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Intravenous immunoglobulin for patients with primary immunodeficiency

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Intravenous immunoglobulin for patients with primary immunodeficiency

Presented by Suvanee Charoenlap, MD.

Published in: Health & Medicine

Intravenous immunoglobulin for patients with primary immunodeficiency

  1. 1. Intravenous immunoglobulin for patients with primary immunodeficiency Presented by.. Suvanee Charoenlap , MD.
  2. 2. Outlines • Introduction • Physiology and pharmacokinetics of IVIG • Mechanism of actions and indications • IVIG for patients with primary immunodeficiency
  3. 3. Introduction Intravenous immunoglobulin (IGIV) : a highly purified antibody product prepared using pooled plasma from blood or plasma donations.
  4. 4. Endogenous IgG Bayry J et al. Nat Clin Pract Rheumatol 2007;3(5)262–272
  5. 5. Exogenous IgG: commercial preparations of IGIV • Derived from human plasma : whole blood donors or plasmapheresis • Plasma pools range from 4000 L to > 50,000 L • Required 1000 donors/lot (WHO original guidelines) • Vary from normal endogenous IgG – The actual percentage of IgG – different amounts of other proteins and immunoglobulins – Fc integrity and function – various excipients Martin TD. International Immunopharmacology 2006;6:517-522
  6. 6. Properties of intravenous immunoglobulin • Composition – > 98% immunoglobulin G (IgG) – > 90% monomeric IgG – Traces of other immunoglobulins and serum proteins – Addition of sugar, amino acids, or albumin stabilizes IgG from aggregation Mark Ballow, Clinical immunology principle and practice; third edition: 1265 - 1280
  7. 7. • Intact Fc receptor important for biological function – Opsonization and phagocytosis – Complement activation – Antibody-dependent cytotoxicity • Normal half-life comparable to serum IgG • Normal proportion of IgG subclasses • Broad spectrum of antibodies to bacterial and viral agents Properties of intravenous immunoglobulin Mark Ballow, Clinical immunology principle and practice; third edition: 1265 - 1280
  8. 8. Plasma Fractionation Purification Stabilization Pathogen removal and inactivation IVIG Donor screening: Hx, PE, CBC, LFT Donor plasma testing : HIV-p24 Ag, HBsAg, and Ab to syphilis, HIV-1, HIV-2, HCV Inventory hold at least 60 days Formulation and composition
  9. 9. Pathogen removal and inactivation • Nanofiltration/ antibody-enhanced nanofiltration • Solvent Detergent(S/D) treatment • Low pH/elevated temperature incubation • Vapour heat treatment • Pasteurization • Chromatography • Cohn fractionation • TSE (prion) removal
  10. 10. Berger M. Immunol Allergy Clin N Am 2008;28:413-437
  11. 11. Current quality control measures for therapeutic IVIg Characteristics QC measure Specifications Physical properties Appearance Clear, no particles pH 4–6, as specified by the manufacturer Osmolality ≥240 mosmol/kg Excipients Should be mentioned in the product label Chemical properties Total protein concentration γ-globulin content Immune aggregates Human origin identity test ≥30 g/l ≥95% ≤3% Positive Viral inactivation components Tri-n-butyl phosphate Polysorbate-80 Permissible level 10 μg/ml Permissible level 100 μg/ml M. Radosevich & T. Burnouf, Vox Sanguinis (2010) 98, 12–28
  12. 12. Current quality control measures for therapeutic IVIg Characteristics QC measure Specifications Protein contaminants Anti-A and anti-B* Negative at HA titer of 1:64 (3% protein preparation) Prekallikrein activator ≤3.5 IU/ml (3% protein preparation) Total hemolytic complement levels ≤1 CH50 per mg of IgG Viral marker tests HBsAg, HIV p24 antigen, anti-HIV-1 antibodies, anti-HIV-2 antibodies and anti-HCV antibodies All negative Safety tests Bacterial sterility test Endotoxin assay Sterile <0.5 IU/ml (5% protein preparation) M. Radosevich & T. Burnouf, Vox Sanguinis (2010) 98, 12–28
  13. 13. Physiology and pharmacokinetics of IVIG
  14. 14. Serum half-lives of immunoglobulins in healthy adults Bonilla FA. Immunol Allergy Clin N Am 2008;28:803-819
  15. 15. Pharmacokinetics of synthetic Ig Intravascular compartment Extravascular compartment Catabolism Loss IVIG SCIG Bonilla FA. Immunol Allergy Clin N Am 2008;28:803-819
  16. 16. Pharmacokinetics of IVIg Bonilla FA. Immunol Allergy Clin N Am 2008;28:803-819
  17. 17. Bonilla FA. Immunol Allergy Clin N Am 2008;28:803-819
  18. 18. Bonilla FA. Immunol Allergy Clin N Am 2008;28:803-819
  19. 19. Mechanism of action
  20. 20. Abbas et al. Cellular and Molecular Immunology. 7th edition. Immunoglobulin
  21. 21. Ballow M. J Allergy Clin Immunol 2011; 127:315–323.
  22. 22. Innate immunity • blockade of Fc receptors on macrophages of RE system • restoration of idiotypic-antiidiotypic network • neutralization of cytokines • block binding of adhesion molecules on leukocytes to vascular endothelium • inhibit complement uptake • neutralize microbial toxins • block Fas ligand-mediated apoptosis • induce apoptosis with anti-Fas antibodies • neutrophil apoptosis • saturate the FcRn receptors • induction of inhibitory FcγRIIB receptors on effector macrophages Adaptive immunity • neutralization of growth factors for B-cells ( B-cell activating factor) • inhibit T-cell proliferative responses • expand and/or activating a population of Treg cells • downregulate the Th17 pathway • inhibit the differentiation and maturation of dendritic cells
  23. 23. Modulating activities of IVIG Ballow M. Curr Opin Allergy Clin Immunol 2014, 14:509–515
  24. 24. Indication
  25. 25. 6 clinical indications in the USA with For FDA approval 1. Treatment of primary immunodeficiencies. 2. Prevention of bacterial infections in patients with hypogammaglobulinaemia and recurrent infection caused by B-cell chronic lymphocytic leukaemia. 3. Prevention of coronary artery aneurysms in Kawasaki disease. 4. Prevention of infections, pneumonia and acute graft versus host disease (GVHD) after bone marrow transplantation. 5. Reduction of serious bacterial infection in children with HIV. 6. Increase of platelet count in ITP to prevent or control bleeding. Orange JS et al. JACI 2006;117:S525-53
  26. 26. IVIG for primary and secondary immunodeficiency Orange JS et al. JACI 2006;117:S525-53
  27. 27. Immunoglobulin replacement is indicated for all patients with the following diagnoses • Severe combined immunodeficiency • X-linked or autosomal recessive agammaglobulinemia • Common variable immunodeficiency • Other combined immunodeficiencies with a significant hypogammaglobulinemia or antibody production defect including but not limited to the following: 1. Wiskott-Aldrich syndrome 2. CD40 ligand deficiency (X-linked hyper-IgM syndrome) 3. Nuclear factor of B essential modifier deficiency 4. Ataxia-telangiectasia 5. DiGeorge syndrome Bonilla FA. Ann Allergy Asthma Immunol 2005;94:S1-S63
  28. 28. Possible mechanisms of action of intravenous immunoglobulin (IVlG) in primary immunodeficiency S. V. Kaveri et al. Clinical and Experimental Immunology,164 (Suppl. 2), 2–5
  29. 29. Uses of IVIG in other diseases Group Diseases Neurology Guillain Barre syndrome, Chronic inflammatory demyelinating polyradiculopathy (CIDP), Dermatomyositis and inflammatory myopathies, Myasthenia gravis, rare childhood epilepsy (Lennox gastaut seizure, Landau kleffner seizure), Opsoclonus myoclonus ataxia, PANDAS (Paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection) OCD, anxiety, depression, emotional lability Haematology ITP, Pure red cell aplasia, Pure white cell aplasia, Immune neutropenia, Immune haemolytic anemia. Orange JS et al. JACI 2006;117:S525-53
  30. 30. Uses of IVIG in other diseases Group Diseases Dermatology Dermatomyositis, Toxic epidermal necrolysis, Blistering diseases, Immune urticaria, Atopic dermatitis, Pyoderma gangrenosum Neonatology Haemolytic disease of newborn due to Rh and ABO incompatibility, Neonatal alloimmune thrombocytopenic purpura, Bacterial sepsis in preterms Others Myocarditis, Systemic lupus erythematosus, Streptococcal toxic shock syndrome, Autoimmune uveitis Orange JS et al. JACI 2006;117:S525-53
  31. 31. IVIG for patients with primary immunodeficiency
  32. 32. Dosing guidelines : IVIG •Agammaglobulinemia or •Severe hypogammaglobulinemia  Loading dose 1 g/kg IV •Dose - 300-400 mg/kg every 3 weeks (maximum 600 mg/kg) - 400-500 mg/kg every 4 weeks (maximum 800 mg/kg) •Interval : 2-4 weeks Bonilla FA.Ann Allergy Asthma Immunol 2005;94:S1-S63
  33. 33. Dosing guidelines : IVIG • High catabolism or more frequent infections : Infusions every 2 to 3 weeks at lower dose • Active infection – Dose should be halved to 200-300 mg/kg – Repeated dose 2 weeks later to achieve a full dose Barlow M. JACI 2008;122(5):1038-1039
  34. 34. Start • 0.01 ml/kg/minute • (0.5 mg/kg/min of 5% solution) Increase • double rate at 15-30 minutes interval Maximum • 0.08 ml/kg/minute • (4 mg/kg/min of 5% solution) • or up to maximum tolerated rate IVIG infusion rate Monitor: Vital signs and patient’s condition before and 5-10 minutes after each rate change Berger M. Immunol Allergy Clin N Am 2008;28:413-437
  35. 35. Monitoring therapy Berger M. Immunol Allergy Clin N Am 2008;28:413-437 Adequate dose ? Control of infection and complication of underlying disease Complication of therapy q 6-12 mo. - CBC -LFT -BUN/Cr -UA -Test for bloodborne disease Measurement of trough serum IgG levels • every 3 months until a steady-state is achieved • then every 6 months if the patients is stable
  36. 36. IVIG dosage relates to IgG trough level in Meta-analysis Orange, J.S., et. al., Clin Immunol 2010, 137:21-30
  37. 37. Relation of IgG trough level to Pneumonia Orange, J.S., et. al., Clin Immunol 2010, 137:21-30
  38. 38. Bonagura VR, Marchlewski R, Cox A, Rosenthal DW. JACI. 2008;122:201-1.
  39. 39. Adverse Reactions Acute adverse reactions (during infusion) Delayed adverse reactions (within 72 hrs)
  40. 40. Severity Clinical Interventions Mild headache, malaise, fatigue, flushing, pruritus • slow infusion • antihistamines and NSAIDs Moderate severe headache, dizziness or nausea, vomiting, myalgia, arthralgia, back pain, urticaria • stop infusion • antihistamines and NSAIDs • Consider steroids Severe altered mental status, hypotension, bronchospasm, anaphylaxis. • stop infusion • epinephrine, antihistamines, steroids • supportive care or resuscitation Acute adverse reactions (during infusion) Bonilla FA.Ann Allergy Asthma Immunol 2005;94:S1-S63
  41. 41. Severity Clinical Interventions Mild headache, malaise, fatigue, flushing, pruritus • antihistamines and NSAIDs Moderate to Severe severe headache, dizziness or nausea, vomiting, myalgia, arthralgia, back pain, urticaria, aseptic meningitis syndrome. • antihistamines and NSAIDs • antimigraine medications • Consider steroids Delayed adverse reactions (within 72 hrs) Bonilla FA.Ann Allergy Asthma Immunol 2005;94:S1-S63
  42. 42. Bonilla FA. JACI 2008;122:1238-1239 • ≥ 20% of patients experience adverse effects • severe reactions occur in < 1% of them
  43. 43. Premedications Bonilla FA.Ann Allergy Asthma Immunol 2005;94:S1-S63
  44. 44. Route Barlow M. JACI 2008;122(5):1038-1039
  45. 45. Barlow M. JACI 2008;122(5):1038-1039
  46. 46. Product consideration Safety Efficacy Cost
  47. 47. • Formulation : Lyophilized Vs Liquid • Volume : concentration • Sodium • Sugar • Osmolality • IgA content • pH Product consideration
  48. 48. Gelfand EW. International Immunopharmacology 2006;6:592-599
  49. 49. Age consideration Neonatal patients pH concerns: -local phlebitis -Met. Acidosis Limit volume infusion Geriatric patients Cardiac, Renal, Pulmonary insufficiency Sodium, Sugar and osmolar load Sodium, Sugar and osmolar load
  50. 50. Stabilizer considerations Stabilizer Cautions Sorbitol Hereditary fructose intolerance Maltose Corn allergy L-proline Hyperprolinemia Glycine - Does not increase glucose level in blood
  51. 51. Characteristics of Gammaglobulin Preparations Licensed in the United States Bonilla FA.Ann Allergy Asthma Immunol 2005;94:S1-S63
  52. 52. Properties of IVIG preparations currently available in the UK S. Jolles et al.Clinical and Experimental Immunology, 142: 1-11
  53. 53. Flebogamma Gammaraas Liv-gamma Formulation 5% liquid 5% liquid 5% liquid Sodium content < 0.032 NA NA Stabilizer D-sorbitol D-sorbitol Maltose Osmolality (mosm/kg) 240-350 300 >240 IgG (g/L) >99% >98.5% > 95% IgM (g/L) N.A. < 0.12 NA IgA (g/L) < 0.05 < 0.07 NA pH 5-6 3.8-4.4 4.0-7.4 Refrigeration 2-25°c 2-8°c 2-8°c Plasma holding (days) 60 60 60 HIV PCR PCR ELISA HBV PCR PCR ELISA HCV PCR PCR PCR Viral inactivation /removal Pasteurization, PEG Nanofiltration Nanofiltration
  54. 54. Take home messages
  55. 55. Eight Guiding Principles for Effective Use of IVIG for Patients with Primary Immunodeficiency
  56. 56. Eight Guiding Principles for Effective Use of IVIG for Patients with Primary Immunodeficiency 1. Indication 2. Diagnoses 3. Frequency of IVIG treatment 4. Dose 5. IgG trough levels 6. Site of care 7. Route 8. Product
  57. 57. Thank you

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