Influenza A viruses are significant human pathogens causing yearly epidemics and occasional pandemics. Past pandemics have resulted in significant morbidity and mortality. The 1918 influenza pandemic was thought to have resulted in the death of at least 675,000 people in the U.S., and 40 million people worldwide. Pandemics in 1957 and 1968, while less severe, were also of major public health importance. In addition, annual epidemic influenza causes are also very significant resulting in approximately 30,000 deaths in the US annually.[unreadable] [unreadable] The pathogenicity of influenza viruses for their different hosts is related to complex viral and host factors and remains to be fully characterized. Experimental animal data with the 1918 influenza virus suggests that virulence is polygenic and depends on a complementary relationship among viral gene segments (1). Biological barriers to viral fitness based on gene segment combination are not well understood; however, pathogenicity, host adaptation, and host-to-host transmissibility are likely independent properties associated with different, and possibly competing, mutational changes. Pandemic viruses of comparatively low (e.g., 1968 H3N2 influenza pandemic), intermediate (eg, 1889 and 1957 H2N2 influenza pandemics), and high (e.g., 1918 H1N1 influenza pandemic) pathogenicity have all adapted to humans and exhibited efficient transmissibility.[unreadable] [unreadable] Mutational changes associated with binding of influenza viruses to receptors on different hosts are complex (2). Adaptation of the viral HA receptor-binding site from a form optimized for binding the avian receptor to a form efficiently binding the human receptor seems to require some loss of specificity for 2,3-linked sialic acids in favor of increased specificity for 2,6-linked sialic acids. [unreadable] [unreadable] To improve the ability to predict influenza pandemics, it is necessary to increase knowledge of the basic biology and ecology underlying host-switching events (3). The genetic changes that are needed to convert an influenza virus from one that has adapted to the enteric tract of wild waterfowl into a respiratory virus of horses, pigs, or humans are not fully understood. Enhanced surveillance and prospective study at the human-animal interface are crucial for understanding viral movement and evolution in an extraordinarily complex ecosystem. The H5N1 panzootic is a potent reminder of the constant and constantly changing risk posed by influenza A viruses. It is unknown whether H5N1 viruses will be able to adapt to humans and cause efficient person-to-person transmission; however, preparation for future influenza pandemics caused by H5N1 and any number of other viral possibilities is important.[unreadable] [unreadable] The histopathology of fatal influenza virus pneumonias as documented over the last 120 years was reviewed (4). Strikingly, the spectrum of pathologic changes described in the 1918 influenza pandemic is not significantly different from the histopathology observed in other less lethal pandemics or even in deaths occurring during seasonal influenza outbreaks. Since pathology studies have emphasized autopsy material, only changes associated with lethal outcomes and predominantly late stage disease have been well characterized. There is a broad spectrum of changes associated with influenza infection, varying with both clinical picture and length of the disease course before death. Coincident or secondary bacterial pneumonias are not only extremely common in severe influenza but also complicate the histopathologic appearance. Nevertheless, the spectrum of observed pathologic changes appears to vary little from pandemic to pandemic or in interpandemic years. What separates 1918 influenza cases from cases seen in less severe pandemics and in seasonal influenza infections is not the spectrum of observed pathology in severe and fatal cases but the significantly higher case fatality rate and in the 1918 pandemic only - unusual age distribution of deaths. In 1918, many previously healthy young adults succumbed to fatal influenza infection, while the elderly had lower than expected fatality rates. In the last two pandemics and especially in interpandemic seasonal influenza cases, fatal cases have tended to occur in persons with underlying chronic illnesses or at the extremes of age.