Background Despite the availability of published data on 4 pandemics that have occurred over the past 120 years, there is little modern information on the causes of death associated with influenza pandemics. Methods We examined relevant information from the most recent influenza pandemic that occurred during the era prior to the use of antibiotics, the 1918–1919 “Spanish flu” pandemic. We examined lung tissue sections obtained during 58 autopsies and reviewed pathologic and bacteriologic data from 109 published autopsy series that described 8398 individual autopsy investigations. Results The postmortem samples we examined from people who died of influenza during 1918–1919 uniformly exhibited severe changes indicative of bacterial pneumonia. Bacteriologic and histopathologic results from published autopsy series clearly and consistently implicated secondary bacterial pneumonia caused by common upper respiratory–tract bacteria in most influenza fatalities. Conclusions The majority of deaths in the 1918–1919 influenza pandemic likely resulted directly from secondary bacterial pneumonia caused by common upper respiratory–tract bacteria. Less substantial data from the subsequent 1957 and 1968 pandemics are consistent with these findings. If severe pandemic influenza is largely a problem of viral-bacterial copathogenesis, pandemic planning needs to go beyond addressing the viral cause alone (e.g., influenza vaccines and antiviral drugs). Prevention, diagnosis, prophylaxis, and treatment of secondary bacterial pneumonia, as well as stockpiling of antibiotics and bacterial vaccines, should also be high priorities for pandemic planning.

The "Spanish" influenza pandemic of 1918-1919, which caused approximately 50 million deaths worldwide, remains an ominous warning to public health. Many questions about its origins, its unusual epidemiologic features, and the basis of its pathogenicity remain unanswered. The public health implications of the pandemic therefore remain in doubt even as we now grapple with the feared emergence of a pandemic caused by H5N1 or other virus. However, new information about the 1918 virus is emerging, for example, sequencing of the entire genome from archival autopsy tissues. But, the viral genome alone is unlikely to provide answers to some critical questions. Understanding the 1918 pandemic and its implications for future pandemics requires careful experimentation and in-depth historical analysis.

The evolutionary interaction between influenza A virus and the human immune system, manifest as 'antigenic drift' of the viral haemagglutinin, is one of the best described patterns in molecular evolution. However, little is known about the genome-scale evolutionary dynamics of this pathogen. Similarly, how genomic processes relate to global influenza epidemiology, in which the A/H3N2 and A/H1N1 subtypes co-circulate, is poorly understood. Here through an analysis of 1,302 complete viral genomes sampled from temperate populations in both hemispheres, we show that the genomic evolution of influenza A virus is characterized by a complex interplay between frequent reassortment and periodic selective sweeps. The A/H3N2 and A/H1N1 subtypes exhibit different evolutionary dynamics, with diverse lineages circulating in A/H1N1, indicative of weaker antigenic drift. These results suggest a sink-source model of viral ecology in which new lineages are seeded from a persistent influenza reservoir, which we hypothesize to be located in the tropics, to sink populations in temperate regions.

The hemagglutinin (HA) structure at 2.9 angstrom resolution, from a highly pathogenic Vietnamese H5N1 influenza virus, is more related to the 1918 and other human H1 HAs than to a 1997 duck H5 HA. Glycan microarray analysis of this Viet04 HA reveals an avian a2-3 sialic acid receptor binding preference. Introduction of mutations that can convert H1 serotype HAs to human a2-6 receptor specificity only enhanced or reduced affinity for avian-type receptors. However, mutations that can convert avian H2 and H3 HAs to human receptor specificity, when inserted onto the Viet04 H5 HA framework, permitted binding to a natural human a2-6 glycan, which suggests a path for this H5N1 virus to gain a foothold in the human population.

The pandemic influenza virus of 1918–1919 killed an estimated 20 to 50 million people worldwide. With the recent availability of the complete 1918 influenza virus coding sequence, we used reverse genetics to generate an influenza virus bearing all eight gene segments of the pandemic virus to study the properties associated with its extraordinary virulence. In stark contrast to contemporary human influenza H1N1 viruses, the 1918 pandemic virus had the ability to replicate in the absence of trypsin, caused death in mice and embryonated chicken eggs, and displayed a high-growth phenotype in human bronchial epithelial cells. Moreover, the coordinated expression of the 1918 virus genes most certainly confers the unique high-virulence phenotype observed with this pandemic virus.

Influenza's Cryptic Constraint Because of the well-known pandemic potential of influenza viruses, it is important to understand the range of molecular interactions between the virus and its host. Despite years of intensive research on the virus, Jagger et al. (p. 199 , published online 28 June; see the Perspective by Yewdell and Ince ) have found that the influenza A virus has been hiding a gene in its small negative-sense RNA genome. An overlapping open reading frame was found contained in the PA viral RNA polymerase gene, which is accessed by ribosomal frameshifting to produce a fusion protein containing the N-terminal messenger RNA (mRNA) endonuclease domain of PA and an alternative C-terminal X domain. The resulting polypeptide, PA-X, selectively degrades host mRNAs and, in a mouse model of infection, modulated cellular immune responses, thus limiting viral pathogenesis.

Influenza viruses are significant human respiratory pathogens that cause both seasonal, endemic infections and periodic, unpredictable pandemics. The worst pandemic on record, in 1918, killed approximately 50 million people worldwide. Human infections caused by H5N1 highly pathogenic avian influenza viruses have raised concern about the emergence of another pandemic. The histopathology of fatal influenza virus pneumonias as documented over the past 120 years is reviewed here. 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.

The influenza A viral heterotrimeric polymerase complex (PA, PB1, PB2) is known to be involved in many aspects of viral replication and to interact with host factors, thereby having a role in host specificity. The polymerase protein sequences from the 1918 human influenza virus differ from avian consensus sequences at only a small number of amino acids, consistent with the hypothesis that they were derived from an avian source shortly before the pandemic. However, when compared to avian sequences, the nucleotide sequences of the 1918 polymerase genes have more synonymous differences than expected, suggesting evolutionary distance from known avian strains. Here we present sequence and phylogenetic analyses of the complete genome of the 1918 influenza virus, and propose that the 1918 virus was not a reassortant virus (like those of the 1957 and 1968 pandemics), but more likely an entirely avian-like virus that adapted to humans. These data support prior phylogenetic studies suggesting that the 1918 virus was derived from an avian source. A total of ten amino acid changes in the polymerase proteins consistently differentiate the 1918 and subsequent human influenza virus sequences from avian virus sequences. Notably, a number of the same changes have been found in recently circulating, highly pathogenic H5N1 viruses that have caused illness and death in humans and are feared to be the precursors of a new influenza pandemic. The sequence changes identified here may be important in the adaptation of influenza viruses to humans.