However recent observations paint a more complex picture of the significance of elevated serum HMGB1 measurements. Sepsis patients with severe organ dysfunction had the lowest serum HMGB1 levels of all sepsis patients tested (72) , which probably points to a well-known sideeffect of acute infection, immunosuppression. We have shown that despite plasma levels of HMGB1 being low at the time of peak mortality in mice infected with A/Japan/305/57 influenza virus (H2N2), HMGB1 may be elevated via its passive release in the lung at this time (73) . Therefore it would be important to first ascertain, using animal models of influenza, how levels of HMGB1, in the serum and/or lung, were associated with pathology and/or fatality. Our own work in this area continues, as does our focus on optimizing the way in which HMGB1 is measured for study. Figure 1 shows the likely sources and role of HMGB1 during infection with influenza virus.