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

Abstract

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 Method We searched MEDLINE, Embase, Web of Science and clinical trial databases for published and unpublished studies, and screened the references of included articles.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.

Efficacy of convalescent plasma for the treatment of severe influenza

“…However, until recently, relevant data pertaining to these recommendations were weak and limited to case reports and case series lacking controls. Compared with the previous meta-analyses [ 10 , 14 , 15 ], our meta-analysis differs in the inclusion criteria utilized, in the number of trials included, and in the summary estimates of treatment effect, which were strengthened by an extensive search, duplicate citation screening, and data abstraction. We focused on high-quality RCTs and estimated not only fatality rates but also both the biological effects (i.e., HAI titers, viral loads, cytokines) and clinical benefits (i.e., length of ICU/hospital stays, number of days on mechanical ventilation, and adverse events).…”

“…Additionally, treatment with convalescent plasma was reported to reduce hospital stays and mortality in patients with SARS-CoV infection [ 10 ] and in patients with severe influenza A (H1N1) [ 13 ]. Some systematic reviews of studies using convalescent plasma concluded that there is evidence of clinical benefits in such patients [ 10 , 14 , 15 ].…”

Global variability of influenza activity and virus subtype circulation from 2011 to 2023

“…Seasonal influenza is a common respiratory infectious disease that circulates in all regions of the world and affects millions of people every year 1 2. As reported by the WHO in 2018, influenza respiratory infections are responsible for 645 832 fatalities worldwide 1.…”

Infection with Influenzavirus A in a murine model induces epithelial bronchial lesions and distinct waves of innate immune-cell recruitment

“…A recent meta-analysis indicated that non-steroidal anti-inflammatory drugs (NSAIDs) are effective in reducing mortality following influenza infection ( 5 ). The treatment of inflammation per se and targeting the mechanisms of innate immunity following an infection may offer new therapeutic targets.…”