Severe influenza is characterized by prolonged immune activation: results from the SHIVERS Cohort Study

SHIVERS Investigation Team

Research output: Contribution to journalA1: Web of Science-articlepeer-review


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 nonhospitalized individuals with influenza-like illness (ILI).

Methods: Peripheral blood lymphocytes were collected from 27 patients with ILI and 27 with SARI, at time of enrollment and then 2 weeks later. Innate and adaptive cellular immune responses were assessed by flow cytometry, and serum cytokine levels were assessed by a bead-based assay.

Results: During the acute phase, SARI was associated with significantly reduced numbers of circulating myeloid dendritic cells, CD192+ monocytes, and influenza virus-specific CD8+ and CD4+ T cells as compared to ILI. By the convalescent phase, however, most SARI cases displayed continued immune activation characterized by increased numbers of CD16+ monocytes and proliferating, and influenza virus-specific, CD8+ T cells as compared to ILI cases. SARI was also associated with reduced amounts of cytokines that regulate T-cell responses (ie, interleukin 4, interleukin 13, interleukin 12, interleukin 10, and tumor necrosis factor β) and hematopoiesis (interleukin 3 and granulocyte-macrophage colony-stimulating factor) but increased amounts of a proinflammatory cytokine (tumor necrosis factor α), chemotactic cytokines (MDC, MCP-1, GRO, and fractalkine), and growth-promoting cytokines (PDGFBB/AA, VEGF, and EGF) as compared to ILI.

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

Original languageEnglish
JournalJournal of Infectious Diseases
Issue number2
Pages (from-to)245-256
Number of pages12
Publication statusPublished - 2018


  • Adaptive Immunity
  • Adolescent
  • Adult
  • Aged
  • Child
  • Cohort Studies
  • Cytokines/blood
  • Dendritic Cells/immunology
  • Female
  • Humans
  • Immunity, Cellular
  • Immunity, Innate
  • Inflammation/immunology
  • Influenza, Human/immunology
  • Lymphocytes/immunology
  • Male
  • Middle Aged
  • Monocytes/immunology
  • Young Adult


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