There have been numerous pandemics throughout human history – syphilis, plague, and cholera being major examples. While it has never reached the sort of prevalence of these great killers, HIV achieved the worldwide spread of a pandemic during the last century. There were also three influenza pandemics in the Twentieth Century, each of which originated in the mutation of an avian flu.

The Spanish flu outbreak of 1918 was one of the deadliest epidemics in recorded history. Over a two-year period, it killed half a million Americans and an estimated fifty to one-hundred-million people worldwide – perhaps one out of every twenty living humans. The number of people who died in that pandemic was far greater than the number who had died in World War One. Two later pandemics – the Asian flu in 1957-1959 and Hong Kong influenza in 1968 - were less virulent, but nonetheless killed a million and three-quarters of a million persons worldwide respectively.

Given the more than three-fold increase in the world's population since 1918, a modern pandemic that was as infectious, pathogenic, and virulent as the Spanish flu could kill as many as 175 to 350 million people. This would be greater than the total number of people killed in all the wars and by the most murderous governments of the Twentieth Century.

Worse yet, the virulence of a pandemic version of H5N1 might be even more virulent than the Spanish flu was. Roughly half of all known cases of this flu have been fatal. It is possible that human cases so far have occurred in persons with a greater than typical susceptibility to the virus. If that is the case, then the virulence of H5N1 may prove to be less in a more widespread epidemic than has been seen in these scattered cases. If, on the other hand, a pandemic of avian flu occurs with a case fatality rate of 50%, it would be comparable to the "Black Death" pandemic of plague.

There are three elements necessary for a pandemic to occur. First, a highly infectious organism – one that is easily spread from person to person. Second, a highly pathogenic organism – one that produces disease in a large proportion of susceptible persons who become infected. Third, a general lack of human immunity to the organism.

In 1918, the H1N1 virus that caused Spanish flu had all three elements for a pandemic. The strain of avian flu now spreading around the world -- H5N1 -- has the second and third elements but, so far, lacks the vital first. While there have been a number of instances of apparent human-to-human transmission of H5N1 all but one of these chains of transmission ended with the second human case, suggesting that the virus does not have the capability to jump easily from one human to the next. In the one documented exception the virus was transmitted from child to mother to aunt but, once again, the spread stopped there,

Unfortunately influenza viruses mutate readily and frequently, so it is possible that H5N1 may mutate into a form that is as infectious in humans as it currently is in birds. Observational studies demonstrate continued evolution of the virus, with the result that infections are now seen pigs, horses, cats, tigers, leopards, whales and seals. One factor in this evolutionary trend has been the tremendous expansion of the domestic bird population in Asia. In China alone the number of domestic chickens has increased from 8 million to 13 billion. This has expanded the reservoir of the infection and increased human contacts with that reservoir.

Viruses also change through the process of reassortment, in which two viruses that have simultaneously infected a host may exchange DNA segments. Thus, every case of human infection with H5N1 creates an opportunity for reassortment between the H5N1 virus and any other viral infection the person may have concurrently. Such reassortment with a common human infection could make the resultant variant of N5N1 more infective of human hosts. A further opportunity for reassortment is provided by other species, such as dogs and pigs, which are susceptible to both avian flu and human viruses. This risk is a serious concern given the increasing numbers of Asian families that own domestic pigs -- a species that has been called "a catalytic mixer of genetic brews".