Subcutaneous literally means: “under the skin”. Subcutaneous injections of gammaglobulin were used by Bruton to treat the first patient diagnosed with agammaglobulinemia, in the early 1950’s. Subsequently, intramuscular (IM) injections of gammaglobulin were used in a large study in the United Kingdom and this became the standard route of administration of IgG for patients with antibody deficiencies. IM “gammaglobulin shots” were also widely used during the 1950’s in patients without PID to prevent outbreaks of infectious diseases such as measles and polio, and were sometimes given to premature babies. The type of gammaglobulin used by Bruton and in the study in the UK is called Immune Serum Globulin (ISG). It is produced as a 16% solution, as compared to most IV preparations which are used at 5 or 10%. The 16% ISG is still used for preventing hepatitis A infection for travelers, and occasionally to prevent infectious disease outbreaks in non-immunized populations. In the late 1970’s, before intravenous immunoglobulin became available, Dr. Melvin Berger and his colleagues used a small battery-powered pump to give 16% ISG to a patient who would not take her ISG shots because they were quite painful. She also had had bad reactions to plasma transfusions, the only alternative to IM shots available at that time (1). The pump gave the ISG slowly- over several hours- and eliminated the pain associated with the deep IM shots. This patient and several others tolerated the ISG quite well using this slow subcutaneous method with the pump, shown in figure 1. This first young woman who used the pump for ISG soon got married and became pregnant, and took subcutaneous ISG throughout her pregnancy. She used up to 20 cc (which contains 3.2 grams of IgG) every day in the last months (2). This allowed her to receive over 22 grams of IgG per week. Both the mother and baby had normal IgG levels at the time of birth, meaning that enough IgG had been given to the mother to transfer across the placenta and give the baby a normal level as well.
After these initial descriptions of the use of pumps to slowly give 16% ISG, the subcutaneous route became widely used in other countries, particularly Sweden, and many more papers on this route have been published (see a list in reference 3). Anne Gardulf and her colleagues in Sweden found that many patients could take the subcutaneous infusions quite rapidly, and have published many papers on the safety and utility of both home and hospital-based subcutaneous infusions (listed in reference 3). Other authors have reported on the use of the subcutaneous route in children (reference 6 and additional papers listed in reference 3). These papers illustrate the great flexibility of the subcutaneous approach. Subcutaneous is still the major route of IgG treatment in Sweden, and overall, is being used by more than10% of the PID patients in a recent survey across the European Union countries (7). In the US, IV preparations were introduced in the early 1980s and have become the most common way to take IgG. However, Dr. Stiehm and his colleagues at UCLA showed that PID patients who had severe reactions to IM or IV infusions could tolerate their IgG quite easily when it was given by the subcutaneous route (8,9). Other doctors have also found that this route of administration may have less side effects than standard IV infusions (summarized in table 1 in reference 3) and may be easier to use in patients in whom starting and maintaining IVs is difficult (10,11). For these reasons, many patients have been allowed to self-infuse their IgG at home using the subcutaneous route. Anne Gardulf and her colleagues have done studies which show that the ability to self-infuse creates a sense of autonomy, which has positive effects for many patients (5).
Several 16% IgG products are available in Europe, but there are none specifically licensed in the US for administration by this route. Some authors have described subcutaneous infusions of 16% ISG, which is still licensed in the US for IM use (12). Other papers have described subcutaneous infusions of products licensed for IV use (10-12). Some of the pumps that have been used are shown in the link “pumps and needles”. Some of these pumps use a motor to push the plunger of a regular syringe, while others use rollers to pump IgG from a plastic reservoir or small bag. In general, 20-40 ml (cc) may be infused into a single subcutaneous site in adults, with lower volumes per site in children, depending on their size. Many patients will infuse their IgG into two sites at once, using a tubing set with a y-connector which infuses via 2 needles at once. Favorite sites include the front or sides of the abdomen, the thighs, or the backs of the upper arms. If more concentrated IgG solutions are used, the volume that must be infused is lower than if less concentrated solutions are used. For example, to take 5 grams of IgG would require 100 ml (cc) if a standard 5% IV solution is used, 50 ml (cc) if a 10 % solution is used, but only 31 ml (cc) if a 16% product is used. It is obviously much easier to take the latter volume, approximately 1 ounce, by the subcutaneous route, as opposed to trying to take 100 ml by this route. In contrast, once an IV is started, the volume administered may be less critical and larger infusions of more dilute products would be more easily given by that route.