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Published in: Journal of Clinical Immunology 2/2021

Open Access 01-02-2021 | Primary Immunodeficiency | Original Article

Immunoglobulin Replacement Therapy Versus Antibiotic Prophylaxis as Treatment for Incomplete Primary Antibody Deficiency

Authors: Bas M. Smits, Ilona Kleine Budde, Esther de Vries, Ineke J. M. ten Berge, Robbert G. M. Bredius, Marcel van Deuren, Jaap T. van Dissel, Pauline M. Ellerbroek, Michiel van der Flier, P. Martin van Hagen, Chris Nieuwhof, Bram Rutgers, Lieke E. A. M. Sanders, Anna Simon, Taco W. Kuijpers, Joris M. van Montfrans

Published in: Journal of Clinical Immunology | Issue 2/2021

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Abstract

Background

Patients with an IgG subclass deficiency (IgSD) ± specific polysaccharide antibody deficiency (SPAD) often present with recurrent infections. Previous retrospective studies have shown that prophylactic antibiotics (PA) and immunoglobulin replacement therapy (IRT) can both be effective in preventing these infections; however, this has not been confirmed in a prospective study.

Objective

To compare the efficacy of PA and IRT in a randomized crossover trial.

Methods

A total of 64 patients (55 adults and 9 children) were randomized (2:2) between two treatment arms. Treatment arm A began with 12 months of PA, and treatment arm B began with 12 months of IRT. After a 3-month bridging period with cotrimoxazole, the treatment was switched to 12 months of IRT and PA, respectively. The efficacy (measured by the incidence of infections) and proportion of related adverse events in the two arms were compared.

Results

The overall efficacy of the two regimens did not differ (p = 0.58, two-sided Wilcoxon signed-rank test). A smaller proportion of patients suffered a related adverse event while using PA (26.8% vs. 60.3%, p < 0.0003, chi-squared test). Patients with persistent infections while using PA suffered fewer infections per year after switching to IRT (2.63 vs. 0.64, p < 0.01).

Conclusion

We found comparable efficacy of IRT and PA in patients with IgSD ± SPAD. Patients with persistent infections during treatment with PA had less infections after switching to IRT.

Clinical Implication

Given the costs and associated side-effects of IRT, it should be reserved for patients with persistent infections despite treatment with PA.
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Literature
1.
go back to reference Picard C, Al-Herz W, Bousfiha A, Casanova JL, Chatila T, Conley ME, et al. Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for primary immunodeficiency 2015. J Clin Immunol. 2015;35(8):696–726.CrossRef Picard C, Al-Herz W, Bousfiha A, Casanova JL, Chatila T, Conley ME, et al. Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for primary immunodeficiency 2015. J Clin Immunol. 2015;35(8):696–726.CrossRef
2.
go back to reference Bousfiha AA, Jeddane L, Ailal F, Al Herz W, Conley ME, Cunningham-Rundles C, et al. A phenotypic approach for IUIS PID classification and diagnosis: guidelines for clinicians at the bedside. J Clin Immunol. 2013;33(6):1078–87 [Internet].CrossRef Bousfiha AA, Jeddane L, Ailal F, Al Herz W, Conley ME, Cunningham-Rundles C, et al. A phenotypic approach for IUIS PID classification and diagnosis: guidelines for clinicians at the bedside. J Clin Immunol. 2013;33(6):1078–87 [Internet].CrossRef
3.
go back to reference Bousfiha A, Jeddane L, Picard C, Al-Herz W, Ailal F, Chatila T, et al. Human inborn errors of immunity: 2019 update of the IUIS phenotypical classification. J Clin Immunol. 2020;40(1):66–81.CrossRef Bousfiha A, Jeddane L, Picard C, Al-Herz W, Ailal F, Chatila T, et al. Human inborn errors of immunity: 2019 update of the IUIS phenotypical classification. J Clin Immunol. 2020;40(1):66–81.CrossRef
4.
go back to reference Kobrynski L, Powell RW, Bowen S. Prevalence and morbidity of primary immunodeficiency diseases, United States 2001–2007. J Clin Immunol. 2014;34(8):954–61.CrossRef Kobrynski L, Powell RW, Bowen S. Prevalence and morbidity of primary immunodeficiency diseases, United States 2001–2007. J Clin Immunol. 2014;34(8):954–61.CrossRef
5.
go back to reference Koenen MHM, van Montfrans JMJ, Sanders EAME, Bogaert DD, Verhagen LML. Immunoglobulin A deficiency in children, an undervalued clinical issue. Clin Immunol. 2019;209:108293 [Internet].CrossRef Koenen MHM, van Montfrans JMJ, Sanders EAME, Bogaert DD, Verhagen LML. Immunoglobulin A deficiency in children, an undervalued clinical issue. Clin Immunol. 2019;209:108293 [Internet].CrossRef
6.
go back to reference 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(3):263–7. 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(3):263–7.
7.
go back to reference Busse PJ, Razvi S, Cunningham-Rundles C. Efficacy of intravenous immunoglobulin in the prevention of pneumonia in patients with common variable immunodeficiency. J Allergy Clin Immunol. 2002;109(6):1001–4.CrossRef Busse PJ, Razvi S, Cunningham-Rundles C. Efficacy of intravenous immunoglobulin in the prevention of pneumonia in patients with common variable immunodeficiency. J Allergy Clin Immunol. 2002;109(6):1001–4.CrossRef
8.
go back to reference Cunningham-Rundles C. Lung disease, antibodies and other unresolved issues in immune globulin therapy for antibody deficiency. Clin Exp Immunol. 2009;157(SUPPL. 1):12–6.CrossRef Cunningham-Rundles C. Lung disease, antibodies and other unresolved issues in immune globulin therapy for antibody deficiency. Clin Exp Immunol. 2009;157(SUPPL. 1):12–6.CrossRef
9.
go back to reference Quinti I, Soresina A, Guerra A, Rondelli R, Spadaro G, Agostini C, et al. Effectiveness of immunoglobulin replacement therapy on clinical outcome in patients with primary antibody deficiencies: results from a multicenter prospective cohort study. J Clin Immunol. 2011;31(3):315–22 [Internet].CrossRef Quinti I, Soresina A, Guerra A, Rondelli R, Spadaro G, Agostini C, et al. Effectiveness of immunoglobulin replacement therapy on clinical outcome in patients with primary antibody deficiencies: results from a multicenter prospective cohort study. J Clin Immunol. 2011;31(3):315–22 [Internet].CrossRef
10.
go back to reference Gelfand EW, Ochs HD, Shearer WT. Controversies in IgG replacement therapy in patients with antibody deficiency diseases. J Allergy Clin Immunol. 2013;131(4):1001–5 [Internet].CrossRef Gelfand EW, Ochs HD, Shearer WT. Controversies in IgG replacement therapy in patients with antibody deficiency diseases. J Allergy Clin Immunol. 2013;131(4):1001–5 [Internet].CrossRef
11.
go back to reference Perez EE, Orange JS, Bonilla F, Chinen J, Chinn IK, Dorsey M, et al. Update on the use of immunoglobulin in human disease: a review of evidence. J Allergy Clin Immunol. 2017;139(3):S1–46 [Internet]. Perez EE, Orange JS, Bonilla F, Chinen J, Chinn IK, Dorsey M, et al. Update on the use of immunoglobulin in human disease: a review of evidence. J Allergy Clin Immunol. 2017;139(3):S1–46 [Internet].
12.
go back to reference Barlan I, Geha RS, Schneider LC. Therapy for patients with recurrent infections and low serum IgG3 levels. J Allergy Clin Immunol. 1993;92:353–5.CrossRef Barlan I, Geha RS, Schneider LC. Therapy for patients with recurrent infections and low serum IgG3 levels. J Allergy Clin Immunol. 1993;92:353–5.CrossRef
13.
go back to reference Huston DP, Kavanaugh AF, Huston MM, Rohane W, Iga S. Immunoglobulin deficiency syndromes and therapy. J Allergy Clin Immunol. 1991;87:1–17.CrossRef Huston DP, Kavanaugh AF, Huston MM, Rohane W, Iga S. Immunoglobulin deficiency syndromes and therapy. J Allergy Clin Immunol. 1991;87:1–17.CrossRef
14.
go back to reference Milota T, Bloomfield M, Kralickova P, Jilek D, Novak V, Litzman J, et al. Czech Hizentra Noninterventional Study With Rapid Push: Efficacy, Safety, Tolerability, and Convenience of Therapy With 20% Subcutaneous Immunoglobulin. Clin Ther. 2019;xxx(xxx):1–8. Milota T, Bloomfield M, Kralickova P, Jilek D, Novak V, Litzman J, et al. Czech Hizentra Noninterventional Study With Rapid Push: Efficacy, Safety, Tolerability, and Convenience of Therapy With 20% Subcutaneous Immunoglobulin. Clin Ther. 2019;xxx(xxx):1–8.
15.
go back to reference Khokar A, Gupta S. Clinical and immunological features of 78 adult patients with primary selective IgG subclass deficiencies. Arch Immunol Ther Exp (Warsz). 2019;67(5):325–34 [Internet].CrossRef Khokar A, Gupta S. Clinical and immunological features of 78 adult patients with primary selective IgG subclass deficiencies. Arch Immunol Ther Exp (Warsz). 2019;67(5):325–34 [Internet].CrossRef
16.
go back to reference Jolles S, Chapel H, Litzman J. When to initiate immunoglobulin replacement therapy (IGRT) in antibody deficiency: a practical approach. Clin Exp Immunol. 2017;188(3):333–41.CrossRef Jolles S, Chapel H, Litzman J. When to initiate immunoglobulin replacement therapy (IGRT) in antibody deficiency: a practical approach. Clin Exp Immunol. 2017;188(3):333–41.CrossRef
17.
go back to reference Wolpert J, Knutsen AP. Natural history of selective antibody deficiency to bacterial polysaccharide antigens in children. Pediatr Asthma, Allergy Immunol. 1998;12(3):183–91.CrossRef Wolpert J, Knutsen AP. Natural history of selective antibody deficiency to bacterial polysaccharide antigens in children. Pediatr Asthma, Allergy Immunol. 1998;12(3):183–91.CrossRef
18.
go back to reference Karaca NE, Karadeniz C, Aksu G, Kutukculer N. Clinical and laboratory evaluation of periodically monitored Turkish children with IgG subclass deficiencies. Asian Pac J Allergy Immunol. 2009;27(1):43–8.PubMed Karaca NE, Karadeniz C, Aksu G, Kutukculer N. Clinical and laboratory evaluation of periodically monitored Turkish children with IgG subclass deficiencies. Asian Pac J Allergy Immunol. 2009;27(1):43–8.PubMed
19.
go back to reference Gandhi A, Brodsky L, Ballow M. Benefits of antibiotic prophylaxis in children with chronic sinusitis: assessment of outcome predictors. Allergy Proc. 1993;14(1):37–43 [Internet].CrossRef Gandhi A, Brodsky L, Ballow M. Benefits of antibiotic prophylaxis in children with chronic sinusitis: assessment of outcome predictors. Allergy Proc. 1993;14(1):37–43 [Internet].CrossRef
20.
go back to reference Abdou NI, Greenwell CA, Mehta R, Narra M, Hester JD, Halsey JF. Efficacy of intravenous gammaglobulin for immunoglobulin g subclass and/or antibody deficiency in adults. Int Arch Allergy Immunol. 2009;149(3):267–74.CrossRef Abdou NI, Greenwell CA, Mehta R, Narra M, Hester JD, Halsey JF. Efficacy of intravenous gammaglobulin for immunoglobulin g subclass and/or antibody deficiency in adults. Int Arch Allergy Immunol. 2009;149(3):267–74.CrossRef
21.
go back to reference Olinder-Nielsen AM, Granert C, Forsberg P, Friman V, Vietorisz A, Björkander J. Immunoglobulin prophylaxis in 350 adults with IgG subclass deficiency and recurrent respiratory tract infections: a long-term follow-up. Scand J Infect Dis. 2007;39(1):44–50.CrossRef Olinder-Nielsen AM, Granert C, Forsberg P, Friman V, Vietorisz A, Björkander J. Immunoglobulin prophylaxis in 350 adults with IgG subclass deficiency and recurrent respiratory tract infections: a long-term follow-up. Scand J Infect Dis. 2007;39(1):44–50.CrossRef
22.
go back to reference van Kessel DA, Hoffman TW, van Velzen-Blad H, Zanen P, Grutters JC, Rijkers GT. Long-term clinical outcome of antibody replacement therapy in humoral immunodeficient adults with respiratory tract infections. EBioMedicine. 2017;18:254–60 [Internet].CrossRef van Kessel DA, Hoffman TW, van Velzen-Blad H, Zanen P, Grutters JC, Rijkers GT. Long-term clinical outcome of antibody replacement therapy in humoral immunodeficient adults with respiratory tract infections. EBioMedicine. 2017;18:254–60 [Internet].CrossRef
23.
go back to reference Bernatowska-Matuszkiewicz E, Pac M, Skopcynska H, Pum M, Eibl MM. Clinical efficacy of intravenous immunoglobulin in patients with severe inflammatory chest disease and IgG3 subclass deficiency. Clin Exp Immunol. 1991;85(2):193–7.CrossRef Bernatowska-Matuszkiewicz E, Pac M, Skopcynska H, Pum M, Eibl MM. Clinical efficacy of intravenous immunoglobulin in patients with severe inflammatory chest disease and IgG3 subclass deficiency. Clin Exp Immunol. 1991;85(2):193–7.CrossRef
24.
go back to reference Hajjar J, Nguyen AL, Constantine G, Kutac C, Syed MN, Orange JS, et al. Prophylactic antibiotics versus immunoglobulin replacement in specific antibody deficiency. J Clin Immunol. 2020;40(1):158–64. Hajjar J, Nguyen AL, Constantine G, Kutac C, Syed MN, Orange JS, et al. Prophylactic antibiotics versus immunoglobulin replacement in specific antibody deficiency. J Clin Immunol. 2020;40(1):158–64.
27.
go back to reference Stegeman CA, Tervaert JW, de Jong PE, Kallenberg CG. Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener’s granulomatosis. Dutch Co-Trimoxazole Wegener Study Group. N Engl J Med. 1996;335(1):16–20 [Internet].CrossRef Stegeman CA, Tervaert JW, de Jong PE, Kallenberg CG. Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener’s granulomatosis. Dutch Co-Trimoxazole Wegener Study Group. N Engl J Med. 1996;335(1):16–20 [Internet].CrossRef
28.
go back to reference Kronbichler A, Kerschbaum J, Gopaluni S, Tieu J, Alberici F, Jones RB, et al. Trimethoprim-sulfamethoxazole prophylaxis prevents severe/life-threatening infections following rituximab in antineutrophil cytoplasm antibody-associated vasculitis. Ann Rheum Dis. 2018;77:1440–7. Kronbichler A, Kerschbaum J, Gopaluni S, Tieu J, Alberici F, Jones RB, et al. Trimethoprim-sulfamethoxazole prophylaxis prevents severe/life-threatening infections following rituximab in antineutrophil cytoplasm antibody-associated vasculitis. Ann Rheum Dis. 2018;77:1440–7.
29.
go back to reference Church JA, Fitzgerald F, Walker AS, Gibb DM, Prendergast AJ. The expanding role of co-trimoxazole in developing countries. Lancet Infect Dis. 2015;15(3):327–39 [Internet].CrossRef Church JA, Fitzgerald F, Walker AS, Gibb DM, Prendergast AJ. The expanding role of co-trimoxazole in developing countries. Lancet Infect Dis. 2015;15(3):327–39 [Internet].CrossRef
31.
go back to reference Kaminski DA, Wei C, Qian Y, Rosenberg AF, Sanz I. Advances in human B cell phenotypic profiling. Front Immunol. 2012;3:302 [Internet].CrossRef Kaminski DA, Wei C, Qian Y, Rosenberg AF, Sanz I. Advances in human B cell phenotypic profiling. Front Immunol. 2012;3:302 [Internet].CrossRef
32.
go back to reference Pasternak G, Lewandowicz-Uszyńska A, Pentoś K. Analysis of differences between total IgG and sum of the IgG subclasses in children with suspected immunodeficiency - indication of determinants. BMC Immunol. 2018;19(1):22 [Internet].CrossRef Pasternak G, Lewandowicz-Uszyńska A, Pentoś K. Analysis of differences between total IgG and sum of the IgG subclasses in children with suspected immunodeficiency - indication of determinants. BMC Immunol. 2018;19(1):22 [Internet].CrossRef
33.
go back to reference Abrahamyan L, Feldman BM, Tomlinson G, Faughnan ME, Johnson SR, Diamond IR, et al. Alternative designs for clinical trials in rare diseases. Am J Med Genet C Semin Med Genet. 2016;172(4):313–31 [Internet]. Abrahamyan L, Feldman BM, Tomlinson G, Faughnan ME, Johnson SR, Diamond IR, et al. Alternative designs for clinical trials in rare diseases. Am J Med Genet C Semin Med Genet. 2016;172(4):313–31 [Internet].
34.
go back to reference Guo Y, Tian X, Wang X, Xiao Z. Adverse effects of immunoglobulin therapy. Front Immunol. 2018;9:1299 [Internet].CrossRef Guo Y, Tian X, Wang X, Xiao Z. Adverse effects of immunoglobulin therapy. Front Immunol. 2018;9:1299 [Internet].CrossRef
35.
go back to reference de Gracia J, Vendrell M, Alvarez A, Pallisa E, Rodrigo M-J, de la Rosa D, et al. Immunoglobulin therapy to control lung damage in patients with common variable immunodeficiency. Int Immunopharmacol. 2004;4(6):745–53 [Internet].CrossRef de Gracia J, Vendrell M, Alvarez A, Pallisa E, Rodrigo M-J, de la Rosa D, et al. Immunoglobulin therapy to control lung damage in patients with common variable immunodeficiency. Int Immunopharmacol. 2004;4(6):745–53 [Internet].CrossRef
36.
go back to reference Bonagura VR, Marchlewski R, Cox A, Rosenthal DW. Biologic IgG level in primary immunodeficiency disease: the IgG level that protects against recurrent infection. J Allergy Clin Immunol. 2008;122(1):210–2 [Internet].CrossRef Bonagura VR, Marchlewski R, Cox A, Rosenthal DW. Biologic IgG level in primary immunodeficiency disease: the IgG level that protects against recurrent infection. J Allergy Clin Immunol. 2008;122(1):210–2 [Internet].CrossRef
37.
go back to reference Threapleton CJ, Janjua S, Fortescue R, Baker EH. Head-to-head oral prophylactic antibiotic therapy for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2019;5(5):CD013024 Threapleton CJ, Janjua S, Fortescue R, Baker EH. Head-to-head oral prophylactic antibiotic therapy for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2019;5(5):CD013024
38.
go back to reference Milito C, Pulvirenti F, Cinetto F, Lougaris V, Soresina A, Pecoraro A, et al. Double-blind, placebo-controlled, randomized trial on low-dose azithromycin prophylaxis in patients with primary antibody deficiencies. J Allergy Clin Immunol. 2019;144(2):584–593.e7.CrossRef Milito C, Pulvirenti F, Cinetto F, Lougaris V, Soresina A, Pecoraro A, et al. Double-blind, placebo-controlled, randomized trial on low-dose azithromycin prophylaxis in patients with primary antibody deficiencies. J Allergy Clin Immunol. 2019;144(2):584–593.e7.CrossRef
39.
go back to reference Cosgrove SE, Carmeli Y. The impact of antimicrobial resistance on health and economic outcomes. Clin Infect Dis. 2003;36(11):1433–7. Cosgrove SE, Carmeli Y. The impact of antimicrobial resistance on health and economic outcomes. Clin Infect Dis. 2003;36(11):1433–7.
40.
go back to reference Mohammadinejad P, Ataeinia B, Kaynejad K, Zeinoddini A, Sadeghi B, Hosseini M, et al. Antibiotic resistance in patients with primary immunodeficiency disorders versus immunocompetent patients. Expert Rev Clin Immunol. 2015;11(10):1163–72 [Internet]. Mohammadinejad P, Ataeinia B, Kaynejad K, Zeinoddini A, Sadeghi B, Hosseini M, et al. Antibiotic resistance in patients with primary immunodeficiency disorders versus immunocompetent patients. Expert Rev Clin Immunol. 2015;11(10):1163–72 [Internet].
41.
go back to reference Brown MT, Bussell J, Dutta S, Davis K, Strong S, Mathew S. Medication Adherence: truth and consequences. Am J Med Sci. 2016;351(4):387–99. Brown MT, Bussell J, Dutta S, Davis K, Strong S, Mathew S. Medication Adherence: truth and consequences. Am J Med Sci. 2016;351(4):387–99.
42.
go back to reference Chapel H, Gardulf A. Subcutaneous immunoglobulin replacement therapy: the European experience. Curr Opin Allergy Clin Immunol. 2013;13(6):623–9 [Internet].CrossRef Chapel H, Gardulf A. Subcutaneous immunoglobulin replacement therapy: the European experience. Curr Opin Allergy Clin Immunol. 2013;13(6):623–9 [Internet].CrossRef
Metadata
Title
Immunoglobulin Replacement Therapy Versus Antibiotic Prophylaxis as Treatment for Incomplete Primary Antibody Deficiency
Authors
Bas M. Smits
Ilona Kleine Budde
Esther de Vries
Ineke J. M. ten Berge
Robbert G. M. Bredius
Marcel van Deuren
Jaap T. van Dissel
Pauline M. Ellerbroek
Michiel van der Flier
P. Martin van Hagen
Chris Nieuwhof
Bram Rutgers
Lieke E. A. M. Sanders
Anna Simon
Taco W. Kuijpers
Joris M. van Montfrans
Publication date
01-02-2021
Publisher
Springer US
Published in
Journal of Clinical Immunology / Issue 2/2021
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI
https://doi.org/10.1007/s10875-020-00841-3

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