title: 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.
authors.affiliation: Faculty of Medicine, Institute of Medical Science, McLaughlin-Rotman Centre for Global Health, University Health Network, University of Toronto, Toronto, ON, Canada.
authors.forename: Ilyse
authors.initials: I
authors.lastname: Darwish
authors.forename: Samira
authors.initials: S
authors.lastname: Mubareka
authors.forename: W Conrad
authors.initials: WC
authors.lastname: Liles
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D042683:Angiopoietin-1 / Q000008:administration & dosage / Q000627:therapeutic use; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use; D005938:Glucocorticoids / Q000008:administration & dosage / Q000627:therapeutic use; D024002:HMGB Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D007155:Immunologic Factors / Q000627:therapeutic use*; D056747:Immunomodulation; D009980:Influenza A virus / Q000187:drug effects* / Q000254:growth & development / Q000276:immunology; D007252:Influenza Vaccines / Q000627:therapeutic use; D007251:Influenza, Human / Q000276:immunology / Q000473:pathology / Q000517:prevention & control / Q000628:therapy / Q000821:virology; D018942:Macrolides / Q000627:therapeutic use; D059630:Mesenchymal Stem Cells / Q000166:cytology; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists / Q000378:metabolism; D033581:Stem Cell Transplantation; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: D042683:Angiopoietin-1; D000998:Antiviral Agents; D052246:Cyclooxygenase 2 Inhibitors; D005938:Glucocorticoids; D024002:HMGB Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007155:Immunologic Factors; D007252:Influenza Vaccines; D018942:Macrolides; D047492:Peroxisome Proliferator-Activated Receptors; D014409:Tumor Necrosis Factor-alpha; D051546:Cyclooxygenase 2; D055372:AMP-Activated Protein Kinases