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Intravenous immunoglobulin

Author: Vanessa Ngan, Staff Writer, 2005. Updated by Dr Eugene Tan, Dermatology Registrar, Waikato Hospital, Hamilton, New Zealand, 2009.


Intravenous immunoglobulin — codes and concepts
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What is intravenous immunoglobulin?

Intravenous immunoglobulin (IVIG) is a blood product derived from the pooled plasma of about 10,000 to 20,000 individuals. It is highly purified from plasma by cold alcohol fractionation. Most of the immunoglobulins in IVIG are of the subtype IgG, but there are small and variable amounts of IgA.

What are the indications for intravenous immunoglobulin?

IVIG is used to prevent or reduce the severity of infections in persons with immunodeficiency. It provides the body with antibodies to protect against bacteria and viruses. Also, IVIG can also neutralise autoantibodies (antibodies directed against one's self) and hence can be used to treat a variety of autoimmune disorders.

It is approved by the US Food and Drug Administration (FDA) for the treatment of 7 conditions.

The first four conditions account for 70% of IVIG use [1].

However, given the broad action of IVIG, it can also be used off-label to treat a variety of other conditions. The majority of the disorders listed in the table below have documented the efficacy of IVIG in small numbers of patients in uncontrolled studies.

Primary immunodeficiency statesSecondary Immunodeficiency states
Haematologic disordersRenal and vasculitic disorders
  • Autoimmune neutropenia
  • Autoimmune haemolytic anaemia
  • Platelet alloimmunisation
  • Heparin-associated thrombocytopenia
  • Post-transfusion purpura
  • Neonatal isoimmune thrombocytopenia
  • Autoimmune von Willebrand disease
  • Anti-factor VIII autoantibodies
  • Membranous nephropathy
  • IgA nephropathy
  • HUS-TTP (haemolytic uraemic syndrome-thrombotic thrombocytopenic purpura)
  • Lupus nephritis
  • Granulomatosis with polyangiitis
Neuromuscular disordersSensitisation to HLA antigens before transplantation
  • Polymyositis and dermatomyositis
  • Inclusion body myositis
  • Guillain-Barré syndrome
  • Myasthenia gravis
 
Respiratory disordersSkin diseases
  • Asthma

The use of IVIG in these and other conditions require further assessment using randomised double-blind placebo-controlled trials.

IVIG for skin diseases

Dermatological conditions account for a small proportion of the total use of IVIG, but it is a rapidly growing indication for its use. Although IVIG has been used to treat several dermatological diseases, it must be noted that its effectiveness has only been shown through the treatment of small and mostly uncontrolled study groups. The exception is the use of IVIG in treating dermatomyositis, where several clinical studies, including a randomised double-blind placebo-controlled trial, have been performed.

The use of IVIG in these and other skin conditions requires further assessment using randomised double-blind placebo-controlled trials.

IVIG in dermatomyositis

The mainstay of dermatomyositis treatment usually involves oral corticosteroids alone or in combination with an immunosuppressive agent such as methotrexate, azathioprine, cyclophosphamide and ciclosporin. These medicines all have significant side effects, and often a less than adequate response is achieved with this conventional therapy.

IVIG is a useful additional therapy for patients with dermatomyositis who fail to respond to conventional treatment or who experience unacceptable side effects. A dose of 1-2 g/kg per month administered over two days or 5 days of each month is recommended (currently there is no apparent difference in efficacy between the 2-day and 5-day regimen). A summary of clinical trials shows an overall response rate of 80% at about two months, with a maximal response at four months. Most patients require ongoing IVIG therapy in conjunction with conventional treatments given at lower and better-tolerated dosages.

With the treatment of other skin conditions, IVIG should also be used as an additional therapy. A review of all reported cases of IVIG use in dermatological diseases showed efficacy to be much more significant when IVIG is used as a complementary therapy, with a response rate of 88% compared with 46% if used alone.3

How is intravenous immunoglobulin given?

IVIG is given as an infusion into a vein over some time, usually from 2 to 24 hours. The frequency that it is given depends on the underlying condition and varies from once a day to once every 3 to 4 weeks. The dose is typically a total of 2 g/kg body weight delivered over 2 to 5 days.

How long do the effects of IVIG last?

The duration of the response from IVIG depends on the individual's metabolism and the disease state. On average, the effects of IVIG can last up to a month after each administration.

Risk of infection from IVIG

The pool of donors is carefully screened to eliminate anyone with abnormal liver function or exposure to viral hepatitis or HIV infection. The process of obtaining IVIG in itself removes viruses and bacteria from the plasma. Therefore, IVIG should not pose any risk of hepatitis C, hepatitis B or HIV transmission. Since the introduction of newer techniques of obtaining IVIG in 1987, there have been no cases of transmission of these viruses.

What are the precautions when having intravenous immunoglobulin?

Although immunoglobulins are antibodies from human plasma, individuals with certain conditions need to use this medication with caution. The following medical conditions warrant discussion with your doctor:

  • Previous blood clots
  • Dehydration
  • Diabetes
  • Kidney disease
  • Heart disease
  • Stroke
  • Pregnant or contemplating pregnancy
  • Breastfeeding.

Who should not have intravenous immunoglobulin?

IVIG should be avoided by:

  • Individuals who have an allergy to immunoglobulins or any other part of this medicine
  • Individuals who have IgA deficiency – Deficiency of IgA occurs in about 1 in 700 of the population and should be screened before IVIG therapy is instituted.

Side effects of intravenous immunoglobulin

Side effects of IVIG therapy are generally mild and self-limiting. The most common side effects occur 30–60 minutes after the onset of the infusion and include:

  • Flushing
  • Urticaria
  • Headache
  • Chills
  • Fever
  • Nausea or vomiting
  • Wheezing
  • Lower back pain
  • Tachycardia (rapid heartbeat)
  • Changes in blood pressure
  • Myalgia (muscle pain).

These symptoms can be managed by stopping the infusion, or a patient can be premedicated with antihistamines and intravenous hydrocortisone.

Other rare side effects include:

  • Acute renal failure
  • Blood clots
  • Haemolysis (destruction of red blood cells)
  • Neutropenia (low white cell count).

What are the adverse reactions on the skin?

Skin reactions to IVIG are uncommon, and the exact incidence is unknown. Of all the reported rashes, a blistering type of eczema is the most common (a type of dermatitis) [2]. It often begins at about 8 to 10 days after exposure to IVIG. The rash characteristically starts as dyshidrotic eczema (pompholyx) with small itchy blisters on the palms, but this may be followed by a more generalised eczematous eruption that spreads throughout the body. The affected individual may become erythrodermic (red all over) and pruritic (itchy).

The skin lesions often resolve within a period of 1 to 4 weeks. The use of topical steroids or systemic steroids controls symptoms and may speed recovery.

Other skin reactions include:

What causes the skin reaction to IVIG?

The exact cause of skin reactions to IVIG is unknown. It is thought that the body's immune system reacts to one or several substances within IVIG, such as a stabilising agent, a part of the immunoglobulin, or T cells. The reaction may differ depending on the batch and type of IVIG as the immunoglobulin is obtained from a different pool of individuals.

What happens upon re-exposure to IVIG?

When an individual develops a skin reaction to IVIG, a second exposure may cause the rash to appear earlier (generally around 8–10 days after infusion) and become more extensive. The immune system has developed memory T cells, and subsequent responses are faster and more severe. Switching the type of IVIG may cause a less severe reaction.

New Zealand approved datasheets are the official source of information for these prescription medicines, including approved uses and risk information. Check the individual New Zealand datasheet on the Medsafe website.

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References

  1. Darabi, K., O. Abdel-Wahab, and W.H. Dzik, Current usage of intravenous immune globulin and the rationale behind it: the Massachusetts General Hospital data and a review of the literature. Transfusion, 2006. 46(5): p. 741-53. Medline.
  2. Vecchietti, G., et al., Severe eczematous skin reaction after high-dose intravenous immunoglobulin infusion: report of 4 cases and review of the literature. Arch Dermatol, 2006. 142(2): p. 213-7. Medline.
  3. Jolles S, Hughes J, Whittaker S. Dermatological Uses of High-Dose Intravenous Immunoglobulin. Archives of Dermatology 1998;134:80-86. Medline.
  4. Enk, A.H., Hadaschik, E.N., Eming, R., Fierlbeck, G., French, L.E., Girolomoni, G., Hertl, M., Jolles, S., Karpati, S., Steinbrink, K., Stingl, G., Volc-Platzer, B. and Zillikens, D. (2016), European Guidelines (S1) on the use of high-dose intravenous immunoglobulin in dermatology. J Eur Acad Dermatol Venereol, 30: 1657–1669. doi:10.1111/jdv.13725. Journal.

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