The Use of IVIG

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Best Practice & Research Clinical Haematology

Volume 19, Issue 1 , March 2006, Pages 3-25

Clinical Use of Plasma and Plasma Fractions

This Document

doi:10.1016/j.beha.2005.01.032

Copyright © 2005 Elsevier Ltd All rights reserved.

1

Use of intravenous immunoglobulin G (IVIG)

R. Looney MD, , Professor of Medicine and Huggins MD,

Fellow

Department of Medicine, Allergy, Immunology, Rheumatology Unit,

School of Medicine and Dentistry, University of Rochester, 595

Elmwood Ave, Room G-6454, Rochester, NY 14642, USA

Available online 23 December 2005.

Intravenous immunoglobulin G (IVIG) has become increasingly important

both as replacement therapy in primary and acquired humoral

immunodeficiency and as an immunomodulatory therapy in autoimmune

disease and transplantation. Multiple potential mechanisms for the

effects of IVIG have now been recognized but the contribution of each

mechanism in different diseases is uncertain. IVIG is generally well

tolerated but serious side effects can occur and need to be

addressed. IVIG has Food and Drug Administration (FDA) approval for a

half dozen indications but these account for only about half the use

of IVIG. This chapter reviews the development of IVIG for primary

immunodeficiency, the evidence for efficacy of IVIG in autoimmune and

inflammatory conditions, the risks associated with administration of

IVIG, and steps that can be taken to minimize adverse events.

Key words: allogenic bone marrow transplant; B cell-chronic

lymphocytic leukemia (CLL); blistering skin disease; chronic

inflammatory demyelinating polyneuropathy; Guillian–Barré syndrome;

immunodeficiency; ITP; IVIG; Kawasaki disease; pediatric HIV; toxic

epidermal necrolysis

Article Outline

History

Pharmacokinetics of IgG

Preparations and administration of IVIG

Adverse events

Infusion reaction

IgA deficiency

Aseptic meningitis

Renal failure

Cardiovascular events

Transmission of infectious agents

Donor selection

Testing of donor plasma

Viral removal and inactivation

Other adverse events

Inhibition of immune responses

Indications

Replacement therapy in primary humoral immunodeficiency

Replacement therapy in secondary humoral immunodeficiency

Immunomodulatory effects of IVIG were first demonstrated in immune

thrombocytopenic purpura

Kawasaki disease

Neurological disease

Skin disease

Rheumatological disease

Infections

References

History

In 1950, Bruton (who was working at the Walter Army Hospital)

described a young boy suffering from recurrent sepsis who was found

to have agammaglobulinemia.1 After an initial subcutaneous injection

of immune human serum globulin (Squibb) resulted in an increase in

serum gammaglobulin from 0 to 4.6%, the patient was treated with

monthly injections and the occurrence of sepsis decreased from 19

episodes over 4 years to zero episodes over 14 months. As a result of

this successful treatment, immunoglobulin administration became the

standard of care for patients with hypogammaglobulinemia. With the

development of intravenous preparations of immunoglobulin, larger

volumes could be administered, allowing near normalization of serum

immunoglobulin levels.

The use of intravenous immunoglobulin G (IVIG) to treat autoimmunity

began after Imbach observed that IVIG administered to two patients

for agammaglobulinemia also improved their coexisiting

thrombocytopenia. In 1981, Imbach reported a series of seven children

with chronic or intermittent idiopathic thrombocytopenia purpura

(ITP) and six patients with acute ITP, whom he treated with five

consecutive days of IVIG at 0.4 mg/kg. All of these patients

experienced a dramatic initial response, with a platelet count

increase from <30 000 to >150 000 platelets/ & #956;L.2 The proposed

mechanism for this dramatic platelet count response to IVIG treatment

was `overloading and blocking the reticuloendothelial system by IgG

catabolism'. The success of IVIG in ITP led to its use in a large

number of autoimmune and inflammatory conditions.

Pharmacokinetics of IgG

The serum half-life of IgG is 23 days, which is much longer than for

IgM (5 days) and IgA (7 days). In the early 1960s, Brambell and

colleagues proposed that for IgG to have such a long half-life there

must be a receptor that binds IgG and prevents its catabolism (the

Brambell hypothesis).3 Furthermore, they proposed that, with low

levels of IgG there would be less competition for binding to the

protective receptor (FcRp) and the half-life of IgG would be longer;

with high levels of IgG there would be more competition for FcRp and

the half-life for IgG would be shorter. Further studies by Brambell

demonstrated that FcRn, the gut Fc receptor responsible for transport

of maternal immunoglobulin from ingested milk to the systemic

circulation, had characteristics similar to those hypothesized for

FcRp. In 1996 two groups simultaneously established that FcRp and

FcRn are the same receptor.4 and 5 We now know that the long serum

half-life of IgG is attributed to this neonatal Fc receptor, named

FcRn, which is composed of a MHC class I-related protein and a & #946;2-

microgloblin.

Practice points

• infusion reactions are caused by aggregates

• patients with hypogammaglobulinemia have more frequent and more

severe infusion reactions

• infusion reactions can be prevented by slowing the rate of infusion

and/or premedicating with steroids

• patients with IgA deficiency are at increased risk for infusion

reactions

• IgG anti-IgA antibodies are the most likely cause of these reactions

• IgE anti-IgA antibodies have been found in these patients but it is

not clear how often they are clinically important

• IVIG with low amounts of IgA (a few & #956;g/mL) can often be tolerated

by patients having infusion reactions due to IgG anti-IgA

• aseptic meningitis is more frequent with rapid infusion of high-

dose IVIG

• pre-medication with steroids may prevent these reactions

• thromboembolic events can be precipitated by IVIG

• patients already at risk for thromboembolic disease are the high-

risk group

• high-risk patients should be well hydration and their infusion

rates should be slow

• prophylaxis with low-dose aspirin or low molecular weight heparin

might be considered

• transmission of infectious agents is rare but continues to be a

concern as new infections emerge in the donor populations

• IVIG is the standard of treatment from primary immunodeficiencies

• home infusion and/or subcutaneous infusion are attractive options

for stable patients

• the dose and frequency of IVIG needs to be individualized

• IVIG may be useful in secondary humoral immunodeficiency makes but

the evidence for efficacy is nowhere as strong as in primary

immunodeficiency

• IVIG is an important and effective therapy for ITP but other

treatments are also effective

• in ITP, IVIG is most appropriate for short-term use in severe

disease or in preparation for a procedure

• a single dose of IVIG at 2 g/kg is the treatment of choice for

Kawasaki disease

• the evidence for effectiveness of IVIG is strongest for Guillain–

Barré syndrome and CIDP, but other therapies are also effective for

these conditions

• IVIG might have efficacy in multifocal motor neuropathy and stiff-

man syndrome, but will probably have to be given indefinitely

• IVIG is effective in dermatomyositis but has generally been

reserved for resistant patients

• there are multiple case series that suggest IVIG is effective for

immune-mediated blistering diseases but no controlled trial

• whether or not IVIG is effective in TENs is unclear but studies

showing that IVIG can block FAS-mediated killing of keratinocytes

provides a possible mechanism

• there is not a lot of evidence that IVIG should play a role in the

treatment of rheumatological diseases unless you include Kawasaki's

disease or dermatomyositis

• there is not much support for using IVIG to treat bacterial

infections except those manifestations that may be mediated by

superantigens (toxic shock syndrome and necrotizing fasciitis)

• IVIG can be effective in the treatment of certain viral infections

such as chronic infection with parvovirus B19

IVIG preparations have a similar blood half-life to endogenous

immunoglobulin, thus monthly replacement therapy is usually adequate.

However, the half-life of IgG can be abnormally short (<10 days) in

certain conditions, e.g. protein-losing enteropathy, nephrotic

syndrome, IgG paraproteinemia, and myotonic dystrophy. Patients with

hypogammaglobulinemia have a prolonged serum half-life of IgG and,

conversely, administering high doses of IVIG accelerates IgG

catabolism and shortens the half-life of IgG. Thus, one of the

proposed mechanisms for the benefit of high-dose IVIG in autoimmunity

is accelerated catabolism of autoantibodies.

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