Administration of these early formulations of immunoglobulin was often complicated by systemic reactions likely due to contamination with impurities and complement activation by protein aggregates. In 1982, the World Health Organization provided standards for the manufacturing of IVIg products. According to these standards, IVIg should be derived from a pool of at least 1,000 donors. It should have minimal quantities of aggregates, but should also be at least 90% intact with maintenance of full biological functions. IVIg should contain as little IgA as possible and also be free of infectious agents.3 In 1984, the first commercial product from the Swiss Red Cross, Sandoglobulin (Sandoz/Novartis), was licensed for use in the United States. Subsequent refinements to the original Cohn cold alcohol fractionation technique, including additives to prevent IgG re-aggregation, have made newer intravenous preparations safe and well tolerated.
Not All Preparations Are Equivalent
Several preparations of IVIg are now licensed and available in the United States, and selecting the best product for a patient can be challenging (See Table 1). Product features that are important to consider include sugar content, sodium concentration, volume load, osmolality, and amount of IgA. The approaches used to minimize formation of IgG aggregates and stabilize preparations account for most of the variations in composition. Sugars, such as sorbitol, maltose, and sucrose, or amino acids are added to some formulations to prevent aggregate formation. The pH also affects stability, and at an optimum but acidic pH of 4.0–4.5, IgG molecules are present mostly as monomers and additional stabilizers are not required.4
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