Background: The immunologic factors underlying severe influenza are poorly understood. To address this, we compared the immune responses of influenza-confirmed hospitalized individuals with severe acute respiratory illness (SARI) to those of non-hospitalized individuals with influenza-like illness (ILI).

Methods: Peripheral blood lymphocytes were collected from ILI (N=27) and SARI-patients (N=27) at time of enrollment and then two weeks later. Innate and adaptive cellular immune responses were assessed by flow-cytometry and serum cytokines were assessed by bead-based assay.

Results: During the acute phase, SARI was associated with significantly reduced numbers of circulating myeloid dendritic cells, CD192+ monocytes, and influenza-specific CD8+ and CD4+ T-cells compared to ILI. By convalescence however, most SARI cases displayed continued immune activation characterized by increased numbers of CD16+ monocytes and proliferating, and influenza-specific, CD8+ T -cells compared to ILI. SARI was also associated with, reduced amounts of cytokines that regulate T-cell responses (IL4, IL13, IL12, IL10, TNFβ) and hematopoiesis (IL3, GM-CSF) but increased amounts of a pro-inflammatory cytokine (TNFα), chemotactic cytokines (MDC, MCP1, GRO, Fractalkine) and growth-promoting cytokines (PDGFBB/AA, VEGF, EGF) compared to ILI.

Conclusions: Severe influenza cases showed a delay in the peripheral immune activation that likely led prolonged inflammation compared to mild influenza.