Use of intravenous immunoglobulin in human disease: A review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology

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Human immunoglobulin prepared for intravenous administration (IGIV) has a number of important uses in the treatment of disease. Some of these are in diseases for which acceptable treatment alternatives do not exist. In this review we have evaluated the evidence underlying a wide variety of IGIV uses and make specific recommendations on the basis of these data. Given the potential risks and inherent scarcity of IGIV, careful consideration of the indications for and administration of IGIV is warranted.

Introduction

Over the past 2½ decades, administration of exogenous pooled human immunoglobulin for intravenous use (IGIV; commonly referred to as IVIG, although licensed in the United States as IGIV) has become an important therapy in clinical medicine. The original use of these immunoglobulin preparations, which contain a broad range of antibody specificities (as opposed to the use of mAbs or sera or immune globulin preparations with high titers of selected specific antibodies), was in antibody replacement therapy. However, a number of other clinical benefits of IGIV treatment have been demonstrated. Many of these other uses result from anti-inflammatory and immunomodulatory effects, which were not anticipated when these polyclonal preparations were first developed. Unfortunately, some frequent or proposed uses are based on relatively little data or anecdotal reports. Because currently available IGIV preparations are produced from human plasma by using a number of preparatory steps, supply of products is finite, and its use should be carefully considered.1 Furthermore, the administration of IGIV can lead to numerous side effects and potential additional adverse consequences.2, 3, 4, 5, 6 Despite this, the appropriate use of immunoglobulin can be life-saving.

This document is focused on the use of standard immunoglobulin preparations specifically manufactured for intravenous administration. These preparations have been in clinical use for more than 20 years and have improved the management of certain disease states. There are currently 6 clinical indications for which IGIV has been licensed by the United States Food and Drug Administration (FDA), as outlined in Table I. These can be summarized as follows: (1) treatment of primary immunodeficiencies; (2) prevention of bacterial infections in patients with hypogammaglobulinemia and recurrent bacterial infection caused by B-cell chronic lymphocytic leukemia; (3) prevention of coronary artery aneurysms in Kawasaki disease (KD); (4) prevention of infections, pneumonitis, and acute graft-versus-host disease (GVHD) after bone marrow transplantation; (5) reduction of serious bacterial infection in children with HIV; and (6) increase of platelet counts in idiopathic thrombocytopenic purpura to prevent or control bleeding.

This document reviews the basis for the FDA-approved indications and will discuss other disease states in which IGIV has been used. Some of these other conditions are extremely rare, making randomized controlled investigations difficult. Others, however, are quite common, and rigorous scientific evaluation of IGIV utility has been possible. IGIV holds great promise as a useful therapeutic agent in some of these diseases, whereas in others it is ineffectual and might actually increase risks to the patient. Thus the evidence supporting the use of IGIV in these conditions has been reviewed and categorized (Table II). Current recommendations for the appropriate use of IGIV are outlined in this summary.

It is noteworthy that this summary is current as of November 2005 and does not reflect clinical research or reports that have become available since that time. Although prior reviews of evidence were considered to arrive at the conclusions contained in this document, primary literature for review on each subject was derived from searching the National Center for Biotechnology Information Pubmed database using the key words “IVIG,” “IGIV,” and “intravenous immunoglobulin,” along with key words specific for each disease-related topic. The recommendations for appropriate use of IGIV stated here are based on this literature review but will most certainly change over time as experience and understanding of these diseases increases.

Section snippets

Primary and secondary immunodeficiency

IGIV is indicated as replacement therapy for patients with primary and selected secondary immunodeficiency diseases characterized by absent or deficient antibody production and, in most cases, recurrent or unusually severe infections (Table III).7, 8

Autoimmune diseases

Intravenous immune globulin has been used with varying efficacy in a number of systemic autoimmune diseases, as outlined in Table IV. These applications are reviewed below.

Use of IGIV in asthma

Asthma is a heterogeneous disease. In some patients upper or lower respiratory tract infections might trigger bronchospasm and excessive mucus production, whereas in others chronic or recurrent bronchial infections might manifest as wheezing and air trapping. Patients who fit these descriptions are occasionally found to have antibody deficiency.126, 127, 128, 129, 130, 131, 132, 133 In some patients with immune abnormalities and infection-associated asthma, replacement doses of IGIV might

IGIV in neurologic disorders

IGIV has demonstrated some degree of effectiveness in a number of inflammatory or immune-mediated demyelinating disorders of the peripheral and central nervous systems (Table V). Mechanisms of action reflect the ability of IGIV to interfere with the activity of humoral components, such as antibody and complement, and to limit cytokine production.146, 147, 148

Transplantation

IGIV has been used for more than 2 decades as part of the supportive treatment of bone marrow transplant recipients and is approved by the FDA for this indication.208 There is also emerging evidence that IGIV might have utility in the treatment of certain complications of solid organ, most notably renal, transplantation.

Uses of IGIV in infectious and infection-related diseases

Despite improvements in antimicrobial therapies, there are a large number of pathogens that remain difficult to control and others for which no specific chemotherapy exists. Thus polyclonal IGIV continues to be used in the treatment of a variety of infectious diseases and infection-related disorders (Table VI). Although there is significant anecdotal experience in a number of settings, the cumulative evidence, along with the cost-effectiveness and risk of complications, must be considered when

Miscellaneous uses

IGIV has been evaluated in a number of other conditions that have been proposed to result from an aberrant immunologic response (Table VII). Some of the reports are purely anecdotal, but others have been well designed and make a definitive statement regarding the use of IGIV in these conditions. Many of these diseases have few or no therapeutic alternatives and warrant consideration of IGIV therapy on the basis of the available evidence.

Immune globulin products, infusions, and practical considerations

A number of practical considerations in the use of IGIV (Table VIII) are central in facilitating patient therapy and improving the life experience of patients receiving IGIV. The safe and effective use of IGIV requires attention to numerous issues that relate to both the product and the patient. The safe and effective administration of IGIV and the diagnosis and management of adverse events are complex and demand expert practice. It is critical for the prescribing physician to carefully assess

Note added in proof

Since completion of this manuscript several important developments have occurred that affect the IGIV community.

The first is that in January 2006 a polyclonal immunoglobulin product was licensed by the FDA specifically for subcutaneous administration for the treatment of patients with primary immunodeficiency (Vivaglobin; ZLB Behring, Melbourne, Australia). This further legitimizes this mode of therapy in the US for patients with primary immunodeficiencies. Importantly, the reader is referred

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    Cover artwork depicts a structural model of IgG. This image was created by Michael Clark, PhD, Department of Pathology, Cambridge University, Cambridge, United Kingdom. Reproduced with permission.

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