Intravenous immune globulin (IVIG) …

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 03.08.2021
Released 02.23.1999
Expires For CME 03.08.2024

Intravenous immune globulin

Author: K K Jain MD†

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Intravenous immune globulin

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Introduction

Historical note and terminology

High-dose intravenous immune globulin has been used for the treatment of autoimmune disorders since 1981, starting with idiopathic thrombocytopenic purpura (22). Although it has been used extensively in neurology during the past decade, some controversies remain about its use and mechanism of action.

Intravenous immune globulin is a purified polyvalent preparation from multiple donor plasma containing all antibodies in a concentrated form with a proportion of IgG of more than 95%. Gamunex^®, 10% caprylate-chromatography purified IVIG, is an FDA-approved product.

Pharmacology

Intravenous immune globulin contains a broad spectrum of antibodies against bacterial, viral, and parasitic antigens that are capable of opsonization of, as well as neutralization of, microbes and toxins. Appropriate doses can restore low IgG levels to normal range.

Pharmacodynamics. Intravenous immune globulin is a modulator of the immune system and affects many different pathways to modulate the immune and inflammatory response (02). Various possible mechanisms of action are:

• Neutralization of pathogenic autoantibodies.
• Suppression of cytokines.
• Inhibition of complement binding.
• Blockade of Fc receptors.
• Modulation of T-cell function.
• Selective modulation of circulating proinflammatory cytokines.
• Activation of regulatory macrophages through the FcγRIIb receptor.
• Modulation of adhesion molecules and cell receptors.

Pharmacokinetics. Important features are as follows:

• Bioavailability is 100% after intravenous injection.
• A 5-fold rise of serum IgG following intravenous injection with a decline to 50% in 3 days and return to normal in 3 to 4 weeks.
• A 2-fold rise of CSF level of IgG following intravenous injection and a return to normal within a week.
• The half-life of intravenous immune globulin varies from 2 to 4 weeks.

Subcutaneous immunoglobulin (SCIG) has emerged as an alternative to intravenous immune globulin, but the dose to be prescribed needs to be determined because its pharmacokinetics differs from that of intravenous immune globulin. Dose-adjustment coefficient is used when patients are switched from intravenous immune globulin to subcutaneous immunoglobulin. A dosing method uses a higher ratio of intravenous immune globulin to subcutaneous immunoglobulin and increase of dose based on clinical status, body weight, and concurrent diseases (15). A highly concentrated (20%) immunoglobulin G preparation for subcutaneous administration provides an effective and well-tolerated therapy for patients previously on intravenous or subcutaneous treatment, without the need for dose adjustment (05).

Indications

FDA-approved indications for the use of intravenous immune globulin are:

(1) The maintenance treatment of primary immunodeficiency states as shown below:
	Category	Disease
	T-lymphocyte disorders	DiGeorge syndrome
	B-lymphocyte disorders	X-linked agammaglobulinemia Common variable immunodeficiency
	Combined T- and B-lymphocyte disorders	Wiskott-Aldrich syndrome Ataxia telangiectasia Severe combined immunodeficiency
(2) Chronic lymphocytic leukemia
(3) Kidney transplantation involving a recipient with a high antibody titer or an ABO-incompatible donor
(4) Autologous bone marrow transplantation
(5) Pediatric HIV infection
(6) Kawasaki disease
(7) Neurologic disorders
	• chronic inflammatory demyelinating polyneuropathy • multifocal motor neuropathy

Additional approved indications with criteria, which include medical certainty of diagnosis, medical necessity owing to the failure of usual treatments, contraindications to usual treatments, rapid progression or relapse, documentation of progress, and attempts to adjust drug dosages without improvement, include the following neuromuscular disorders (19):

• Guillain-Barré syndrome
• relapsing-remitting multiple sclerosis
• myasthenia gravis
• refractory polymyositis
• polyradiculoneuropathy
• Lambert-Eaton myasthenic syndrome
• opsoclonus-myoclonus
• birdshot retinopathy
• refractory dermatomyositis

A retrospective review of prescribing practices of intravenous immune globulin in the intensive care unit revealed that it was used infrequently, and among the neurologic conditions, the most common indication was Guillain-Barré syndrome (18).

In Guillain-Barré syndrome patients with contraindications for plasma exchange, intravenous immune globulin may be beneficial. Therapeutic intravenous immune globulin is capable of neutralizing neuromuscular blocking antibodies in Guillain-Barré syndrome by a dose-dependent, antibody-mediated mechanism, which may partly explain its therapeutic efficacy. Intravenous immune globulin was used successfully to treat a patient with sarcoidosis who developed Guillain-Barré syndrome; the patient experienced full recovery of neurologic function (17).

Intravenous immune globulin is a therapeutic option for multifocal motor neuropathy. Intravenous immune globulin is considered an effective and safe treatment for autoimmune neuropathies, especially in comparison to the alternative treatments such as corticosteroids, chemotherapy, and plasmapheresis. A review of intravenous immune globulin use at the Massachusetts General Hospital showed that it was most commonly used in the treatment of chronic neuropathy, which included chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy (09). A randomized placebo-controlled trial has shown the short-term and long-term efficacy as well as safety of intravenous immune globulin for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (21). The ICE study showed intravenous immune globulin to be clinically effective for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy in both the short and long term (30). The evidence from randomized controlled trials in The Cochrane Database of Systematic Reviews shows that intravenous immunoglobulin improves disability for at least 2 to 6 weeks compared with placebo (12).

Intravenous immunoglobulin treatment for acute exacerbations of myasthenia gravis has been shown in several open-label studies. Intravenous immunoglobulin maintenance therapy is also a valid method of treatment for patients with myasthenia gravis who are resistant to conventional therapy (29).

Conditions for which use of intravenous immune globulin is not recommended. According to the guidelines on the use of intravenous immune globulin for neurologic conditions, intravenous immune globulin was not recommended for 8 conditions, including adrenoleukodystrophy, amyotrophic lateral sclerosis, autism, critical illness polyneuropathy, inclusion body myositis, intractable childhood epilepsy, paraproteinemic neuropathy, and POEMS syndrome (16).

Off-label and investigational uses. An extensive review of the unlabeled uses of intravenous immune globulin showed that the most common off-label indications include graft-versus-host disease in transplant patients, prevention of antiphospholipid syndrome in miscarriage, and progression of human immunodeficiency virus after delivery (23). Intravenous immune globulin is prescribed for 90 different indications in Canada, 6 of which are licensed. The use of intravenous immune globulin in neurologic disorders is considered in antibody-mediated autoimmune disorders. It has been used in the following conditions:

	• Severe acute disseminated encephalomyelitis
	• Pontine myelinolysis
	• Stiff-man syndrome
	• Dysphagia of inclusion body myositis
	• Hereditary recurrent brachial plexus neuropathy
	• Intravenous immune globulin is effective in preventing attacks and enhancing neurologic recovery in relapses of neuromyelitis optica (13).
	• Diabetic amyotrophy
	• Hereditary inclusion body myopathy
	• Alzheimer disease
	• Low-dose intravenous immunoglobulin may substantially reduce pain in some patients with refractory complex regional pain syndrome (20).
	• Treatment with intravenous immune globulin has been reported to benefit 80% of children with unexplained pain syndromes and evidence of small-fiber polyneuropathy (27).
	• A systematic review and metaanalysis of literature concluded that the use of intravenous immune globulin is associated with significant reduction in disease activity of systemic lupus erythematosus (28).
	• Statin-triggered autoimmune myopathy (25)
	• Idiopathic inflammatory myopathies that are refractory to other treatments or in patients with severe dysphagia or concomitant infections (26)
	• Intravenous immune globulin therapy has been reported to result in the complete reversal of the movement and sleep disorders in postencephalitic parkinsonism (07).
	• Intravenous immunoglobulin followed by dexamethasone treatment has been reported to result in recovery from coma in a patient with Hashimoto encephalitis, a complication of Hashimoto thyroiditis with antineuronal antibodies to glutamate receptor alfa-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR), which is important for synaptic transmission (36).
	• A patient with Gastaut-Geschwind syndrome had symptomatic relief following treatment with steroids and intravenous immune globulin (03).
	• Steroids plus intravenous immune globulin has been used for treatment of immune-mediated necrotizing myopathy (24).
	• Effectiveness of intravenous immune globulin in COVID-19 is controversial. In an uncontrolled study, intravenous immune globulin was claimed to reduce the use of artificial ventilation, shorten the length of hospital stay, and reduce mortality in COVID-19 patients with severe pneumonia (35). Findings of a randomized placebo-controlled trial did not support the use of intravenous immunoglobulin in combination with hydroxychloroquine and lopinavir/ritonavir in treatment of severe COVID-19 cases (31).
	• A patient with COVID-19-associated meningoencephalitis improved after treatment with intravenous immunoglobulin (14).

Adverse effects

Although intravenous immunoglobulins are plasma-derived and may, therefore, carry the risk of transmitting viral infections, they have been used safely for years. This is due to the well-established fractionation and viral inactivation procedures used in their production. Adverse reactions are rare and occur in less than 1% of patients. The following are worth noting:

	• A retrospective study of the use of intravenous immune globulin for patients with neuromuscular disorders has shown that it is generally safe, but women, myasthenia gravis patients, and those receiving their first course or a higher total dose of the drug are at an increased risk of experiencing an adverse event (33).
	• Patients who receive intravenous immune globulin treatment for the first time may have an acute inflammatory reaction manifested by fever, nausea, and vomiting, which may lead to shock. The patient's vital signs should be monitored, and epinephrine should be available for treatment of an acute anaphylactic reaction.
	• Thromboembolic events due to increased serum viscosity are liable to occur in patients with hypercholesterolemia and cryoglobulinemia. Because of this effect, a warning has been issued by the manufacturer and the FDA since 2002. Hemodilution therapy may be required. Although the exact cause of the clot-related problems is unknown, rapid infusion of intravenous immunoglobulin is considered a possible risk factor. Statements advising caution in administering intravenous immunoglobulin to patients with cardiovascular disease or previous clot-related problems have been added to the labeling of the product, and healthcare workers have been advised to carefully evaluate patients with risk factors such as coronary artery disease, hypertension, cerebrovascular disease, and diabetes. In a retrospective study on patients with hypogammaglobulinemia secondary to chronic lymphocytic leukemia or multiple myeloma on intravenous immune globulin therapy, a statistically insignificant increase in risk of 0.3% compared with a baseline risk of 1.1% was observed for the venous thromboembolic endpoint (01).

A patient with Miller Fisher syndrome made an unremarkable recovery with intravenous immunoglobulin therapy but later developed a cerebral infarct with hemorrhagic transformation, which was attributed to a combination of circulating intravenous immunoglobulins and low blood pressure (08). As a preventive measure, a lower rate of infusion and smaller dosages of intravenous immune globulin should be used with close monitoring of patients for potential stroke.

	• Intravenous immune globulin-induced nephropathy. Acute renal tubular necrosis may occur rarely with intravenous immune globulin therapy in patients with preexisting renal disease, and it is likely due to intravenous solutions containing hypertonic sucrose. Dilution of intravenous immune globulin preparation and a slowing of the rate of infusion lower the risk.
	• Cases of aseptic meningitis have been reported. Aseptic meningitis has observed in both low-dose and high-dose regimens of intravenous immune globulin, and females are affected nearly 4 times more frequently than males, but subcutaneous administration may be associated with a lower rate of this adverse reaction compared with intravenous administration (04).
	• Headache is a common adverse effect associated with the administration of IVIG. Migraine headaches could be triggered in patients with a previous history of migraine. This can be prevented by pretreatment with propranolol. The headache can be managed by sumatriptan. A personalized approach should take into consideration the patient's condition, specific IVIG product used, history of migraine, and previously failed and successful therapies (32).
	• Cerebrovascular events have been reported: hemiplegia, cerebral infarction, and encephalopathy believed to be due to reversible cerebral vasospasm. Acute hypertension, leukoencephalopathy, ischemic as well as hemorrhagic strokes, and reversible cerebral arterial vasoconstriction developed shortly after initiating intravenous immune globulin therapy in a patient with Guillain-Barré syndrome (11). In most of the cases, patients recovered after discontinuation of intravenous immune globulin, and no special treatment was required.
	• Transmission of viral infections is extremely rare; although hepatitis C has been reported. There is a theoretical concern about Creutzfeldt-Jakob disease, but no case has been reported so far.

References

01: Ammann EM, Jones MP, Link BK, et al. Intravenous immune globulin and thromboembolic adverse events in patients with hematologic malignancy. Blood 2016;127(2):200-7. PMID 26443622
02: Ballow M. The IgG molecule as a biological immune response modifier: Mechanisms of action of intravenous immune serum globulin in autoimmune and inflammatory disorders. J Allergy Clin Immunol 2011;127(2):315-23. PMID 21185071
03: Benhamou OJ, Tavakkoli M, Okan H, Nobler M. Gastaut-Geschwind syndrome, faciobrachial dystonic seizure, and autoimmune limbic encephalitis. Case Rep Psychiatry 2018;2018:3835819. PMID 30631627
04: Berg R, Fuellenhals E. Aseptic meningitis following therapy with immune globulins: a combination of product features and patient characteristics? Transfusion 2016;56(12):3021-3028. PMID 27807853
05: Borte M, Kriván G, Derfalvi B, et al. Efficacy, safety, tolerability and pharmacokinetics of a novel human immune globulin subcutaneous, 20%: a Phase 2/3 study in Europe in patients with primary immunodeficiencies. Clin Exp Immunol 2017;187(1):146-59. PMID 27613250
06: Branch DR. Serologic problems associated with administration of intravenous immune globulin (IVIg). Immunohematology 2019;35(1):13-5.** PMID 30908073
07: Brunetti V, Testani E, Iorio R, et al. Post-encephalitic Parkinsonism and sleep disorder responsive to immunological treatment: a case report. Clin EEG Neurosci 2016;47(4):324-329. PMID 27118763
08: Chang T, de Alwis JS, Samarasekara N, Rajapakse S. Cerebral infarction 3 weeks after intravenous immunoglobulin for Miller Fisher syndrome: a case report. J Med Case Rep 2014;8:100. PMID 24661403
09: Darabi K, Abdel-Wahab O, Dzik WH. 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):741-53. PMID 16686841
10: Donofrio PD, Bril V, Dalakas MC, et al; IGIV-C CIDP Efficacy (ICE) Study Group. Safety and tolerability of immune globulin intravenous in chronic inflammatory demyelinating polyradiculoneuropathy. Arch Neurol 2010;67(9):1082-8. PMID 20837852
11: Doss-Esper CE, Singhal AB, Smith MS, Henderson GV. Reversible posterior leukoencephalopathy, cerebral vasoconstriction, and strokes after intravenous immune globulin therapy in Guillain-Barré syndrome. J Neuroimaging 2005;15:188-92. PMID 15746232
12: Eftimov F, Winer JB, Vermeulen M, de Haan R, van Schaik IN. Intravenous immunoglobulin for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev 2009;(1):CD001797. PMID 19160200
13: Elsone L, Panicker J, Mutch K, Boggild M, Appleton R, Jacob A. Role of intravenous immunoglobulin in the treatment of acute relapses of neuromyelitis optica: experience in 10 patients. Mult Scler 2014;20(4):501-4. PMID 23986097
14: El-Zein RS, Cardinali S, Murphy C, Keeling T. COVID-19-associated meningoencephalitis treated with intravenous immunoglobulin. BMJ Case Rep 2020;13(9):e237364. PMID 32895254**
15: Fadeyi M, Tran T. Calculating the dose of subcutaneous immunoglobulin for primary immunodeficiency disease in patients switched from intravenous to subcutaneous immunoglobulin without the use of a dose-adjustment coefficient. P T 2013;38(12):768-70. PMID 24391400
16: Feasby T, Banwell B, Benstead T, et al. Guidelines on the use of intravenous immune globulin for neurologic conditions. Transfus Med Rev 2007;21(2 Suppl 1):S57-107. PMID 17397768
17: Findik S, Bulbul R, Ozbenli T, et al. Sarcoidosis and Gullain-Barré syndrome. Acta Neurol Belg 2011;111(1):72-5. PMID 21510240
18: Foster R, Suri A, Filate W, et al. Use of intravenous immune globulin in the ICU: a retrospective review of prescribing practices and patient outcomes. Transfus Med 2010;20(6):403-8. PMID 20663105
19: Gelfand EW. Intravenous immune globulin in autoimmune and inflammatory diseases. N Engl J Med 2013;368(8):777. PMID 23425181
20: Goebel A, Baranowski A, Maurer K, Ghiai A, McCabe C, Ambler G. Intravenous immunoglobulin treatment of the complex regional pain syndrome: a randomized trial. Ann Intern Med 2010;152(3):152-8. PMID 20124231
21: Hughes RA, Donofrio P, Bril V, et al. Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomised placebo-controlled trial. Lancet Neurol 2008;7(2):136-44. PMID 18178525
22: Imbach P, Barandun S, d'Apuzzo V, et al. High dose intravenous gammaglobulin for idiopathic thrombocytopenic purpura in childhood. Lancet 1981;1:1128-31. PMID 6112565
23: Leong H, Stachnik J, Bonk ME, Matuszewski KA. Unlabeled uses of intravenous immune globulin. Am J Health Syst Pharm 2008;65(19):1815-24. PMID 18796422
24: Liang E, Rastegar M. Immune-mediated necrotising myopathy: a rare cause of hyperCKaemia. BMJ Case Rep 2018;2018;pii:bcr-2017-223870. PMID 29691272
25: Mammen AL, Tiniakou E. Intravenous immune globulin for statin-triggered autoimmune myopathy. N Engl J Med 2015;373(17):1680-2.** PMID 26488714
26: Moghadam-Kia S, Oddis CV, Aggarwal R. Modern therapies for idiopathic inflammatory myopathies (IIMs): role of biologics. Clin Rev Allergy Immunol 2017;52(1):81-7. PMID 26767526
27: Oaklander AL, Klein MM. Evidence of small-fiber polyneuropathy in unexplained, juvenile-onset, widespread pain syndromes. Pediatrics 2013;131(4):e1091-100. PMID 23478869
28: Sakthiswary R, D'Cruz D. Intravenous immunoglobulin in the therapeutic armamentarium of systemic lupus erythematosus: a systematic review and meta-analysis. Medicine (Baltimore) 2014;93(16):e86. PMID 25310743
29: Sorgun MH, Sener HO, Yucesan C, Yucemen N. Intravenous immunoglobulin for prophylaxis of acute exacerbation in Myasthenia Gravis. Neurol Sci 2014;35(6):891-6. PMID 24399309
30: Stangel M, Hartung HP, Gold R, Kieseier BC. The significance of intravenous immunoglobulin in treatment of immune-mediated polyneuropathies. Nervenarzt 2009;80(6):678-87. PMID 19139838
31: Tabarsi P, Barati S, Jamaati H, et al. Evaluating the effects of intravenous immunoglobulin (IVIg) on the management of severe COVID-19 cases: a randomized controlled trial. Int Immunopharmacol 2021;90:107205. PMID 33214093
32: Thornby KA, Henneman A, Brown DA. Evidence-based strategies to reduce intravenous immunoglobulin-induced headaches. Ann Pharmacother 2015;49(6):715-26. PMID 25757469
33: Waheed W, Ayer GA, Jadoo CL, et al. Safety of intravenous immune globulin in an outpatient setting for patients with neuromuscular disease. Muscle Nerve 2019;60(5):528-37. PMID 31443119
34: Walgaard C, Jacobs BC, van Doorn PA. Emerging drugs for Guillain-Barré syndrome. Expert Opin Emerg Drugs 2011;16(1):105-20. PMID 21352072
35: Xie Y, Cao S, Dong H, et al. Effect of regular intravenous immunoglobulin therapy on prognosis of severe pneumonia in patients with COVID-19. J Infect 2020;81(2):318-56. PMID 32283154
36: Zhu M, Yu X, Liu C, et al. Hashimoto's encephalitis associated with AMPAR2 antibodies: a case report. BMC Neurol 2017;17(1):37. PMID 28222692

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Intravenous immune globulin

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Intravenous immune globulin (IVIG) …

Intravenous immune globulin

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview.
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to access the full version.

Questions or Comment?

Also in This Category

Paraneoplastic syndromes

Anti-IgLON5 disease

Anti-LGI1 encephalitis

Progressive encephalomyelitis with rigidity and myoclonus and glycine receptor antibodies

Drug-induced myasthenic syndromes

Giant cell arteritis

Acupuncture

Chronic inflammatory demyelinating polyradiculoneuropathy

Intravenous immune globulin

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Paraneoplastic syndromes

Anti-IgLON5 disease

Anti-LGI1 encephalitis

Progressive encephalomyelitis with rigidity and myoclonus and glycine receptor antibodies

Drug-induced myasthenic syndromes

Giant cell arteritis

Acupuncture

Chronic inflammatory demyelinating polyradiculoneuropathy

This is an article preview.
Start a Free Account
to access the full version.