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November 3, 2005

Avian Influenza Is a Threat To Our Collective Security

By Donald S. Burke

President Bush has announced his emergency plan for "Pandemic Influenza Preparations and Response" -- with a price tag of $7.1 billion. Having learned a lesson from Hurricane Katrina, where spot-on predictive scientific models of bursting levees and disastrous flooding were ignored, the White House -- to its credit -- now takes the threat of a global influenza pandemic quite seriously. But exactly how good is epidemic prediction? Worth a $7 billion bet?

Donald S. Burke, MD

Donald S. Burke, MD

Why the concern? From the study of prior pandemics -- such as occurred in 1918, 1957 and 1968 -- it is certain that global pandemics originate when bird influenza viruses or bird-derived influenza virus genes enter humans and adapt to become human-to-human transmissible. Influenza viruses routinely infect waterfowl; the vastness of the global reservoir of influenza viruses in wild ducks and shorebirds is astonishing. At any given time, as many as 10% to 20% of otherwise healthy waterfowl may be infected with one or more of the major avian influenza types. (Influenza virus types are named according to the proteins on their surfaces: The H, or Hemagglutinin protein, allows the virus to attach to and enter a cell, where it replicates, and the N, or Neuraminidase protein, is necessary for the newly replicated virus particles to exit and escape from a cell. There are at least 15 known H types and nine known N types, which can be present together in any combination.)

Every day, millions of billions of virus particles are silently replicating, swapping genes, mutating and evolving in waterfowl. Occasionally, an otherwise mild avian influenza virus changes to become a highly pathogenic virus that can infect, kill and start epidemics in domestic poultry. In 1997, the H5N1-type avian virus emerged in Hong Kong by gene-swapping between bird viruses -- not in itself a particularly unusual event. But for the first time, this new virus began to infect and cause illness in humans. Subsequently the virus continued to evolve by acquiring different genes from other bird viruses and ignited epidemics among domestic poultry and ducks throughout Southeast Asia, then Central Asia and most recently Europe.

In the last two years H5N1 viruses have infected 112 persons and killed 57 of these. As its geographic range has spread, the virus has ominously continued to change for the worse: Its range of avian species has increased, its pathogenicity in experimental mammals (mice and ferrets) has increased, and it has developed molecular changes indicative of adaptation to mammals. The scientific community is united in interpreting the evidence of increasing viruses, increasing virulence and widening spread as a serious impending threat.

Where will it start? All of the 112 known human cases have occurred in Southeast Asia, and almost all have had direct contact with infected birds. Five family case clusters have been detected; but it is unproven if the second cases have been infected from the first household case or -- more likely -- from the same avian source.

If and when a human pandemic does ignite, it will begin as a chain of transmissions: firstly bird to human, then human to human to human. The exact location of the initial human chain of transmission will be determined by where the bird viruses are being transmitted to humans. This in turn is a function of the intensity of infection in the local avian populations and the intimacy of contact between humans and birds. Human surveillance for influenza must be intensified in regions where H5N1 avian flu is prevalent in birds if we are to catch and quench the initial human pandemic burst.

How fast will it move? Different epidemic diseases have different chain-reaction kinetics. In the SARS epidemic, each infected person on average infected three others, with an infection-to-infection generation time of about 10 days. Each index case multiplied into three new second-generation infections at day 10, nine third-generation infections at day 20, and 27 fourth-generation infections by day 30, etc.

By comparison, typical influenza has a reproductive number of two infections per infection. But it has a very fast generation time of three days, so that after 30 days one flu case multiplies into 1,024. Influenza is a very rapidly transmitting disease. Preliminary data on bird-to-human H5N1 cases suggests that illness began about two to four days after exposure to the infected bird. If human-to-human chains do begin, avian influenza will move very quickly. In most U.S. cities, the great 1918 influenza epidemic began, peaked and wreaked its devastation in less than 60 days. Today, with rapid global transportation, the entire global pandemic -- after the initial burst -- will flash and be done in less than three months. We should take no false comfort in the relative ease with which SARS was contained.

How severe will it be? Because virulence and transmissibility may be delinked -- viruses that cause substantial illness or death can be poorly transmissible, and vice versa -- this is the least predictable feature of the threat. However, given that no humans are immune to H5N1, virtually everyone on the planet is at risk of becoming infected. The key variable will be the ratio of deaths per infected person. There is a range of possibilities: At one extreme the case fatality ratios seen in Southeast Asia could be maintained (57 deaths in 112 cases, about 50% mortality), in which case the human species might face extinction. This scenario is deemed unlikely. The fatality ratio might be comparable to the 1918 pandemic, or 1% to 2% of infected cases, with a few million deaths in the U.S. This scenario, while not as extreme as the first, would be catastrophic. Lastly, we might be very lucky, and virulence could drop to zero. However, there is little in the history of influenza to support this rosy outlook.

Can we stop it? My public health and computational modeling colleagues have been furiously at work devising strategies to stop an epidemic or mitigate its impact. Our models show that it may be possible to identify a human outbreak at the earliest stage, while there are fewer than 100 cases, and deploy international resources -- such as a WHO stockpile of antiviral drugs -- to rapidly quench it. This "tipping point" strategy is highly cost-effective. More reactive strategies, in which the U.S. protects its own borders in the face of a growing global pandemic, will have limited success. U.S. leadership in the International Partnership of Avian and Pandemic Influenza is a visionary step. Epidemics are global in nature, and demand a concerted international response if they are to be thwarted. The new mindset should be one that focuses upstream on the earliest events, emphasizing prediction and prevention before a pandemic begins. Surveillance and response, the hallmarks of epidemiology, should be part, not all, of our strategy.

The president should be congratulated and his plan supported. Avian influenza is an immediate and real threat to our collective security.

Dr. Burke is professor of international health and epidemiology at the Johns Hopkins Bloomberg School of Public Health.

Op-ed article published in the November 3, 2005, edition of The Wall Street Journal.

“Reprinted from The Wall Street Journal © 2005 Dow Jones & Company, Inc. All rights reserved.”

Public Affairs media contacts for the Johns Hopkins Bloomberg School of Public Health: Kenna Lowe or Tim Parsons at 410-955-6878 or paffairs@jhsph.edu. Photographs of Donald Burke are available upon request.