The Lancet Respiratory Medicine NOVEMBER 15, 2019

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

Richard T. Davey Jr., et al.

Bottom Line

This international randomized controlled trial found that the addition of hyperimmune intravenous immunoglobulin (hIVIG) to standard of care does not improve clinical outcomes in adults hospitalized with influenza A or B infection.

Key Findings

1. The primary outcome of clinical status at day 7, measured on a six-category ordinal scale, did not differ significantly between groups, with a common odds ratio of 1.25 (95% CI 0.79–1.97; p=0.33).

2. Treatment with hIVIG induced robust increases in haemagglutination inhibition titres against influenza A and smaller increases for influenza B, yet these laboratory improvements failed to translate into clinical benefit.

3. Subgroup analysis for patients specifically infected with influenza A also showed no statistically significant clinical advantage for the hIVIG arm compared to the placebo arm.

Study Design

Design

RCT

Double-Blind

Sample

313

Patients

Duration

28 days

Median

Setting

Multicenter, international

Population Adults (>=18 years) hospitalized with laboratory-confirmed influenza A or B infection and symptom onset within 7 days.

Intervention Standard care plus a single 500-mL infusion of high-titre anti-influenza hIVIG (0.25 g/kg bodyweight, 24.75 g maximum).

Comparator Standard care plus a saline placebo infusion.

Outcome Six-category ordinal scale of clinical status at day 7, ranging from death to resumption of normal activities after discharge.

Study Limitations

• The study was limited by a smaller-than-anticipated enrollment, which may have reduced the power to detect smaller clinical differences.

• The timing of administration (up to 7 days from symptom onset) might have been too late in the disease course to alter the clinical trajectory, despite the biological activity of the infused antibodies.

• The broad inclusion criteria including both influenza A and B may have obscured potential benefits restricted to a specific viral subtype or patient subgroup.

Clinical Significance

The trial provides robust evidence that passive immunotherapy via hIVIG, when added to current standard-of-care treatments (primarily oseltamivir), is not an effective therapeutic strategy for adults hospitalized with severe influenza. These findings suggest that focusing resources on novel direct-acting antivirals or host-directed therapies remains a higher priority for managing hospitalized influenza patients.

Historical Context

Since the 1918 influenza pandemic, interest in passive immunotherapy—using convalescent plasma or hyperimmune globulin—has persisted based on limited non-randomized data and small trials. While these approaches have shown theoretical promise for neutralizing viral loads, definitive large-scale randomized trials were previously lacking to confirm whether these immunological interventions could significantly impact morbidity and mortality in hospitalized patients.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Explain the biological rationale for using hyperimmune IVIG (hIVIG) over standard IVIG in the treatment of severe influenza, and why the timing of administration is critical to its proposed mechanism.

Key Response

hIVIG is derived from plasma donors with high titers of specific antibodies against circulating influenza strains, providing concentrated passive immunity. The rationale is to neutralize viral particles before they infect host cells; however, because influenza pathology in hospitalized patients is often driven by a late-stage 'cytokine storm' or secondary immunopathology rather than just viral replication, the window for effective antibody therapy may have already passed by the time of admission.

Resident

In a hospitalized patient with influenza A who has been symptomatic for 5 days, how does the FLU-IVIG trial evidence influence your decision to add adjunctive therapies to standard neuraminidase inhibitors?

Key Response

The FLU-IVIG trial demonstrated that adding hIVIG to standard of care (like oseltamivir) did not improve clinical status at day 7 or reduce mortality. For a patient already five days into symptoms, the study suggests that escalating to expensive, blood-product-based therapies like hIVIG offers no clinical benefit over standard antiviral therapy and should not be pursued.

Fellow

Considering the heterogeneity of influenza (A vs. B and various subtypes), how might the 'antigenic match' between the hIVIG donor pool and the circulating virus affect the interpretation of this trial's neutral findings?

Key Response

The efficacy of hIVIG depends heavily on the presence of neutralizing antibodies against the specific hemagglutinin and neuraminidase of the infecting strain. If the donor plasma was collected from a previous season where the dominant strains differed (antigenic drift), the polyclonal antibodies might have low affinity for the current virus. This study highlights the logistical challenge of producing a 'pre-matched' hyperimmune product in real-time for seasonal variations.

Attending

The FLU-IVIG trial included patients with a median symptom duration of 4 days. Does this 'late' presentation represent a failure of the intervention itself, or a failure of our current clinical trial infrastructure to capture the window of opportunity for passive immunotherapy?

Key Response

This is a classic 'too little, too late' dilemma. By the time patients are sick enough to be hospitalized (the trial's inclusion criteria), viral titers may have already peaked. While the study is practice-changing by proving hIVIG is ineffective for the typical hospitalized patient, it leaves open the question of whether hIVIG would work if administered in the first 24-48 hours, which is rarely feasible for a hospital-based therapy.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Analyze the choice of a 7-point ordinal scale as the primary endpoint in this trial. What are the statistical implications of using this approach versus a time-to-event endpoint like 'time to hospital discharge' in a critical care setting?

Key Response

An ordinal scale (e.g., from death to discharged) captured at a specific time point (Day 7) can be more sensitive than a simple binary outcome but risks missing the 'trajectory' of recovery. Statistical power for ordinal scales often relies on the proportional odds assumption; if the treatment benefit is non-proportional (e.g., it prevents death but doesn't speed discharge for survivors), the analysis might fail to detect a significant effect that a time-to-event model might better characterize.

Journal Editor

A key critique of this trial is the inclusion of both influenza A and B. Given the biological differences between these viruses, should the authors have performed a stratified randomization, and how does the low prevalence of influenza B (under 10% in this cohort) threaten the internal validity of the combined result?

Key Response

Including both viruses increases generalizability but introduces noise. If hIVIG were specifically effective for B but not A, the small sample size of B patients would lead to a Type II error for that subgroup. As an editor, one would flag that the 'null' result is robust for influenza A, but the study is significantly underpowered to make any definitive claims regarding influenza B.

Guideline Committee

Current IDSA guidelines recommend against the routine use of adjunctive corticosteroids for influenza but are less definitive regarding other immunomodulators. Based on the FLU-IVIG trial, what should be the strength and quality of evidence for a recommendation regarding hIVIG in future updates?

Key Response

The FLU-IVIG trial provides high-quality (Level I) evidence from a double-blind, randomized controlled trial. Given the lack of benefit across primary and secondary endpoints and the costs/risks associated with blood products, the committee should issue a 'Strong Recommendation' against the routine use of hIVIG for hospitalized influenza, aligning it with the existing negative recommendations for other unproven adjunctive therapies.

Clinical Landscape

Noteworthy Related Trials

2010

NEJM H1N1 Immunoglobulin Study

n = 31 · NEJM

Tested

Convalescent plasma

Population

Patients with severe H1N1 influenza A infection

Comparator

Standard care

Endpoint

Mortality at 28 days

Key result: Treatment with convalescent plasma was associated with a reduction in viral load and lower mortality compared to control groups.

2012

Intravenous Oseltamivir for Influenza

n = 334 · JAMA

Tested

Intravenous oseltamivir

Population

Hospitalized patients with suspected or confirmed influenza

Comparator

Oral oseltamivir

Endpoint

Time to alleviation of influenza symptoms

Key result: The study found no significant difference in the time to symptom alleviation between intravenous and oral oseltamivir administration.

2018

ITW-01 Trial

n = 146 · J Infect Dis

Tested

Nitazoxanide

Population

Patients with uncomplicated influenza

Comparator

Placebo

Endpoint

Time to improvement of symptoms

Key result: Nitazoxanide significantly reduced the time to improvement of influenza symptoms compared to placebo.

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