Collectively, the data presented here suggest that extrapulmonary tissue responses are part of the pathophysiology of infections with highly pathogenic influenza viruses. This is in accord with recent clinical observations in human patients [46] , where treatment for hypoxia improved survival rates. This would also appear to link in with the observed expression of HIF-1α, which in our study appeared to reflect the extent and kinetics of lung inflammation following infection of macaques with these various influenza viruses and, notably, was an indicator of extrapulmonary tissue reactions in the absence of frank pathology or virus replication. Thus, measurement of HIF-1 expression, e.g. in peripheral blood mononuclear cells, might be used as a prognostic biomarker in severe respiratory infections.  Using Complementary and Alternative Medicines to Target the Host Response during Severe Influenza It is now accepted that an overwhelming inflammatory response is the cause of human deaths from avian H5N1 influenza infection. With this in mind we sought to examine the literature for examples of complementary and alternative medicines that reduce inflammation, and to place the results of this search in the context of our own work in a mouse model of influenza disease, using a pharmaceutical agent with anti-inflammatory properties. Two Chinese herbs, Angelica sinensis (Dang Gui) and Salvia miltiorrhiza (Danshen), have been recently shown to protect mice during lethal experimental sepsis via inhibition of the novel inflammatory cytokine High Mobility Group Box 1 protein (HMGB1). Biochanin A, a ligand of the peroxisome proliferator activated receptors (PPAR) alpha and gamma and the active isoflavone in Trifolium pratense (red clover), has anti-inflammatory properties, and thus could be used as an influenza treatment. This is of great interest since we have recently shown that gemfibrozil, a drug used to treat hyperlipidemia in humans and a synthetic ligand of PPAR alpha, significantly reduces the mortality associated with influenza infections in mice. The inflammation-modulating abilities of these natural agents should be considered in light of what is now known about the mechanisms of fatal influenza, and tested as potential candidates for influenza treatments in their own right, or as adjunct treatments to antivirals. It is now generally accepted that the infectious agent in isolation does not cause the illness and fatal outcome seen in acute systemic infectious diseases. Instead, the pathogen induces host cells to generate excessive amounts of pro-inflammatory cytokines, the prototypic example being tumor necrosis factor (TNF), that alter organ function and host metabolism, thus generating the disease we observe (1, 2) . This general concept, originally proposed to describe the severe disease caused by malaria infection (3) , then sepsis (4) and influenza (5) , has taken root in the mainstream, and is now often referred to as the 'cytokine storm' (6) .