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››Why the application of IVIG could be beneficial in patients with COVID-19

Why the application of IVIG could be beneficial in patients with COVID-19

By Richard Lyons
February 1, 2022
36
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In Respiratory Medicine The Lancet, Aurélien Mazeraud and colleagues showed that the application of intravenous immunoglobulin (IVIg) in patients with moderate to severe acute respiratory distress syndrome induced by COVID-19 did not improve clinical outcomes, but had an association not significant with more adverse events.
1
  • Mazeraud A
  • James M
  • Mancusi RL
  • et al.
Intravenous immunoglobulins in patients with moderate to severe acute respiratory distress syndrome (ICAR) associated with COVID-19: a multicentre, double-blind, placebo-controlled phase 3 trial.

We would like to address the reasons for the lack of effect that were not discussed in the article by Mazeraud and colleagues.

The rationale for the application of IVIGs in infectious diseases can either be to target hyperinflammation or to use the anti-infective properties of IVIGs to treat the primary infection, or both. Beyond that, IVIG could offer protection against secondary infections and thus reduce morbidity and mortality. Early evidence shows that the beneficial effects of IVIG may depend on the composition of the IVIG preparation, the patient’s immune status and the severity of the disease.
2
  • Guell E
  • Martin-Fernandez M.
  • From the Torre M
  • et al.
Impact of the number of lymphocytes and neutrophils on the risk of mortality in severe community-acquired pneumonia with or without septic shock.

Regarding the preparation of the IVIG solution, those consisting mainly of IgG (as applied in the study by Mazeraud and colleagues) were found to have little or no effect in patients with sepsis.
3
  • Werdan K
  • Pilz G
  • Bujdoso O
  • et al.
Score-based immunoglobulin G therapy in patients with sepsis: the SBITS study.

,

4
  • Brocklehurst P
  • Farrell B
  • King A
  • et al.
Treatment of neonatal sepsis with intravenous immunoglobulins.

On the other hand, the first published data on the IgM-enriched IVIG solution are encouraging.

5
  • World T
  • Dellinger PR
  • H belt
  • et al.
Efficacy and safety of trimodulin, a new polyclonal antibody preparation, in patients with severe community-acquired pneumonia: a randomized, placebo-controlled, double-blind, multicenter, phase II trial (CIGMA study).

,

6
Immunoglobulin M: an ancient antiviral weapon – rediscovered.

Regarding the immune status of patients, Mazeraud and his colleagues did not study the parameters of immune function. In particular, in several studies, increased mortality was associated with low serum immunoglobulin levels at baseline, as shown for example by influenza.
seven
  • Krautz C
  • Maier SL
  • Brunner M
  • et al.
Reduced levels of circulating B cells and plasma IgM are associated with decreased survival in sepsis – a meta-analysis.

,

8
  • Justel M
  • L-Companies
  • Almansa R
  • et al.
Plasma IgM levels predict the outcome of severe pandemic influenza.

From a pathophysiological point of view, it would be possible that beneficial effects of IVIG substitution were observed only in these patients, but not in those with normal or elevated basal immunoglobulin levels.

In this context, we would like to draw attention to a 2018 phase 2 randomized controlled trial in 160 patients with severe community-acquired pneumonia who required invasive mechanical ventilation.
5
  • World T
  • Dellinger PR
  • H belt
  • et al.
Efficacy and safety of trimodulin, a new polyclonal antibody preparation, in patients with severe community-acquired pneumonia: a randomized, placebo-controlled, double-blind, multicenter, phase II trial (CIGMA study).

In this double-blind study, in addition to standard care, an IgM-enriched IVIG solution (42 mg IgM/kg per day) was applied. The combined primary endpoint of ventilator-free days and all-cause mortality at 28 days was not statistically different in the intent-to-treat cohort (22.2% vs. 27 8%). More importantly, in a predefined subgroup analysis of patients with high level of inflammation (C-reactive protein levels greater than 70 mg/L), low serum IgM levels (less than 0.8 g /L) or both, mortality was significantly reduced, with the highest level of mortality reduction in the cohort with high C-reactive protein concentrations and low IgM levels.

Therefore, contrary to the conclusion of Mazeraud and colleagues, we hypothesize that the application of IVIG in patients with COVID-19 could be beneficial if a specific IgM-enriched IVIG solution is applied in patients with COVID-19. patients with low levels of IgM and a high level of inflammation.

DKM received conference fees from Biotest. All other authors declare no competing interests.

The references

  1. 1.
    • Mazeraud A
    • James M
    • Mancusi RL
    • et al.

    Intravenous immunoglobulins in patients with moderate to severe acute respiratory distress syndrome (ICAR) associated with COVID-19: a multicentre, double-blind, placebo-controlled phase 3 trial.

    Respir Med lancet. 2022; ten: 158-166

  2. 2.
    • Guell E
    • Martin-Fernandez M.
    • From the Torre M
    • et al.

    Impact of the number of lymphocytes and neutrophils on the risk of mortality in severe community-acquired pneumonia with or without septic shock.

    J Clin Med. 2019; 8: 754

  3. 3.
    • Werdan K
    • Pilz G
    • Bujdoso O
    • et al.

    Score-based immunoglobulin G therapy in patients with sepsis: the SBITS study.

    Crit Care Med. 2007; 35: 2693-2701

  4. 4.
    • Brocklehurst P
    • Farrell B
    • King A
    • et al.

    Treatment of neonatal sepsis with intravenous immunoglobulins.

    N Engl J Med. 2011; 365: 1201-1211

  5. 5.
    • World T
    • Dellinger PR
    • H belt
    • et al.

    Efficacy and safety of trimodulin, a new polyclonal antibody preparation, in patients with severe community-acquired pneumonia: a randomized, placebo-controlled, double-blind, multicenter, phase II trial (CIGMA study).

    Intensive Care Med. 2018; 44: 438-448

  6. 6.

    Immunoglobulin M: an ancient antiviral weapon – rediscovered.

    Immunol before. 2020; 111943

  7. seven.
    • Krautz C
    • Maier SL
    • Brunner M
    • et al.

    Reduced levels of circulating B cells and plasma IgM are associated with decreased survival in sepsis – a meta-analysis.

    Critical care J. 2018; 45: 71-75

  8. 8.
    • Justel M
    • L-Companies
    • Almansa R
    • et al.

    Plasma IgM levels predict the outcome of severe pandemic influenza.

    J Clin Virol. 2013; 58: 564-567

Item Information

Publication history

Identification

DO I: https://doi.org/10.1016/S2213-2600(21)00549-X

Copyright

© 2021 Elsevier Ltd. All rights reserved.

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