Immunomodulatory therapy for severe influenza

Abstract

Influenza A virus is a significant cause of morbidity and mortality worldwide. Severe influenza is recognized as a clinical syndrome, characterized by hyperinduction of proinflammatory cytokine production, otherwise known as hypercytokinemia or a ‘cytokine storm’. Research focused on therapeutics to modulate influenza virus-induced inflammation is currently underway. In this review, we discuss the limitations of current antiviral drug treatment strategies, describe the influenza viral and host pathogenicity determinants, and present the evidence supporting the use of immunomodulatory therapy to target the host inflammatory response as a means to improve clinical outcome in severe influenza. We then review the experimental data on investigational immunomodulatory agents targeting the host inflammatory response in severe influenza, including anti-TNF therapy, statins, glucocorticoids, cyclooxygenase-2 inhibitors, macrolides, peroxisome proliferator-activated receptor agonists, AMP-activated protein kinase agonists and high mobility group box 1 antagonists. We then conclude with a rationale for the use of mesenchymal stromal (stem) cells and angiopoietin-1 therapy against deleterious influenza-induced host responses that mediate end-organ injury and dysfunction.

Keywords::

• angiopoietin-1
• COX-2 inhibitors
• cytokines
• glucocorticoids
• HMGB1 antagonists
• immunomodulation
• influenza virus
• mesenchymal stromal (stem) cells
• PPAR agonists
• statins

Acknowledgements

The authors would like to thank the reviewers for their thorough and thoughtful comments.

Financial & competing interests disclosure

This work was supported by Canada Research Chair in Infectious Diseases and Inflammation from the Canadian Institutes of Health Research (W Conrad Liles), the Canadian Foundation for Innovation (W Conrad Liles, Samira Mubareka), Pandemic Preparedness Catalyst Grant from the Canadian Institutes of Health Research (Samira Mubareka) and a Frederick Banting and Charles Best Canada Graduate Scholarship from the Canadian Institutes of Health Research (Ilyse Darwish). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.