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Subcutaneous and intramuscular immune globulin therapy

Subcutaneous and intramuscular immune globulin therapy
Literature review current through: May 2024.
This topic last updated: Apr 27, 2023.

INTRODUCTION — Human immune globulin therapy is used for the treatment of immunodeficiency, prophylaxis of infectious diseases, and in the management of a variety of other inflammatory and autoimmune disorders [1-4]. There are two main routes of administration: intravenous (IV) and subcutaneous (SC). A third route is intramuscular (IM), although this is uncommonly used, except for hyperimmune globulins (eg, rabies immune globulin). There are also three different methods of administering immune globulin subcutaneously: traditional, facilitated subcutaneous, and subcutaneous rapid push.

The available preparations, dosing, administration, and adverse effects of SC and IM preparations of immune globulin will be reviewed here, particularly as used in antibody deficiency states. Comparisons between the methods of delivery are also discussed. Intravenous immune globulin (IVIG) and hyperimmune globulins are reviewed in greater detail separately. (See "Overview of intravenous immune globulin (IVIG) therapy" and "Immune globulin therapy in inborn errors of immunity" and "Intravenous immune globulin: Adverse effects".)

Background — SC injections of immune globulin were originally employed by Bruton in the first patient diagnosed with agammaglobulinemia and in a follow-up paper 10 years later in 1962 [5,6]. Bruton also used animal-derived hyaluronidase to facilitate IM administration [6]. However, when IV preparations became available, the IV route became preferred because of the larger volumes that could be administered. Subsequently, subcutaneous immune globulin (SCIG) dramatically gained popularity for routine replacement therapy in inborn errors of immunity (formerly "primary immunodeficiencies") as clinicians became aware that SC administration was quicker and had fewer systemic adverse effects compared with IV administration [7,8].

IM preparations are uncommonly used in the treatment of antibody deficiencies. However, intramuscular immune globulin (IMIG) can be given in single doses for short-term prevention of specific infectious diseases (eg, hepatitis A) following exposure or travel to a country where these disorders are endemic. Some hyperimmune globulins are animal antitoxins and antisera, and certain monoclonal antibody preparations are injected SC and IM as well. (See "Plasma derivatives and recombinant DNA-produced coagulation factors", section on 'Hyperimmune globulins'.)

TERMINOLOGY

Immune globulin, intravenous (human) will be referred to as IVIG in this review because this term is commonly used by clinicians, although the abbreviation used by industry and various regulatory agencies is IGIV.

Immune globulin, subcutaneous will be abbreviated as SCIG. When given with (facilitated by) hyaluronidase, it will be abbreviated fSCIG.

Immune globulin, intramuscular will be abbreviated as IMIG.

AVAILABLE PRODUCTS — Multiple polyclonal immune globulin products for SC and IM administration are available (table 1). Note that they are different from hyperimmune globulin products, which are enriched for antibodies to specific pathogens. Hyperimmune globulins are discussed separately. (See "Overview of intravenous immune globulin (IVIG) therapy", section on 'Uses for hyperimmune globulin'.)

Differences in concentration — Immune globulin products specifically intended for SC and IM administration are generally more concentrated than those designed for IV use in order to reduce the volume needed to deliver the required amount of immunoglobulin G (IgG). As an example, the amount of IgG in 10 mL of a 10% IV product (1 g) would be delivered in 6.25 mL of a 16% SC or IM product or 5 mL of a 20% SC product. The more concentrated 16 and 20% products have not been evaluated for IV use and should not be given intravenously.

Several 10% liquid products for IV use are also licensed for SC use by the US Food and Drug Administration (FDA) (table 1).

Subcutaneous — There are three ways to administer immune globulin subcutaneously. These differ in both the frequency of administration and how the SCIG is given. The first uses infusion pumps to give infusions at individualized intervals that range from several per week to one every two weeks, with weekly infusions being most common (called "traditional" in this topic review). The second, termed "rapid-push SC," is given using only a syringe and needle (or a winged infusion set). Syringes for rapid-push SC may be prefilled by the manufacturer (prefilled syringe [PFS]) or drawn up from an immunoglobulin vial. The third is hyaluronidase-facilitated SCIG (fSCIG), usually given every three to four weeks [1,9].

Traditional subcutaneous — In the United States, available traditional products for SC use include (table 1) [10-13]:

10% Gammagard

10% Gamunex-C

10% Gammaked

16.5% Cutaquig

20% Hizentra

20% Cuvitru

20% Xembify

In Europe, other 16 and 16.5% concentration SC products are available, and the use of 10% SC, other than fSCIG, would be unusual:

16% Subgam

16.5% Gammanorm

20% Hizentra

20% Cuvitru

Hyaluronidase-facilitated subcutaneous — HyQvia became available in Europe in 2013 and in the United States in 2014 [14] and is licensed for children, adolescents, and adults. It is given using a two-step delivery system. The hyaluronidase and immune globulin are supplied together as separate bottles containing 5 mL of recombinant human hyaluronidase (rHuPH20) per 10 g (100 mL) of 10% IVIG. The IgG component of HyQvia is 10% Gammagard (Kiovig in Europe). The hyaluronidase is drawn up into a separate single syringe and infused alone by manual push from the syringe before the SCIG is given (combining the rHuPH20 vials is done if more than one set of the hyaluronidase/immune globulin is prescribed for injection into a single site). Immune globulin administration should commence within 10 minutes following hyaluronidase infusion.

If multiple vials of fSCIG are needed to obtain the desired therapeutic dose, it is necessary to acclimate the patient and SC space to the increased fluid volumes. This is achieved by four infusions over seven weeks as recommended in the prescribing information and presented in the table (table 2).

Injection of rHuPH20 immediately before the IgG temporarily breaks down tissue hyaluronan, which is then reconstituted over the next 24 to 48 hours. This significantly increases the dispersion space for absorption of the immune globulin. This allows much larger doses to be administered per infusion than with traditional SCIG. As a result, this product can be dosed every two to four weeks, rather than weekly. fSCIG therefore has some of the properties of both SCIG and IVIG administration (figure 1).

Potential adverse effects — The formation of non-neutralizing antibodies to rHuPH20 was noted in 13 out of 83 patients in the product's pivotal study. However, they were not associated with reactions or with diminished activity of the hyaluronidase [15]. The clinical significance of these antibodies is unclear, though low levels are found in normal human immune globulin, implying that these antibodies are also generated in individuals not receiving rHuPH20. The recommendations from both United States and European regulatory authorities have allowed use in pregnancy. Ongoing long-term human safety and pregnancy outcome data are being collected. (See 'Safety in special populations' below.)

Known systemic hypersensitivity to hyaluronidase or rHuPH20 is a contraindication to the use of HyQvia. Hyaluronidase preparations are also used in the management of drug extravasations and as an adjuvant in bupivacaine-lidocaine mixtures (eg, in retrobulbar/peribulbar blocks) [16,17].

Intramuscular — IMIG for immunodeficiency has few advantages compared with SC and IV preparations and is rarely used. Injections are painful, the amount that can be injected is limited, there is risk of local tissue injury (such as nerve damage), and there is a higher risk of reactions. It is also not possible, in practice, to attain serum IgG levels in the normal range using the IM route. Because IMIG is rarely used for chronic therapy, there have been no studies comparing the efficacy of IM administration with other routes for more than 20 years. However, the studies that were performed suggested that IMIG was not as effective in preventing infections as IVIG [18].

A small supply of 16% IMIG is available in the form of GammaSTAN S/D (table 1). Since the purification process for IMIG is similar to that for IVIG (ie, solvent/detergent treatment), it has the same level of safety from transmission of bloodborne infections [19].

IMIG injections are generally used only in single doses to provide short-term protection against infection. Examples of situations in which IMIG might be used include:

A local outbreak of measles or another infectious disease against which certain individuals have not been immunized. (See "Measles, mumps, and rubella immunization in adults", section on 'Post-exposure prophylaxis'.)

IMIG can be used in unimmunized persons to prevent hepatitis A infection in individuals traveling to endemic areas. (See "Hepatitis A virus infection: Treatment and prevention", section on 'Protection following exposure'.)

IM varicella-zoster immune globulin is used for prophylaxis against chicken pox in unimmunized high-risk individuals, such as immunocompromised children or in first trimester pregnant females, to prevent in utero varicella. (See "Post-exposure prophylaxis against varicella-zoster virus infection", section on 'Target groups' and "Post-exposure prophylaxis against varicella-zoster virus infection", section on 'Passive immunoprophylaxis'.)

COMPARISON OF SCIG WITH IVIG — SCIG and IVIG are similarly effective at preventing infections. SC administration of immune globulin offers some significant advantages over IV administration.

Effectiveness — Multiple prospective trials in both children and adults indicate that SCIG is as effective as IVIG in protecting patients with inborn errors of immunity from infection [11,20,21]. In addition, a randomized crossover trial compared the two forms of therapy in 40 patients with primary antibody deficiencies and found no significant difference in the number of infections reported between the two routes of administration [22]. An analysis of pooled data (from seven studies of four different SCIG products from three different manufacturers) showed that the incidence of infection decreases linearly with increased IgG levels while on SCIG therapy [23]. SCIG is also being increasingly used in secondary antibody deficiency [24].

The efficacy of IVIG for prevention of serious bacterial infections is reviewed separately. (See "Immune globulin therapy in inborn errors of immunity", section on 'Efficacy'.)

IVIG and SCIG products now contain anti-coronavirus disease 2019 (COVID-19) antibodies following natural infection and/or vaccination of donors with the caveat that a protective level has not been defined.

Use in different types of diseases — In most cases, only IVIG is used when high doses are desired (eg, 2 g/kg) in acute situations, such as in the management of Kawasaki disease, Guillain-Barré syndrome, and immune thrombocytopenia. IVIG is generally used for multifocal motor neuropathy (MMN) and other neurologic or chronic autoimmune diseases. However, SCIG is also increasingly used for immunomodulatory indications, such as chronic demyelinating polyneuropathy, and is being studied in myasthenia gravis and MMN [25-28]. In theory, hyaluronidase-facilitated SCIG (fSCIG) might be an option for patients requiring high-dose immune globulin who wish to self-infuse at home or have poor venous access or other problems tolerating IVIG, although this will require further studies, and the product is not labeled for use in these disorders.

Advantages of SCIG — Advantages of SCIG (including rapid-push SCIG and fSCIG) compared with IVIG include fewer systemic reactions, more consistent serum levels of IgG, and the convenience of home infusion without the need for venous access [29,30].

SCIG administration causes few serious systemic adverse events. Systemic reactions associated with SCIG have been reported in 0 to 3 percent of patients, with most studies reporting rates <1 percent [8,31]. For comparison, systemic reaction rates with IVIG preparations range from 2 to 6 percent [2]. (See 'Systemic reactions' below.)

SCIG is also tolerated by most patients who had previous serious systemic reactions to IVIG or IMIG [32]. The lack of systemic adverse effects is likely related to the slower rate with which SCIG is absorbed into the circulation, which prevents the high peak in serum IgG that occurs following IVIG infusions.

SCIG given weekly (or more frequently) provides more even, physiologic serum IgG levels and avoids the low trough levels occurring near the end of the three- or four-week dosing period of IVIG or fSCIG (figure 1), which can be a period of increased susceptibility to infections in some patients [33]. In addition, fatigue, myalgias, and arthralgias (sometimes called "wear-off" effects) are not usually reported with traditional SCIG.

The ability to self-administer SCIG at home improves the patient's sense of autonomy and frees them from trips to a medical facility, with the accompanying exposure to nosocomial infections. Positive effects of home/self-infusion on health-related quality of life have been well documented [34,35].

SCIG infusions may be particularly useful in patients for whom venous access is problematic and circumvents the need for implantable venous access devices. Note that implantable venous ports are not recommended for the sole purpose of administering IVIG [31].

SCIG can safely be administered to most patients with common variable immunodeficiency, including those who have anti-immunoglobulin A (IgA) antibodies and the majority of patients who previously experienced systemic reactions to IVIG. (See 'IgA-deficient patients' below.)

SCIG can be more cost effective than IVIG [36].

Disadvantages of SCIG — Some parents/caregivers feel uncomfortable infusing their young children, and some adults may not be compliant or have difficulty with self-infusion. The leading complaints about SCIG therapy are the frequency of infusions, number of needles, and the common occurrence of local reactions, such as pain, redness, and swelling [37]. Using an every-other-week SCIG schedule with optimization of tolerated volume per site or fSCIG every three to four weeks can circumvent the first issue for many patients, and local reactions improve with time in most cases.

A switch to fSCIG given every three to four weeks abolishes the IgG peak observed with IVIG but yields similar trough serum IgG levels. The longer dosing intervals affect the "steady-state" IgG levels, resulting in peak and trough levels in between those of IVIG and traditional SCIG (figure 1).

Cost issues — The primary cost of regular immune globulin therapy is the immune globulin product itself, as all forms of immune globulin are expensive. However, cost estimates are complex with significant differences among health care systems in terms of both the cost of the product and home care arrangements.

In Europe, Australia, and Canada, self-administered SCIG therapy is significantly less expensive because it avoids medical facility and nursing costs, and, in some cases, the product itself costs less [31,37-41]. However, the cost of pumps, ancillary items, and home delivery must also be taken into account.

In the United States, where medications are relatively more expensive, the cost differential between IVIG and SCIG administration is smaller, and, in some cases, IVIG is less expensive, especially if administered at home [42,43].

Rapid-push administration of SCIG can reduce costs further [36,44]. This delivery method is discussed below. (See 'Rapid-push SCIG' below.)

ADMINISTRATION AND DOSING OF SCIG

Patient selection — Many patients can be readily trained to infuse SCIG themselves at home, or parents/caregivers may administer the infusions to their children. This is true in many older adults (>75 years) as well, including those on anticoagulant and/or platelet inhibitor therapy [1,45].

Reliability of the patient is an important consideration in selecting those to whom self-administration at home should be offered. Patients must be prepared to keep records of the lot numbers of all products administered and continue regular follow-ups with their clinicians. Mobile applications are available from some manufacturers to facilitate electronic record keeping, communication with the clinician, and confirmation of adherence to the SCIG regimen. (See 'Monitoring' below.)

Conversion from IVIG — To convert a patient from IVIG to SCIG (by pump or rapid push), the total monthly IV dose given is divided by four and given weekly. This approach will, after several months, result in steady-state IgG levels equivalent or higher than the levels achieved with a similar dose of IVIG [46]. A dose of 100 to 150 mg/kg per week may be a good starting dose for most patients (adults and children).

The dosing for hyaluronidase-facilitated SCIG (fSCIG) is essentially the same as that of IVIG, as discussed below. (See 'Hyaluronidase-facilitated SCIG' below.)

Immune globulin given by the SC route has a lower bioavailability (approximately 67 percent of IVIG) as determined by the area under the curve (AUC). This is partly due to truncation of the peak IgG levels, which occurs just after IV dosing (figure 1) [7,33,46-48]. The monthly dose of SCIG required to give the same monthly AUC is 1.37 times the dose of IVIG [11,20,46-51].

In the United States, the US Food and Drug Administration (FDA) has required that a "dose adjustment" be included in the labeling of SCIG products. However, a review of a large United States insurance database suggests that doses used for replacement therapy in immunodeficiencies are the same regardless of whether the route is IV or SC and that most clinicians do not adjust the dose when converting from IV to SC administration [52].

Regulatory authorities in Europe require that IgG trough levels on new SCIG products be comparable with those achieved with the same monthly dose of IVIG or other licensed SCIG products.

There has been no head-to-head comparison of the efficacy of matching AUCs rather than IgG trough levels, and studies using 1:1 dosing regimens in Europe have shown similar incidences of infection as United States studies using the "dose adjustments" [11,20,23,49-51]. More importantly, a variety of studies suggest that different patients require different serum IgG levels to prevent infection [53,54]. Therefore, each patient's dosing regimen should be individualized to a level that keeps the patient relatively infection free.

Skin preparation, premedication, and needles — Infusion sites include the lower abdomen, upper/outer thighs, or backs of the arms. Infusion sites are prepared by wiping with alcohol or chlorhexidine. Extensive scrubbing or povidone iodine are not required. Children may prefer application of a local anesthetic cream like lidocaine-prilocaine (eutectic mixture of local anesthetics) or cold spray to the needle site. Infusions into infected or inflamed skin should be avoided.

Premedication is usually not required with SCIG.

Winged infusion sets (eg, butterfly), "soft-set," or Neria button-type needles are commonly used [55]. Several manufacturers produce needles specially designed for SCIG use with the needle mounted perpendicular to the "wings." Shorter needles may be needed for very lean patients and young children. Inadvertent intradermal infusion should be avoided, and patients with local site reactions may do better with longer needles. If butterfly needles are used, 23- to 25-gauge needles that are three-fourths of an inch (1.9 cm) in length work well for most adults [32,56]. Narrower needles increase resistance and may lengthen infusion times. For infants, 24- to 27-gauge butterflies, 4 to 6 mm in length, are appropriate [1].

The tip of the infusion needle should be inserted 1 to 1.5 cm into the SC tissue, usually perpendicular to the skin surface for button-type needles and at 45 degrees for winged needles. If needle placement is too shallow, intradermal infusion can cause pain and local reactions [57]. In addition, patients should be trained to make sure that the infusion needle is not in a blood vessel, as inadvertent IV administration of SCIG preparations could increase the risk of systemic reactions [31]. A two-step check for blood return in the infusion line is suggested. First, the patient pulls back on the syringe and checks for blood return. Next, the patient removes the syringe from the infusion set and waits for 15 seconds before starting the IVIG to assure that no blood appears in the tubing [31,58]. After an infusion, a simple elastic bandage/plaster can be placed over the infusion site. Recommendations for safe disposal of needles and other medical waste should be given.

Loading doses and time to steady state — Following infusion, SCIG is absorbed from the SC space over several days. Peak serum levels occur two to three days later (figure 1).

Therapeutic plasma levels are not attained as rapidly with SCIG compared with IVIG [48]. Thus, patients newly starting SCIG can be given a single loading dose of IVIG and then switched within seven days to an SC product [20]. An alternative method is to give five SC doses, each equivalent to the planned weekly dose, on consecutive days during the first week of therapy [59] or load with two infusions per week for two weeks [60]. This practice often facilitates education/training of the patient/caregiver in the proper technique for SC infusion for home therapy. With loading by these methods, steady state is achieved within one to two weeks. Without loading, steady state with weekly infusions is reached after approximately 12 to 24 weeks of therapy. Of note, if dose adjustments are made, the time to reach a new steady state is similarly gradual.

Obese patients — It is unclear whether patients with obesity (body mass index [BMI] >30) should be dosed based on ideal or actual body weight. One study found that higher doses of SCIG were required to achieve AUCs equal to those they attained previously with IVIG [46], although this was not seen in other studies [61]. Another study of patients with obesity and either immunodeficiency or neurologic indications for immune globulin suggested that BMI could not be used to reliably predict dose restriction, and the authors concluded that immune globulin should be dosed on clinical outcome rather than body weight [62].

Dose and dosing frequency — With all immune globulin products, initial doses are based upon weight but should be rounded to the nearest full vial or prefilled syringe (PFS) of drug to avoid wastage. Another approach to avoid wasting drug is to adjust the dose up or down slightly on alternate weeks (for traditional SCIG). As an example, if the drug is supplied in 10 mL vials, a patient requiring 45 mL per week could alternate between 40 mL one week and 50 mL the next week [31].

Dosing for traditional SCIG and fSCIG are distinct.

Traditional SCIG — Compared with IVIG, traditional SCIG is administered in smaller doses and given more frequently. An empiric starting dose for SCIG is 100 mg/kg per week for both adults and children. SCIG can also be administered at a dose of 200 mg/kg every two weeks (sometimes called biweekly) [1,56,58] or in doses less than 100 mg/kg given more than once per week. However, while often used in Europe and the United States, these alternative schedules are not in the US FDA-approved labeling for available products (except for biweekly administration of the 20% product, Hizentra).

Pumps — Most patients use battery- or spring-driven pumps to deliver their weekly dose of SCIG over approximately one to two hours. During the infusion, patients can ambulate and engage in usual, nonstrenuous activities.

Syringe driver pumps, such as the Freedom60, with 40 to 60 mL syringes are convenient. An example of a smaller battery-operated pump is the Crono range (Crono PID 20, 50, and 100), which is used for administering 10 to 100 mL infusions of the available SCIG products to adults and children.

Between 5 and 60 mL of traditional SCIG (without hyaluronidase) can be infused at a given site, depending upon the patient's body habitus, age, and previous experience with the product being used. Patients requiring larger volumes should generally infuse at multiple sites simultaneously. Individual tolerance of volume per site is variable. Some patients who are able to infuse higher volumes comfortably (some over 80 mL) may choose to do so to limit sites and needles. Tubing sets with two or more bifurcations and/or the use of multiple pumps simultaneously facilitates infusion into several sites. For most adults, infusions of 40 to 60 mL are conveniently given over approximately two hours by using two sites simultaneously. Patients who tolerate infusion rates of 20 mL/hour can try increasing to 40 mL/hour to reduce the infusion time. The maximum rate approved by the US FDA is 50 mL/hour given into several sites [63]. Some patients who require large volumes of IgG may choose to divide the total volume into separate infusions given on different days.

Rapid-push SCIG — SCIG can be administered more frequently than once a week using only a syringe and needle. Some products are available in prefilled syringes as well. This technique, called "rapid push," simplifies and shortens the infusion time. Up to 20 mL can be given at a single site, usually over a period of 3 to 20 minutes, as is comfortable to the patient, noting that the patient can vary the rate based on tolerability during the infusion [61,64]. In comparison, a weekly infusion of SCIG given by pump takes approximately one to two hours [61,64]. Simplicity, cost savings of pumps, and speed are balanced against frequency of infusion and number of needles.

In one study of 104 patients, the rapid-push method was preferred by the majority of patients beginning SCIG therapy [65]. Subjects were given information about administration with pumps versus rapid push, and 71 percent chose rapid push. Patients self-administered 3 to 20 mL, usually at one site, three times weekly on average. One-third experienced local reactions, but they were considered "mild to moderate" and were easily tolerated. Only two patients later changed to pump delivery. Use of the rapid-push technique has grown significantly in health care settings where access to infusion pumps is limited.

Equipment — Rapid-push administration requires either prefilled syringes, if available, or standard, disposable 10 or 20 mL syringes and either infusion needles or special SCIG button-style needles (mostly used in the United States) [65]. (See 'Skin preparation, premedication, and needles' above.)

Hyaluronidase-facilitated SCIG — The dosing of fSCIG is essentially the same as IVIG dosing. An empiric starting dose is 400 mg/kg, with a range of 300 to 600 mg/kg (requiring 2 to 6 mL/kg) every three to four weeks. This may be given at a single SC site through a single needle or divided over two sites.

When fSCIG is given once every three or four weeks, the initial peak will still be lower than that of IVIG given at the same intervals, but the trough serum IgG levels will be similar (figure 1).

Training and equipment — A number of aspects of administration differ significantly for fSCIG compared with other forms of SCIG. They include pump choice, needle gauge, initial infusion rate, adjustment of the position of the infusion site, and patient information about the mechanism of action and management of possible local side effects.

A four-dose/seven-week "ramping up" is recommended when initiating therapy with fSCIG, an example of which is provided in the table (table 2) [66]. During this ramping-up period, the patient becomes accustomed to the product and procedure and trained in its proper administration [67].

Training for home therapy with fSCIG is similar to that for conventional SCIG. Once established on fSCIG (after four infusions), it has been possible to save time by initiating infusions at 50 mL/hour for the first two minutes and then increasing to the maximum rate tolerated by the patient during the "ramping-up" period of up to 300 mL/hour [9].

fSCIG is given using a two-step delivery system. The hyaluronidase and immune globulin are supplied together in separate bottles containing 5 mL rHuPH20 per 10 g (100 mL) of 10% IVIG. The hyaluronidase is drawn up into a single syringe (combining the different rHuPH20 vials from the sets of hyaluronidase/immune globulin units if more than one set is needed) and infused subcutaneously by syringe at 1 to 2 mL/minute (or more quickly if tolerated comfortably). Immune globulin administration should commence after the hyaluronidase infusion is completed.

Peristaltic pumps (such as the Bodyguard 323 volumetric infusion pump) may be preferable for fSCIG rather than the syringe driver pumps used for conventional SCIG, given the greater infusion volume. Peristaltic pumps are the same pumps used for IV infusions. However, they may need to be programmed to avoid the back pressure alarms that are designed to warn of extravasation during an IV infusion since the pressure for fSCIG is higher than with an IV infusion (but lower than traditional SCIG) [9]. The larger PID Crono 100 pump can also be used for fSCIG.

The needles used for fSCIG are optimally 23 or 24 gauge [1].

The sites used for fSCIG are generally similar to those used for traditional SCIG, although there is a small risk of genital edema due to the gravitational movement of the larger volume of SC fluid. Thus, abdominal infusions sites should be located slightly higher, near the level of the umbilicus. Patients should be warned about the small risk of genital edema.

MONITORING

Target serum levels — Freedom from infections should be the main determinant of the necessary IgG level, and multiple studies show that different patients require very different IgG levels to remain infection free [53,54]. Several studies have confirmed the clinical impression that higher serum IgG levels are associated with increased freedom from infection [23,54,68].

Serum IgG levels can be drawn at any time relative to infusions with traditional SCIG once steady state has been reached, which is usually after 12 to 24 weeks of SCIG therapy in the absence of a loading regimen. The concept of a "trough level" is not applicable, since serum levels remain relatively constant.

For hyaluronidase-facilitated SCIG (fSCIG), trough levels should be obtained just prior to the next infusion. Beginning approximately six days after administration, IgG levels are similar to those for IVIG (figure 1).

The amount of immune globulin required to achieve and maintain a desired serum IgG level depends upon the patient's initial IgG concentration, the frequency of administration, and the half-life within that particular patient. Increased catabolism or loss can also be seen when patients are infected, have bronchiectasis, are under physiologic stress, or in the context of renal or gastrointestinal losses, such as with chronic norovirus infection in common variable immunodeficiency [69]. Some patients appear to metabolize or lose immune globulin more rapidly than others, and some (such as X-linked agammaglobulinemia patients) require more to remain protected from infections [54]. The reasons for these individual differences are not always known, although they may be related to differences in IgG recycling by the neonatal Fc receptor (FcRn) [70-72].

Optimizing the dose — Plotting the patient's serum IgG levels over time and noting when infections occur has been suggested as a means of determining the optimal dose for a given individual [53]. A form is provided for patient use as well as an example of how the form could be completed (form 1 and form 2). Some patients reportedly demonstrate a threshold level above which the incidence of infections dramatically decreases. The weekly IgG dose may be increased in increments of 10 to 20 percent, or one extra dose per month may be added. When increasing the dose, volumes per site and number of sites per week need to be considered.

Once the dose has been altered, 12 weeks or more may be needed to reach a new steady-state serum IgG level, and several months may be necessary to assure that the desired clinical efficacy has been achieved.

In patients with chronic infections, monitoring the white blood cell count and/or laboratory indicators of infection and/or inflammation, such as the erythrocyte sedimentation rate and/or the C-reactive protein, may provide additional information to guide dosing.

Patients with normal pretreatment IgG levels — Patients with specific antibody deficiency who have normal or elevated total IgG levels cannot be monitored simply by checking serum IgG levels. Instead, the patient should keep careful records of the dose of SCIG and any infections, and this should be reviewed regularly with the clinician to determine the dose which successfully reduces the incidence and severity of infections for that individual. A form is provided for patient use as well as an example of how the form could be completed (form 1 and form 2).

Examples of disorders with normal or high total IgG levels include:

Deficient responses to certain types of antigens, such as bacterial polysaccharide antigens. (See "Specific antibody deficiency".)

Deficiency of one or more specific subclasses of IgG, provided that impaired vaccine responses have also been demonstrated. (See "IgG subclass deficiency".)

The combination of IgA deficiency and IgG2 subclass deficiency with poor response to pneumococcal polysaccharide antigens. IgA deficiency alone is not an indication for immune globulin treatment.

Specific antibody deficiency coexisting with monoclonal gammopathy or polyclonal B cell activation. Patients with such disorders may actually require higher doses of immune globulin because they may have accelerated catabolism potentially due to saturation of FcRn recycling, resulting in a reduced replacement efficiency of the administered antibodies [70,72].

The adequacy of treatment in such patients is primarily assessed by freedom from infection. In some, it may also be helpful to confirm that antibodies to pneumococcal polysaccharides are in the protective range while on therapy.

Monitoring for bloodborne illnesses — Although all licensed products are believed to be safe from transmission of known bloodborne infections, past experiences with hepatitis C transmission due to contaminated IVIG and occasional recalls of blood products due to the retrospective diagnosis of Creutzfeldt-Jacob disease in donors make it clear that some risk is always present. (See "Intravenous immune globulin: Adverse effects", section on 'Infectious risks'.)

The lot or batch number, expiration date, and manufacturer of any blood product infused into any patient should be recorded (stickers with this information may be detached from the bottles and put into patient logs). Serum should be banked prior to the initiation of immune globulin replacement, whenever an immune globulin product is switched, and annually in patients on long-term therapy to allow "look-back" and risk stratification procedures if an infection is suspected. Patients need to keep logs for this purpose, in addition to documentation in the medical record. Several manufacturers of immune globulin provide specialized logbooks for this purpose, which also allows the patient to record adverse effects and significant infections. There are also some applications available, though these have not been established across all products.

SAFETY IN SPECIAL POPULATIONS

Pregnancy — SCIG can be safely used in pregnancy but may require adjustment of both dose upward as the pregnancy advances and infusion site from the abdomen to the thighs [73,74]. The option of temporarily switching to IVIG should also be available if required. Placental passage of immune globulin is discussed separately. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Intravenous immune globulin'.)

The maintenance of normal serum immunoglobulin levels in pregnant females with inborn errors of immunity may have benefits for both mother and fetus. In addition, the presence of normal immunoglobulin levels protects the mother through pregnancy and the peripartum period and provides protective antibody for the newborn, which is especially important because adequate IgG production in the baby is not achieved until six months of age. Since most of the IgG present in the newborn is transferred transplacentally during the third trimester, preterm babies can have very low IgG levels, putting them at increased risk of infection. (See "Recognition of immunodeficiency in the first three months of life".)

The dose during pregnancy should be increased as the mother gains weight to ensure that serum IgG levels are adequate and that there is sufficient IgG for transfer across the placenta [74]. We suggest monitoring of IgG needs (monthly) in order to ensure dose adjustments can be made in a timely manner. Patients may prefer to switch infusion sites from the abdomen to the thighs during pregnancy [73].

Children — SCIG products are often used in infants and children because of difficulty of IV access. Only a few have been specifically studied in pediatric populations.

IgA-deficient patients — SCIG may be safely administered to patients with inborn errors of immunity who lack IgA, such as those with common variable immunodeficiency and undetectable IgA levels. Note that immune globulin replacement is not indicated in most patients with selective IgA deficiency and should be reserved for those who have also been demonstrated to be lacking in specific IgG antibodies and suffering from recurrent infections. (See "Selective IgA deficiency: Management and prognosis".)

Caution should always be used in patients who might be at risk for development of anti-IgA antibodies or have known high titers of anti-IgA antibodies [75]. However, patients who have not been able to tolerate IVIG due to reactions are often able to tolerate SCIG, and a previous reaction to IVIG is not a contraindication to SCIG [76].

Anaphylaxis due to IgA in SC products has not been reported, and all SC preparations contain some IgA. There are no SC preparations that are particularly low in IgA as there are with IV preparations. Some studies suggest that SC infusions might even induce tolerance to IgA in previously sensitized patients [75,77]. Anaphylaxis to immune globulin and other blood products is reviewed separately. (See "Selective IgA deficiency: Management and prognosis", section on 'Reactions to blood products'.)

Initial infusions in patients lacking IgA or with known high titer anti-IgA antibodies should be given slowly, under observation, and in an appropriate setting with resuscitation facilities. The routine prescription of an epinephrine autoinjector was discontinued in the United Kingdom following a large study of over 13,000 home infusions with IVIG in which no serious reactions occurred [78].

ADVERSE REACTIONS OF SCIG — SCIG has many fewer systemic side effects than IVIG. The most common minor adverse effects with SCIG are local swellings at the infusion site(s). Other minor adverse effects include headache, diarrhea, fever, fatigue, back pain, and nausea [79]. There is a degree of burden associated with immune globulin therapy, although route of administration did not impact overall quality of life in a survey of patients receiving immune globulin for immunodeficiency, and the majority of patients were not bothered or minimally bothered by treatment [79]. Clinicians should address this and work to individualize therapy to maximize convenience and comfort.

Although SCIG has distinct advantages over IVIG, it can still cause most of the potentially serious adverse effects that are associated with immune globulin, including thromboembolic complications, hemolytic anemia, aseptic meningitis, transfusion associated acute lung injury, and hypersensitivity reactions, albeit less frequently compared with IVIG. Adverse effects of IVIG are reviewed separately. (See "Intravenous immune globulin: Adverse effects".)

Both IVIG and SCIG can interfere with the efficacy of vaccinations. This is discussed separately. (See "Immunizations in patients with inborn errors of immunity", section on 'Interference with vaccine response'.)

Local reactions — The majority of patients experience some degree of local swelling and discomfort at the infusion site(s). This may decrease in severity or frequency after the first few infusions [21]. Redness, burning, and/or itching are also common. These reactions usually clear within 12 to 24 hours. The patient should be informed about these local side effects and swelling due to the SC fluid depot. Short-term measures that may be helpful include cold compresses, topical corticosteroid cream, and oral antihistamines for pruritus, although treatment is not usually required.

Local reactions often subside after 8 to 10 weeks of therapy. In a study of 32 patients self-infusing SCIG, the percentage of subjects with transient local swelling declined from 75 percent at week 1 to 25 percent at week 10 [21]. If local reactions continue to occur after the first few infusions and are bothersome to the patient, adjustments in rate, site, volume per site, and needle size and depth may be helpful. It is sometimes recommended that patients rotate infusion sites, although it has also been argued that rotating sites does not allow the site to acquire "tolerance" to local reactions with time, and comparative studies are lacking. No long-term adverse effects have been reported at sites used repeatedly. Rarely, local skin necrosis may occur, which is believed to be due to pressure on the cutaneous microvasculature. This complication may potentially be caused by too shallow a depth of administration [57]. This heals over several weeks and may be treated with topical antibiotic ointment (eg, mupirocin 2%) or, if necessary, oral antibiotics to prevent bacterial infection. Occasionally, usually nontender, "pea-sized" SC nodules may occur at infusion sites; they tend to resolve over several weeks with a change of infusion site. Very rarely, persistent local reactions may necessitate switching to an alternative product.

Systemic reactions — Reported rates of systemic adverse reactions associated with SCIG are ≤3 percent [7,8,20-22]. In one review of 10 series including >55,000 infusions, the rate of systemic reactions was <1 percent in eight of the studies [31]. Life-threatening anaphylactic reactions have not been reported with SCIG.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)

SUMMARY AND RECOMMENDATIONS

Advantages of subcutaneous over intravenous immune globulin – Subcutaneous immune globulin (SCIG) offers several advantages over intravenous immune globulin (IVIG). It is as effective as IVIG in preventing infections in patients with immunodeficiency and causes fewer systemic reactions. It provides more consistent serum levels of immunoglobulin G (IgG) and can be infused by patients at home (with or without a pump), leading to improved quality of life. (See 'Available products' above and 'Comparison of SCIG with IVIG' above.)

In contrast, intramuscular immune globulin (IMIG) has few advantages over IVIG or SCIG and is not recommended for immunodeficiency patients. Occasionally, single injections of IMIG are used for postexposure prevention of infectious diseases. (See 'Intramuscular' above.)

Methods of SC administration – There are three ways to administer immune globulin subcutaneously. They differ in both the frequency of administration and how the SCIG is given. The first (traditional) uses infusion pumps to give weekly infusions (most commonly). The second (rapid push) is given using only a syringe and needle or prefilled syringes at frequencies ranging from daily to several times per week. The third is hyaluronidase-facilitated SCIG (fSCIG), usually given every three to four weeks. (See 'Available products' above and 'Administration and dosing of SCIG' above.)

SCIG and IMIG are usually more concentrated than IVIGImmune globulin products specifically intended for SC and IM administration are generally more concentrated than those designed for IV use, allowing more immune globulin to be administered in lower volumes. Some 10% IVIG preparations can be given intravenously or subcutaneously (table 1).

Representative dosing – SCIG is usually given in smaller doses (eg, 100 mg/kg) at weekly intervals, although there are other schedules that may be preferable for certain patients. (See 'Administration and dosing of SCIG' above.)

Hyaluronidase-facilitation allows for monthly SC dosing – Hyaluronidase-facilitated SCIG (fSCIG) is a 10% immune globulin preparation, which uses recombinant human hyaluronidase (rHuPH20) given immediately before the immune globulin to allow up to a full monthly dose to be given in a single SC infusion. fSCIG is given in larger doses (eg, 400 mg/kg) every three to four weeks. (See 'Available products' above.)

Monitoring – To monitor SCIG therapy, serum immunoglobulin G (IgG) levels can be drawn at any time relative to infusions once steady state has been reached, which is usually after 12 to 24 weeks of SCIG therapy. The patient's clinical condition should be the main determinant of the necessary IgG level, and different patients may require very different IgG levels to remain infection-free. (See 'Monitoring' above.)

Adverse reactions – Local swelling at the site of infusion, usually lasting less than 12 to 24 hours, is the most common adverse effect and occurs at least initially in the majority of patients. Local reactions usually improve with time. Systemic reactions are uncommon, and life-threatening anaphylactic reactions have not been reported with SCIG. (See 'Adverse reactions of SCIG' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Melvin Berger, MD, PhD, who contributed as an author to earlier versions of this topic review, and E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.

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Topic 3942 Version 25.0

References

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