The Induction of Proinflammatory Cytokines in Response to Avian Influenza H5N1 Infections and their Role in Pathogenesis and the Enhancement of Virulence

Avian H5N1 influenza viruses first emerged as members of a new human influenza A subtype in Hong Kong in 1997 and there are continuing concerns that members of the subtype will be the cause of the next pandemic. Human-tohuman transmission is rare, but mortality rates associated with avian-to-human transmission are significantly higher than for current human epidemic strains. Severe human H5N1 infections are associated with severe viral pneumonia, diffuse alveolar damage and reactive hemophagocytic syndrome (RHS). A characteristic of RHS, and one of the key determinants of H5N1-mediated pathology, is dysfunctional cytokine production resulting in a cytokine storm. Factors contributing to cytokine dysregulation include viral load, apoptosis and the intrinsic properties of H5N1 virus strains. Here, we review the cytokine response to influenza and try to address the relationship between hypercytokinemia and severe H5N1 pathology.