Medication Summary
The goals of pharmacotherapy are to reduce morbidity and to prevent complications. In the modern era, this includes not only preventing acute, severe, life-threatening infections but also preventing morbidity from the slow development of end organ damage due to subclinical chronic infection. Since most of these patients require life-long immunoglobulin replacement, an additional goal is to provide optimal therapy without compromising the patient’s quality of life. [33]
Concentrated safe and effective immunoglobulin products can now be delivered subcutaneously, intramuscularly, or intravenously. [35]
Immune globulins (human)
Class Summary
Accepted medical therapy for patients with IgG deficiency. Purified human IgG may be given intravenously (IVIG) or subcutaneously (IGSC). Intramuscular IgG and plasma are rarely employed for chronic use in the current era. IVIG and IGSC for use in the United States are derived from human plasma obtained from carefully screened and tested US donors. All preparations available in the United States contain all 4 IgG subclasses, with an antibody distribution approximately the same as human serum. The traditional methods of preparation of different commercial products consist of cold ethanol fractionation followed by further purification, usually employing additional precipitations and one or more steps of chromatography, followed by specific steps to remove or inactivate potential viral pathogens.
Although many physicians use different IVIG preparations interchangeably and with similar overall efficacy, the individual products differ from each other in final purification steps, IgA content, and excipients. Different products may be tolerated differently by different patients. Thus, a patient on established therapy with one particular product may have increased adverse effects if given a different product. Most products in the US market are labeled for use in primary immune deficiency and immune thrombocytopenic purpura (ITP), but other uses are common, and an evidence-based review of the multiple on- and off-label uses of IgG has recently been published. [36] Immune globulin preparations may have individual differences, and more detailed descriptions may be obtained from other sources, including the Physicians' Desk Reference.
Although generally safe, IVIG has been associated with some adverse reactions in certain patient populations. For example, IVIG should not be given to patients with isolated IgA deficiency. Use of this product in these patients has been associated with severe complications, including anaphylactic shock and death. However, this problem is rare. Most patients have some IgA or no antibody production at all, so production of IgE antibodies against IgA is not common.
In patients with preexisting risk factors for coronary artery disease and atherosclerosis, the administration of IVIG has been associated with thromboembolic events. Reports of myocardial infarction, transient ischemic attacks, and stroke, although rare, have been described in the literature. [34] Infusion of IVIG may affect the cardiovascular system by different, possibly synergistic, mechanisms. A recent comprehensive review covers many aspects of IVIG therapy. [33]
IVIG regimens usually are given in the form of infusions of 300-600 mg/kg every 3-4 weeks, since the half-life of IgG in the circulation is approximately 21 days. Higher doses are often preferred in patients with chronic lung or sinus infections. High doses may lead to increased plasma and blood viscosity, leading to decreased myocardial perfusion; preparations containing higher sodium concentrations may contribute to fluid overload; and some preparations may contain activated clotting factors. Furthermore, some preparations may contain leukoagglutinins, antibodies which can lead to microaggregation of white blood cells, causing transfusion-related acute lung injury. [34] Acute renal failure, positive Coombs tests and frank hemolysis have also been reported following IVIG infusions. [34] IVIG infusions are frequently accompanied by rate-related adverse effects such as headache, chills fever, myalgia, nausea, or vomiting.
Usually, infusions are started at a slow rate (0.01 mg/kg/min), which is increased in a stepwise manner, as tolerated by the patient. If symptoms of an infusion reaction begin, these can usually be controlled by slowing or temporarily stopping the infusion. Often, however, medications such as nonsteroid anti-inflammatory drugs (NSAIDs), other antipyretics, or antihistamines may be helpful. Some immunologists may pretreat patients with these medications, corticosteroids, or both to prevent or ameliorate symptoms of infusion reaction. In addition to headaches that accompany infusions, many patients develop headaches as much as 48-72 hours after the infusion is completed. These headaches may range in severity and may include features of migraine, which may respond to triptans. Severe headaches with meningeal signs and aseptic meningitis have also been reported. [34]
IgG is also frequently administered subcutaneously, usually using small battery-powered ambulatory infusion pumps. In general, one fourth of the monthly IgG dose is administered weekly into 2 or more subcutaneous sites using small (ie, 25-27 gauge) needles over approximately 2 hours. [37, 38] These infusions rarely induce systemic adverse effects, although local redness, swelling, or other injection site reactions may occur.
Many patients report relief from headaches or other reactions associated with IVIG infusions when they switch to IGSC. Because of this freedom from systemic adverse reactions, and since intravenous access is not required, home therapy independent from nurses or other medical professionals is possible and has been reported to result in better health-related quality of life. [37, 32] With IGSC regimens, the IgG is slowly absorbed into the bloodstream, peaking at 48-72 hours, so adverse effects associated with the high peaks achieved with intravenous therapy are obviated. Because additional doses are usually given within a week, before the IgG level drops very much, low troughs and wear-off effects reported by many patients on monthly intravenous infusions are also obviated. [37]
Immune globulin, subcutaneous (Vivaglobin)
16% human immune serum globulin, pasteurized
Immune globulin, intravenous, 5-10% liquids (Flebogamma, Gammagard, Gamunex, Privigen, Carimune)
Immune globulin purified from human plasma, usually supplied as 5% or 10% liquid
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Immunoglobulin G deficiency. Schematic representation of an immunoglobulin G molecule. CH indicates constant region of heavy chain; CL, constant region of light chain; VH, variable region of heavy chain; and VL, variable region of light chain.
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Immunoglobulin G deficiency. Human immunoglobulin G subclasses.
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Immunoglobulin G deficiency. Changes in serum immunoglobulin G concentrations during infancy and childhood.
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Immunoglobulin G deficiency. Schematic representation of the molecular interaction of CD40 on B cells, with CD40L on T cells involved in the switch from immunoglobulin M to immunoglobulin G.
