We previously reported that H5N1 virus as well as reassortant H1N1 viruses containing the HA and NA genes from the 1918 pandemic influenza virus induce a severe pneumonia within 24 h of challenge, but that only the former virus gives rise to a sustained inflammatory response and massive parenchymal necrosis in the respiratory tract [23] . In this study, we show that this also applies to the tonsils, and it is accompanied by reactions in extrapulmonary tissues consistent with a systemic cytokinemia. The 1918, HA and NA genes significantly increased the virulence of a seasonal human H1N1 virus of low pathogenicity but did not confer a virulence phenotype comparable to that of the H5N1 virus or the complete 1918 pandemic influenza virus [33] , suggesting that other viral genes, such as PB1 [34] , probably also play significant roles in the pathogenesis. Furthermore, only the H5N1 virus appeared to spread beyond the respiratory tract to lymphoid tissues, intestines and meninges. Previous studies with other H5N1 isolates and the fully reconstructed 1918 virus in macaques similarly found evidence of only very limited virus spread outside the respiratory tract [12, 33] , whereas in cats and mice, H5N1 virus spread more widely [9, 13, 35] . Virus has also been isolated from or detected at extrapulmonary sites in human patients succumbing to H5N1 virus infection, including brain and intestine [4] . Thus, it would appear that the virus strain, timing postinfection, species, age and infection dose play important roles in determining virus spread beyond the respiratory tract, or at least the possibility of detecting it.