intravenous immunoglobulin for patients with primary immunodeficiency
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Intravenous immunoglobulin for patients with primary immunodeficiency
Presented by.. Suvanee Charoenlap , MD.
Outlines
• Introduction
• Physiology and pharmacokinetics of IVIG
• Mechanism of actions and indications
• IVIG for patients with primary immunodeficiency
Introduction
Intravenous immunoglobulin (IGIV)
: a highly purified antibody product prepared using pooled plasma from blood or plasma donations.
Endogenous IgG
Bayry J et al. Nat Clin Pract Rheumatol 2007;3(5)262–272
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
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
• 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
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
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
Berger M. Immunol Allergy Clin N Am 2008;28:413-437
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
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
Physiology and pharmacokinetics of IVIG
Serum half-lives of immunoglobulins in healthy adults
Bonilla FA. Immunol Allergy Clin N Am 2008;28:803-819
Pharmacokinetics of synthetic Ig
Intravascular
compartment Extravascular compartment
Catabolism Loss
IVIG SCIG
Bonilla FA. Immunol Allergy Clin N Am 2008;28:803-819
Pharmacokinetics of IVIg
Bonilla FA. Immunol Allergy Clin N Am 2008;28:803-819
Bonilla FA. Immunol Allergy Clin N Am 2008;28:803-819
Bonilla FA. Immunol Allergy Clin N Am 2008;28:803-819
Mechanism of action
Abbas et al. Cellular and Molecular Immunology. 7th edition.
Immunoglobulin
Ballow M. J Allergy Clin Immunol 2011; 127:315–323.
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
Modulating activities of IVIG
Ballow M. Curr Opin Allergy Clin Immunol 2014, 14:509–515
Indication
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
IVIG for primary and secondary immunodeficiency
Orange JS et al. JACI 2006;117:S525-53
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
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
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
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
IVIG for patients with primary immunodeficiency
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
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
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
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
IVIG dosage relates to IgG trough level in Meta-analysis
Orange, J.S., et. al., Clin Immunol 2010, 137:21-30
Relation of IgG trough level to Pneumonia
Orange, J.S., et. al., Clin Immunol 2010, 137:21-30
Bonagura VR, Marchlewski R, Cox A, Rosenthal DW. JACI. 2008;122:201-1.
Adverse Reactions
Acute adverse reactions (during infusion)
Delayed adverse reactions (within 72 hrs)
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
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
Bonilla FA. JACI 2008;122:1238-1239
• ≥ 20% of patients experience adverse effects • severe reactions occur in < 1% of them
Premedications
Bonilla FA.Ann Allergy Asthma Immunol 2005;94:S1-S63
Route
Barlow M. JACI 2008;122(5):1038-1039
Barlow M. JACI 2008;122(5):1038-1039
Product consideration
Safety
Efficacy
Cost
• Formulation : Lyophilized Vs Liquid
• Volume : concentration
• Sodium
• Sugar
• Osmolality
• IgA content
• pH
Product consideration
Gelfand EW. International Immunopharmacology 2006;6:592-599
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
Stabilizer considerations
Stabilizer Cautions
Sorbitol Hereditary fructose intolerance
Maltose Corn allergy
L-proline Hyperprolinemia
Glycine -
Does not increase glucose level in blood
Characteristics of Gammaglobulin Preparations Licensed in the United States
Bonilla FA.Ann Allergy Asthma Immunol 2005;94:S1-S63
Properties of IVIG preparations currently available in the UK
S. Jolles et al.Clinical and Experimental Immunology, 142: 1-11
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
Take home messages
Eight Guiding Principles for Effective Use of IVIG for Patients with Primary Immunodeficiency
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
Thank you
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