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Intravenous Immunoglobulin for Pandemic Influenza

By Amesh A. Adalja, MD, January 7, 2011

During the 1918 H1N1 pandemic—before both antibiotics and antivirals—passive immunotherapy, in the form of transfusions of convalescent sera, was used as a salvage therapy, reportedly with some success.1 This type of therapy also has been used in the treatment of the highly pathogenic and lethal H5N1 avian influenza virus. Now, a team of Australian researchers has published the results of their study of the use of intravenous immunoglobulin (IVIG) during the 2009 H1N1 pandemic.1

Rationale for IVIG with 2009 H1N1

In 1918 and with H5N1, convalescent sera was administered as a salvage therapy to certain patients irrespective of documented deficiencies in antibodies. The patients who received IVIG in this study all exhibited a deficiency of the IgG2 antibody subclass—a phenomenon first uncovered earlier during the pandemic by the same group of researchers.2 While IVIG is not the equivalent to convalescent sera, it does contain cross-reacting antibodies to the pandemic virus.3

Five Patients Received IVIG

After failing antiviral therapy, 5 patients with documented IgG2 deficiencies were administered IVIG as salvage therapy. Each of the 5 patients had known risk factors for severe influenza, had been on mechanical ventilation, and had been on oseltamivir. Two patients also had been administered intravenous zanamivir. EMCO was used for 3 of the patients. IVIG was administered after 8 to 17 days of illness (mean = 11 days), with 2 patients receiving 3 administrations, and 3 patients receiving one dose.1

Three of Five Patients Survived

Of the 5 patients who received IVIG, 3 survived. Anecdotally, the authors noted an association with IVIG administration and improvement in the surviving patients. Interestingly, in the 3 patients receiving ECMO, IgG2 levels remained low despite IVIG, suggesting a possible interaction between immunoglobulin and the ECMO circuit components.1

Additional Study Needed

The study raises the question of whether IVIG can be used more widely in management of severe influenza. Although no solid recommendations can be made based on the results from a sample size of 5, this study does point to several areas in need of further investigation:

  • Is IgG2 subclass deficiency pathogenically linked to severe cases of influenza, or is it the result of severe infection?
  • What would have been the effect of earlier administration of IVIG? Would it have affected the course of the fatal cases who, paradoxically, received their IVIG on days 4 or 5?
  • Would patients who were not IgG2 deficient benefit from IVIG?
  • Would true convalescent sera (vs. commercial IVIG) provide a greater benefit due to presumed higher neutralizing antibody titers?

As more data accumulates regarding the use of IVIG and nature of the IgG2 deficiency, pandemic planning may need to reflect the potential role of IVIG, which is already a scarce resource, for severe influenza cases.

References

  1. Gordon CL, Langan K, Charles PGP, et al. Pooled human immunoglobulin therapy in critically ill patients with pandemic 2009 influenza A (H1N1) pneumonitis and immunoglobulin G2 subclass deficiency. Clin Infect Dis 2011; first published online December 16, 2010 doi:10.1093/cid/ciq082. http://cid.oxfordjournals.org/content/early/2010/12/16/cid.ciq082.full. Accessed January 4, 2011.
  2. Gordon CL, Johnson, PD, Permezel M, et al. Association between severe pandemic 2009 influenza A (H1N1) virus infection and immunoglobulin G(2) subclass deficiency. Clin Infect Dis 2010; 50:672-678.
  3. Hong DK, Tremoulet AH, Burns JC, et al. Cross-reactive neutralizing antibody against pandemic 2009 H1N1 influenza A virus in intravenous immunoglobulin preparations. Pediatr Infect Dis J 2011; 30:67-69.