Increasing evidence from mouse models and humans suggests that certain infl ammatory mediators are potent drivers of the disease. If this is true, this could have important implications for developing new therapeutics. Acute respiratory distress syndrome, hemophagocytosis, or both, develop in a substantial fraction of patients with infl uenza (H5N1) infection; both of these conditions are thought to be promoted by overproduction of proinfl ammatory cytokines (known as a "cytokine storm") (37) . Consistent with these observations, cytokine release was markedly enhanced in human macrophages after infection with infl uenza (H5N1) (38) . Further, marked enhancement of chemokine and cytokine levels was observed in infl uenza (H5N1)-infected persons, particularly in those who died, and these correlated with high and disseminated viral replication (4). Additionally, infl uenza (H5N1) viruses appear relatively resistant to the inhibitory effects of host antiviral cytokines, such as interferons (IFNs) (39) . Thus, the severity of human infl uenza (H5N1) infection may be related to the induction of excessive proinfl ammatory responses that can accompany a primary infection and high viral shedding. Increased infl ammation was associated with viral replication in the respiratory and extrarespiratory organs of cats experimentally infected with infl uenza (H5N1) (3) . Mice infected with the highly pathogenic infl uenza (H5N1) strain A/HK/156/97, originally obtained from diseased chickens and an ill child in Hong Kong, China (HK), showed reduced ability to activate transforming growth factor-β (TGF-β), a potent antiinfl ammatory cytokine, compared to mice infected with less virulent A/Env/HK437/99 viruses (2) . The reduced ability to activate TGF-β may produce greater infl ammation at the site of infection and thus cause more severe disease. Alternatively, the low levels of activated TGF-β in the sera of A/HK/156/97-infected mice may allow the viruses to replicate and spread unchecked in the respiratory tracts of the mice, causing more severe disease. Recently, the impact of the nonstructural (NS) gene variation of Hong Kong (H5N1)/97 on cytokine production was illustrated (40) . The NS gene reassortant induced elevated pulmonary concentrations of the infl ammatory cytokines IL-1α, IL-1β, IL-6, IFN-γ, and chemokine KC and decreased concentrations of the anti-infl ammatory cytokine IL-10. This cytokine imbalance is reminiscent of the clinical fi ndings in humans infected with infl uenza (H5N1)/97 virus and may explain the unusual severity of the disease.