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Lancet Respir Med. 2019 Sep 30. pii: S2213-2600(19)30253-X. doi: 10.1016/S2213-2600(19)30253-X. [Epub ahead of print]

Anti-influenza hyperimmune intravenous immunoglobulin for adults with influenza A or B infection (FLU-IVIG): a double-blind, randomised, placebo-controlled trial.

Collaborators (153)

Davey RT, Fernández-Cruz E, Markowitz N, Pett S, Babiker AG, Wentworth D, Khurana S, Engen N, Gordin F, Jain MK, Kan V, Polizzotto MN, Riska P, Ruxrungtham K, Temesgen Z, Lundgren J, Beigel JH, Lane HC, Neaton JD, Butts J, Denning E, DuChene A, Krum E, Harrison M, Meger S, Peterson R, Quan K, Shaughnessy M, Thompson G, Vock D, Metcalf J, Dewar R, Rehman T, Natarajan V, McConnell R, Flowers E, Smith K, Hoover M, Coyle EM, Munroe D, Aagaard B, Pearson M, Cursley A, Webb H, Hudson F, Russell C, Sy A, Purvis C, Jackson B, Collaco-Moraes Y, Carey D, Robson R, Sánchez A, Finley E, Conwell D, Losso MH, Gambardella L, Abela C, Lopez P, Alonso H, Touloumi G, Gioukari V, Anagnostou O, Avihingsanon A, Pussadee K, Ubolyam S, Omotosho B, Solórzano C, Petersen T, Vysyaraju K, Rizza SA, Whitaker JA, Nahra R, Baxter J, Coburn P, Gardner EM, Scott JA, Faber L, Pastor E, Makohon L, MacArthur RA, Hillman LM, Farrough MJ, Polenakovik HM, Clark LA, Colon RJ, Kunisaki KM, DeConcini M, Johnson SA, Wolfe CR, Mkumba L, Carbonneau JY, Morris A, Fitzpatrick ME, Kessinger CJ, Salata RA, Arters KA, Tasi CM, Panos RJ, Lach LA, Glesby MJ, Ham KA, Hughes VG, Schooley RT, Crouch D, Muttera L, Novak RM, Bleasdale SC, Zuckerman AE, Manosuthi W, Thaonyen S, Chiewcharn T, Suwanpimolkul G, Gatechumpol S, Bunpasang S, Angus BJ, Anderson M, Morgan M, Minton J, Gkamaletsou MN, Hambleton J, Price DA, Llewelyn MJ, Sweetman J, Carbone J, Arribas JR, Montejano R, Lobo Beristain JL, Martinez IZ, Barberan J, Hernandez P, Dwyer DE, Kok J, Borges A, Brandt CT, Knudsen LS, Sypsas N, Constantinou C, Markogiannakis A, Zakynthinos S, Katsaounou P, Kalomenidis I, Mykietiuk A, Alzogaray MF, Obed M, Macias LM, Ebensrtejin J, Burgoa P, Nannini E, Lahitte M, Perez-Patrigeon S, Martínez-Orozco JA, Ramírez-Hinojosa JP.

Author information

National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA. Electronic address:
Hospital General Universitario Gregorio Marañón, Servicio de Immunología Clínica, Madrid, Spain.
Henry Ford Hospital, Division of Infectious Diseases, Detroit, MI, USA.
Medical Research Council Clinical Trials Unit, University College London, London, UK.
Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA.
Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
Veteran Affairs Medical Center, Washington, DC, USA.
UT Southwestern Medical Center, Dallas, TX, USA.
The Kirby Institute, University of New South Wales Australia, Sydney, NSW, Australia.
Montefiore Medical Center, Bronx, NY, USA.
Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; The HIV Netherlands Australia Thailand Research Collaboration, Thai Red Cross AIDS Research Centre, Bangkok, Thailand.
Mayo Clinic Hospital, Saint Marys Campus, Rochester, MN, USA.
CHIP Centre of Excellence for Health, Immunity, and Infections, Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.
National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.



Since the 1918 influenza pandemic, non-randomised studies and small clinical trials have suggested that convalescent plasma or anti-influenza hyperimmune intravenous immunoglobulin (hIVIG) might have clinical benefit for patients with influenza infection, but definitive data do not exist. We aimed to evaluate the safety and efficacy of hIVIG in a randomised controlled trial.


This randomised, double-blind, placebo-controlled trial was planned for 45 hospitals in Argentina, Australia, Denmark, Greece, Mexico, Spain, Thailand, UK, and the USA over five influenza seasons from 2013-14 to 2017-18. Adults (≥18 years of age) were admitted for hospital treatment with laboratory-confirmed influenza A or B infection and were randomly assigned (1:1) to receive standard care plus either a single 500-mL infusion of high-titre hIVIG (0·25 g/kg bodyweight, 24·75 g maximum; hIVIG group) or saline placebo (placebo group). Eligible patients had a National Early Warning score of 2 points or greater at the time of screening and their symptoms began no more than 7 days before randomisation. Pregnant and breastfeeding women were excluded, as well as any patients for whom the treatment would present a health risk. Separate randomisation schedules were generated for each participating clinical site using permuted block randomisation. Treatment assignments were obtained using a web-based application by the site pharmacist who then masked the solution for infusion. Patients and investigators were masked to study treatment. The primary endpoint was a six-category ordinal outcome of clinical status at day 7, ranging in severity from death to resumption of normal activities after discharge. The choice of day 7 was based on haemagglutination inhibition titres from a pilot study. It was analysed with a proportional odds model, using all six categories to estimate a common odds ratio (OR). An OR greater than 1 indicated that, for a given category, patients in the hIVIG group were more likely to be in a better category than those in the placebo group. Prespecified primary analyses for safety and efficacy were based on patients who received an infusion and for whom eligibility could be confirmed. This trial is registered with, NCT02287467.


313 patients were enrolled in 34 sites between Dec 11, 2014, and May 28, 2018. We also used data from 16 patients enrolled at seven of the 34 sites during the pilot study between Jan 15, 2014, and April 10, 2014. 168 patients were randomly assigned to the hIVIG group and 161 to the placebo group. 21 patients were excluded (12 from the hIVIG group and 9 from the placebo group) because they did not receive an infusion or their eligibility could not be confirmed. Thus, 308 were included in the primary analysis. hIVIG treatment produced a robust rise in haemagglutination inhibition titres against influenza A and smaller rises in influenza B titres. Based on the proportional odds model, the OR on day 7 was 1·25 (95% CI 0·79-1·97; p=0·33). In subgroup analyses for the primary outcome, the OR in patients with influenza A was 0·94 (0·55-1·59) and was 3·19 (1·21-8·42) for those with influenza B (interaction p=0·023). Through 28 days of follow-up, 47 (30%) of 156 patients in the hIVIG group and in 45 (30%) of 152 patients in the placebo group had the composite safety outcome of death, a serious adverse event, or a grade 3 or 4 adverse event (hazard ratio [HR] 1·06, 95% CI 0·70-1·60; p=0·79). Six (4%) patients in the hIVIG group and five (3%) in the placebo group died, but these deaths were not necessarily related to treatment.


When administered alongside standard care (most commonly oseltamivir), hIVIG was not superior to placebo for adults hospitalised with influenza infection. By contrast with our prespecified subgroup hypothesis that hIVIG would result in more favourable responses in patients with influenza A than B, we found the opposite effect. The clinical benefit of hIVIG for patients with influenza B is supported by antibody affinity analyses, but confirmation is warranted.


NIAID and NIH. Partial support was provided by the Medical Research Council (MRC_UU_12023/23) and the Danish National Research Foundation.

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