The infectious disease community has been concerned about the possibility of pandemic influenza for almost two decades, and the U.S. government began to draft a Pandemic Emergency Plan in 1991. But it was not until the aftermath of Hurricane Katrina that our country's lack of preparedness for handling major disasters became evident to all.

If any good can come of this season's hurricanes, the tsunami in Indonesia, and the earthquake in Pakistan, it is a recognition of the vulnerability of all countries to natural disasters--including pandemic infectious diseases--and the need to plan in advance.

The most obvious threat at the moment is the avian influenza virus known as A/H5N1. This pathogenic subtype has caused flu outbreaks in birds in at least 15 countries, from Croatia to Japan and Indonesia, killing or causing the culling of over 140 million birds. Alongside these massive avian outbreaks, there have been 134 confirmed human cases, more than half of whom have died. Nearly all of these human cases are traceable to exposures to infected birds; mercifully, H5N1 thus far lacks the ability to be transmitted efficiently between humans. Spurred by the concern that this or another strain of influenza virus could spark a pandemic in the coming years, President George W. Bush outlined on November 1 his $7.1 billion plan, almost 50 times the current funding level, for pandemic preparation. Recognizing that no single measure can stop a pandemic or blunt its impact, the plan appropriately includes funding for a wide range of activities. The threat of a flu pandemic has policymakers' attention. Now it is essential that the new resources be used wisely to deal with the threat at all levels, from local public health to international surveillance.

LESSONS FROM HISTORY
Scientists cannot predict whether or when a mutation might occur in the H5N1 bird flu strain--or in any of 20 other avian influenza strains--that would enable it to be transmitted readily to and between humans. What would a pandemic look like if H5N1, or another strain, were to acquire the capacity for extensive human-to-human transmission while remaining highly virulent? The best model we have for such a scenario is the 1918 influenza pandemic. That year at Camp Devens, Mass., there were 12,604 cases and 727 deaths within just two weeks of the first case, in September. Within five months, a quarter of the U.S. population was struck and about one in 200 Americans died. Worldwide, 20 million to 50 million people succumbed to the disease.

Since 1700, there have been influenza pandemics that have spread rapidly and widely at irregular intervals at least three times a century, the last pandemic being in 1968, 37 years ago. In one of the great scientific detective stories of all time, scientists at the U.S. Centers of Disease Control and Prevention (CDC) obtained the genome sequences of 1918 influenza from samples isolated from a person who perished and was preserved in the Alaskan permafrost, and from pathology specimens saved at the Armed Forces Institute of Pathology since 1918. Studies of a virus reconstructed from these genome sequences have recently revealed many features that contributed to the virus's unusual virulence. Another inference from the molecular genetic analysis is that the 1918 flu was very likely a bird flu.

The last emerging virus that threatened to spark a potential pandemic was SARS, which a team of HSPH epidemiologists, including Megan Murray, James Robins and one of the present authors, Marc Lipsitch, modeled in real time. Their model of transmission indicated that the virus's transmissibility (R0 value) was such that each infectious case gave rise to about 3 secondary infectious cases, while the average time between the primary and secondary cases (serial interval) was about 8.4 days. If appropriate isolation of infectious patients and quarantine of exposed contacts were carried out, the model predicted that transmission would be broken. As the researchers were drafting their paper, the evidence in Singapore (and, later, mainland China, Hong Kong, Toronto, and elsewhere) proved that combining those interventions was working to diminish transmission--and the epidemic was controlled.

Unfortunately, the same models predict that a bird flu capable of efficient transmission between humans is likely to be much more difficult to control than SARS. Analyses of the 1918 flu pandemic by an HSPH graduate student, Christina Mills, working with our infectious disease epidemiology team, revealed that the 1918 flu virus was no more, and possibly less, transmissible between humans than the SARS virus (R0 = 2-3). But the time between infectious cases, or the serial interval, as measured in seasonal flu, is estimated to be approximately four days, with people being infectious as early as the first or second day after infection, often before they are aware they have the flu. Notably, even in the fatal cases of H5N1 observed in Asia so far, the earliest symptoms were also relatively mild, only becoming life-threatening after a week or longer.

These contrasts in the natural history of flu and SARS have striking implications for the current planning for a possible pandemic. With so little time for the public health system to intervene effectively, the tools that worked so well for SARS--isolation of infected individuals, and quarantine of persons exposed to infected individuals--are simply unlikely to be very effective in the case of a virulent flu pandemic. In the case of SARS, screening at international borders proved to be of limited benefit because so few infected people were traveling (in all, SARS infected just over 8,000 people). For flu, the rapid spread characteristic of a pandemic will cause just the opposite problem for border controls: many infected people will likely be traveling, with many not yet showing signs of infection. With over a million travelers entering the United States each day, stopping 95 or even 99 percent of infected people at borders would not be sufficient once a pandemic was under way in other parts of the world. At least a few infected individuals would pass undetected through even the best-organized system, carrying the potential to seed new epidemics. Governments will likely feel strong political pressure to try to localize a pandemic and keep it outside their borders, but such efforts are likely to fail rapidly. Once an epidemic is under way in a particular place, further efforts to stop importation will be of little benefit.

URGENT MEASURES
How can the world protect itself against the next pandemic? There are drugs that, if taken within two days of the onset of symptoms, will reduce the duration and severity of illness, based on our understanding of how they affect current seasonal flu strains. Although these drugs work against H5N1 in cell culture, their clinical value in H5N1 patients is unclear, and mutants with some resistance to the major drug, oseltamavir (Tamiflu), have already emerged. More to the point, existing supplies of this drug, even in the richest countries, will be orders of magnitude too small to curb transmission of H5N1 once a pandemic is under way. A few countries, like the UK, have ordered enough Tamiflu to treat up to a quarter of the population and perhaps reduce the morbidity and mortality associated with the infection. But in most wealthy countries, including the U.S., and in developing countries, supplies are far more limited. The World Health Organization (WHO) is planning to try to snuff out an incipient pandemic while outbreaks remain localized, but even the strongest proponents of such a strategy admit that the challenges are formidable.

Other measures are urgently needed to reduce the number of introductions of H5N1 viruses into humans, thereby reducing the risk that a pandemic-ready strain could emerge as the virus adapts genetically to people. Despite the massive culling of infected birds to date, international health and agriculture authorities have stated that current funding is inadequate to give farmers an incentive to report infections in poultry. These authorities also indicate that farmers, veterinarians, and health care workers in rural areas need basic education about how to identify potential animal and human cases, and how to minimize the risk that the infection will be transmitted. China's Minister of Health, Gao Qiang, was asked during his visit to HSPH in October whether China was covering up cases of avian flu. He denied such a cover-up, but stated that he was seriously concerned that cases might be going unreported, given that local officials do not know what to look for or might not report cases quickly enough to the central government.

Surveillance efforts in Asia are critical to reducing the number of human cases and delaying the emergence of a pandemic as we undertake preparations at home. Such efforts are also essential to give us early warning of changes in the drug-resistance patterns and the immunological determinants of circulating strains--information that will permit drug and vaccine strategies to keep up with the evolution of the virus. Despite the clear need for such efforts, less than 5 percent of the budget in President Bush's plan is directed to overseas surveillance.

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