The more you understand about primary immunodeficiency (PI), the better you can live with the disease or support others in your life with PI. Learn more about PI, including the various diagnoses and treatment options.
Immunoglobulin (Ig) replacement therapy is the standard treatment for individuals with antibody deficiencies. Ig is given intravenously (IVIG) or subcutaneously (SCIG) and replaces the antibodies a person should be making.
Treating antibody deficiencies
Immunoglobulin (Ig) replacement therapy is the standard treatment for individuals with PI who lack antibodies, also known as immunoglobulins, or whose antibodies do not function properly. These types of PI, such as common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA), are known as antibody deficiencies. Because antibodies have an important role in the immune system neutralizing bacteria and viruses and enhancing the destruction of microbes by other immune system cells, antibody deficiencies are characterized by an increased risk of infections. Ig replacement therapy treats antibody deficiencies by providing individuals with functional antibodies that allow their bodies to fight off infections.
The immunoglobulin used in Ig therapy is made from donated human plasma, the liquid component of blood that contains antibodies. Ig replacement therapy can be given either intravenously (IVIG) or subcutaneously (SCIG). All therapies, regardless of route, must be individualized to meet the patient’s needs. There are many options available for therapy and individuals should thoroughly discuss these options with their prescribers.
Regardless of how it is given, Ig only provides temporary protection, typically for 1-4 weeks. Most antibodies, whether produced by the individual’s immune system or given in the form of Ig replacement, are used up by the body and must be constantly replenished. Repeat doses of Ig are required at regular intervals to provide those with antibody deficiencies with high enough Ig levels to ward off infection.
In addition, the Ig given to people with PI only replaces what the body should be making, and does not stimulate the individual’s own immune system to make Ig. Since Ig only replaces the missing end product but does not correct the person’s underlying deficiency, Ig replacement therapy is usually necessary for the individual’s lifetime.
Immunoglobulin derived from human plasma was first introduced as a treatment option in 1952 when it was injected intramuscularly (IM) to treat people with recurrent infections who had antibody deficiencies. Dosing was very difficult because only small amounts of immunoglobulin could be given in each painful shot. Scientific investigations in the 1960s and 1970s finally led to a suitable immunoglobulin product that could be used intravenously. In 1980, the first commercial immunoglobulin product for IVIG was approved in the U.S. People with antibody disorders have been successfully treated with IVIG for over 40 years.
With the discovery of well-tolerated preparations of IVIG in the 1980s, the suboptimal, painful IM administration was no longer used. This shift to IVIG changed the face of PI treatment. SCIG was used as early as the 1970s, but it did not gain approval from the FDA in the U.S. until 2006.
Ig manufacturing and safety
There are a variety of Ig products approved for use in the U.S. Ig products are typically 95-98% pure IgG (which is a specific class of antibodies) with only small amounts of other classes of antibodies like IgA and IgM. These products vary in a number of ways, including the overall concentration of IgG, distribution of IgG subclasses, stabilizers, and approved infusion route(s). All Ig products are made from donated human source plasma though, and there are multiple steps in the production process designed to ensure the safety of the resulting product, including initial donor screening, viral removal, and inactivation of viruses.
All plasma donors undergo a rigorous screening process that includes a detailed history of infections and risk behaviors, and testing of their plasma for certain viruses using very sensitive techniques. Donors can only give plasma if they pass this screening. Donors are asked specific questions about risk factors that could affect the safety of the donation and are excluded from donation if risk factors are identified.
Plasma centers can also look at the donation history of each donor and the U.S. Food and Drug Administration (FDA) requires centers to maintain lists of unsuitable donors to prevent further donations from people who have been rejected previously. As an added protection, plasma donors must return to donate a second time within a set timeframe, at which time they are rescreened for viruses and risk factors. If a donor does not return within that timeframe, their prior plasma donation is discarded.
After donation, the individually donated plasma is tested for infectious agents before being pooled with plasma from thousands of other donors. Once the plasma is pooled, the entire pool is tested for the markers of HIV and hepatitis A, B, and C viruses. The pooled plasma is then divided up and different methods of fractionation and filtration help to separate out a specific class of antibodies, called IgG. At multiple times throughout this process, the pool is tested for viral safety.
In the mid-1990s, rare clusters of non-A, non-B hepatitis (now known to be caused by hepatitis C virus (HCV)) were documented after the use of some IVIG products. This prompted the addition of an extra viral inactivation step in the manufacturing process. Now multiple safety measures, including pasteurization, low pH, low pH with an enzyme called pepsin, and solvent detergent help dissolve lipid-enveloped viruses, including HCV. An additional safety step is chromatography, a technique widely used to obtain pure ingredients from mixtures. More recently, a final ultrafiltration or depth filtration step has been added to remove the possibility of transmission of prion-related diseases such as mad cow disease. Transmission of HIV, which is destroyed in the first ethanol fractionation step in the production of Ig, has never been documented with the use of any Ig product.
Usually, a given lot of Ig product is derived from approximately 10,000 donors. This ensures that all lots contain a broad spectrum of antibodies to specific microbes that are found in the general population, which then provide protection to people with PI. All Ig products licensed in the U.S. must be made from source plasma that has been collected in the U.S.
Resources just for you
If you are living with PI, think you might have PI, are a caregiver, or healthcare professional, perhaps these resources will help.
The goal of Ig replacement therapy for antibody disorders—no matter the setting, dosing, or route of administration—is to provide protection from infection. An individual’s adherence to therapy is very important for achieving this goal. Any barriers to therapy, real or potential, need to be addressed to ensure that the individual remains on schedule for their infusions.
Ig replacement therapy is typically dosed based on the recipient’s weight. The prescriber, however, considers many factors when the medication is prescribed. Typically, a starting dose is between 400-600mg/kg/month. Doses are adjusted for clinical efficacy, with the expectation of minimizing the frequency and severity of infections while minimizing the side effects of the medication. IgG levels are usually monitored over time and correlated with the response to therapy. The goal is to keep the Ig in the bloodstream above a certain level even when the level is at its lowest point (the trough level) right before the next infusion is due.
It is also important to remember several things when considering Ig replacement therapy:
Not all infections can be prevented. After starting Ig replacement therapy, individuals may still get infections. The hope, however, is that the frequency and severity of infections will significantly decrease so that permanent organ damage, like bronchiectasis, can be prevented.
One size does not fit all. An individualized Ig replacement therapy regimen must be developed for each individual and modified as necessary to achieve treatment goals and the needs of each person.
Once a diagnosis of PI involving antibody production and/or function has been made, Ig replacement therapy is likely needed for life. In some instances, reevaluation of the diagnosis may be undertaken. This must be done cautiously, as Ig replacement therapy must be stopped for four months to obtain accurate repeat lab tests.
Use this table to discuss the options with healthcare providers when immunoglobulin (Ig) replacement therapy is determined to be the treatment of choice and is deemed medically necessary. Decisions on which therapy is best should be made with some of these factors in mind.
Tests to complete beforehand
Before starting Ig replacement therapy, it is important that a healthcare provider completes all immune studies needed to demonstrate that the individual’s Ig levels are not only low but also that the individual does not make specific antibodies.
This is because people who do not have antibody disorders normally make antibodies during and after natural infections and in response to immunization with vaccines, so their Ig levels are not constant. To confirm that an individual cannot make functional antibodies to a specific antigen, immunologists generally use tetanus toxoid and pneumococcal vaccines.
Blood drawn before giving the vaccine is used to measure the vaccine-specific antibody levels, which should be low. After vaccination, a second blood sample is drawn 4-6 weeks later to determine how well specific antibodies were made to these vaccines. It is important that the individual completes this second blood draw to determine the response to the vaccine within this 4-6-week timeframe. These results provide important information about the individual’s immune condition and insurance companies often review this information before approving Ig replacement therapy. Once Ig replacement therapy is started, it is not possible to get accurate results for these important tests without stopping Ig treatment for a few months.
Options for administration
Ig replacement therapy is generally administered as either IVIG or SCIG. SCIG can be given in two ways: conventional or facilitated. The facilitated method uses an additional enzyme medication to increase the amount of Ig that can be delivered during each subcutaneous infusion.
IVIG allows the infusion of higher doses over a short time, but it must be administered by a healthcare professional. SCIG does not require venous access and results in the slow release of Ig from the subcutaneous tissues into the blood, which enables IgG levels to remain more consistent between infusions. With SCIG, there is a steady level of IgG present in the bloodstream due to a more frequent dosing regimen and a slower rate of absorption. With IVIG, the dosing at longer intervals may cause peaks and valleys, called troughs.
Many practical considerations need to be taken into account when deciding if IVIG or SCIG is the right choice. Because IVIG requires healthcare provider supervision, IVIG used to require travel to outpatient settings. However, more insurance companies, as well as Medicare, now cover the supplies and services needed for home IVIG.
SCIG provides the freedom to administer Ig at home or anywhere else at any time of day because medical supervision is not required. While this flexibility and control have been shown to enhance many individuals’ quality of life, the ability of the individual to adhere to the treatment regimen is an important consideration for SCIG since there are no fixed appointments.
In addition, fear of needles and poor manual dexterity, or an inability to make coordinated hand and finger movements to manipulate objects, can be limiting factors for SCIG. For fear of needles, strategies like using topical numbing creams can help. Manual dexterity is required for SCIG in order to draw up the Ig and manage the pump. IVIG requires less frequent infusions and only one infusion site, which is established by the administering healthcare provider.
SCIG is associated with a lower rate of systemic side effects, making this route of administration a good option for those experiencing unwanted adverse effects from IVIG. Also, administration of more frequent, smaller volumes provides a steady level of Ig, avoiding high peak levels that may be associated with side effects of IVIG, such as headaches, and symptoms of wear-off. College students and those whose jobs require frequent travel should seriously consider SCIG.
The following are considerations for choosing SCIG over IVIG:
Extreme prematurity (mainly infants born before 30 weeks).
In addition, the Centers for Medicare and Medicaid Services (CMS) has indicated that only certain ICD-10 diagnostic codes for primary immunodeficiency (PI) warrant immunoglobulin replacement therapy under Medicare Part B. Other diagnostic codes may be covered under Medicare Part D. Adapted from CMS.
IVIG is typically given through a vein every 3-4 weeks at a dose determined by the prescriber. Infusions can be given in various settings, including inpatient or outpatient infusion suites, physicians’ offices, or at home. IVIG must be administered by a healthcare professional, with the procedure scheduled in advance. In special extenuating circumstances, individuals can be instructed to self-infuse this therapy after they are stable on the treatment, as long as IV access can be established. Healthcare professionals should, however, stay with the individual for the length of the infusion because of the risk of serious side effects.
Most immunologists strongly discourage the use of central venous catheters (also known as ports) to administer IVIG due to the increased risk of serious blood infections and the development of blood clots. Given the very serious risk involved with the use of implantable ports, individuals with poor venous access should instead consider switching to SCIG.
Side effects of IVIG
Although IVIG has been safely and effectively administered since the early 1980s, IVIG can cause side effects, both local to the site of infusion and body-wide (systemic). Systemic reactions to IVIG infusion occur in approximately 3-15% of individuals. Common infusion reactions include headache (particularly for those with a history of migraines), nausea, fever, chills, flushing, wheezing, vomiting, backache, muscle aches, joint aches, or chest tightness. Individuals are at increased risk for developing an adverse reaction during their first IVIG infusion, if they have active infections or pre-existing conditions (such as pneumonia or bronchiectasis), or if they are switching products.
These side effects usually resolve on their own and can be avoided by decreasing the rate of the infusion, hydrating well before and during the infusion, and making sure that the product is at room temperature when it is infused. Pre-medicating with acetaminophen (Tylenol), diphenhydramine (Benadryl), non-steroidal anti-inflammatory drugs (NSAIDs like aspirin or ibuprofen), or corticosteroids can also help prevent side effects during and after an infusion. It is important to note, however, that repeated use of corticosteroids for managing side effects may lead to long-term problems.
Side effects experienced during an infusion of Ig are almost always related to infusing too fast or the temperature of the product. Stopping or slowing the infusion is usually the only intervention needed to alleviate these symptoms. Sometimes, a switch in Ig products is successful in alleviating side effects, as some individuals simply tolerate one brand better than another.
Headache caused by aseptic meningitis (inflammation of the membranes that surround the brain and spinal cord) has been seen up to 72 hours after infusion of IVIG and may be more prevalent in people with a history of migraines. Hydrating prior to IVIG can prevent this side effect. It is important to note that not every person who develops a post-infusion headache necessarily has aseptic meningitis. The prescriber should be notified if the individual experiences severe headaches that do not respond to standard medications like acetaminophen or ibuprofen.
Anaphylaxis, a severe, whole-body allergic reaction, is very rare and may be associated with IgE antibodies against human IgA in some people who have IgA deficiency, although the role of these antibodies in causing anaphylaxis is still controversial. Currently, there are no tests for these IgE antibodies. Newer, liquid IVIG products have low concentrations of IgA. In addition, reactions due to anti-IgA antibodies do not occur with SCIG, and SCIG has been safely given to people with PI suspected of having anti-IgA IgE antibodies.
Acute renal failure has been seen after infusion of IVIG. However, 90% of these cases occurred with sucrose-based products, which are no longer in use. Individuals over age 65 or who have pre-existing kidney disease may be at an increased risk of adverse kidney effects.
Blood clots causing stroke, heart attack, or pulmonary embolism, have been associated with IVIG infusions. The relationship between IVIG infusion and an increased risk of blood clots is thought to be due to an enzyme contaminant in plasma preparations called factor XIa that manufacturers now test for and eliminate in the final product to reduce this risk. Risk factors for blood clots include heart disease, advanced age, previous thrombotic event, clotting disorder, hypertension, diabetes, high cholesterol, renal disease, obesity, and immobility. Adequate hydration prior to administering the IVIG is very important, as is not exceed the recommended rate of infusion.
Hemolytic anemia resulting in low numbers of red blood cells is a rare but reported side effect of IVIG. The risk of significant hemolytic anemia appears greater in those who receive high-dose IVIG for autoimmune disorders than in those who are receiving replacement therapy.
The individual with PI or a caregiver should report all side effects and any discomfort experienced during or after an infusion of IVIG to the prescriber, the healthcare professional administering the therapy, the product's manufacturer, and MedWatch at the Food and Drug Administration (FDA).
Optimizing the IVIG infusion experience
A healthcare provider trained in IVIG replacement therapy and an appropriate setting for administering IVIG is important. Many of the side effects that happen during an infusion are related to the infusion rate. The healthcare provider should be experienced in infusing Ig and aware of when to slow down or stop the infusion if necessary.
It is important to be well-hydrated going into an infusion of IVIG. Not only will being hydrated help the healthcare provider get an IV started, but it will also decrease the risk of headaches and other side effects afterward. Likewise, it is important to take the pre-medication as prescribed since it is designed to prevent side effects.
Individuals or caregivers should record each infusion experience in an infusion log (available from many Ig manufacturers) so that any adverse experience can be reported to the healthcare provider and the prescriber prior to the next infusion. It is important to report adverse experiences so that adjustments can be made to the infusion rate, pre-medication regimen, Ig dose, or other variables.
Subcutaneous immunoglobulin replacement therapy (SCIG) has gained popularity in the U.S. since the approval of the first SCIG Ig product in 2006. Currently, there are several products available that can be administered subcutaneously using a number of regimens. These products differ based on concentration, stabilizers, and infusion specifics.
In general, SCIG regimens require the individual with PI or a caregiver to learn how to administer infusions at home. Both forms of SCIG allow for self-administration at home, but facilitated SCIG may also be administered at home or in-office by a nurse, depending on insurance coverage and preference.
The following are currently available for subcutaneous use: 10%, 16.5%, and 20% IgG preparations for conventional SCIG, and a 10% IgG preparation plus an enzyme called hyaluronidase for facilitated SCIG. The Ig is infused under the skin, into the subcutaneous layer of the abdomen, thighs, or outer buttocks at one or multiple sites, depending on the volume being infused. The total monthly dose is calculated by the prescriber based on the individual’s weight, then divided according to the interval between infusions. The number of needle sticks (infusion sites) is also calculated for the individual depending on the volume and the concentration of Ig to be infused. Larger intervals between infusions require the infusion of larger volumes of product to achieve the same total dose per month.
In general, SCIG is delivered using a small needle attached to tubing and a syringe, which is placed in a pump. The Ig products come in a variety of vial sizes depending on the manufacturer. Several needle and tubing sizes are available, and troubleshooting problems with SCIG often involves reviewing that the equipment being used, such as needle sets, tubing, and pump, are appropriate for the individual receiving the therapy.
Conventional SCIG can be given daily, weekly, every two weeks, or multiple times per week, as long as the total monthly dose is divided appropriately. Some individuals may prefer or better tolerate SCIG delivered by subcutaneous push instead of a pump, meaning that a small amount of SCIG is injected daily under the skin without the use of a pump.
Facilitated SCIG is given every 3-4 weeks to deliver the total monthly dose at once into the subcutaneous space. This is facilitated by hyaluronidase, a naturally occurring enzyme in the subcutaneous tissues. Hyaluronidase is injected into the subcutaneous space before the Ig to expand the space and allow more medication to be infused into each site. The effects of the hyaluronidase enzyme are very short-lived, and the tissues revert back to normal in 24-48 hours. In facilitated SCIG, about 300-600ml can be delivered in one site or divided into two or more sites as tolerated.
The benefit of facilitated SCIG is a decrease in the frequency of infusions, as it allows for an entire 3-4 week dose to be administered at one time. The length of the infusion varies depending on the volume infused, but generally takes up to 1-2 hours.
As in IVIG, the typical starting dose for SCIG is between 400-600mg/kg/month. The prescriber adjusts the dose to clinical effect, with the expectation of minimizing the frequency and severity of recurrent infections. IgG levels are monitored over time, correlated with clinical outcomes, and the dose is adjusted as necessary. With conventional SCIG, there is a steady level of IgG present in the bloodstream (no peaks or troughs like IVIG) because of the more frequent infusions. With facilitated SCIG, there are peak and trough levels, but the peak levels are not as high and the trough levels are not as low as with IVIG.
Side effects of SCIG
In general, SCIG is associated with fewer side effects than IVIG. SCIG is an option to consider when an individual does not tolerate IVIG well, when there is poor venous access, or when the individual’s lifestyle is more compatible with SCIG than IVIG. SCIG is an option for children, adults, pregnant women, the elderly, and for individuals with IgA deficiency secondary to having antibodies against IgA (very rare).
Pre-medication is usually not required for SCIG and systemic side effects are typically mild. Severe reactions rarely occur, but individuals who have had severe reactions to IVIG may be at a higher risk of severe reactions to SCIG.
The most common side effect of SCIG is local redness, swelling, and irritation at the injection site. Usually, these mild localized reactions improve with repeated infusions. In rare cases, the injection site reactions can be severe. To improve or avoid the infusion site reactions, and decrease the chance of other problems, individuals need thorough training to ensure they use proper technique to access the subcutaneous tissue. Local skin reactions may be due to inadequate needle length preventing the Ig from being infused into the subcutaneous tissue. For those with a fear of needles, a topical numbing medicine or ice can be applied to the skin prior to infusion.
The individual with PI or a caregiver should report all side effects and any discomfort experienced during or after an infusion of SCIG to the prescriber, the healthcare professional administering the therapy, the product's manufacturer, and MedWatch at the Food and Drug Administration (FDA).
Optimizing the SCIG infusion experience
Several SCIG variables allow individuals to optimize their infusion experience, including the number and location of infusion sites, the volume infused per site, needle length, and pump type. The number of needle sticks can be reduced by increasing the volume infused per site or using the more concentrated 16.5% or 20% IgG products. Conversely, more sites may be needed when using less concentrated 10% IgG products. With facilitated SCIG, the dose can be divided between 1-2 sites, depending on how the infusion is tolerated.
If the individual is experiencing discomfort using abdominal infusion sites, other sites such as the thighs can be used. For those who have issues tolerating infusions, smaller volumes of SCIG daily may be needed. Several needle lengths are also available; the important thing is to use a needle long enough to ensure that the Ig is being administered into the subcutaneous tissues rather than the skin. A variety of infusion pumps are available ranging from simple, portable mechanical pumps to more complicated programmable pumps. Most importantly, SCIG can provide freedom of scheduling for those who self-infuse, resulting in fewer school and workday losses.
Monitoring Ig replacement therapy
The prescriber will order routine lab tests to monitor individuals on Ig replacement therapy, such as complete blood counts (CBC) and measures of kidney and liver function. None of the currently available Ig products are stabilized with sucrose, making kidney complications less likely. The smaller doses for SCIG also minimize fluid overload risks. Most importantly, the prescriber will monitor the person on Ig replacement therapy for infections to make sure it is having the intended therapeutic effect.
For those on IVIG treatment, the prescriber may also order tests measuring IgG levels just before an infusion to assess trough levels. With SCIG, IgG is at a steady state in the bloodstream, so IgG levels may not be monitored as closely.
Products approved for IVIG and/or SCIG in the U.S.
All products can be stored either refrigerated or at room temperature (not to exceed 77°F or 25°C) for at least four weeks; check package inserts to see if your specific product can be stored for longer. Once a product has reached room temperature, it should not be returned to refrigerated temperature.
Products should never be frozen and should be discarded if they become frozen. Refer to product package inserts for additional storage details.
Octapharma and Pfizer both distribute Cutaquig. Each company has its own product website and may have its own copay assistance program. If your infusion center or hospital supplies Cutaquig, it is typically distributed by Octapharma. If you get Cutaquig through a specialty pharmacy/for home care, it is distributed by Pfizer.
Report side effects/adverse reactions at 201-604-1137.
Administration: IVIG Concentration: 5% (50 mg/mL) or 10% (100 mg/mL)* * Octagam 10% is approved for chronic immune thrombocytopenia and dermatomyositis. Approved for: Ages 6+
Octapharma and Pfizer both distribute Octagam. Each company has its own product website and may have its own copay assistance program. If your infusion center or hospital supplies Octagam, it is typically distributed by Octapharma. If you get Octagam through a specialty pharmacy/for home care, it is distributed by Pfizer.
Report side effects/adverse reactions at 201-604-1137.
Octapharma and Pfizer both distribute Panzyga. Each company has its own product website and may have its own copay assistance program. If your infusion center or hospital supplies Panzyga, it is typically distributed by Octapharma. If you get Panzyga through a specialty pharmacy/for home care, it is distributed by Pfizer.
Report side effects/adverse reactions at 201-604-1137.
This page contains general medical and/or legal information that cannot be applied safely to any individual case. Medical and/or legal knowledge and practice can change rapidly. Therefore, this page should not be used as a substitute for professional medical and/or legal advice.