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Influenza Immunoglobulin for Adults Hospitalized with Influenza

123 Pages Posted: 5 Apr 2019

See all articles by Richard T. Davey

Richard T. Davey

Government of the United States of America - National Institute of Allergy and Infectious Diseases (NIAID)

Eduardo Fernandez-Cruz

Gregorio Marañón Hospital

Norman Markowitz

Henry Ford Health System - Henry Ford Hospital

Sarah Pett

University College London

Abdel Babiker

University College London

Deborah Wentworth

University of Minnesota - Minneapolis

Surender Khurana

Government of the United States of America - Food and Drug Administration (FDA)

Nicole Engen

University of Minnesota - Minneapolis

Fred Gordin

Washington DC VA Medical Center (deceased)

Mamta K Jain

University of Texas at Dallas - Southwestern Medical Center

Virginia Kan

Government of the United States of America - Washington DC VA Medical Center

Mark N Polizzotto

University of New South Wales (UNSW) - Kirby Institute

Paul Riska

Montefiore Medical Center

Kiat Ruxrungtham

Chulalongkorn University - Chulalongkorn University Hospital

Zelalem Temesgen

Mayo Clinic - Mayo Clinic Hospital

Jens Lundgren

University of Copenhagen - Centre of Excellence for Health, Immunity and Infections CHIP

John Beigel

Government of the United States of America - National Institute of Allergy and Infectious Diseases (NIAID)

Henry Clifford Lane

Government of the United States of America - National Institute of Allergy and Infectious Diseases (NIAID)

James D Neaton

University of Minnesota - Minneapolis

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Abstract

Background: Despite treatment with licensed antiviral agents, high rates of influenza-related morbidity and mortality occur worldwide.

Methods: Adults hospitalized with laboratory-confirmed influenza were randomized (1:1) to a single double-blind infusion of high-titer anti-influenza intravenous immunoglobulin (hIVIG) or saline placebo. The primary endpoint was an ordered categorical outcome, ranging in severity from death to post-discharge resumption of normal activities, assessed at Day 7. The odds ratio (OR) (hIVIG versus placebo) of a favorable outcome was estimated with a proportional odds model.

Findings: Of 308 randomized patients, 73% and 27% had influenza A and B, respectively; antiviral use was 95%. As expected, hIVIG produced a robust rise in influenza A hemagglutination inhibition (HAI) titers, and smaller rises in influenza B titers. Viral load declined after 3 days by 1.99 (hIVIG) versus 2.32 log10 copies/mL (placebo) (p=0.49). The OR for favorable outcome was 1.25 (95% confidence interval [CI] 0.79-1.97, p=0.33). ORs for influenza A and B were 0.94 (95% CI: 0.55-1.59) and 3.19 (95% CI: 1.21-8.42), respectively (p=0.02 for difference). This difference between influenza A and B was mirrored for secondary clinical outcomes, changes in viral load, and in sensitivity analyses, overall and by strain. To investigate this outcome further, anti-HA antibody affinities were measured in the hIVIG lots administered, and much stronger antibody affinities for B strains were observed than for A in hIVIG used.

Interpretation: Overall, hIVIG was not superior to placebo for adults hospitalized with influenza. In contrast to our pre-study subgroup hypothesis based upon conventional HAI titers in hIVIG, benefit was evident for those with influenza B but not A. Consistent with findings of a contemporaneous anti-influenza plasma trial (IRC005), adjunctive immunotherapy appears ineffective for severe influenza A. The beneficial effect of hIVIG for influenza B is supported by antibody affinity analyses, but confirmation of clinical benefit is warranted.

Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT02287467.

Funding: NIAID, NIH.

Declaration of Interest: There are no competing interests to declare in regard to this manuscript submission.

Ethical Approval: The trial was approved by the institutional review board or ethics committee for each clinical site. All patients provided written informed consent.

Keywords: immunotherapy, influenza, intravenous immunoglobulin

Suggested Citation

Davey, Richard T. and Fernandez-Cruz, Eduardo and Markowitz, Norman and Pett, Sarah and Babiker, Abdel and Wentworth, Deborah and Khurana, Surender and Engen, Nicole and Gordin, Fred and Jain, Mamta K and Kan, Virginia and Polizzotto, Mark N and Riska, Paul and Ruxrungtham, Kiat and Temesgen, Zelalem and Lundgren, Jens and Beigel, John and Lane, Henry Clifford and Neaton, James D, Influenza Immunoglobulin for Adults Hospitalized with Influenza (April 3, 2019). Available at SSRN: https://ssrn.com/abstract=3365086

Richard T. Davey (Contact Author)

Government of the United States of America - National Institute of Allergy and Infectious Diseases (NIAID) ( email )

Bethesda, MD 20892-9806
United States

Eduardo Fernandez-Cruz

Gregorio Marañón Hospital

Calle del Dr. Esquerdo, 46
Madrid, 28007
Spain

Norman Markowitz

Henry Ford Health System - Henry Ford Hospital

Detroit
United States

Sarah Pett

University College London

Gower Street
London, WC1E 6BT
United Kingdom

Abdel Babiker

University College London

Gower Street
London, WC1E 6BT
United Kingdom

Deborah Wentworth

University of Minnesota - Minneapolis

110 Wulling Hall, 86 Pleasant St, S.E.
308 Harvard Street SE
Minneapolis, MN 55455
United States

Surender Khurana

Government of the United States of America - Food and Drug Administration (FDA)

5600 Fishers Lane
Rockville, MD 20857-0001
United States

Nicole Engen

University of Minnesota - Minneapolis

110 Wulling Hall, 86 Pleasant St, S.E.
308 Harvard Street SE
Minneapolis, MN 55455
United States

Fred Gordin

Washington DC VA Medical Center (deceased)

50 Irving Street NW
Washington, DC 20422
United States

Mamta K Jain

University of Texas at Dallas - Southwestern Medical Center

2601 North Floyd Road
Richardson, TX 75083
United States

Virginia Kan

Government of the United States of America - Washington DC VA Medical Center

50 Irving Street NW
Washington, DC 20422
United States

Mark N Polizzotto

University of New South Wales (UNSW) - Kirby Institute

Sydney
Australia

Paul Riska

Montefiore Medical Center

111 East 210th Street
Bronx, NY 10467
United States

Kiat Ruxrungtham

Chulalongkorn University - Chulalongkorn University Hospital

Bangkok, 10330,
Thailand

Zelalem Temesgen

Mayo Clinic - Mayo Clinic Hospital

200 First Street Southwest
Rochester, MN 55905
United States

Jens Lundgren

University of Copenhagen - Centre of Excellence for Health, Immunity and Infections CHIP

Copenhagen, DK-2100
Denmark

John Beigel

Government of the United States of America - National Institute of Allergy and Infectious Diseases (NIAID)

Bethesda, MD 20892-9806
United States

Henry Clifford Lane

Government of the United States of America - National Institute of Allergy and Infectious Diseases (NIAID) ( email )

Bethesda, MD 20892-9806
United States

James D Neaton

University of Minnesota - Minneapolis

110 Wulling Hall, 86 Pleasant St, S.E.
308 Harvard Street SE
Minneapolis, MN 55455
United States

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