Immunoglobulin therapy

1. IMMUNOGLOBULIN
THERAPY
Mathurange Krishnapillai
MBBS, DTM, MD TM

2. What is it?
How do we prepare it?
How does it work?
Where do we use it?
Problems?

3.  IVIG contains pooled immunoglobulin G (IgG) immunoglobulins from plasma of
approximately a thousand or more blood donors.
 Primarily IgG, with only trace amounts of IgA and IgM; IgA concentrations
vary between products
 may contain cytokines and other molecules including soluble cytokine
inhibitors, soluble CD4 and major histocompatibility complex (MHC) class
II. Stabilizing agents, mainly various sugars (maltose and sucrose) also
present.

4. Two routes:
 Intravenous - for immunomodulation and for giving higher doses of IgG
and for some children/young people on long-term replacement. Usually
best option for patients with a central line in situ.
Currently available preparations of IVIG are available as 5% (5 g/100 mL) or 10% (10
g/100 mL) solutions
 Subcutaneous - suitable for IgG replacement and ideal in younger
children with poor venous access.
Three of the products approved by the FDA for SC administration in PIDD (all 10% IG)
also have approval for IV administration. One SCIG product approved solely for SC
administration (20% IG)
(Use with caution if patient has low platelets, but it is not contraindicated.
The risk of adverse reactions is also reduced compared with IVIg.)

5. Subcutaneous immunoglobulins
 Slow s.c. immunoglobulin (SCIg) infusions using
portable syringe drivers were introduced in the United
States in 1980,
 The infusions were time-consuming and the volume
that could be administered in a single infusion was still
limited.
 SCIg administration method has been developed
further and was reintroduced in 1991 as rapid SCIg
therapy (20 ml/h/pump) , This method has become
standard practice for replacement therapy in many
countries.

8.  ‘Replacement dose’ - 200–400 mg/kg body weight,
given approximately 3-weekly- immune deficiency
disorders
 ‘High dose’ IVIG (hd IVIG)- Autoimmune and
inflammatory disorders- standard immunomodulatory
dose of 2 g/kg is usually divided into five daily infusions
of 0.4 g/kg
patients in whom responses last <6 weeks may need 1 g/kg infusions once
every 3 weeks; those patients with responses lasting 6–8 weeks need
approximately 0.5g/kg infusions every 3 weeks; and those patients with
longer-lasting responses can be given 0.25 g/kg infusions every 3 weeks.

9. Duration of immunoglobulin treatment
 Short-term treatment
▪ Three prescribed doses of up to 2 g/kg, given at appropriate clinical
intervals
▪ ≤3 months
 Long-term treatment
▪ ≥3 months
▪ Treatment reviews should be conducted annually.

10. Body weight-adjusted dose
 Calculate ideal body weight (IBW) (kg):
IBW for males = 50 + [2.3 x (height in inches - 60)]
IBW for female = 45.5 + [2.3 x (height in inches - 60)]
 Calculate dose-determining weight (DDW) (kg):
DDW = IBW + 0.4 [actual body weight (kg) – IBW]
Use DDW for calculating the IVIg dose required

11. Indications for immunoglobulin therapy
 Primary antibody deficiency and other complex immune
deficiency disorders, to prevent life-threatening
infections.
Eg: Severe combined immunodeficiency
Common variable immunodeficiency
 As supportive therapy for secondary immunodeficiency
where extrinsic factors such as chemotherapy cause
damage to the immune system
Eg: following stem cell transplantation where
immunoglobulin levels remain low

12. shown to be effective in a wide range of diseases
where 'modulation' of the immune system is
required, although the mechanism of action is not
well understood.
Anecdotal evidence for the use of immunoglobulin
in autoimmune disease, and some other conditions,
although these are unlicensed at present.

13. Indications
Red and Blue categories! (NHS-UK)
RED→ Adequate evidence based; potentially life saving
(treatment is considered the highest priority because of a risk
to life without treatment)
BLUE→ A reasonable evidence based but other treatment
options are available
Grey →diseases for which the evidence is weak, in many cases
because the disease is rare.

14. High-priority (‘red’) indications for intravenous
immunoglobulin – an adequate evidence based and
potentially life-saving
‘Blue’ indications for intravenous immunoglobulin – a
reasonable evidence based but other treatment options are
available
Primary and secondary
antibody deficiency states
Secondary antibody deficiency (any cause)
Haematology Acquired red cell aplasia
Autoimmune haemolytic anaemia
Clotting factor inhibitors
Haemophagocytic syndrome
Post-transfusion purpura
Neurology Chronic inflammatory demyelinating
polyradiculoneuropathy (chronic)
Inflammatory myelopathies
Myasthenia gravis
Multifocal motor neuropathy
Rasmussen syndrome
Stiff person syndrome
Others Autoimmune congenital heart block
Autoimmune uveitis
Immunobullous diseases
Necrotising staphylococcal sepsis
Severe or recurrent Clostridium difficile colitis
Staphylococcal or streptococcal toxic shock
syndrome
Antibody-mediated rejection after solid organ
transplantation
Primary and secondary antibody
deficiency states
Primary immunodeficiencies
Thymoma with immunodeficiency
HSC transplant in primary
immunodeficiencies
Specific antibody deficiency
Haematology Alloimmune thrombocytopenia
(feto-maternal/neonatal)
Haemolytic disease of the
newborn
Idiopathic thrombocytopenic
purpura (ITP) – acute and
persistent
Neurology Chronic inflammatory
demyelinating
polyradiculoneuropathy (acute)
Guillain–Barré syndrome
Paraprotein-associated
demyelinating neuropathy
Others Kawasaki disease
Toxic epidermal necrolysis

15. Condition Short
duration
Long
duration
Primary and secondary immunodeficiency states
Primary immunodeficiencies
Thymoma with immunodeficiency
HSCT in primary immunodeficiencies
Specific antibody deficiency
Secondary antibody deficiency

16. Haematology Short
duration
Long
duration
Acquired red cell aplasia
Allo immune thrombocytopenia (Feto
maternal/neonatal)
Auto immune haemolytic anaemia
Coagulation factor inhibitors
Haemolytic disease of the newborn
ITP (Acute and persistent)
PTP

17. Neurology Short
duration
Long
duration
Chronic inflammatory demyelinating
radiculoneuropathy
Guillian- Barre Syndrome
Inflammatory myopathies
Myasthenia gravis
Multi focal moto neuropathy
Paraprotein associated demyelinating neuropathy
Rasmussen syndrome

18. Others Short
duration
Long
duration
Autoimmune congenital heart block
Autoimmune uvetis
Immunobullous disease
Kawasaki disease
Necrotising staphylococcal sepsis
Steven Johnsons Syndrome
Transplantation (Solid organ)

19. ITP
Blockade of macrophage Fc receptors is considered the
primary mechanism of action of immunoglobulin.
Goal of treatment is to achieve a platelet count that is
associated with adequate haemostasis, rather than a
“normal” platelet count.
IVIg is only recommended in children with moderate-to-
severe symptomatic ITP (e.g. overt mucosal bleeding, or
suspected internal bleeding), or prior to procedures likely
to induce bleeding

20. Acquired hemophilia due to autoantibodies
against factor Vlll
IVIg is only recommended for patients with acquired
haemophilia with life or limb threatening haemorrhage who
have not responded to other treatments.

21. Haemolytic disease of the foetus and newborn
(isoimmune haemolytic jaundice in neonates)
 The aim of therapy is to avoid bilirubin encephalopathy, which
causes kernicterus and has devastating effects.
 IVIg significantly reduced the need for exchange transfusion in
neonates with HDN.
 Use immunoglobulin (0.5 g/kg over 4 hours) as an adjunct to
continuous multiple phototherapy in cases of Rhesus haemolytic
disease or ABO haemolytic disease.

22. Kawasaki disease and dermatomyositis
 Inhibit the generation of membrane attack complexes (C5b-C9) and
subsequent complement-mediated tissue damage by binding the
activated components C3b and C4b, thus preventing their deposition on
target surfaces.
 In persons with dermatomyositis, IVIG induces a decrease in plasma levels
of membrane attack complex and a substantial decrease in the amounts
of C3b and membrane attack complex deposited in endomysial
capillaries.

23. Adverse reactions to immunoglobulin
therapy
Mild Reactions:
 Flushing, headache, mild changes in heart rate or
blood pressure.
 These types of reaction may be rate dependent
and may respond to a reduction in the rate of
infusion.
 Closely observe the patient and reduce the rate of
infusion

24. Moderate to Severe Reactions:
 Haemolysis
IVIg contains blood group antibodies which may act as haemolysins
and coat red cells with immunoglobulin.
This may result in a positive direct antiglobulin test and occasionally
haemolytic anaemia
 Thromboembolic events
Infusion of IVIg may lead to a relative increase in blood viscosity.
Patients should be adequately hydrated prior to commencement of
the infusion.
IVIg should NOT be infused rapidly to patients at increased risk of
thromboembolic and renal adverse events, particularly when using
the higher concentration IVIg products.

25.  Renal impairment
patients receiving IVIg have an increased risk of
renal failure or dysfunction.
Assess renal function prior to product
commencement.
 Aseptic meningitis syndrome
Has been reported to occur after IVIg treatment
 Anaphylaxis is a rare ( documented adverse effect)
In IgA deficient patients, product with the lowest
level of IgA should be selected.

26. References
1. Clinical uses of intravenous immunoglobulin
2. Subcutaneous immunoglobulin therapy: a new option for patients with
primary immunodeficiency diseases
3. Clinical guidelines for immunoglobulin use- July 2011 (NHS-UK)
4. Clinical applications of intravenous immunoglobulins (IVIg) – beyond
immunodeficiencies and neurology

27. Thank you!