The Mystery of IVIg

The carbohydrate content of a preparation is particularly important for patients with diabetes mellitus, as glucose-containing products may acutely affect glycemic control. In addition, a disproportionate share of renal adverse events is associated with sucrose-containing products.^3,4 Sugar and sodium content also both affect osmolality, and increased osmolality may be of concern in patients with a history of renal dysfunction, elevated blood pressure or heart failure. Lyophilized products needing reconstitution also tend to have higher osmolality than liquid formulations of IVIg. Patients who cannot tolerate increased osmolality may also not tolerate a high volume load, mostly determined by IVIg dose and product concentration. Lastly, all IVIg preparations contain a small amount of IgA, and patients with IgA deficiency may be at risk of anaphylaxis because of their production of IgE anti-IgA antibodies, particularly with prior exposure to blood products containing IgA. Anaphylaxis is rare, however, and most patients with IgA deficiency tolerate products with low IgA content.⁴

Safety and Infusion-Related Adverse Events

A majority of the side effects associated with IVIg are minor, self-limited, and typically related to the infusion rate (see Table 2). The most commonly reported side effects are headache, nausea, myalgia, arthralgias, urticaria, low-grade fever, chest discomfort, and tachycardia. Milder reactions can often be reduced or prevented by decreasing the speed of the infusion or temporarily discontinuing the infusion and restarting at a lower rate after symptoms resolve. If a patient continues to experience adverse reactions with treatment, a trial of premedications including antihistamines, analgesics, and rarely corticosteroids is reasonable. Switching to a different brand of product is also worth considering.³

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Figure 1: A schematic representation of the proposed mechanisms of action of IVIg on cellular immunity. IVIg targets the cellular immune compartment at multiple levels, including innate and adaptive immune cells. IVIg interacts with dendritic cells (DCs), macrophages (MØ), and granulocytes, mainly via activating and inhibitory FcγRs. Monomeric IgG in IVIg preparations can block the interaction of immune complexes with activating FcγRs, thereby inhibiting endocytosis and phagocytosis by DCs and macrophages and activation of granulocytes. IgG dimers in IVIg preparations binding to activating FcγRs on macrophages induce the expression of the inhibitory FcγRIIb and suppress expression of IFNγR2, thereby inhibiting macrophages functions. In addition, IgG dimers promote antibody-dependent cellular cytotoxicity of DCs by NK cells, resulting in reduced T-cell activation. IgG dimers suppress macrophage and B-cell functions by ligating FcγRIIb. In addition, F(ab’)2–mediated effects of natural antibodies present in IVIg have been described for DCs (activation mainly via CD40), granulocytes (induction of apoptosis via siglec), and B cells (idiotype-mediated inhibition of B-cell receptors). Interactions between IVIg and Treg cells via as yet unknown mechanisms lead to expansion and increased suppressive function of Treg cells. The immunological effects depicted are not mutually exclusive and are likely to work in synergy. Credit: Reprinted with permission from Elsevier from Trends Immunol. 2008;29:608-615.

Major side effects of IVIg therapy include aseptic meningitis, acute renal failure, thrombotic complications, and, rarely, anaphylaxis. Patients with a history of migraine headaches in particular have a predisposition toward aseptic meningitis. Prehydration, slower infusion rates, and premedication with analgesics and a migraine-specific medication such as sumatriptan may help prevent this complication. Acute renal failure is thought to be due to an osmotic nephrosis leading to acute tubular necrosis. As previously mentioned, the literature estimates that 90% of cases of acute renal failure are associated with the infusion of sucrose-containing preparations of IVIg. A significant number of patients developing this complication also have other comorbid conditions, including baseline renal insufficiency, hypertension, and diabetes mellitus. Thrombotic events are likely related to increases in plasma viscosity above the physiologyic range of 285–295 mOsmol/kg. Myocardial infarction and stroke are rare and potentially fatal side effects that may be due to increases in serum viscosity. Lower-concentration solutions and slower speeds of infusion may decrease the potential for thrombotic complications. For high doses of IVIg, however, lower concentrations may demand larger volumes of fluid and providers should be careful of volume overload.^3,4