Short Analytical ReviewSubcutaneous immunoglobulin replacement in primary immunodeficiencies
Introduction
Bruton [1] treated the first patient to be diagnosed with agammaglobulinemia with subcutaneous injections of immune serum globulin (ISG). However, intramuscular injections were preferred by Janeway et al. [2] and Gitlin and Janeway [3] in Boston, and soon became the standard of care in the US. The adoption in 1955 of weekly IM injections of 0.025 mg/kg of ISG by the MRC working group on hypogammaglobulinemia in the UK [4] helped establish IM injection as the method of choice worldwide. Local pain at the injection sites is a major factor limiting the doses that can be given by IM injection and frequently led to poor compliance on the part of the patient. Before 1980, the major alternative to IM injections of ISG was intravenous infusion of plasma [5]. Although this proved satisfactory in children, the large volumes required to give satisfactory quantities of IgG prohibited its widespread use in adults. In the late 1970s, faced with patients who were poorly compliant with recommended schedules of IM injections, some of whom had adverse effects from plasma as well, we introduced the use of small, battery-powered pumps initially developed for prolonged infusions of desferrioximine to slowly administer IM ISG by the subcutaneous route [6], [7]. Administration of 16% ISG at rates of 1–2 ml/h allowed diffusion into the subcutaneous tissues and adsorption into the bloodstream with remarkably little local swelling or pain and no systemic reactions [6]. IV administration of preparations available at that time was still impossible because of serious systemic adverse effects. Most of these adverse effects were thought to be due to complement activation by aggregates or the presence of active enzymes of the kallikrien and kinin pathways in the ISG [8], [9]. The subsequent development of IV preparations in which aggregation of the IgG was minimized by low pH or the inclusion of stabilizers such as sugars overcame many of these problems, and it was later shown that monomeric IgG preparations can inhibit complement activation or deposition [10], [11]. This is believed to be an important explanation for the efficacy of current IVIG preparations in autoimmune diseases [11]. However, such stabilized preparations were not yet available in the late 1970s or early 1980s.
It soon became apparent that slow subcutaneous infusions were remarkably free from the limitations of IM injections and the systemic adverse effects of the early IV preparations. Subsequent reports showed that higher doses of 16% IM preparations including as much as 100 mg (0.625 ml)/kg once a week or 20 ml (approximately 0.33 ml/kg) per day could be given for prolonged periods to improve patients' overall control of infection [12], [13] or in special situations such as for persistent echovirus infection [13] and pregnancy [7]. These doses allowed maintenance of higher serum IgG levels [7], [12], [13]. Slow subcutaneous infusions were also found to allow tolerance of ISG in patients who had repeated anaphylactic reactions to IM injections [14] and to promote development of tolerance to IgA in patients sensitive to that isotype [15]. This method was adopted in some centers in Scandinavia and the UK. However, the introduction in the early to mid-1980s of preparations which were safe for IV administration, and the higher doses that could be administered by that route, led IVIG to become the major modality used in the US and most of Europe. The availability in Scandinavia of large stocks of IM ISG, which were less expensive than IV preparations [16], and contamination of an early IVIG product with hepatitis C virus [17] led to the persistent use of IM preparations by the subcutaneous route in that region. Protocols for rapid infusion [16], [18], [19], use of multiple sites at one time [16], [19], and home treatment were developed [18], [19], [20], [21]. In recent years, there has been a resurgence of interest in subcutaneous infusion in the US, primarily because this route does not require IV access, which is problematic in some patients, particularly children; and because it may obviate adverse effects associated with large IV infusions [22], [23]. Subcutaneous infusions are generally given more often than IV infusions and therefore allow better maintenance of consistent serum IgG levels [21], [23]. Finally, the lack of a requirement for vascular access and the freedom from serious adverse effects may promote patient autonomy by allowing self-administration [21]. A review of immunoglobulin usage by primary immunodeficiency patients in our university-based referral practice indicates that about 10% of them receive IgG replacement by the subcutaneous route [24], and a recent survey of immunoglobulin usage by 1243 patients with primary immunodeficiencies in 16 European countries showed that 93 patients, or 7%, employ this method; Eighty-six percent of them receiving their infusions at home [25].
Section snippets
Technique for subcutaneous administration of IgG
In developing our initial protocol for subcutaneous administration of the standard 16% ISG preparations available in the late 1970s, we were cognizant of warnings that patients should not be skin tested with IgG concentrates because of a high incidence of local reactions following intradermal injections. We reasoned that these reactions might be due, at least in part, to release of mediators from mast cells in the skin triggered by anaphylatoxins generated during activation of complement by
Adsorption and pharmacokinetics
Published data are insufficient to allow calculation of traditional pharmacokinetic parameters such as the maximal concentration in serum (Cmax), the time necessary to reach that concentration after completion of an infusion (Tmax), the volume of distribution, or the completeness of adsorption of subcutaneously administered IgG. One early study of an 125I-labelled anti-Rh(D) IgG preparation showed approximately equivalent net uptake of 125I into the circulation after subcutaneous as compared to
Costs and effects on quality of life
A comparison of the costs of subcutaneous vs. intravenous IgG replacement therapy published from Sweden in 1995 showed that whether administered in a hospital setting or in the home, a year's treatment by the subcutaneous route would only cost about 25–33% of the cost of IV treatment [36]. However, close examination of the figures in that study suggests that the costs of the ISG preparation(s) used for IM or subcutaneous administration were only 18% of those used for IV administration [36].
Conclusions
Subcutaneous administration of IgG by infusion from a small pump is safe and easy to learn, and readily facilitates self-treatment at home as well as treatment of young children by their parents. Parameters of the treatment regimen such as the dose and duration of each infusion as well as the schedule of infusions can be individualized to fit many patients' needs or preferences. Potential advantages and disadvantages of the subcutaneous and intravenous routes are summarized in Table 2. For
Acknowledgements
Previously unpublished data contained in the manuscript are from a clinical trial of subcutaneous IgG replacement (CE 1200) sponsored by Aventis-Behring, LLC, King of Prussia, PA, and are reported with permission of Dr. Michael Sumner of Aventis-Behring.
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