Subcutaneous Immunoglobulin for Primary and Secondary Immunodeficiencies: an Evidence-Based Review
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Substitution with immunoglobulin can be administered intravenously (IV) or subcutaneously (SC) to patients with immunodeficiency, but it is not clear which route is to be preferred.
The aim of this study was to compare IV and SC administration of immunoglobulin regarding efficacy, safety, health-related quality of life and health economics in patients with primary or secondary immunodeficiency.
PubMed and other databases were searched. Reference lists of retrieved articles were scanned and major immunoglobulin producers were contacted for additional articles. Randomized and non-randomized clinical studies that compared SC with IV immunoglobulin substitution in patients with immunodeficiency were included. The validity of the findings in the included studies was evaluated and summarized in accordance with the GRADE approach.
Twenty-five studies were included; two randomized and 17 non-randomized studies of patients with primary immunodeficiency, one non-randomized study of patients with secondary immunodeficiency and five studies of health economics. The quality of evidence as assessed by the GRADE score was found to be moderate or low for all outcomes. Both IV and SC administration of immunoglobulin was found to be highly effective in preventing serious bacterial infections. IgG trough levels were higher with SC immunoglobulin substitution. Both therapy forms were concluded to be safe, as no serious adverse event was reported. Minor adverse events, consisting of local symptoms that were usually mild, were more frequent with SC immunoglobulin substitution. Health-related quality of life improved when patients switched from hospital-based IV immunoglobulin substitution to SC immunoglobulin substitution at home. The studies that evaluated health economics all found that SC administration was considerably more cost effective in comparison with IV immunoglobulin substitution. The main difference was that the number of lost work or school days was lower in patients with SC administration.
Both SC and IV immunoglobulin substitution offer protection from serious bacterial infections and have good safety. On the basis of available studies it is not possible to rate one of the two substitution modes as superior to the other, at least not regarding efficacy and safety. Improvement of health-related quality of life with SC immunoglobulin substitution largely seems to be related to home therapy. Studies including patients with secondary immunodeficiency were few, as were randomized studies of patients with primary immunodeficiency.
- Cohn, EJ, Oncley, JL, Strong, LE (1944) Chemical, clinical, and immunological studies on the products of human plasma fractionation. I. The characterization of the protein fractions of human plasma. J Clin Invest 23: pp. 417-432 CrossRef
- Bruton, OC (1952) Agammaglobulinemia. Pediatrics 9: pp. 722-728
- Bruton, OC (1962) A decade with agammaglobulinemia. J Pediatr 60: pp. 672-676 CrossRef
- Record, BR, Gunn, W (1946) Human gammaglobulin. Br Med J 1: pp. 101 CrossRef
- Eijkhout, HW, Meer, JW, Kallenberg, CG (2001) The effect of two different dosages of intravenous immunoglobulin on the incidence of recurrent infections in patients with primary hypogammaglobulinemia: a randomized, double-blind, multicenter crossover trial. Ann Intern Med 135: pp. 165-174 CrossRef
- Ochs, HD, Fischer, SH, Wedgwood, RJ (1984) Comparison of high dose and low-dose intravenous immunoglobulin therapy in patients with primary immunodeficiency diseases. Am J Med 76: pp. 78-82 CrossRef
- Roifman, CM, Levison, H, Gelfand, EW (1987) High-dose versus low-dose intravenous immunoglobulin in hypogammaglobulinaemia and chronic lung disease. Lancet 1: pp. 1075-1077 CrossRef
- Slade, HB (1994) Human immunoglobulins for intravenous use and hepatitis C viral transmission. Clin Diagn Lab Immunol 1: pp. 613-619
- Gardulf, A, Hammarström, L, Smith, CI (1991) Home treatment of hypogamma-globulinaemia with subcutaneous gammaglobulin by rapid infusion. Lancet 338: pp. 162-166 CrossRef
- Guidelines for diagnosis and treatment of primary immunodeficiency [in Swedish)], 3rd ed. 2011. http://www.slipi.nu/klinik/Broschyr_Riktlinjer_V3_2011.pdf.
- Guidelines for diagnosis and treatment of primary immunodeficiency [in Danish], 2nd ed. 2013. ISBN 978-87-92568-01-4 http://www.immundefekt-diagnostik.dk.
- Liberati, A, Altman, DG, Tetzlaff, J (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med 6: pp. e1000100 CrossRef
- Food and Drug Administration. Guidance for industry safety, efficacy, and pharmacokinetic studies to support marketing of immune globulin intravenous (human) as replacement therapy for primary humoral immunodeficiency. 2008. http://www.fda.gov/cber/guidelines.htm.
- Chapel, HM (1994) Consensus on diagnosis and management of primary antibody deficiencies. BMJ 308: pp. 581-585 CrossRef
- Berger, M (2004) Subcutaneous immunoglobulin replacement in primary immunodeficiencies. J Clin Immunol 112: pp. 1-7 CrossRef
- Chinen, J, Shearer, WT (2004) Subcutaneous immunoglobulins: alternative for the hypogammaglobulinemic patient?. J Allergy Clin Immunol 114: pp. 934-935 CrossRef
- Busse, J, Hoffman, F, Schlieben, S (2005) Subcutaneous immunoglobulin substitution in primary B-cell defects. Review of the literature and experiences with 17 patients over a period of 6 years [in German]. Tagliche Praxis 46: pp. 185-192
- Chouksey, A, Duff, K, Wasserbauer, N (2005) 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 1: pp. 120-130
- Durandy, A, Wahn, V, Petteway, S (2005) Immunoglobulin replacement therapy in primary antibody deficiency diseases: maximizing success. Int Arch Allergy Immunol 136: pp. 217-229 CrossRef
- Gardulf, A, Nicolay, U (2006) 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 6: pp. 434-442 CrossRef
- Hernandez, M, Bastian, JF (2006) Immunodeficiency in childhood. Curr Allergy Asthma Rep 6: pp. 468-474 CrossRef
- Helbert, M, Farragher, A (2007) Subcutaneous immunoglobulin for patients with antibody deficiency. Br J Hosp Med (Lond) 68: pp. 206-210
- Ballow, M (2008) Immunoglobulin therapy: methods of delivery. J Allergy Clin Immunol 122: pp. 1038-1039 CrossRef
- Berger, M (2008) Principles and advances in immunoglobulin replacement therapy for primary immunodeficiency. Immunol Allergy Clin N Am 28: pp. 413-437 CrossRef
- Bonilla, FA (2008) Pharmacokinetics of immunoglobulin administered via intravenous or subcutaneous routes. Immunol Allergy Clin N Am 28: pp. 803-819 CrossRef
- Moore, ML, Quinn, JM (2008) Subcutaneous immunoglobulin replacement therapy for primary antibody deficiency: advancements into the 21st century. Ann Allergy Asthma Immunol 101: pp. 114-121 CrossRef
- Stiehm, ER, Keller, MA, Vyas, GN (2008) Preparation and use of therapeutic antibodies primarily of human origin. Biologicals 36: pp. 363-374 CrossRef
- Kirmse, J (2009) The nurse’s role in intravenous immunoglobulin therapy. Home Healthc Nurse 27: pp. 104-111 CrossRef
- Misbah, S, Sturzenegger, MH, Borte, M (2009) Subcutaneous immunoglobulin: opportunities and outlook. Clin Exp Immunol 158: pp. 51-59 CrossRef
- Moore, ML, Quinn, JM (2009) Subcutaneous immunoglobulin therapy in pediatric primary antibody deficiency. Ped Health 3: pp. 231-240 CrossRef
- Notarangelo, LD (2010) Primary immunodeficiencies. J Allergy Clin Immunol 125: pp. 182-194 CrossRef
- Berger, M (2011) Choices in IgG replacement therapy for primary immune deficiency diseases: subcutaneous IgG vs. intravenous IgG and selecting an optimal dose. Curr Opin Allergy Clin Immunol 11: pp. 532-538 CrossRef
- Hoernes, M, Seger, R, Reichenbach, J (2011) Modern management of primary B-cell immunodeficiencies. Pediatr Allergy Immunol 22: pp. 758-769 CrossRef
- Maarschalk-Ellerbroek, LJ, Hoepelman, IM, Ellerbroek, PM (2011) Immunoglobulin treatment in primary antibody deficiency. Int J Antimicrob Agents 37: pp. 396-404 CrossRef
- Misbah, S, Kuijpers, T, Heijden, J (2011) Bringing immunoglobulin knowledge up to date: how should we treat today?. Clin Exp Immunol 166: pp. 16-25 CrossRef
- Rezaei, N, Abolhassani, H, Aghamohammadi, A (2011) Indications and safety of intravenous and subcutaneous immunoglobulin therapy. Expert Rev Clin Immunol 7: pp. 301-316 CrossRef
- Abolhassani, H, Sadaghiani, MS, Aghamohammadi, A (2012) Home-based subcutaneous immunoglobulin versus hospital-based intravenous immunoglobulin in treatment of primary antibody deficiencies: systematic review and meta analysis. J Clin Immunol 32: pp. 1180-1192 CrossRef
- Borte, M, Baumann, U, Pittrow, D (2012) Immunoglobulins in PID, SID and neurological autoimmune disease [in German]. Dtsch Med Wochenschr 137: pp. 675-680 CrossRef
- Haddad, E, Barnes, D, Kafal, A (2012) Home therapy with subcutaneous immunoglobulins for patients with primary immunodeficiency diseases. Transfus Apher Sci 46: pp. 315-321 CrossRef
- Hernandez-Trujillo, HS, Chapel, H, Lo Re, V (2012) Comparison of American and European practices in the management of patients with primary immunodeficiencies. Clin Exp Immunol 169: pp. 57-69 CrossRef
- Kobrinsky, L (2012) Subcutaneous immunoglobulin therapy: a new option for patients with primary immunodeficiency diseases. Biologics 6: pp. 277-287
- Atkins, D, Best, D, Briss, PA (2004) Grading quality of evidence and strength of recommendations. BMJ 328: pp. 1490-1494 CrossRef
- Schünemann H, Brożek J, Oxman A, editors. GRADE handbook for grading quality of evidence and strength of recommendation. Version 3.2 (updated March 2009). The GRADE Working Group, 2009. Available from http://www.cc-ims.net/gradepro.
- Checklist from SBU regarding randomized controlled trials http://www.sahlgrenska.se/upload/SU/HTA-centrum/Hj%c3%a4lpmedel%20under%20projektet/B02_Granskningsmall%20f%c3%b6r%20randomiserad%20kontrollerad%20pr%c3%b6vning.doc. [Accessed 2012 Jan 03].
- Checklist from SBU regarding cohort studies. Version 2010:1. http://www.sahlgrenska.se/upload/SU/HTA-centrum/Hj%c3%a4lpmedel%20under%20projektet/1/B03_Granskningsmall%20f%c3%b6r%20kohortstudier%20med%20kontrollgrupp%20modifierad%20OS%20IT.doc. [Accessed 2012 Jan 03].
- Checklist from SBU regarding economic studies. Version 2012:1 http://www.sbu.se/upload/ebm/metodbok/Mall_modell_halsoekonomi.pdf. [Accessed 2012 Jan 03].
- Gardulf, A, Andersen, V, Björkander, J (1995) Subcutaneous immunoglobulin replacement in patients with primary antibody deficiencies: safety and costs. Lancet 345: pp. 365-369 CrossRef
- Gaspar, J, Gerritsen, B, Jones, A (1998) Immunoglobulin replacement treatment by rapid subcutaneous infusion. Arch Dis Child 79: pp. 48-51 CrossRef
- Chapel, HM, Spickett, GP, Ericson, D (2000) The comparison of the efficacy and safety of intravenous versus subcutaneous immunoglobulin replacement therapy. J Clin Immunol 20: pp. 94-100 CrossRef
- Gardulf, A, Nicolay, U, Math, D (2004) Children and adults with primary antibody deficiencies gain quality of life by subcutaneous IgG self-infusions at home. J Allergy Clin Immunol 114: pp. 936-942 CrossRef
- Högy, B, Keinecke, H, Borte, M (2005) Pharmacoeconomic evaluation of immunoglobulin treatment in patients with antibody deficiencies from the perspective of the German statutory health insurance. Eur J Health Econ 6: pp. 24-29 CrossRef
- Nicolay, U, Kiessling, P, Berger, M (2006) Health-related quality of life and treatment satisfaction in North American patients with primary immunodeficiency diseases receiving subcutaneous IgG self-infusions at home. J Clin Immunol 26: pp. 65-72 CrossRef
- Gardulf, A, Nicolay, U, Asensio, O (2006) Rapid subcutaneous IgG replacement therapy is effective and safe in children and adults with primary immunodeficiencies: a prospective, multi-national study. J Clin Immunol 26: pp. 177-185 CrossRef
- Haddad, L, Perrinet, M, Parent, D (2006) Economic evaluation of at home subcutaneous and intravenous immunoglobulin substitution [in French]. Rev Med Interne 27: pp. 924-926 CrossRef
- Kittner, JM, Grimbacher, B, Wulff, W (2006) Patients’ attitude to subcutaneous immunoglobulin substitution as home therapy. J Clin Immunol 26: pp. 400-405 CrossRef
- Ochs, HD, Gupta, S, Kiessling, P (2006) Safety and efficacy of self-administered subcutaneous immunoglobulin in patients with primary immunodeficiency diseases. J Clin Immunol 26: pp. 265-273 CrossRef
- Fasth, A, Nyström, J (2007) Safety and efficacy of subcutaneous human immunoglobulin in children with primary immunodeficiency. Acta Paediatr 96: pp. 1474-1478 CrossRef
- Fasth, A, Nyström, J (2008) Quality of life and health-care resource utilization among children with primary immunodeficiency receiving home treatment with subcutaneous human immunoglobulin. J Clin Immunol 28: pp. 370-378 CrossRef
- Desai, SH, Chouksey, A, Poll, J (2009) Pilot study of equal doses of 10 % IGIV given intravenously or subcutaneously. J Allergy Clin Immunol 124: pp. 854-856 CrossRef
- Maroto Hernando M, Soler Palacín P, Martin Nalda N, et al. Subcutaneous gammaglobulin in common variable immunodeficiency: first experience in Spain [in Spanish]. An Pediatr 2009;70:111–9.
- Beauté, J, Levy, P, Millet, V (2010) Economic evaluation of immunoglobulin replacement in patients with primary antibody deficiencies. Clin Exp Immunol 160: pp. 240-245 CrossRef
- Hoffmann, F, Grimbacher, B, Thiel, J (2010) Home-based subcutaneous immunoglobulin G replacement therapy under real-life conditions in children and adults with antibody deficiency. Eur J Med Res 15: pp. 238-245
- Shapiro, R (2010) Subcutaneous immunoglobulin therapy by rapid push is preferred to infusion by pump: a retrospective analysis. Clin Immunol 30: pp. 301-307 CrossRef
- Wasserman, RL, Irani, AM, Tracy, J (2010) Pharmacokinetics and safety of subcutaneous immune globulin (human), 10 % caprylate/chromatography purified in patients with primary immunodeficiency disease. Clin Exp Immunol 161: pp. 518-526 CrossRef
- Jolles, S, Bernatowska, E, Gracia, J (2011) Efficacy and safety of Hizentra® in patients with primary immunodeficiency after a dose-equivalent switch from intravenous or subcutaneous replacement therapy. Clin Immunol 141: pp. 90-102 CrossRef
- Wasserman, RL, Melamed, I, Kobrynski, L (2011) 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 31: pp. 323-331 CrossRef
- Wasserman, RL, Melamed, I, Nelson, RP (2011) Pharmacokinetics of subcutaneous IgPro20 in patients with primary immunodeficiency. Clin Pharmacokinet 50: pp. 405-411 CrossRef
- Sundin, M, Nordin, K, Jostemyr, Y (2012) Subcutaneous IgG replacement after pediatric SCT. Pediatric Transpl 16: pp. 866-871 CrossRef
- Wasserman, RL, Melamed, I, Stein, MR (2012) IGSC, 10 % with rHuPH20 Study Group. Recombinant human hyaluronidase-facilitated subcutaneous infusion of human immunoglobulins for primary immunodeficiency. J Allergy Clin Immunol 130: pp. 951-957 CrossRef
- Martin, A, Lavoie, L, Goetghebeur, M (2013) Economic benefits of subcutaneous rapid push versus intravenous immunoglobulin infusion therapy in adult patients with primary immune deficiency. Transfus Med 23: pp. 55-60 CrossRef
- Ducruet, T, Levasseur, MC, Des Roches, A (2013) Pharmacoeconomic advantages of subcutaneous versus intravenous immunoglobulin treatment in a Canadian pediatric center. J Allergy Clin Immunol 131: pp. 585-587 CrossRef
- Orange, JS, Hossny, EM, Weiler, CR (2006) Use of intravenous immunoglobulin in human disease: a review of evidence by members of the primary immunodeficiency committee of the American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol 117: pp. S525-S553 CrossRef
- Gennery, AR, Slatter, MA, Grandin, L (2010) Long term survival and transplantation of haematopoietic stem cells for primary immunodeficiencies: report of the European experience 1968–2005. J Allergy Clin Immunol 126: pp. 602-610 CrossRef
- Eapen, M, Ahn, KW, Orchard, PJ (2012) Long-term survival and late deaths after hematopoietic cell transplantation for primary immunodeficiency diseases and inborn errors of metabolism. Biol Blood Marrow Transpl 18: pp. 1438-1445 CrossRef
- Caress, JB, Hobson-Webb, L, Passmore, LV (2009) Case-control study of thromboembolic events associated with IV immunoglobulin. J Neurol 256: pp. 339-342 CrossRef
- Al-Riyami, AZ, Lee, J, Connolly, M (2011) Cerebral sinus thrombosis following IV immunoglobulin therapy of immune thrombocytopenia purpura. Pediatr Blood Cancer 57: pp. 157-159 CrossRef
- FDA Safety Communication: New boxed warning for thrombosis related to human immune globulin products. 2013. http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm355986.htm.
- European Medicines Agency. Hizentra. Product information. EMEA/H/C/002127-II/0020/G. 2013 http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002127/human_med_001440.jsp&mid=WC0b01ac058001d124.
- Orange, JS, Grossman, WJ, Navickis, RJ (2010) Impact of trough IgG on pneumonia incidence in primary immunodeficiency: a meta-analysis of clinical studies. Clin Immunol 137: pp. 21-30 CrossRef
- Orange, JS, Belohradsky, BH, Berger, M (2012) Evaluation of correlation between dose and clinical outcomes in subcutaneous immunoglobulin replacement therapy. Clin Exp Immunol 169: pp. 172-181 CrossRef
- Berger, M, Jolles, S, Orange, JS (2013) Bioavailability of IgG administered by the subcutaneous route. J Clin Immunol 33: pp. 984-990 CrossRef
- Huang, F, Feuille, E, Cunningham-Rundles, C (2013) Home care use of intravenous and subcutaneous immunoglobulin for primary immunodeficiency in the United States. J Clin Immunol 33: pp. 49-54 CrossRef
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