Potential and challenges of serotherapy for severe influenza
Authors: Nelson Lee, David S C Hui
Journal: The Lancet Respiratory Medicine (2017)

We congratulate John Beigel and colleagues1Beigel JH Tebas P Elie-Turenne MC et al.IRC002 Study TeamImmune plasma for the treatment of severe influenza: an open-label, multicentre, phase 2 randomised study.Lancet Respir Med. 2017; 5: 500-511Summary Full Text Full Text PDF PubMed Scopus (90) Google Scholar in doing the first randomised-controlled, multicentre trial on adjunctive immune plasma for severe influenza, and reported clinical benefits when given before 5 days of illness, compared with neuraminidase inhibitor treatment alone. Our region's experiences with serotherapy (convalescent plasma or serum and hyperimmune intravenous immunoglobulin [IVIG]) in severe acute respiratory syndrome (SARS)-coronavirus infection, avian (A/H5N1 and A/H7N9) virus infections, and pandemic (A/H1N1pdm09) influenza virus infection, have suggested probable benefits. Notably, these reports also described an absence of efficacy when serotherapy was given later in the disease course (SARS-coronavirus >10 days; A/H1N1pdm09 >5 days).2Hui DS Lee N Chan PK Adjunctive therapies and immunomodulatory agents in the management of severe influenza.Antiviral Res. 2013; 98: 410-416Crossref PubMed Scopus (42) Google Scholar Available evidence suggests that viral replication is most active and viral load is at its peak during the earlier periods, which could have affected the therapeutic time window for antiviral agents (eg, ≤5 days for neuraminidase inhibitors, with highest benefits when given ≤2 days), in these severe infections.3Lee N Leo YS Cao B et al.Neuraminidase inhibitors, superinfection and corticosteroids affect survival of influenza patients.Eur Respir J. 2015; 45: 1642-1652Crossref PubMed Scopus (79) Google Scholar Such observations and the futility of non-specific IVIG suggest that the predominant role of serotherapy could be neutralisation and inhibition of the invading virus, although other mechanisms such as immunomodulation might coexist.2Hui DS Lee N Chan PK Adjunctive therapies and immunomodulatory agents in the management of severe influenza.Antiviral Res. 2013; 98: 410-416Crossref PubMed Scopus (42) Google Scholar Viral load reduction was not shown in Beigel and colleagues' main analysis, but sub-analysis of their data according to virus subtype and the respective virus neutralising antibody titre, and future data from the low (haemagglutination inhibition titre ≤1:10) versus high (haemagglutination inhibition titre ≥1:80) antibody concentration plasma trial (NCT02572817) might provide additional insight and help to define the actual effective titre or dose by bodyweight. If efficacy can be established, it would be important to define the patient group that would benefit most from adjunctive serotherapy in addition to neuraminidase inhibitors, which is currently considered as the standard of care. Several prognostic indexes based on presenting clinical and laboratory parameters (eg, PaO2 to FIO2 ratio, Acute Physiology and Chronic Health Evaluation [APACHE] II, and metabolomics) have been proposed, and might assist risk stratification.4Banoei MM Vogel HJ Weljie AM et al.Canadian Critical Care Translational Biology Group (CCCTBG)Plasma metabolomics for the diagnosis and prognosis of H1N1 influenza pneumonia.Crit Care. 2017; 21: 97Crossref PubMed Scopus (47) Google Scholar The magnitude of improvement in outcomes over neuraminidase inhibitor treatment alone, and its risk-to-benefit ratio will need to be further addressed because of several potential safety concerns and practical challenges with this approach (eg, antibody-dependent enhancement, immune-mediated adverse reactions, and blood-borne infections; panel).2Hui DS Lee N Chan PK Adjunctive therapies and immunomodulatory agents in the management of severe influenza.Antiviral Res. 2013; 98: 410-416Crossref PubMed Scopus (42) Google Scholar, 5Lee N Wong CK Chan MCW et al.Anti-inflammatory effects of adjunctive macrolide treatment in adults hospitalized with influenza: a randomized controlled trial.Antiviral Res. 2017; 144: 48-56Crossref PubMed Scopus (67) Google Scholar Preliminary safety data from Beigel and colleagues' study and previous studies have been reassuring. Humanised monoclonal antibodies that are broadly neutralising (both group 1 and group 2 influenza viruses) and target the more conservative regions of the virus (eg, anti-haemagglutinin stalk) might circumvent some of the practical issues, such as an emerging virus strain, without evoking adverse host immune responses (eg, complement activation in antibody-dependent enhancement).6Corti D Cameroni E Guarino B Kallewaard NL Zhu Q Lanzavecchia A Tackling influenza with broadly neutralizing antibodies.Curr Opin Virol. 2017; 24: 60-69Crossref PubMed Scopus (101) Google ScholarPanelPotential safety concerns and practical challenges of serotherapySafety concerns•Immune-mediated reactions (eg, transfusion reactions, transfusion-related lung injury, or ADE)•Increased risk of infection (eg, Zika virus infection, cytomegalovirus infection, hepatitis E virus infection, and other blood-borne viral and bacterial pathogen infections)•Infusion risk (eg, thromboembolism or volume expansion in ARDS)Practical challenges•Obtaining convalescent serum or plasma (eg, donor willingness, availability and access issues, timing for collection after recovery from illness, or variation in antibody titre)•Evolving virological target (eg, seasonal variation or emerging virus strains)ADE=antibody-dependent enhancement. ARDS=acute respiratory distress syndrome. Safety concerns •Immune-mediated reactions (eg, transfusion reactions, transfusion-related lung injury, or ADE)•Increased risk of infection (eg, Zika virus infection, cytomegalovirus infection, hepatitis E virus infection, and other blood-borne viral and bacterial pathogen infections)•Infusion risk (eg, thromboembolism or volume expansion in ARDS) Practical challenges •Obtaining convalescent serum or plasma (eg, donor willingness, availability and access issues, timing for collection after recovery from illness, or variation in antibody titre)•Evolving virological target (eg, seasonal variation or emerging virus strains) ADE=antibody-dependent enhancement. ARDS=acute respiratory distress syndrome. NL has received research grants from F Hoffmann–La Roche; consultancy fees from GlaxoSmithKline, Janssen Pharmaceuticals, Theraclone Sciences, and Visterra; speaker fees from AstraZeneca; and travel fees from Sanofi-Aventis, Merck Sharp & Dohme, Pfizer, AstraZeneca, and Gilead Sciences, all outside of this submitted work. DSCH declares no competing interests. Immune plasma for the treatment of severe influenza: an open-label, multicentre, phase 2 randomised studyAlthough there was no significant effect of plasma treatment on the primary endpoint, the treatment seemed safe and well tolerated. A phase 3 randomised trial is now underway to further assess this intervention. Full-Text PDF