Anaphylaxis to IVIG

  • Sharon Julie Williams
  • Sudhir Gupta


Anaphylactic reactions are a known complication in some IgA-deficient patients receiving blood or plasma transfusions. It is of particular interest that anaphylaxis has been observed in patients with common variable immunodeficiency (CVID) who are receiving intravenous gammaglobulin (IVIG), and in that, although these patients have an impaired response to common vaccines, they retain the ability to produce autoantibodies. In this study, we review IgA antibodies (both IgG- and IgE-mediated reactions) in patients with CVID and hypogammaglobulinemia, anaphylaxis in antibody immunodeficient patients receiving IVIG, and proposed mechanisms of desensitization and prevention of anaphylactic reactions in immunodeficient patients receiving IVIG. We summarize and assess the 23 case reports documented in the literature that have described anaphylactic reactions in immunodeficient patients receiving IVIG since 1962 until currently, and make a comparison of their immunoglobulin levels, IgG anti-IgA, IgE anti-IgA, concentration of IVIG, IgA content in IVIG, method used to detect antibodies, length of treatment, and any subsequent tolerated treatment documented.


Anaphylaxis Anaphylactic IVIG CVID Autoantibodies IgA IgE IgG 


  1. Ahrens N, Höflich C, Bombard S et al (2008) Immune tolerance induction in patients with IgA anaphylactoid reactions following long-term intravenous IgG treatment. Clin Exp Immunol 151:455–458CrossRefPubMedPubMedCentralGoogle Scholar
  2. Barandun S, Isliker H (1986) Development of immunoglobulin preparations for intravenous use. Vox Sang 51:157–160CrossRefPubMedGoogle Scholar
  3. Barandun S, Kistler P, Jeunet F et al (1962) Intravenous administration of human gamma-globulin. Vox Sang 7:157–174CrossRefPubMedGoogle Scholar
  4. Bjerrum OJ, Jersild C (1971) Class-specific anti-IgA associated with severe anaphylactic transfusion reactions in a patient with pernicious anaemia. Vox Sang 21:411–424CrossRefGoogle Scholar
  5. Björkander J, Hammarström L, Smith CI et al (1987) Immunoglobulin prophylaxis in patients with antibody deficiency syndromes and anti-IgA antibodies. J Clin Immunol 7:8–15CrossRefPubMedGoogle Scholar
  6. Burks AW, Sampson HA, Buckley RH (1986) Anaphylactic reactions after gamma globulin administration in patients with hypogammaglobulinemia. Detection of IgE antibodies to IgA. N Engl J Med 314:560–564CrossRefPubMedGoogle Scholar
  7. Cohn EJ (1945) Blood proteins and their therapeutic value. Science 101:51–56CrossRefPubMedGoogle Scholar
  8. Cunningham-Rundles C, Zhou Z, Mankarious S et al (1993) Long-term use of IgA-depleted intravenous immunoglobulin in immunodeficient subjects with anti-IgA antibodies. J Clin Immunol 13:272–278CrossRefPubMedGoogle Scholar
  9. de Albuquerque Campos R, Sato MN, da Silva Duarte AJ (2000) IgG anti-IgA subclasses in common variable immunodeficiency and association with severe adverse reactions to intravenous immunoglobulin therapy. J Clin Immunol 20:77–82CrossRefGoogle Scholar
  10. Domen RE, Hoeltge GA (2003) Allergic transfusion reactions: an evaluation of 273 consecutive reactions. Arch Pathol Lab Med 127:316–320PubMedGoogle Scholar
  11. Eijkhout HW, van den Broek PJ, van der Meer JW (2003) Substitution therapy in immunodeficient patients with anti-IgA antibodies or severe adverse reactions to previous immunoglobulin therapy. Neth J Med 61:213–217PubMedGoogle Scholar
  12. Ferreira A, Garcia Rodriguez MC, Lopez-Trascasa M et al (1988) Anti-IgA antibodies in selective IgA deficiency and in primary immunodeficient patients treated with gamma-globulin. Clin Immunol Immunopathol 47:199–207CrossRefPubMedGoogle Scholar
  13. Gallagher PE, Buckley RH (1962) Anaphylactic reactions and anti-IgA antibodies in common variable agammaglobulinemia: IgA deficient plasma treatment. J Allergy Clin Immunol 69:120CrossRefGoogle Scholar
  14. Hedderich U, Kratzsch G, Stephen W et al (1986) Immunoglobulin substitution therapy in a patient with primary hypogammaglobulinaemia and anti-IgA antibodies. Clin Allergy 16:339–344CrossRefPubMedGoogle Scholar
  15. Horn J, Thon V, Bartonkova D et al (2007) Anti-IgA antibodies in common variable immunodeficiency (CVID): diagnostic workup and therapeutic strategy. Clin Immunol 122:156–162CrossRefPubMedGoogle Scholar
  16. Kiani-Alikhan S, Yong PF, Grosse-Kreul D et al (2010) Successful desensitization to immunoglobulin A in a case of transfusion-related anaphylaxis. Transfusion 50:1897–1901CrossRefPubMedGoogle Scholar
  17. Kleinman S, Chan P, Robillard P (2003) Risks associated with transfusion of cellular blood components in Canada. Transfus Med Rev 17:120–162CrossRefPubMedGoogle Scholar
  18. Klemperer MR, Donaldson VH, Rosen FS (1968) Effect of C’1 esterase on vascular permeability in man: studies in normal and complement-deficient individuals and in patients with hereditary angioneurotic edema. J Clin Invest 47:604–611CrossRefPubMedPubMedCentralGoogle Scholar
  19. Marcus DM (1960) A study of the mechanism of the anticomplementary activity of gamma-globulin. J Immunol 84:273–284PubMedGoogle Scholar
  20. Oltean S, Epure A, Lindström K et al (2014) Detection of anti-IgA antibodies using the particle gel immunoassay: a rapid test for increased patient safety. Blood Transfus 12:334–339PubMedPubMedCentralGoogle Scholar
  21. Oxelius VA, Laurell AB, Lindquist B et al (1981) IgG subclasses in selective IgA deficiency: importance of IgG2-IgA deficiency. N Engl J Med 304:1476–1477CrossRefPubMedGoogle Scholar
  22. Pereira LF, Sapiña AM, Arroyo J et al (1997) Prevalence of selective IgA deficiency in Spain: more than we thought. Blood 90:893PubMedGoogle Scholar
  23. Petty RE, Palmer NR, Cassidy JT et al (1979) The association of autoimmune diseases and anti-IgA antibodies in patients with selective IgA deficiency. Clin Exp Immunol 37:83–88PubMedPubMedCentralGoogle Scholar
  24. Pineda AA, Taswell HF (1975) Transfusion reactions associated with anti-IgA antibodies: report of four cases and review of the literature. Transfusion 15:10–15CrossRefPubMedGoogle Scholar
  25. Rachid R, Castells M, Cunningham-Rundles C et al (2011) Association of anti-IgA antibodies with adverse reactions to γ-globulin infusion. J Allergy Clin Immunol 128(228–230):e1Google Scholar
  26. Salama A, Schwind P, Schönhage K et al (2001) Rapid detection of antibodies to immunoglobulin A molecules by using the particle gel immunoassay. Vox Sang 81:45–48CrossRefPubMedGoogle Scholar
  27. Salama A, Temmesfeld B, Hippenstiel S et al (2004) A new strategy for the prevention of IgA anaphylactic transfusion reactions. Transfusion 44:509–511CrossRefPubMedGoogle Scholar
  28. Sandler SG, Eckrich R, Malamut D et al (1994) Hemagglutination assays for the diagnosis and prevention of IgA anaphylactic transfusion reactions. Blood 84:2031–2035PubMedGoogle Scholar
  29. Sandler SG, Mallory D, Malamut D et al (1995) IgA anaphylactic transfusion reactions. Transfus Med Rev 9:1–8CrossRefPubMedGoogle Scholar
  30. Strait RT, Morris SC, Finkelman FD (2006) IgG-blocking antibodies inhibit IgE-mediated anaphylaxis in vivo through both antigen interception and Fc gamma RIIb cross-linking. J Clin Invest 116:833–841CrossRefPubMedPubMedCentralGoogle Scholar
  31. Sundin U, Nava S, Hammarström L (1998) Induction of unresponsiveness against IgA in IgA-deficient patients on subcutaneous immunoglobulin infusion therapy. Clin Exp Immunol 112:341–346CrossRefPubMedPubMedCentralGoogle Scholar
  32. Vamvakas EC, Pineda AA (2001) Allergic and anaphylactic reactions. In: Popovsky MA (ed) Transfusion reactions, 2nd edn. American Association of Blood Banks Press, Bethesda, pp 83–127. Google Scholar
  33. van der Heijden J, Geissler J, van Mirre E et al (2013) A novel splice variant of FcγRIIa: a risk factor for anaphylaxis in patients with hypogammaglobulinemia. J Allergy Clin Immunol 131(1408–1416):e5Google Scholar
  34. Vassallo RR (2004) Review: IgA anaphylactic transfusion reactions. Part I. Laboratory diagnosis, incidence, and supply of IgA-deficient products. Immunohematology 20:226–233PubMedGoogle Scholar
  35. Vyas GN, Perkins HA, Fudenberg HH (1968) Anaphylactoid transfusion reactions associated with anti-IgA. Lancet 2:312–315CrossRefPubMedGoogle Scholar

Copyright information

© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2016

Authors and Affiliations

  1. 1.Division of Basic and Clinical ImmunologyUniversity of California IrvineIrvineUSA

Personalised recommendations