Adequate patient's outcome achieved with short immunoglobulin replacement intervals in severe antibody deficiencies

Cinzia Milito, Federica Pulvirenti, Anna Maria Pesce, Maria Anna Digiulio, Franco Pandolfi, Marcella Visentini, Isabella Quinti, Cinzia Milito, Federica Pulvirenti, Anna Maria Pesce, Maria Anna Digiulio, Franco Pandolfi, Marcella Visentini, Isabella Quinti

Abstract

Purpose: The optimal immune globulin replacement dosages required over time to minimize infection risks in patients with Primary Antibody Deficiencies are not definitely established. As with many interventions, there may be specific subgroups of patients who are more likely to benefit from treatment with higher or lower dosages. The aim of the study was to verify the efficacy of a rationale for individualized immune globulin utilization and to elucidate the effects of care on patient outcome.

Methods: Single centre interventional study on 108 patients with Primary Antibody Deficiencies. The objective was to determine for each patient the best interval between immune globulins administration in order to: • Keep IgG trough levels >500 mg/dL, • Minimize of major infections (pneumonias and infections requiring hospitalization), • Minimize of adverse events (AE).

Results: Ninthly eight per cent of patients achieved the objective of the study. Patients who had low switched memory B cells and low IgA serum levels and/or are affected by bronchiectasis and/or enteropathy and/or continued to experience adverse events despite pre-medications, achieved the study objective by shortening the administration intervals to 2-weeks or to 1-week without the need to increase the monthly cumulative immunoglobulin dosage and its relative cost. The adverse events were reduced by administrating low Ig dosages in a single setting. Patients without risk factors achieved the study objective with immune globulin replacement administered with the widely used interval of 3 or 4 weeks.

Conclusions: The exact timing and optimal immunoglobulin prophylaxis regimen might be tailored according to clinical and immunological markers.

Figures

Fig. 1
Fig. 1
Flow chart of the study design. Numbers of patients enrolled in the different arms of the study are shown
Fig. 2
Fig. 2
IgG trough levels and cumulative immune globulin monthly dosages. Cumulative monthly Ig dose (mg/kg/month) administered (a) and serum IgG trough levels (mg/dL) (b) in PAD patients grouped according to the replacement intervals of IVIG administration: 1-week, 2-weeks, 3-weeks, 4-weeks. Statistical differences between groups are shown
Fig. 3
Fig. 3
Immunological phenotype of patients treated at different Ig administration intervals. (a) IgA serum levels; (b) percentages of peripheral blood switched B memory B cells (CD19 + CD27 + IgM-IgD-) in PAD patients grouped according to the replacement intervals of IVIG administration: 1-week, 2-weeks, 3-weeks, 4-weeks. Statistical differences between groups are shown

References

    1. Orange JS, Hossny EM, Weiler CR. 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. 2006;117:S525–53. doi: 10.1016/j.jaci.2006.01.015.
    1. Yong PL, Boyle J, Ballow M. Use of intravenous immunoglobulin and adjunctive therapies in the treatment of primary immunodeficiencies: a working group report of and study by the Primary Immunodeficiency Committee of the American Academy of Allergy Asthma and Immunology. Clin Immunol. 2010;135:255–63. doi: 10.1016/j.clim.2009.10.003.
    1. Notarangelo LD. Primary immunodeficiencies. J Allergy Clin Immunol. 2010;125:S182–94. doi: 10.1016/j.jaci.2009.07.053.
    1. Cunningham-Rundles C, Siegal FP, Smithwick EM. Efficacy of intravenous immunoglobulin in primary humoral immunodeficiency disease. Ann Intern Med. 1984;101:435–9. doi: 10.7326/0003-4819-101-4-435.
    1. Cunningham-Rundles C, Bodian C. Common variable immunodeficiency:
    1. clinical and immunological features of 248 patients. Clin Immunol 1999;92:34–48.
    1. Jolles S, Kaveri SV, Orange J. Intravenous immunoglobulins. Current understanding and future directions. Clin Exp Immunol. 2009;1:68–70. doi: 10.1111/j.1365-2249.2009.04029.x.
    1. Chapel H, Cunningham-Rundles C. Update in understanding common variable immunodeficiency disorders (CVIDs) and the management of patients with these conditions. Br J Haematol. 2009;145:709–27. doi: 10.1111/j.1365-2141.2009.07669.x.
    1. Ochs HD, Fischer SH, Wedgwood RJ. Comparison of high-dose and low-dose intravenous immunoglobulin therapy in patients with primary immunodeficiency diseases. Am J Med. 1984;76:78–82. doi: 10.1016/0002-9343(84)90324-3.
    1. Orange JS, Grossman WJ, Navickis RJ, Wilkes MM. Impact of trough IgG on pneumonia incidence in primary immunodeficiency: a meta-analysis of clinical studies. Clin Immunol. 2010;137:21–30. doi: 10.1016/j.clim.2010.06.012.
    1. Gabriel SE, Normand SL. Getting the methods right–the foundation of patient-centered outcomes research. N Engl J Med. 2012;367:787–90. doi: 10.1056/NEJMp1207437.
    1. 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;122:210–2. doi: 10.1016/j.jaci.2008.04.044.
    1. Lucas M, Hugh-Jones K, Welby A, Misbah S, Spaeth P, Chapel H. Immunomodulatory therapy to achieve maximum efficacy: doses, monitoring, compliance, and self-infusion at home. J Clin Immunol. 2010;30:S84–9. doi: 10.1007/s10875-010-9400-y.
    1. Lucas M, Lee M, Lortan J, Lopez-Granados E, Misbah S, Chapel H. Infection outcomes in patients with common variable immunodeficiency disorders: relationship to immunoglobulin therapy over 22 years. J Allergy Clin Immunol. 2010;125:1354–60. doi: 10.1016/j.jaci.2010.02.040.
    1. Chapel H, Lucas M, Lee M. Common variable immunodeficiency disorders: division into distinct clinical phenotypes. Blood. 2008;112:277–86. doi: 10.1182/blood-2007-11-124545.
    1. Quinti I, Soresina A, Guerra A, Rondelli R, Spadaro G, Agostini C, et al. IPINet Investigators. 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;31:315–22. doi: 10.1007/s10875-011-9511-0.
    1. Cavaliere FM, Milito C, Martini H, Schlesier M, Dräger R, Schütz K, et al. Quantification of IgM and IgA Anti Pneumococcal Capsular Polysaccharides by a New ELISA Assay: a Valuable Diagnostic and Prognostic Tool for Common Variable Immunodeficiency. J Clin Immunol. 2013;33:838–46. doi: 10.1007/s10875-012-9856-z.
    1. Carsetti R, Rosado MM, Donnanno S, Guazzi V, Soresina A, Meini A, et al. The loss of IgM memory B cells correlates with clinical disease in common variable immunodeficiency. J Allergy Clin Immunol. 2005;115:412–7. doi: 10.1016/j.jaci.2004.10.048.
    1. Salzer U, Warnatz K, Peter HH. Common variable immunodeficiency - an update. Arthritis Res Ther. 2012;14:223. doi: 10.1186/ar4032.
    1. Ko J, Radigan L, Cunningham-Rundles C. Immune competence and switched memory B cells in common variable immunodeficiency. Clin Immunol. 2005;116:37. doi: 10.1016/j.clim.2005.03.019.
    1. Warnatz K, Denz A, Drager R, Braun M, Groth C, Wolff-Vorbeck G, et al. Severe deficiency of switched memory B cells (CD27(+)IgM(−)IgD(−)) in subgroups of patients with common variable immunodeficiency: a new approach to classify a heterogeneous disease. Blood. 2002;99:1544–51. doi: 10.1182/blood.V99.5.1544.
    1. Conley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies) Clin Immunol. 1999;93:190–7. doi: 10.1006/clim.1999.4799.
    1. Andersen P, Permin H, Andersen V, Schejbel L, Garred P, Svejgaard A, et al. Deficiency of somatic hypermutation of the antibody light chain is associated with increased frequency of severe respiratory tract infection in common variable immunodeficiency. Blood. 2005;105:511–7. doi: 10.1182/blood-2003-12-4359.
    1. 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. 2013;109:1001–4. doi: 10.1067/mai.2002.124999.
    1. Wehr C, Kivioja T, Schmitt C, Ferry B, Witte T, Eren E, et al. The EUROclass trial: defining subgroups in common variable immunodeficiency. Blood. 2008;11:77–85. doi: 10.1182/blood-2007-06-091744.
    1. Gelfand EW, Ochs HD, Shearer WT. Controversies in IgG replacement therapy in patients with antibody deficiency diseases. J Allergy Clin Immunol. 2013;131:1001–5. doi: 10.1016/j.jaci.2013.02.028.
    1. Schroeder HW, Jr, Dougherty CJ. Review of intravenous immunoglobulin replacement therapy trials for primary humoral immunodeficiency patients. Infection. 2012;40:601–11. doi: 10.1007/s15010-012-0323-9.
    1. Mikolajczyk MG, Concepcion NF, Wang T, Frazier D, Golding B, Frasch CE. Scott DE Characterization of antibodies to capsular polysaccharide antigens of Haemophilus influenzae type b and Streptococcus pneumoniae in human immune globulin intravenous preparations. Clin Diagn Lab Immunol. 2004;11:1158–64.
    1. Hagan JB, Fasano MB, Spector S. Efficacy and safety of a new 20 % immunoglobulin preparation for subcutaneous administration, IgPro20, in patients with primary immunodeficiency. J Clin Immunol. 2010;30:734–45. doi: 10.1007/s10875-010-9423-4.
    1. Kaveri SV, Maddur MS, Hegde P, Lacroix-Desmazes S, Bayry J. Intravenous immunoglobulins in immunodeficiencies: more than mere replacement therapy. Clin Exp Immunol. 2011;164:2–5. doi: 10.1111/j.1365-2249.2011.04387.x.
    1. Durandy A, Kaveri SV, Kuijpers TW. Intravenous immunoglobulins understanding properties and mechanisms. Clin Exp Immunol 2009;158:2–13.
    1. Ballow M. The IgG molecule as a biological immune response modifier: mechanisms of action of intravenous immune serum globulin in autoimmune and inflammatory disorders. J Allergy Clin Immunol. 2013;127:315,323.
    1. Francisco A. Bonilla Intravenous immunoglobulin: adverse reactions and management. J Allergy Clin Immunol. 2013;122:1238–9.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅