Passive immune therapy and other immunomodulatory agents for the treatment of severe influenza: Systematic review and meta‐analysis

BACKGROUND: A range of immunomodulatory therapies have been proposed as adjuncts to conventional antivirals to suppress harmful inflammation during severe influenza infection. We conducted a systematic review to assess available data of the effect of adjunctive non‐corticosteroid immunomodulatory therapy and potential adverse effects. METHOD: We searched MEDLINE, Embase, Web of Science and clinical trial databases for published and unpublished studies, and screened the references of included articles. We included RCTs, quasi‐RCTs and observational studies of virologically confirmed influenza infections in hospitalised patients. We did not restrict studies by language of publication, influenza type/subtype or age of participants. Where possible, we pooled estimates of effect using random‐effects meta‐analysis models. RESULTS: We identified 11 eligible studies for inclusion: five studies (4 RCTs and 1 observational; 693 individuals) of passive immune therapy; four studies (3 RCTs and 1 observational; 1120 individuals) of macrolides and/or non‐steroidal anti‐inflammatory drugs (NSAIDs), one RCT of mTOR inhibitors (38 individuals), and one RCT of statin therapy (116 individuals). Meta‐analysis of RCTs of passive immune therapy indicated no significant reduction in mortality (OR 0.84, 0.37‐1.90), but better clinical outcomes at Day 7 (OR 1.42, 1.05‐1.92). There was a significant reduction in mortality associated with macrolides and/or NSAIDs (OR 0.28; 0.10‐0.77). CONCLUSIONS: Passive immune therapy is unlikely to offer substantial mortality benefit in treatment of severe seasonal influenza, but may improve clinical outcomes. The effect of other immunomodulatory agents is uncertain, but promising. There is a need for high‐quality RCTs with sufficient statistical power to address this evidence gap.