Influenza: lessons from past pandemics, warnings from current incidents

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Abstract
Influenza pandemics are caused when influenza viruses that possess a viral surface protein — haemagglutinin (HA) — to which the majority of people lack immunity spreads from human to human within the population. There were four influenza pandemics in the 20th century: the Spanish influenza of 1918–1919, which was caused by an H1N1 virus and killed at least 40 million people; the 1957 Asian influenza, which was caused by an H2N2 virus; the 1968 Hong Kong influenza, which was caused by an H3N2 virus; and the 1977 Russian influenza, which was caused by an H1N1 virus. With the exception of the Russian pandemic strain, which was identical to H1N1 viruses that circulated in humans in the 1950s and is therefore suspected to have been reintroduced to the population from a freezer somewhere, all 20th century pandemics were characterized by the acquisition of HAs from avian viruses. Clues to the molecular changes that give rise to human pandemic strains are therefore being sought in the avian virus reservoir. Avian influenza viruses are classified into two main types, on the basis of virulence: highly pathogenic avian influenza (HPAI) viruses cause systemic lethal infection with high mortality, whereas low-pathogenic avian influenza (LPAI) viruses cause localized infections with much lower mortality. The viral HA has been identified as having a key role in this variable pathogenicity. A precursor HA molecule must undergo post-translational proteolytic cleavage. The HAs of LPAI viruses possess a single basic residue at the cleavage site and are usually cleaved by proteases found in only a limited number of organs, whereas the HAs of HPAI viruses possess a series of basic amino acids at the cleavage site, which are cleaved by proteases present in a range of different host cells. Can avian viruses be transmitted directly to humans? Until 1997, it was thought that the answer to this question was no, but epidemiological evidence from an outbreak of H5N1 influenza in Hong Kong in May 1997 suggested direct transmission of the virus from birds to humans, although serological evidence of human-to-human transmission was limited. A more extensive outbreak of H5N1 influenza in poultry in 2003–2004 in Asia also spread to humans and resulted in 53 deaths. From the limited pathological information available, it is possible that cytokine dysregulation might have contributed to the pathogenesis of H5N1 disease in humans. Other outbreaks in which avian viruses have been transmitted directly to humans include an H7N7 outbreak in the Netherlands and two separate H9N2 outbreaks in Hong Kong. Efforts are underway to try and identify the molecular features that are important for human infection, although it is expected that the growth and pathogenicity of influenza viruses is multifactorial. Some of the viral gene products and functions that have been implicated include the role of HA in receptor specificity, the role of a viral RNA polymerase protein (PB1) in viral replication and host cell tropism and the role of the viral non-structural protein in pathogenicity in humans. Whether H5N1 viruses will acquire the ability to spread rapidly through human populations remains uncertain. However, in the event that an avian virus acquires specificity for human cell receptors and the other necessary genetic changes for human-to-human transmission, the resultant pandemic will have a devastating global impact.