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Clarifying the Use of Immunoglobulin Treatment in Primary Immunodeficiency

Introduction

Over 120 forms of primary immunodeficiency disorders (PIDs) in 9 categories have been clinically characterized.1 PIDs may be generally classified as defects in either the innate immune system, such as complement deficiencies, or the adaptive immune systems, such as T-cell defects. While PIDs typically lead to increased susceptibility to infections, the degree of immune compromise and specific infection types vary widely across specific conditions. A survey conducted in 2007 estimates the overall prevalence of PIDs as 1 in 1200 persons in the United States, but differs widely depending on the type of disorder.2

With the identification of the first PIDs in the 1950s, administration of immunoglobulin (IG) has provided lifesaving treatment for patients with antibody deficiencies. The initial products available for the treatment of antibody deficiency required administration via the subcutaneous (SC) or intramuscular (IM) routes, with intravenous (IV)IG not being introduced to the market until the 1970s. Since then, the marketed IG products have evolved substantially. The current products provide the safest and most effective choices for treatment. The most important changes include the reduced reliance on sugars for antibody stabilization, the normalization of osmolarity and osmolality, and the availability of premixed, ready-to-use concentrated products that can be given in the ambulatory and home care settings.3-5

IG replacement, by either the IVIG or SCIG routes, is the mainstay of treatment for many PIDs.6 The product selection, dosage, and monitoring characteristics of each IG product require careful consideration on the part of the therapy team involved in the patient’s care. This activity will focus on the immune system, primary immunodeficiencies, and IG treatment considerations.

The Normal Immune System

To understand PIDs and the role of IG therapy in these disorders, you must understand the basics of the human immune system, which consists of a number of interconnected and interdependent components.7,8 The innate immune system is the first line of defense, comprising macrophages, dendritic cells, natural killer cells, and other cells responsible for generating an inflammatory response. The adaptive immune system represents the second line of defense and requires the expansion of antigen-specific B- and T-cells, which leads to the development of memory.

The innate immune response is dependent on the recognition of unique features of foreign antigens, known as pathogen-associated molecular patterns (PAMPs), by pattern recognition receptors (PRRs). Following recognition of a PAMP by a PRR, effector cells of the innate immune system such as macrophages and dendritic cells are activated, thereby releasing pro-inflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-1β (IL-1β). These cytokines lead to the activation of the complement system and chemotaxis of neutrophils toward the site of infection.9 There happens to be an entire category of PIDs related to deficiencies of the innate immune system.1

Next, the immune system needs to form the bridge between the innate and adaptive immune system. The dendritic cells are a type of antigen-presenting cell (APC). When an APC encounters a foreign antigen, the cell migrates through the lymphatic system and begins to interact with T-cells. The foreign antigen is presented to a T-cell through a major histocompatibility complex (MHC) molecule on the surface of the APC. MHC I is expressed by all nucleated cells and presents intracellular antigens, such as viral proteins, and leads to the activation of CD8+, or cytotoxic,T-cells. Only dendritic cells, macrophages, and B-cells express MHC II, which, in turn, expresses extracellular antigens such as bacterial toxins and activates CD4+, or helper, T-cells.10

Once activated, CD8+ T-cells migrate to cells that express the targeted foreign antigen. Following contact with these cells, CD8+ T-cells release proteins, which cause the targeted cell to undergo apoptosis within minutes. In contrast, most CD4+ T-cells serve to further activate additional arms of the immune system. After interacting with MHC II molecules, the subset of CD4+ T-cells, known as TH1 cells, release interferon-γ (IFN-γ), which has many roles, but in this case leads to activation of macrophages. Macrophages are responsible for the phagocytosis and defense against a variety of bacteria, fungi, and parasites, such as Toxoplasma gondii and Pneumocystis jiroveci.11 This series of interactions represents the cell-mediated component of the adaptive immune response.

The other subset of CD4+ T-cells, TH2, aids in the expansion and maturation of B-cells, which recognize free antigen and do not require the presence of MHC molecules.12 Antigens are recognized by a cell-surface IG, such as immunoglobulin M (IgM) for immature B-cells and IgM and immunoglobulin D (IgD) in mature B-cells, which are present at the B-cell receptor. The B-cell receptor has the same antigen specificity as the memory B-cells that will eventually be produced. Following binding of the antigen to the surface-bound antibody, the antigen is internalized, processed, and re-expressed on the surface of the B-cell bound to an MHC II molecule. The outcome is then recognized by TH2 cells, which are activated, undergo clonal expansion, and allow for activation and maturation as well as differentiation of B-cells.

There are 2 predominant forms of mature B-cells. The first form of mature B-cells, memory B-cells, may exist for years or decades and is responsible for the rapid immunologic response on repeat exposure to a foreign antigen.13 In contrast to immature B-cells, which may react to any antigen, memory B-cells are highly specific and express IgM or IgD that bind to only one antigen. The second type of mature B-cells are plasma cells, which are typically short-lived and produce massive quantities of antigen-specific antibodies. The activation, expansion, and maturation of B-cells and the resultant IG production is the humoral arm of the adaptive immune system.

Earlier, IG was mentioned briefly as an important part of the immune system. IGs exist in several forms, including IgA, IgD, IgE, IgG, and IgM, all of which are produced by plasma cells and all play important roles in the immune system. However, IgG plays the most important role with regard to the development of antibody-mediated immunity. Each IG consists of an Fc (fragment-crystallizable) region, which binds to the Fc receptor on effector cells (i.e., a lymphocyte, such as cytotoxic T cell, that has been induced to differentiate into a form capable of mounting a specific immune response), and Fab (fragment antibody) region, which recognizes the antigen.14 Once antigen binds to IgG, a cascade of events occurs. First, there is activation of the classical pathway of the complement system through the formation of IgG complexes. This allows for the opsonization and phagocytosis of pathogens.15 In addition, binding of IgG complexes to the FcγR leads to activation of macrophages, forming a link to cell-mediated immunity.16

Types of Primary Immunodeficiency Disorders

Although there are more than 120 described PIDs, understanding those that are the most common and clinically significant is of the utmost importance. Table 1 provides a list of the most common PIDs. PIDs are primary because the baseline immune system is the cause and most are genetic defects that are typically inherited. Secondary immune deficiencies are so called because they have been caused by other conditions. For example, treatment with chemotherapy can cause a secondary immune deficiency by causing depletion of antibody-producing cells. For the purposes of this particular review, the focus will be on common variable immune deficiency, severe combined immunodeficiency, and Wiskott-Aldrich syndrome.

Table 1. Common Primary Immunodeficiencies
Primary Immune Deficiencies
Congenital agammaglobulinemia
Common variable immune deficiency (CVID)
Wiskott-Aldrich syndrome (WAS)
X-linked agammaglobulinemia (XLA)
Severe combined immunodeficiency (SCID)
Hyper IgM syndrome (HIGM)
DiGeorge syndrome
Ataxia Telangiectasia (A-T)

Common variable immune deficiency

Common variable immune deficiency (CVID) is a heterogeneous group of disorders that is primarily characterized by a reduction in the serum levels of IgG, IgA, or IgM. While still uncommon in the overall population, CVID is the most frequent and symptomatic of PIDs, with a prevalence estimated at between 1 in 25,000 and 1 in 50,00017 and its hallmark being primary hypogammaglobulinemia. Current diagnostic criteria supported by the Pan-American Group for Immunodeficiency (PAGID) and the European Society for Immunodeficiencies (ESID) require 3 components to support a diagnosis of CVID: 1) Decrease in serum IgG and IgA levels at least 2 standard deviations below the mean for age; 2) At least 2 years of age; 3) Poor vaccine response and/or absence of isohemagglutinins; 4) Exclusion of other causes of hypogammaglobulinemia.18 New diagnostic criteria also call for the presence of such symptoms as recurrent, severe, or unusual infections to determine CVID.18

In addition to substantial infections, patients with CVID also present with a number of other complications. In 1 large, prospective cohort of CVID patients followed over a 40-year time frame, 68% experienced autoimmune or inflammatory conditions, 28.5% developed chronic lung disease, 15.4% had noninfectious gastrointestinal disease, and nearly 20% developed malignancy.19 Treatment with IVIG has decreased mortality from 29% to 19.6%, primarily because of a reduction in infectious complications.19

Severe combined immunodeficiency

Severe combined immunodeficiency (SCID) is another group of heterogeneous disorders characterized by the inability of T-cells to differentiate. In contrast to CVID, patients with SCID present early in life with severe infections. Without treatment, the majority will die within 1 year.20 The prevalence of SCID is estimated between 1 in 50,000 and 1 in 500,000 live births. X-linked SCID (X-SCID) and adenosine deaminase deficiency (ADA), the most common forms, account for 45.4% and 14.8% of cases, respectively.21 Those with X-SCID have defects in the IL-2 receptor γ chain, leading to an almost complete loss of T-cells and natural killer cells, but retain normal counts of B-cells that are defective and nonfunctional, while those with ADA deficiency develop an accumulation of deoxyadenosine leading to a complete loss of functional T, B, and NK-cells.22

Patients with SCID generally present with severe opportunistic infections at the age of 3 to 6 months. The most common infections are of the respiratory system, such as Pneumocystis jiroveci, and gastrointestinal tract.20 Without treatment, all forms of SCID are universally fatal. Therapy with hematopoietic stem cell transplantation (HSCT) remains the treatment of choice for those with SCID.23 In addition to serving as a temporizing measure prior to HSCT, IVIG is a standard treatment option for patients with inadequate B-cell function following transplantation.24

Wiskott-Aldrich syndrome

In contrast to both CVID and SCID, Wiskott-Aldrich syndrome (WAS) is linked to 1 of several defects in a single gene on the X-chromosome known as the Wiskott-Aldrich syndrome protein (WASp).25 WASp is a protein in the cytoplasm of hematopoietic cells, with mutations leading to deficiencies in both B- and T-cell signaling and antigenic response.25 Certain defects in WASp may lead to other clinical phenotypes without primary immune deficiency, such as X-linked thrombocytopenia or X-linked neutropenia, but the classical phenotype previously described is the most common, occurring in 1 to 10 out of every 1 million live births.25

Patients with WAS characteristically present with thrombocytopenia, eczema, autoimmune disorders, and malignancy as well as increased infections.25 Thrombocytopenia occurs in varying degrees, with about one-half of patients having small platelets. The majority of individuals have near-normal levels of IgG, but approximately 70% will present with an inadequate response to pneumococcal polysaccharide antigens following immunization.26 Patients with the most severe phenotypes, such as those developing autoimmune complications, have a poor prognosis that requires HSCT.27 Until that time, supportive measures that include splenectomy, antibiotic prophylaxis, and IVIG improve short- and medium-term survival for patients with WAS.28

Product Characteristics

With the evolution of IG products on the U.S. market, safety and efficacy have improved and products are considered to be in the 3rd or 4th generation and are formulated to have specific quantities of IgG subclasses in a similar distribution to that of normal plasma. The products vary with regard to IgA content, stabilizers, and preservatives. Differences among the products are from variations in the manufacturing process that can affect the IG components, the pH, sodium content, osmolality, and stability of the final product. Distinctions between the current products are summarized in Table 2.3,29,30 Another important difference is the final concentration of the product. Some of the more concentrated products, those with 10% to 20%, can be SC infused. Products with concentrations of 10% that are IV administered can generally be infused over a shorter period of time than the less concentrated products with 3% to 6%. The variations in these products can potentially free up infusion space in the ambulatory clinic, reduce nursing time, and also provide convenience for the patient.31

Table 2. Product Characteristics
Brand Name Concentration Stabilizer Sodium
Content		 IgA Content mcg/mL Sugar Content pH Osmolarity/
Osmolality (mOsm/kg)		 Latex-free
Packaging		 Route of Administration
Bivigam Liquid 10% Glycine 0.100–0.140 M ≤ 200 None 4.0–4.6 ≤ 510 Yes IV
Carimune NF Lyophilized
3%–12% 		Sucrose < 20 mg/g protein 720 1.67 g sucrose/g protein 6.4–6.8 192–1074 No IV
Flebogamma 5%/10% Liquid
5% or 10% 		D-sorbitol Trace < 3 5% D-sorbitol 5.0–6.0 240–370 No IV
Gammagard Liquid Liquid 10% Glycine None 37 None 4.6–5.1 240–300 Yes IV, SC
Gammagard S/D Lyophilized
5%, 10% 		Glucose 8.5 mg/mL;
17 mg/mL 		≤ 2.2 20 mg/mL;
40 mg/mL 		6.8±0.4 636; 250 (mOsm/L) No IV
Gammaked Liquid 10% Glycine Trace 46 None 4.0–4.5 258 Yes IV, SC
Gammaplex Liquid 5% Glycine 30–50  mmol/L <4 5%
D-sorbitol (polyol) 		4.6–5.1 460–500 Yes IV
Gamunex-C Liquid 10% Glycine Trace 46 None 4.0–4.5 258 Yes IV, SC
Hizentra Liquid 20% Proline Trace ≤ 50 None 4.6–5.2 380 Yes SC
HyQvia Liquid 10% Glycine None 37 None 4.6–5.1 240–300 Yes SC
Octagam 5%/10% Liquid
5% or 10% 		Maltose ≤ 30 mmol/L < 100 100 mg/mL maltose 5.1–6.0 310–380 Yes IV
Privigen Liquid 10% Proline Trace ≤ 25 None 4.8 Isotonic 320 Yes IV
IgA = immunoglobulin A; IgG = immunoglobulin G; IV = intravenous; SC = subcutaneous

Stability of the IG molecules is of the utmost importance in ensuring that the product is efficacious and will be well-tolerated. Stabilizers are used to prevent aggregation, fragmentation, oxidation, and dimer formation; sugars such as maltose, sucrose, glucose, and sorbitol can be used. To decrease osmolarity, which can become elevated with sugars, the amino acids glycine and L-proline have been added to the 4th-generation formulations.3,30 Hyperosmolar solutions are typically seen with the older lyophilized IVIG products, whereas the 4th-generation products have a more physiologic osmolarity of around 300 mOsm/kg. The specific stabilizer used can play an important role in the tolerability of any one product, and higher osmolarity solutions tend to cause more local venous irritation at the infusion site.32

Maltose-stabilized IG products can pose an important safety consideration that warrants attention from health care professionals. Glucose monitoring technologies using the glucose dehydrogenase pyrroloquinoline quinone (GDH-PQQ) methodology cannot distinguish between glucose and maltose. When using a GDH-PQQ glucose test strip, it will produce a substantially elevated glucose result if maltose is present in a blood sample. This can lead to inappropriate dosing and the administration of insulin, potentially resulting in hypoglycemia, coma, or death.33 In addition, cases of actual hypoglycemia may go unrecognized if the patient and health care providers rely solely on the test result obtained with the GDH-PQQ glucose test strips. Other glucose test strip methodologies are not affected by the presence of maltose, and laboratory-based blood glucose assays do not use GDH-PQQ methodology and are not subject to falsely elevated results from maltose. If a maltose-stabilized IG product is to be used within a health care system or by a patient, it is important to investigate the technology being used to measure blood glucose. Manufacturers of glucose test strips have been diligent in converting to alternative methods of measuring blood glucose, but clinicians should be able to identify the at-risk products that are still available.3

Adverse Events

The earliest IG products had a relatively high incidence of infusion-related adverse effects that were the result of complement-activating aggregated IG. Since then, the implementation of manufacturing steps that avoid the formation of aggregates has significantly decreased the number of infusion-related reactions.3,30 Other types of serious adverse events such as acute renal failure, aseptic meningitis, hemolysis, and thrombosis have been observed. Some can be attributed to either certain IG products, to the size of the dose administered for specific indications, to the rate of infusion, or to characteristics of the patient receiving the treatment. In general, IG therapy is well-tolerated, and considering patient and product characteristics can mitigate many risks. For the purposes of this review, the adverse events discussed are those that have specifically been attributed to different patient or product characteristics.

Anaphylactoid Reactions

Anaphylactoid reactions typically manifest during or just after the IG infusion and result from an inflammatory response elicited by components of the IG product such as IgG complexes, immune globulin fragments, stabilizers, the temperature of the infused solution, acute complement activation, IgA, low molecular weight polypeptides, and alloantibodies to blood type A/B.34 The original IG products contained IgG complexes that occurred as a result of the tackiness of the IGs that cause aggregation during purification from other plasma proteins. Modern manufacturing processes have eliminated these complexes, so severe reactions have become relatively uncommon. Currently available products can still cause anaphylactoid reactions, however.35 The most common anaphylactoid responses are headache, flushing, chest tightness, dyspnea, back pain, nausea, vomiting, and diarrhea, as well as rare cases of hypotension.36,37

Headache is the most frequently reported adverse effect with IG treatment, the incidence of which does not appear to be related to the indication for the therapy. But the occurrence of headache is much less common when a low dose is used.

More serious anaphylactoid reactions develop most frequently in previously untreated persons with agammaglobulinemia. In these individuals, IG treatment may lead to acute complement activation with the production of anaphylatoxins C3a and C5a. Anaphylatoxins with acutely formed antigen/antibody complexes can trigger mast cells and polymorphonuclear granulocytes to release histamine and cytokines. These side effects are relatively rare in those who do not meet this profile.38

Common reactions that are considered milder include fever, malaise, and myalgia, which may occur during or within hours after finishing the infusion. These symptoms are self-limited and often resolve by slowing the infusion rate. IG infusions cause the release of such cytokines as tumor necrosis factor, interleukins, and interferon because of their mechanism of action. The variability in the donor pools from batch to batch or from product to product and the amount of IgA in a given preparation may all influence the risk for such events.35,37

Today’s products contain varying amounts of contaminating IgA (Table 2), which can lead to the formation of anti-IgA antibodies in patients who are IgA-deficient. When infusing IG in a person that is IgA-deficient, these anti-IgA antibodies can cause anaphylactic reactions traceable to IgE development against IgA. The prevalence of IgA deficiency is approximately 1 in 1000 and has been linked to other autoimmune disorders. The risk of a serious anaphylactic reaction in these patients is anticipated, but the incidence appears low given the total number of these reported outcomes compared with the overall number of individuals with IgA deficiency. Based on the low incidence, screening for IgA deficiency prior to IG administration is not routinely recommended; however, patients who are known to develop anaphylactic reactions to IgA and still have to receive IG therapy should be treated with the IG products containing the lowest IgA content.35

Low-molecular-weight polypeptides are also thought to contribute to the occurrence of the less severe adverse effects described above. Allergic reactions to foreign IgG with a resultant release of IgE may also contribute to these events.35 When symptoms begin to manifest, the infusion should be slowed or stopped immediately. For less severe results, the infusion may be resumed as tolerated. However, in the case of persistent or more severe reactions, the infusion bottle should be preserved for further examination, with treatment only resuming when a cause for the reaction is identified. These more severe side effects should also be reported to the manufacturer. The sample can be sent to the manufacturer for extensive analysis and comparison with other lots from the same batch. Most often, the causes of these events are idiosyncratic and the events resolve without further intervention. Pretreatment with acetaminophen and diphenhydramine at the time of the infusion can mitigate some risk of the more minor events happening. The routine use of corticosteroid injections has not been recommended, but they may have some role in the prevention of future adverse effects for those with a history of severe reactions or in treating severe reactions as they occur. 35,37

Acute Renal Failure

Approximately 40 cases of acute renal failure associated with IVIG treatments have been reported,39 and it is important to note that most of these patients had existing renal disease prior to treatment. The histologic finding identified in most cases was swelling and vacuolization of proximal tubular cells, with preservation of brush borders.39 The mechanism of this renal injury is related to the carbohydrates added to stabilize IG preparations. Sucrose, a stabilizing agent for certain IVIG products, has been implicated most often. A high level of vigilance is recommended when using high-dose IVIG in patients with moderate or severe renal insufficiency.35 It is practical to exercise caution when treating patients that have mild renal impairment with a sucrose-stabilized product, even when the treatment only requires a low dose of IG. Avoidance of products that contain sucrose is the standard for mitigating adverse renal events in high-risk patients and, when possible, products containing low solute loads should be considered the preferred agents (Table 2). Renal function testing, including serum creatinine and urine output, before and after therapy, should be closely monitored in patients treated with high doses of sucrose-containing IVIG formulations. All patients administered IVIG products stabilized with carbohydrate products such as glucose, sorbitol, or maltose should be monitored because treatment can potentially lead to renal dysfunction, especially if the product has a high solute load.35

Aseptic Meningitis

As mentioned earlier, headache is the most commonly reported adverse effect associated with IG infusions, and its incidence tends to increase as larger doses are infused over a shorter period of time. Most of these headaches are mild in nature and self-limiting, so an interruption in therapy is not required.35 Cases of aseptic meningitis requiring discontinuation of IG treatment have been reported over the years, and strategies to minimize these neurologic adverse events can be employed. Aseptic meningitis presents initially as severe acute headache, nuchal rigidity, lethargy, fever, photophobia, painful eye movements, nausea, and vomiting.40 The cerebrospinal fluid (CSF) samplings show polymorphonuclear pleocytosis (up to 1200 cells/mL) and increased protein content (up to 1 g/L); glucose content is typically normal and without indication of an infectious source. Symptoms are self-limiting, usually persisting for 3 to 5 days.35 The overall presentation and symptoms resemble those associated with bacterial meningitis. Patients reporting a history of migraine are more prone to developing an episode of aseptic meningitis regardless of the commercial preparation administered, and simultaneous treatment with corticosteroids does not appear to have any protective effect.35

The exact mechanism of aseptic meningitis has not been established. As noted, these cases are associated with an increased CSF protein level, which may be the result of an allergic hypersensitive meningeal reaction caused by entrance of the allogeneic IG into the CSF. Some allogeneic IgG does cross the blood-brain barrier and has been verified in the CSF studies that involve IG recipients.41 While rare, the exact frequency of aseptic meningitis has not been established, but the incidence does appear to be related to the dose used.42 Dosages of 1 g/kg or greater, administered during a 24-hour period, may warrant closer monitoring for this adverse event.35

Hemolysis

Plasma products derived from human blood can contain anti-blood-group antibodies such as anti-A/B IgG directed at the histo-blood-group ABO antigens.35 IG preparations are no exception and, thus, contain amounts of anti-A/B antibodies that vary among products and even among batches of the same product. Manufacturers attempt to remove these complement activating anti-A/B antibodies to some extent, but they remain present in all marketed products. Determining the precise titer of these antibodies requires the clinician to contact the manufacturer because the titers are not reported on the product label. Identified risk factors for hemolysis include the following: recipient with A, AB, and B blood types, high total doses, such as 2 g/kg, and administration of IG preparations with high titer anti-A/B antibodies.43,44 Monitoring high-risk patients administered hemoglobin 48 to 72 hours after IVIG infusion is recommended. In cases where the hemoglobin decreases more than 2 g/dL, a full hemolytic work-up should be completed and a transfusion of O-type blood may even be required for those with severe cases of anemia. At-risk patients receiving large doses of IVIG should also be counseled to report the presence of darkly colored urine within the first several days after infusion to a clinician; this symptom could indicate the presence of red blood cell destruction.35, 37

Thrombosis

Thromboembolic complications such as myocardial or cerebral infarction, deep vein thrombosis, and pulmonary embolism have recently received increased notice as substantial events that can be precipitated by IG infusion.45 The overall rate of thromboembolic events is approximately 3%, and this estimate includes thrombophlebitis at the infusion site.46 Several mechanisms have been proposed as the cause of these events, including hyperviscosity that may result from rapid infusions of high doses into a volume-depleted hyperviscous bloodstream or infusions in patients with established arteriolosclerosis and the diminished ability to autoregulate vascular tone.47 Even more importantly, the elevated levels of activated Factor XI in IG products have been shown to increase the risk of thromboembolic events.48 Manufacturers attempt to minimize the presence of activated factor XI in their final product and perform quality control tests to minimize this risk. Even with these cautionary measures, the risk of thrombosis should be evaluated before initiating IG therapy and clinicians may choose to avoid IG treatment or take extra precaution, such as breaking up infusions over several days or slowing the rate of infusion, when managing patients known to be in a hypercoagulable state or those with a history of thrombotic events.49 SC administration of IG has also been associated with a higher risk of thromboembolic complications when compared with IV administration.46

IV Versus SC Administration

Patients with PIDs, specifically those with antibody deficiencies, require chronic, life long IG therapy.1,50,52 Given the long duration of treatment required, choosing a treatment plan to which they can adhere and adjust it as needed is important for long-term outcomes. This choice can significantly impact health and quality of life because improperly managed PIDs would leave patients susceptible to repeated and serious infections.50,52 Advantages and disadvantages of IVIG and SCIG should be considered for each patient. These considerations are discussed below.

The treatment regimen for IgG replacement may require a substantial time commitment that can disrupt normal daily activities of patients and caregivers.53 For those with PIDs, IG administration typically requires 2 to 4 hours or even longer for patients with a low tolerability to IG infusions and once every 3 to 4 weeks in a clinical or home setting by the IV route.54,55 Alternatively, SC formulations require a commitment of 1 to 2 hours once or twice weekly at home.56-59 The dosing interval for conventional SCIG may be extended for more highly concentrated IG formulations, such as 20% concentrations.60

There is a recently U.S. Food and Drug Administration (FDA)- approved SC-administered IG product, IG infusion 10% with recombinant human hyaluronidase (HyQvia [IGHy]), that employs the same route of administration as conventional SCIG, but uses a separate enzyme (rHuPH20) that is administered prior to IgG administration.61 RHuPH20 increases the bioavailability of IG by transiently depolymerizing a component of the extracellular matrix, hyaluronan, which normally restricts the absorption and dispersion of IG during conventional SC infusions. This allows for IG infusion volumes and rates approximately 10- to 15-fold higher than with conventional SCIG administration.58,62,63 Therefore, self-administration of a full 3- or 4- week dose of IG in a single SC infusion site over a median duration of approximately 2 hours is possible with IGHy,62 which has a safety and tolerability profile similar to that of conventional SCIG.

The differences among the approaches in IVIG, SCIG, and IGHy treatments affect the pharmacokinetics of IG. IVIG may achieve higher peak serum levels of IG, often more than twice the pre-infusion trough level, than with conventional SCIG because of the higher dose per infusion for IVIG than conventional SCIG and the direct delivery of IgG into the intravascular compartment.64-66 A rapid decline in IG levels occurs in the days following IV infusion when IG is redistributed into the extravascular compartment, resulting in a large peak-to-trough variation.65,66 When administered SC, IG needs to be taken up from the site of infusion into the lymphatic system before entering the intravascular compartment. This dampens the peak concentration of IG and delays the time to achieve peak concentration.64-66 Also, the greater frequency of dosing with conventional SCIG than IVIG results in more steady-state IG levels similar to those found in healthy individuals.64,66 IGHy administered at a similar dose and frequency as IVIG provides similar trough levels and the area under the curve (AUC) to IVIG while achieving a lower peak concentration of IG than IVIG and a peak-to-trough variation more similar to conventional SCIG.61,62,67

The design of a treatment plan that includes selection of an IG formulation, dose, frequency, and route of administration for patients with PIDs should take into consideration such challenges as time commitment and effect on quality of life. Because IVIG, SCIG, and IGHy have different adverse-reactions profiles, patient tolerability is an important factor in choosing the route of administration. Those receiving IVIG may incur an increased incidence of systemic side effects, compared with SC administration, which may affect overall quality of life.48,49,54,68 This is associated with the rapid attainment of high peak levels of IG concentration from IVIG compared with SCIG.57,59,62 Common reactions, such as those discussed previously, may be managed with premedication that includes acetaminophen, antihistamines, and corticosteroids; however, there is currently no data from well-controlled clinical trials to support these treatments that lessen rates of systemic adverse events.50 Alternatively, reduction of the infusion rate may also alleviate some adverse reactions.55,59 In contrast, systemic side effects with SCIG and IGHy are less frequent, thereby reducing the need for premedication and close monitoring once tolerability is established.53-55

Conversely, the risk for local adverse reactions is higher with SCIG than with IVIG. Patients receiving SCIG often experience swelling and redness at the site of infusion. The U.S. FDA recommends alternating infusion sites, which is also the practice in U.S. clinical studies. The incidence of local adverse reactions may be reduced by proper technique and use of a needle of an appropriate length to prevent intradermal infusions that may cause tissue necrosis and pain.57 Local negative events such as pain, bleeding, and bruising at the infusion site are rare for patients receiving IVIG, but those with difficult venous access have reported prolonged pain and swelling.59

The route of IG delivery affects the volume of IG that may be delivered at each site. A large volume of IG might arrive at a single IV site with IVIG or at 1 or 2 SC sites for IGHy.62,65 Patients with poor venous access may opt for SCIG or IGHy with a choice of infusion sites. The abdomen—accounting for 90% of infusions in the phase 3 trial—and the thighs are recommended for IGHy infusions. For SCIG, the suggested infusion sites also include the abdomen and thighs, but the upper arms and the lower back/hip as well. SCIG, however, requires multiple infusion sites, ranging from 4 to 8, and a similar amount of sessions because of the volume capacity limitations in the SC tissue.55,65 The selection of an IG formulation of a higher concentration (perhaps 20%) could reduce the volume of the required dose for SC administration.60 Alternatively, IGHy allows for the full dose of an every 3- to 4-week dose of IG to be infused into 1 or 2 SC sites over a median of about 2 hours.62

For patients requiring life long IG treatment, quality-of-life issues should be carefully considered when designing a treatment plan. Each route of administration has inherent attributes that different populations may prefer. Individuals previously receiving IVIG treatment have reported a better quality of life after switching to conventional SCIG self-administration at home because of improved tolerability, including reduction in the incidence of systemic adverse reactions, fewer absences from school or work, and freedom from the need to travel to infusion appointments.65-67

Cost may be an important consideration in the decision between IVIG and SCIG because patients may assume a portion of their health care expenses as out-of-pocket costs. Cost considerations comprise many issues, including such direct costs as IG formulation, services of a health care provider, and facility charges, as well as indirect costs such as travel to medically related appointments outside the home and the cost of time lost from traveling to those appointments and recovering from the adverse reactions. Although there are many considerations, the major differences in cost may arise from some of the following factors as well: who administers the IG, the site of administration, the dose adjustment by switching from IVIG to SCIG, and the acquisition costs of individual products.

Summary

IG therapy is an important component when treating patients with PIDs. There are several considerations that should be taken into account when selecting an IG product for a person, including number and frequency of administration, adverse events, quality of life, and cost. These considerations can help the patient and the provider develop the most appropriate care plan for the individual based on both product and patient factors.

References

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