Confronting the next influenza pandemic with anti-inflammatory and immunomodulatory agents: why they are needed and how they might work

Abstract

Despite the best efforts of influenza scientists, companies and health officials to prepare for the next pandemic, most of the world's people will not have access to affordable supplies of vaccines and antiviral agents. They will have to rely on 19th century public health 'technologies' to see them through. In the 21st century, science ought to be able to provide something better. Influenza scientists study the molecular characteristics of influenza viruses and their signaling effects in cell culture and animal models of infection. While these studies have been enormously informative, they have been unable to explain the system-wide effects of influenza on the host, the increased mortality of younger adults in the 1918 influenza pandemic and the much lower mortality rates in children who were more commonly infected with the 1918 virus. Experiments by non-influenza scientists have defined common cell signaling pathways for acute lung injury caused by different agents, including inactivated H5N1 influenza virus. These pathways include several molecular targets that are up-regulated in acute lung injury and down-regulated by anti-inflammatory and immunomodulatory agents, including statins, fibrates, and glitazones. These agents also help reverse the mitochondrial dysfunction that accompanies multi-organ failure, something often seen in fatal Influenza. Observational studies suggest that statins are beneficial in treating patients with pneumonia (there are no such studies for fibrates and glitazones). Other studies suggest that these agents might be able to 'roll back' the self-damaging host response of young adults to the less damaging response of children and thus save lives. Research is urgently needed to determine whether these and other agents that modify the host response might be useful in managing H5N1 influenza and the next pandemic.

Figure 1

Panel (A) shows the estimated age group‐specific influenza case rates and panel (B) shows the estimated age group‐specific pneumonia rates and mortality rates based on household surveys conducted in 10 US communities [from figure 5 in Ref. (24)].

Figure 2

Schematic diagram of the signaling cascade that leads from Toll‐like receptor 4 (TLR4) through TIR‐domain‐containing adaptor‐inducing IFN‐β (TRIF), tumor necrosis factor‐receptor associated factor (TRAF6), and NF‐kappaB to the up‐regulation of pro‐inflammatory cytokines and resultant acute lung injury [from figure 2(J) in Ref. (42)].