Intravenous immunoglobulin (IVIG) is a polyclonal mixture of immunoglobulin G (IgG) antibodies that can be administered intravenously. IVIG is used primarily as replacement therapy in a variety of disorders marked by IgG deficiency. In large doses, IVIG has anti-inflammatory and immune-modulatory functions and plays a role in the treatment of various autoimmune disorders.
There are at least eleven licensed IVIG products commercially available in the United States, in addition to four preparations licensed for subcutaneous administration. IVIG is manufactured from pooled human plasma obtained from thousands of donors who are screened for infection with human immunodeficiency virus (HIV) 1 and 2, hepatitis B and C, and syphilis. Besides donor screening, most IVIG preparations undergo multiple purification steps that further reduce the potential risk of viral contamination. These purification steps involve ethanol fractionation followed by chromatography, pasteurization, solvent/detergent treatment, protease treatment, acid treatment, or low-salt treatment. The final product is stabilized with sugars such as sucrose, amino acids such as glycine, or human albumin. All IVIG preparations have trace amounts of IgA antibodies. Although there have been no documented cases of HIV transmission from IVIG, more than 200 patients had documented hepatitis C transmission from IVIG in the early 1990s, before screening for hepatitis C became standard.1
The mechanisms of action of IVIG are multiple and complex and have not been completely elucidated. The prophylactic effects of IVIG against infection are easily explained, as IVIG contains high titer antibodies against common pathogens, including viruses such as varicella, and bacteria such as Streptococcus pneumoniae. Prophylaxis against infection can usually be achieved with “replacement” doses of approximately 0.4 g/kg.
The anti-inflammatory activity of IVIG is less well understood, and multiple theories have been proposed. To achieve an anti-inflammatory effect, IVIG is usually used at doses of 1 to 2 g/kg. Activation of inhibitory Fc receptors and down-regulation of activating Fc receptors, binding to serum complement proteins and cytokines, inhibition of pathogenic autoantibodies, and modulation of T- and B-cell function are among the described roles.2 A series of recent studies suggests that only a small fraction of the immunoglobulins, modified by the addition of sialic acid, are responsible for IVIG’s anti-inflammatory activity.3,4 Work done in animal models suggests that these modified immunoglobulins activate an anti-inflammatory pathway on dendritic cells and macrophages. High-dose IVIG may also induce plasma cells to undergo apoptosis.5
The US Food and Drug Administration (FDA) has approved seven applications of IVIG or SCIG: primary immunodeficiency, acute immune thrombocytopenic purpura, secondary immunodeficiency due to leukemia, prevention of infection and graft-versus-host disease in bone marrow or stem cell transplant recipients, prevention of infection in pediatric HIV disease, chronic inflammatory demyelinating polyneuropathy, and prevention of coronary sequelae of Kawasaki disease. Dosing recommendations for these approved indications are provided in Table 50-1. There are also many off-label uses, some of which are discussed later.6
| FDA Indication | Suggested Dose and Regimen |
|---|---|
| Primary immunodeficiency | 400–500 mg/kg every 3–4 wk |
| Immune thrombocytopenic purpura | 0.8–1 g/kg × 1 dose (low dose) |
| or | |
| 1 g/kg/day × 2 days | |
| or | |
| 400 mg/kg/day × 5 days | |
| Chronic lymphocytic leukemia | 400 mg/kg every 3–4 wk |
| Stem cell transplantation | 500 mg/kg/wk prn (IgG <500) |
| HIV infection | 400 mg/kg every 4 wk |
| Kawasaki disease | 2 g/kg × 1–2 doses |
| Chronic inflammatory demyelinating polyneuropathy | 2 g/kg loading dose, followed by 1 g/kg every 3 wk |
Antibody replacement for primary immunodeficiency is indicated for patients with hypogammaglobulinemia and increased susceptibility to infection. Disorders in this category include severe combined immunodeficiency, agammaglobulinemia, common variable immunodeficiency, and specific antibody deficiency. In addition, use of IVIG is common in Wiskott-Aldrich syndrome (thrombocytopenia, eczema, frequent infections), hyper-IgM syndrome, hyper-IgE syndrome, nuclear factor essential modulator immunodeficiency, transient hypogammaglobulinemia of infancy, and ataxia-telangiectasia, especially when there are low IgG levels or defective specific antibody responses.
Past studies established the benefit of keeping pre-infusion levels above 500 mg/dL to decrease the risk of bacterial and Pneumocystis pneumonia.7,8 Recently, some experts have advocated keeping trough levels greater than 800 mg/dL, although supporting evidence is limited. One recent double-blind crossover trial using a dose of 800 mg/kg every 4 weeks in children resulted in fewer infections and no increase in adverse effects over the usual dosing regimen.9
Acute immune thrombocytopenic purpura seldom requires treatment, but it is indicated for overt bleeding, surgical procedures, failure of other therapies, and a platelet count below 10,000/mm3 with substantial cutaneous bleeding. In these situations, use of IVIG has become standard practice in pediatrics. Most patients studied benefit from IVIG, with a rapid increase in platelet counts of 50,000/mm3 or more. Trials using dose regimens other than those recommended (see Table 50-1) or substituting anti-D antibody (WinRho) show slower or less impressive responses in platelet count.
A secondary immunodeficiency can occur with B-cell chronic lymphocytic leukemia. In such patients with hypogammaglobulinemia and a history of infections, IVIG therapy is indicated. Randomized trials have demonstrated a beneficial decrease in infections at recommended doses.10-14
IVIG has many potential roles in preventing infection and decreasing the risk of acute graft-versus-host disease during hematopoietic stem cell transplantation (see Chapter 134). The minimally effective dose is controversial, but most experts recommend standard dosing with adjustments to maintain trough IgG levels of at least 500 mg/dL. There is some evidence that higher doses and higher trough levels reduce the risk and severity of graft-versus-host disease.15
Kawasaki disease is a pediatric vasculitis of unclear cause. Aneurysmal damage to the coronary (or other) arteries is an infrequent but serious sequela. Numerous studies have demonstrated the benefit of preventing coronary artery aneurysms by using an immunosuppressive dose of IVIG in the first 7 to 10 days of the disease.16 A second dose may be necessary after 36 hours if the fever persists.16 For more information, see Chapter 147.
Pediatric HIV infection (Chapter 108) is marked by frequent viral and bacterial infections. Because of this, the efficacy of IVIG in reducing these infections was studied in large crossover, placebo-controlled, randomized, double-blind trials in the early 1990s. These trials demonstrated conclusive benefits in children with CD4 counts greater than 200 cells/μL.17,18 In addition to having fewer infections, the CD4 counts of patients receiving IVIG decreased at a slower pace than those receiving placebo.
Chronic inflammatory demyelinating polyneuropathy, which some believe to be a chronic form of Guillain-Barré syndrome, is the most recently FDA-approved indication for IVIG therapy.19 Long-term treatment with IVIG resulted in less disability and longer time to relapse.
Off-label uses of IVIG include nearly 100 disorders, most with a presumed pathophysiologic basis in immune dysfunction. The role of IVIG in these disorders is controversial and is often not supported by convincing clinical evidence, especially in pediatrics.6
Guillain-Barré syndrome is a polyradiculoneuritis with a presumed immune-mediated cause. It typically follows viral respiratory infections and can lead to respiratory failure in children. In adults, numerous trials of IVIG have demonstrated a benefit similar to plasma exchange in hastening the recovery of walking.20 Consequently, use of IVIG has been incorporated into the latest American Academy of Neurology practice parameters for Guillain-Barré syndrome.21 Several small trials in children have also demonstrated benefits similar to plasma exchange.20,21 Dosing of 2 g/kg divided over 2 days or 5 days appears to be equally effective.20
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