Intravenous immunoglobulin (IVIG) is prepared from pooled human plasma and contains concentrated IgG antibodies. It is used to treat primary immunodeficiencies in patients who do not produce sufficient antibodies. IVIG is administered monthly at a dose of 300-600 mg/kg to maintain protective IgG trough levels. The dosage may be increased or decreased based on the patient's clinical response and infection history. IVIG treatment requires monitoring for efficacy and adverse reactions. The appropriate IVIG product and administration method depends on the individual patient's diagnosis, medical history, and tolerability.

1. Intravenous immunoglobulin for
patients with primary immunodeficiency
Presented by.. Suvanee Charoenlap , MD.

2. Outlines
• Introduction
• Physiology and pharmacokinetics of IVIG
• Mechanism of actions and indications
• IVIG for patients with primary
immunodeficiency

3. Introduction
Intravenous immunoglobulin (IGIV)
: a highly purified antibody product prepared
using pooled plasma from blood or plasma
donations.

4. Endogenous IgG
Bayry J et al. Nat Clin Pract Rheumatol 2007;3(5)262–272

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. 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. • 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. 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. 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. Berger M. Immunol Allergy Clin N Am 2008;28:413-437

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. 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. Physiology and pharmacokinetics
of IVIG

14. Serum half-lives of immunoglobulins
in healthy adults
Bonilla FA. Immunol Allergy Clin N Am 2008;28:803-819

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. Pharmacokinetics of IVIg
Bonilla FA. Immunol Allergy Clin N Am 2008;28:803-819

18. Bonilla FA. Immunol Allergy Clin N Am 2008;28:803-819

19. Bonilla FA. Immunol Allergy Clin N Am 2008;28:803-819

20. Mechanism of action

21. Abbas et al. Cellular and Molecular Immunology. 7th edition.
Immunoglobulin

22. Ballow M. J Allergy Clin Immunol 2011; 127:315–323.

23. 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

24. Modulating activities of IVIG
Ballow M. Curr Opin Allergy Clin Immunol 2014, 14:509–515

25. Indication

26. 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

27. IVIG for primary and secondary immunodeficiency
Orange JS et al. JACI 2006;117:S525-53

28. 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

29. 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

30. 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

31. 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

32. IVIG for patients with
primary immunodeficiency

33. 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

34. 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

35. 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

36. 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

37. IVIG dosage relates to IgG trough level
in Meta-analysis
Orange, J.S., et. al., Clin Immunol 2010, 137:21-30

38. Relation of IgG trough level to Pneumonia
Orange, J.S., et. al., Clin Immunol 2010, 137:21-30

39. Bonagura VR, Marchlewski R, Cox A, Rosenthal DW. JACI. 2008;122:201-1.

40. Adverse Reactions
Acute adverse reactions (during infusion)
Delayed adverse reactions (within 72 hrs)

41. 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

42. 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

43. Bonilla FA. JACI 2008;122:1238-1239
• ≥ 20% of patients experience adverse effects
• severe reactions occur in < 1% of them

44. Premedications
Bonilla FA.Ann Allergy Asthma Immunol 2005;94:S1-S63

45. Route
Barlow M. JACI 2008;122(5):1038-1039

46. Barlow M. JACI 2008;122(5):1038-1039

47. Product consideration
Safety Efficacy Cost

48. • Formulation : Lyophilized Vs Liquid
• Volume : concentration
• Sodium
• Sugar
• Osmolality
• IgA content
• pH
Product consideration

49. Gelfand EW. International Immunopharmacology 2006;6:592-599

50. 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

51. Stabilizer considerations
Stabilizer Cautions
Sorbitol Hereditary fructose intolerance
Maltose Corn allergy
L-proline Hyperprolinemia
Glycine -
Does not increase glucose level in blood

52. Characteristics of Gammaglobulin Preparations
Licensed in the United States
Bonilla FA.Ann Allergy Asthma Immunol 2005;94:S1-S63

53. Properties of IVIG preparations
currently available in the UK
S. Jolles et al.Clinical and Experimental Immunology, 142: 1-11

54. 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

55. Take home messages

56. Eight Guiding Principles for
Effective Use of IVIG for Patients
with Primary Immunodeficiency

57. 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

58. Thank you