Local and systemic immune responses predict clinical outcomes in influenza virus infection independently of age and viral titer (P3000)

Influenza infection can result in mild or serious illness in some individuals, and studies suggest that increased inflammatory mediators have a role in disease severity. To investigate the role of inflammation in clinical disease, we performed a prospective, longitudinal study, sampling symptoms, blood, nasal lavages, and viral loads from participants during natural influenza infection. Surprisingly, clinical disease defined by symptoms or hospitalization did not correlate with viral dynamics, but consistent with other clinical reports, age was associated with hospitalization. There was no association between age and viral dynamics, though a strong inverse correlation between age and cytokine levels in the nasal lavage was maintained even when adjusted for prior immunity, indicating that children mount more aggressive inflammatory responses independently of pathogen dynamics. Correcting for this age-association, analysis of cytokine levels in nasal lavages revealed that MCP3 and IFNα were predictors of respiratory symptoms, while plasma MCP3 and IL-10 predicted symptom severity and hospitalization. In all cases, associations were not dependent on viral load. The association between IL-10 and symptom severity was confirmed in an independent cohort. In summary, children suffer significantly higher local inflammation, and a small subset of cytokines, including MCP3 and IL-10, serve as diagnostic markers for clinical outcome of influenza infection in all age groups.