible to the virus, for example--as was the case in 1957 and 1968--or if they are found to be an important source of community spread, then governments may consider closing schools.
Treatment: What Can Be Done for the Sick?
If two billion become sick, will 10 million die? Or 100 million? Public health specialists around the world are struggling to quantify the human toll of a future flu pandemic. Casualty estimates vary so widely because until it strikes, no one can be certain whether the next pandemic strain will be mild, like the 1968 virus that some flu researchers call a "wimp"; moderately severe, like the 1957 pandemic strain; or a stone-cold killer, like the "Great Influenza" of 1918.
For now, planners are going by rules of thumb: because no one would have immunity to a new strain, they expect 50 percent of the population to be infected by the virus. Depending on its virulence, between one third and two thirds of those people will become sick, yielding a clinical attack rate of 15 to 35 percent of the whole population. Many governments are therefore trying to prepare for a middle-ground estimate that 25 percent of their entire nation will fall ill.
No government is ready now. In the U.S., where states have primary responsibility for their residents' health, the Trust for America's Health (TFAH) estimates that a "severe" pandemic virus sickening 25 percent of the population could translate into 4.7 million Americans needing hospitalization. The TFAH notes that the country currently has fewer than one million staffed hospital beds.
For frontline health workers, a pandemic's severity will boil down to the sheer number of patients and the types of illness they are suffering. These, in turn, could depend on both inherent properties of the virus and susceptibility of various subpopulations to it, according to Maryland's pandemic planner, Jean Taylor. A so-called mild pandemic, for example, might resemble seasonal flu but with far larger numbers infected.
Ordinarily, those hardest hit by annual flu are people who have complications of chronic diseases, as well as the very young, the very old and others with weak immune systems. The greatest cause of seasonal flu-related deaths is pneumonia brought on by bacteria that invade after flu has depleted the body's defenses, not by the flu virus itself. Modeling a pandemic with similar qualities, Dutch national health agency researchers found that hospitalizations might be reduced by 31 percent merely by vaccinating the usual risk groups against bacterial pneumonia in advance.
In contrast, the 1918 pandemic strain was most lethal to otherwise healthy young adults in their 20s and 30s, in part because their immune systems were so hardy. Researchers studying that virus have discovered that it suppresses early immune responses, such as the body's release of interferon, which normally primes cells to resist attack. At the same time, the virus provokes an extreme immune overreaction known as a cytokine storm, in which signaling molecules called cytokines summon a ferocious assault on the lungs by immune cells.
Doctors facing the same phenomenon in SARS patients tried to quell the storm by administering interferon and cytokine-suppressing corticosteroids. If the devastating cascade could not be stopped in time, one Hong Kong physician reported, the patients' lungs became increasingly inflamed and so choked with dead tissue that pressurized ventilation was needed to get enough oxygen to the bloodstream.
Nothing about the H5N1 virus in its current form offers reason to hope that it would produce a wimpy pandemic, according to Frederick G. Hayden, a University of Virginia virologist who is advising WHO on treating avian flu victims. "Unless this virus changes dramatically in pathogenicity," he asserts, "we will be confronted with a very lethal strain." Many H5N1 casualties have suffered acute pneumonia deep in the lower lungs caused by the virus itself, Hayden says, and in some cases blood tests indicated unusual cytokine activity. But the virus is not always consistent. In some patients, it also seems to multiply in the gut, producing severe diarrhea. And it is believed to have infected the brains of two Vietnamese children who died of encephalitis without any respiratory symptoms.
Antiviral drugs that fight the virus directly are the optimal treatment, but many H5N1 patients have arrived on doctors' doorsteps too late for the drugs to do much good. The version of the strain that has infected most human victims is also resistant to an older class of antivirals called amantadines, possibly as a result of those drugs having been given to poultry in parts of Asia. Laboratory experiments indicate that H5N1 is still susceptible to a newer class of antivirals called neuraminidase inhibitors (NI) that includes two products, oseltamivir and zanamivir, currently on the market under the brand names Tamiflu and Relenza. The former comes in pill form; the latter is a powder delivered by inhaler. To be effective against seasonal flu strains, either drug must be taken within 48 hours of symptoms appearing.
The only formal test of the drugs against H5N1 infection, however, has been in mice. Robert G. Webster of St. Jude Children's Research Hospital reported in July that a mouse equivalent of the normal human dose of two Tamiflu pills a day eventually subdued the virus, but the mice required treatment for eight days rather than the usual five. The WHO is organizing studies of future H5N1 victims to determine the correct amount for people.
Even at the standard dosage, however, treating 25 percent of the U.S. population would require considerably more Tamiflu, or its equivalent, than the 22 million treatment courses the U.S. Department of Health and Human Services planned to stockpile as of September. An advisory committee has suggested a minimum U.S. stockpile of 40 million treatment courses (400 million pills). Ninety million courses would be enough for a third of the population, and 130 million would allow the drugs to also be used to protect health workers and other essential personnel, the committee concluded.
Hayden hopes that before a pandemic strikes, a third NI called peramivir may be approved for intravenous use in hospitalized flu patients. Long-acting NIs might one day be ideal for stockpiling because a single dose would suffice for treatment or offer a week's worth of prevention.
These additional drugs, like a variety of newer approaches to fighting flu, all have to pass clinical testing before they can be counted on in a pandemic. Researchers would also like to study other treatments that directly modulate immune system responses in flu patients. Health workers will need every weapon they can get if the enemy they face is as deadly as H5N1.
Fatality rates in diagnosed H5N1 victims are running about 50 percent. Even if that fell to 5 percent as the virus traded virulence for transmissibility among people, Hayden warns, "it would still represent a death rate double [that of] 1918, and that's despite modern technologies like antibiotics and ventilators." Expressing the worry of most flu experts at this pivotal moment for public health, he cautions that "we're well behind the curve in terms of having plans in place and having the interventions available."
Never before has the world been able to see a flu pandemic on the horizon or had so many possible tools to minimize its impact once it arrives. Some mysteries do remain as scientists watch the evolution of a potentially pandemic virus for the first time, but the past makes one thing certain: even if the dreaded H5N1 never morphs into a form that can spread easily between people, some other flu virus surely will. The stronger our defenses, the better we will weather the storm when it strikes. "We have only one enemy," CDC director Gerberding has said repeatedly, "and that is complacency.