Could treatment with immunomodulatory agents targeting IL-1, IL-6, or JAK signalling improve outcomes in patients with severe influenza pneumonia? A systematic and narrative review

Background: Influenza is a global cause of morbidity and mortality and a significant risk for a future pandemic infection. Host hyperinflammation, similar to that seen in COVID-19, may occur in response to influenza virus pneumonia, with Janus kinase (JAK) signalling and proinflammatory cytokines Interleukin (IL)-1 and IL-6 involved. Immune modulation treatment of hospitalised and critically ill COVID-19 patients, including with IL-6 and JAK inhibitors, has been found to be beneficial. Significant interest exists in the use of immunomodulatory agents targeting these pathways in the treatment of severe influenza pneumonia. Methods: We conducted a review with both systematic and narrative methods to assess whether, in patients with severe influenza pneumonia, treatment with immunomodulatory agents targeting IL-1, IL-6 or JAK signalling, in comparison to no immune modulation, is beneficial and improves clinical outcomes. Results: Our systematic search screened 5409 records and found no randomised controlled trials of IL-1, IL-6 or JAK immunomodulatory agents in patients with severe influenza pneumonia. To support this systematic search, we provide a narrative review of the biological rationale, previous use of these agents, including in hospitalised patients with COVID-19, and an overview of their safety profiles. Conclusions: Although immune modulation has proven successful in treating hospitalised and critically ill patients with COVID-19 and a biological rationale exists for testing these agents in influenza, no agents targeting IL-1, IL-6 or JAK signalling have been assessed in randomised controlled trials of patients with severe influenza pneumonia. This highlights a significant evidence gap.