Skip to main content

Advertisement

SpringerLink
Log in

Home-Based Subcutaneous Immunoglobulin Versus Hospital-Based Intravenous Immunoglobulin in Treatment of Primary Antibody Deficiencies: Systematic Review and Meta Analysis

  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Immunoglobulin replacement by the subcutaneous route (SCIg) for the prophylactic treatment of primary or secondary antibody deficient patients has been introduced as an alternative to conventional intravenous administration (IVIg). This is a systematic review of all eligible studies comparing efficacy and safety of IVIg and SCIg. Retrospective and prospective cohort studies and randomized, controlled trials comparing SCIg to IVIg were identified from MEDLINE, EMBASE, CINAHL, AMED, CSR, ISI and Cochrane Database without restriction on publication date and language. If possible, meta-analysis was performed by using the Review Manager software. A total of 47 articles with 1,484 compared cases were reviewed. Subcutaneous immunoglobulin replacement achieved acceptable IgG trough level, low incidence of side effects, efficacy similar to IVIg infusions, better health related quality of life and treatment satisfaction, and faster functional recovery with less time off work. Because of the heterogeneity of the reports, meta-analysis had to be performed by random effect method for IgG trough levels [OR (odds ratio) = 1.00, range = 0.84–1.15; p < 0.01], infection rates (OR = 0.59, range = 0.36–0.97; p = 0.04), and adverse events (OR = 0.09, range = 0.07–0.11; p < 0.001), which showed significant preference of SCIg over IVIg. Based on the analysis of published reports, changing immunoglobulin replacement therapy from IVIg to SCIg may be of benefit to qualified patients with primary immunodeficiency. These advantages, having been demonstrated in numerous studies,make medical, practical and economic sense to consider switching patients with antibody deficiency from IVIg to SCIg.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

SCIg:

Subcutaneous immunoglobulin

IVIg:

Intravenous immunoglobulin

PAD:

Primary antibody deficiency

Ig:

Immunoglobulin

IMIg:

Intramuscular immunoglobulin

OR:

Odds ratio

HR:

Hospitalization rate

References

  1. Radosevich M, Burnouf T. Intravenous immunoglobulin G: trends in production methods, quality control and quality assurance. Vox Sang. 2010;98:12–28.

    Article  PubMed  CAS  Google Scholar 

  2. Rezaei N, Abolhassani H, Aghamohammadi A, Ochs HD. Indications and safety of intravenous and subcutaneous immunoglobulin therapy. Expert Rev Clin Immunol. 2011;7:301–16.

    Article  PubMed  CAS  Google Scholar 

  3. Berger M, Cupps TR, Fauci AS. Immunoglobulin replacement therapy by slow subcutaneous infusion. Ann Intern Med. 1980;93:55–6.

    PubMed  CAS  Google Scholar 

  4. Cunningham-Rundles C, Siegal FP, Smithwick EM, Lion-Boule A, Cunningham-Rundles S, O'Malley J, et al. Efficacy of intravenous immunoglobulin in primary humoral immunodeficiency disease. Ann Intern Med. 1984;101:435–9.

    PubMed  CAS  Google Scholar 

  5. Quartier P, Debre M, De Blic J, de Sauverzac R, Sayegh N, Jabado N, et al. Early and prolonged intravenous immunoglobulin replacement therapy in childhood agammaglobulinemia: a retrospective survey of 31 patients. J Pediatr. 1999;134:589–96.

    Article  PubMed  CAS  Google Scholar 

  6. Webb DB, Kendra JR, Gross E, Stamatakis JD. Infusion of intravenous immunoglobulin via implantable subcutaneous catheter. Lancet. 1991;337:1617–8.

    Article  PubMed  CAS  Google Scholar 

  7. Gaspar J, Gerritsen B, Jones A. Immunoglobulin replacement treatment by rapid subcutaneous infusion. Arch Dis Child. 1998;79:48–51.

    Article  PubMed  CAS  Google Scholar 

  8. Arora R, Newton TC, Nelson MR. Subcutaneous immunoglobulin therapy in an 11-year-old patient with common variable immunodeficiency and von Willebrand disease. Ann Allergy Asthma Immunol. 2007;99:367–70.

    Article  PubMed  CAS  Google Scholar 

  9. Gardulf A, Hammarstrom L, Smith CI. Home treatment of hypogammaglobulinaemia with subcutaneous gammaglobulin by rapid infusion. Lancet. 1991;338:162–6.

    Article  PubMed  CAS  Google Scholar 

  10. Chapel HM, Spickett GP, Ericson D, Engl W, Eibl MM, Bjorkander J. The comparison of the efficacy and safety of intravenous versus subcutaneous immunoglobulin replacement therapy. J Clin Immunol. 2000;20:94–100.

    Article  PubMed  CAS  Google Scholar 

  11. Thomas MJ, Brennan VM, Chapel HH. Rapid subcutaneous immunoglobulin infusions in children. Lancet. 1993;342:1432–3.

    Article  PubMed  CAS  Google Scholar 

  12. Abrahamsen TG, Sandersen H, Bustnes A. Home therapy with subcutaneous immunoglobulin infusions in children with congenital immunodeficiencies. Pediatrics. 1996;98:1127–31.

    PubMed  CAS  Google Scholar 

  13. Nicolay U, Kiessling P, Berger M, Gupta S, Yel L, Roifman CM, et al. Health-related quality of life and treatment satisfaction in North American patients with primary immunedeficiency diseases receiving subcutaneous IgG self-infusions at home. J Clin Immunol. 2006;26:65–72.

    Article  PubMed  CAS  Google Scholar 

  14. Ochs HD, Gupta S, Kiessling P, Nicolay U, Berger M. Safety and efficacy of self-administered subcutaneous immunoglobulin in patients with primary immunodeficiency diseases. J Clin Immunol. 2006;26:265–73.

    Article  PubMed  CAS  Google Scholar 

  15. Eibl MM. History of immunoglobulin replacement. Immunol Allergy Clin North Am. 2008;28:737–64.

    Article  PubMed  Google Scholar 

  16. Gardulf A, Nicolay U. Replacement IgG therapy and self-therapy at home improve the health-related quality of life in patients with primary antibody deficiencies. Curr Opin Allergy Clin Immunol. 2006;6:434–42.

    Article  PubMed  Google Scholar 

  17. Jolles S, Sleasman JW. Subcutaneous immunoglobulin replacement therapy with Hizentra, the first 20 % SCIG preparation: a practical approach. Adv Ther. 2011;28:521–33.

    Article  PubMed  CAS  Google Scholar 

  18. Liu Z, Albon E, Hyde C. The effectiveness and cost effectiveness of immunoglobulin replacement therapy for primary immunodeficiency and chronic lymphocytic leukaemia: a systematic review and economic evaluation. West Midlands Health Technology Assessment Collaboration. 2005;54:1–154.

    Google Scholar 

  19. Ho C, Membe SK, Cimon K. An overview of subcutaneous vs. intravenous immunoglobulin for primary immunodeficiencies: systematic review and economic analysis. Canadian Agency for Drugs and Technologies in Health HTA. 2008;36:1–8.

    Google Scholar 

  20. Berger M. Subcutaneous administration of IgG. Immunol Allergy Clin North Am. 2008;28:779–802.

    Article  PubMed  Google Scholar 

  21. Moore ML, Quinn JM. Subcutaneous immunoglobulin replacement therapy for primary antibody deficiency: advancements into the 21st century. Ann Allergy Asthma Immunol. 2008;101:114–21.

    Article  PubMed  CAS  Google Scholar 

  22. Kittner JM, Grimbacher B, Wulff W, Jager B, Schmidt RE. Patients' attitude to subcutaneous immunoglobulin substitution as home therapy. J Clin Immunol. 2006;26:400–5.

    Article  PubMed  CAS  Google Scholar 

  23. Hoffmann F, Grimbacher B, Thiel J, Peter HH, Belohradsky BH. Home-based subcutaneous immunoglobulin G replacement therapy under real-life conditions in children and adults with antibody deficiency. Eur J Med Res. 2010;15:238–45.

    PubMed  CAS  Google Scholar 

  24. Thepot S, Malphettes M, Gardeur A, Galicier L, Asli B, Karlin L, et al. Immunoglobulin dosage and switch from intravenous to subcutaneous immunoglobulin replacement therapy in patients with primary hypogammaglobulinemia: decreasing dosage does not alter serum IgG levels. J Clin Immunol. 2010;30:602–6.

    Article  PubMed  CAS  Google Scholar 

  25. Jolles S, Bernatowska E, de Gracia J, Borte M, Cristea V, Peter HH, et al. Efficacy and safety of Hizentra((R)) in patients with primary immunodeficiency after a dose-equivalent switch from intravenous or subcutaneous replacement therapy. Clin Immunol. 2011;141:90–102.

    Article  PubMed  CAS  Google Scholar 

  26. Fasth A, Nystrom J. Quality of life and health-care resource utilization among children with primary immunodeficiency receiving home treatment with subcutaneous human immunoglobulin. J Clin Immunol. 2008;28:370–8.

    Article  PubMed  CAS  Google Scholar 

  27. Gardulf A, Andersen V, Bjorkander J, Ericson D, Froland SS, Gustafson R, et al. Subcutaneous immunoglobulin replacement in patients with primary antibody deficiencies: safety and costs. Lancet. 1995;345:365–9.

    Article  PubMed  CAS  Google Scholar 

  28. Fasth A, Nystrom J. Safety and efficacy of subcutaneous human immunoglobulin in children with primary immunodeficiency. Acta Paediatr. 2007;96:1474–8.

    Article  PubMed  Google Scholar 

  29. Berger M, Murphy E, Riley P, Bergman GE. Improved quality of life, immunoglobulin G levels, and infection rates in patients with primary immunodeficiency diseases during self-treatment with subcutaneous immunoglobulin G. South Med J. 2010;103:856–63.

    Article  PubMed  Google Scholar 

  30. Melamed I, McDonald A, Neff A, Beck A. An analysis of safety and tolerability data on 10%, 16%, and 20% formulations of subcutaneous immunoglobulin (IGSC). J Allergy Clin Immunol. 2011;127:AB16.

    Article  Google Scholar 

  31. Stiehm ER. Human intravenous immunoglobulin in primary and secondary antibody deficiencies. Pediatr Infect Dis J. 1997;16:696–707.

    Article  PubMed  CAS  Google Scholar 

  32. Chouksey A, Duff K, Wasserbauer N, Berger M. Subcutaneous immunoglobulin-g replacement therapy with preparations currently available in the United States for intravenous or intramuscular use: reasons and regimens. Allergy Asthma Clin Immunol. 2005;1:120–30.

    PubMed  Google Scholar 

  33. Gardulf A, Nicolay U, Asensio O, Bernatowska E, Böck A, Carvalho BC, et al. Rapid subcutaneous IgG replacement therapy is effective and safe in children and adults with primary immunodeficiencies—a prospective, multi-national study. J Clin Immunol. 2006;26:177–85.

    Article  PubMed  CAS  Google Scholar 

  34. Ratko TA, Burnett DA, Foulke GE, Matuszewski KA, Sacher RA. Recommendations for off-label use of intravenously administered immunoglobulin preparations. JAMA. 1995;273:1865–70.

    Article  PubMed  CAS  Google Scholar 

  35. Eijkhout HW, van den Broek PJ, van der Meer JW. Substitution therapy in immunodeficient patients with anti-IgA antibodies or severe adverse reactions to previous immunoglobulin therapy. Neth J Med. 2003;61:213–7.

    PubMed  CAS  Google Scholar 

  36. Sundin U, Nava S, Hammarstrom L. Induction of unresponsiveness against IgA in IgA-deficient patients on subcutaneous immunoglobulin infusion therapy. Clin Exp Immunol. 1998;112:341–6.

    Article  PubMed  CAS  Google Scholar 

  37. Borte M, Oertelt C, Hogy B. Treatment of patients with primary antibody deficiencies in Germany. Klin Padiatr. 2005;217:276–80.

    Article  PubMed  CAS  Google Scholar 

  38. Beauté J, Levy P, Millet V, Debré M, Dudoit Y, Le Mignot L, et al. Economic evaluation of immunoglobulin replacement in patients with primary antibody deficiencies. Clin Exp Immunol. 2010;160:240–5.

    Article  PubMed  Google Scholar 

  39. Membe SK, Ho C, Cimon K, Morrison A, Kanani A, Roifman CM. Economic assessment of different modalities of immunoglobulin replacement therapy. Immunol Allergy Clin North Am. 2008;28:861–74.

    Article  PubMed  Google Scholar 

  40. Hogy B, Keinecke H, Borte M. Pharmacoeconomic evaluation of immunoglobulin treatment in patients with antibody deficiencies from the perspective of the German statutory health insurance. Eur J Health Econ. 2005;6:24–9.

    Article  PubMed  Google Scholar 

  41. Berger M. Subcutaneous immunoglobulin replacement in primary immunodeficiencies. Clin Immunol. 2004;112:1–7.

    Article  PubMed  CAS  Google Scholar 

  42. Ochs H, Fischer S, Lee M, Delson E, Kingdon H, Wedgwood R. Intravenous Ig home treatment for patients with primary immunodeficiency diseases. Lancet. 1986;1:610–1.

    Article  PubMed  CAS  Google Scholar 

  43. Ashida E, Saxon A. Home intravenous Ig therapy by self-administration. J Clin Immunol. 1986;6:306–9.

    Article  PubMed  CAS  Google Scholar 

  44. Gardulf A, Bjorvell H, Gustafson R, Hammarstrom L, Smith CI. Safety of rapid subcutaneous gammaglobulin infusions in patients with primary antibody deficiency. Immunodeficiency. 1993;4:81–4.

    PubMed  CAS  Google Scholar 

  45. Chapel H, Brennan V, Delson E. Immunoglobulin replacement therapy by self-infusion at home. Clin Exp Immunol. 1988;73:160–2.

    PubMed  CAS  Google Scholar 

  46. Quinti I, Pierdominici M, Marziali M, Giovannetti A, Donnanno S, Chapel H, et al. European surveillance of immunoglobulin safety–results of initial survey of 1243 patients with primary immunodeficiencies in 16 countries. Clin Immunol. 2002;104:231–6.

    Article  PubMed  CAS  Google Scholar 

  47. Berger M, Rojavin M, Kiessling P, Zenker O. Pharmacokinetics of subcutaneous immunoglobulin and their use in dosing of replacement therapy in patients with primary immunodeficiencies. Clin Immunol. 2011;139:133–41.

    Article  PubMed  CAS  Google Scholar 

  48. Koleba T, Ensom M. Pharmacokinetics of intravenous immunoglobulin: a systematic review. Pharmacotherapy. 2006;26:813–27.

    Article  PubMed  CAS  Google Scholar 

  49. Gustafson R, Gardulf A, Hansen S, Leibl H, Engl W, Linden M, et al. Rapid subcutaneous immunoglobulin administration every second week results in high and stable serum immunoglobulin G levels in patients with primary antibody deficiencies. Clin Exp Immunol. 2008;152:274–9.

    Article  PubMed  CAS  Google Scholar 

  50. Notarangelo LD, Plebani A, Mazzolari E, Soresina A, Bondioni MP. Genetic causes of bronchiectasis: primary immune deficiencies and the lung. Respiration. 2007;74:264–75.

    Article  PubMed  Google Scholar 

  51. Dani B, Platz R, Tzannis S. High concentration formulation feasibility of human IgG for subcutaneous administration. J Pharm Sci. 2007;96:1504–17.

    Article  PubMed  CAS  Google Scholar 

  52. Frost G. Recombinant human hyaluronidase (rHUPH20): an enabling platform for subcutaneous drug and fluid administration. Expert Opin Drug Deliv. 2007;4:427–40.

    Article  PubMed  CAS  Google Scholar 

  53. Misbah S, Sturzenegger MH, Borte M, Shapiro RS, Wasserman RL, Berger M, et al. Subcutaneous immunoglobulin: opportunities and outlook. Clin Exp Immunol. 2009;158:51–9.

    Article  PubMed  CAS  Google Scholar 

  54. Hizentra Assessment report,CSL Behring European Medicines Agency. 2011;2127 1-56.

  55. http://www.baxter.com/products/biopharmaceuticals/downloads/gamliquid_PI.pdf. In.

  56. Borte M, Pac M, Serban M, Gonzalez-Quevedo T, Grimbacher B, Jolles S, et al. Efficacy and safety of hizentra(R), a new 20 % immunoglobulin preparation for subcutaneous administration, in pediatric patients with primary immunodeficiency. J Clin Immunol. 2011;31:752–61.

    Article  PubMed  CAS  Google Scholar 

  57. Wasserman RL, Melamed I, Kobrynski L, Strausbaugh SD, Stein MR, Sharkhawy M, et al. Efficacy, safety, and pharmacokinetics of a 10 % liquid immune globulin preparation (GAMMAGARD LIQUID, 10 %) administered subcutaneously in subjects with primary immunodeficiency disease. J Clin Immunol. 2011;31:323–31.

    Article  PubMed  CAS  Google Scholar 

  58. Wasserman RL, Irani AM, Tracy J, Tsoukas C, Stark D, Levy R, et al. Pharmacokinetics and safety of subcutaneous immune globulin (human), 10 % caprylate/chromatography purified in patients with primary immunodeficiency disease. Clin Exp Immunol. 2010;161:518–26.

    Article  PubMed  CAS  Google Scholar 

  59. Shapiro R. Subcutaneous immunoglobulin therapy by rapid push is preferred to infusion by pump: a retrospective analysis. J Clin Immunol. 2010;30:301–7.

    Article  PubMed  CAS  Google Scholar 

  60. http://www.gamunex-c.com/media/Gamunex-C_PI_QA_Brochure_GX197-1110.pdf.

  61. Maroto Hernando M, Soler Palacin P, Martin Nalda N, Oliveras Arenas M, Espanol Boren T, Figueras Nadal C. [Subcutaneous gammaglobulin in common variable immunodeficiency. First experience in Spain]. An Pediatr (Barc). 2009;70:111–9.

    Article  CAS  Google Scholar 

  62. Desai SH, Chouksey A, Poll J, Berger M. A pilot study of equal doses of 10 % IGIV given intravenously or subcutaneously. J Allergy Clin Immunol. 2009;124:854–6.

    Article  PubMed  CAS  Google Scholar 

  63. Quinti I, Soresina A, Agostini C, Spadaro G, Matucci A, Sfika I, et al. Prospective study on CVID patients with adverse reactions to intravenous or subcutaneous IgG administration. J Clin Immunol. 2008;28:263–7.

    Article  PubMed  CAS  Google Scholar 

  64. Gardulf A, Borte M, Ochs HD, Nicolay U. Prognostic factors for health-related quality of life in adults and children with primary antibody deficiencies receiving SCIG home therapy. Clin Immunol. 2008;126:81–8.

    Article  PubMed  CAS  Google Scholar 

  65. Horn J, Thon V, Bartonkova D, Salzer U, Warnatz K, Schlesier M, et al. Anti-IgA antibodies in common variable immunodeficiency (CVID): diagnostic workup and therapeutic strategy. Clin Immunol. 2007;122:156–62.

    Article  PubMed  CAS  Google Scholar 

  66. Sigstad HM, Stray-Pedersen A, Froland SS. Coping, quality of life, and hope in adults with primary antibody deficiencies. Health and Quality of Life Outcomes. 2005;3:1–31.

    Article  Google Scholar 

  67. Pac M, Bernatowska E. Polish experience with immunoglobulin replace ment treatment by subcutaneous infusion. Centr Eur J Immunol. 2005;30:78–82.

    CAS  Google Scholar 

  68. Nicolay U, Haag S, Eichmann F, Herget S, Spruck D, Gardulf A. Measuring treatment satisfaction in patients with primary immunodeficiency diseases receiving lifelong immunoglobulin replacement therapy. Qual Life Res. 2005;14:1683–91.

    Article  PubMed  CAS  Google Scholar 

  69. Kirmse J, Weiler CR. Subcutaneous immunoglobulin (SCIG) therapy: review of 51 patients. J Allergy Clin Immunol. 2005;115:S86.

    Article  Google Scholar 

  70. Johnson N, Dash CH, Gooi HC, Toolan J, Exley A, Henderson K, et al. Patients’ views on subcutaneous IgG (SCIG) Home Therapy: results from The UK Subgam® Study. BPL. 2004;1:1.

    Google Scholar 

  71. Gardulf A, Nicolay U, Math D, Asensio O, Bernatowska E, Bock A, et al. Children and adults with primary antibody deficiencies gain quality of life by subcutaneous IgG self-infusions at home. J Allergy Clin Immunol. 2004;114:936–42.

    Article  PubMed  CAS  Google Scholar 

  72. Radinsky S, Bonagura VR. Subcutaneous immunoglobulin infusion as an alternative to intravenous immunoglobulin. J Allergy Clin Immunol. 2003;112:630–3.

    Article  PubMed  CAS  Google Scholar 

  73. Radinsky S, Bonagura VR. Subcutaneous immunoglobulin infusion as an alternative to intravenous immunoglobulin: a fllow-up of three patients. J Allergy Clin Immunol. 2002;109:S187.

    Article  Google Scholar 

  74. Stiehm ER, Casillas AM, Finkelstein JZ, Gallagher KT, Groncy PM, Kobayashi RH, et al. Slow subcutaneous human intravenous immunoglobulin in the treatment of antibody immunodeficiency: use of an old method with a new product. J Allergy Clin Immunol. 1998;101:848–9.

    Article  PubMed  CAS  Google Scholar 

  75. Gardulf A, Bjorvell H, Andersen V, Bjorkander J, Ericson D, Froland SS, et al. Lifelong treatment with gammaglobulin for primary antibody deficiencies: the patients' experiences of subcutaneous self-infusions and home therapy. J Adv Nurs. 1995;21:917–27.

    Article  PubMed  CAS  Google Scholar 

  76. Waniewski J, Gardulf A, Hammarstrom L. Bioavailability of gamma-globulin after subcutaneous infusions in patients with common variable immunodeficiency. J Clin Immunol. 1994;14:90–7.

    Article  PubMed  CAS  Google Scholar 

  77. Gardulf A, Bjorvell H, Gustafson R, Hammarstrom L, Smith CI. The life situations of patients with primary antibody deficiency untreated or treated with subcutaneous gammaglobulin infusions. Clin Exp Immunol. 1993;92:200–4.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant (89-04-30-12253) from Tehran University of Medical Sciences.

Author information

Authors and Affiliations

  1. Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Dr Qarib St, Keshavarz Blvd, Tehran, 14194, Iran

    Hassan Abolhassani, Mohammad Salehi Sadaghiani, Asghar Aghamohammadi & Nima Rezaei

  2. Department of Pediatrics, University of Washington and Seattle Children’s Hospital Research Institute, Seattle, WA, USA

    Hans D. Ochs

  3. Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran

    Nima Rezaei

  4. Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Nima Rezaei

  5. Department of Infection and Immunity, School of Medicine and Biomedical Sciences, The University of Sheffield, Sheffield, UK

    Nima Rezaei

Authors
  1. Hassan Abolhassani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mohammad Salehi Sadaghiani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Asghar Aghamohammadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hans D. Ochs
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nima Rezaei
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Hans D. Ochs or Nima Rezaei.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Abolhassani, H., Sadaghiani, M.S., Aghamohammadi, A. et al. Home-Based Subcutaneous Immunoglobulin Versus Hospital-Based Intravenous Immunoglobulin in Treatment of Primary Antibody Deficiencies: Systematic Review and Meta Analysis. J Clin Immunol 32, 1180–1192 (2012). https://doi.org/10.1007/s10875-012-9720-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-012-9720-1

Keywords

Search

Navigation