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INTRODUCTION

For more than half a century, administration of immune globulin therapies have provided lifesaving treatment for patients with antibody deficiency. The initial products available for the treatment of antibody deficiency required administration via the subcutaneous or intramuscular routes. In the 1970s, intravenous immune globulin was developed and introduced to the market. During the past 4 decades, the marketed immune globulin products have evolved substantially. The current armamentarium of immune globulin medications available for use in the clinical setting will provide safer and more 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 advent of premixed, ready-to-use concentrated products that can easily be given in the ambulatory and home care settings.^1-3

The evolution of immune globulin product composition has decreased the risk of infusion-related reactions and other adverse events. However, there remain important product differences that require active management by clinicians to mitigate the risk of untoward events affecting the recipients of immune globulin therapy. Such adverse events include the following: acute renal failure, anaphylactoid reactions, aseptic meningitis, hemolysis, and thrombosis.^4-6

Herein, this review will focus on polyvalent immune globulin products approved for the treatment of primary immunodeficiency, while also discussing the role of immune globulin in the treatment of inflammatory, autoimmune, and infectious diseases.

PLASMA COLLECTION, ISOLATION, AND PURIFICATION

Immune globulin is prepared from plasma pooled from thousands of healthy donors. Approximately one-third of the plasma used for the production of commercial immune globulin products is acquired from the fractionation of whole blood from donors and the remainder of the plasma is acquired from plasmapheresis. Donating plasma by plasmapheresis is similar to a whole blood donation; but, during this process, red blood cells, white blood cells, and platelets are all returned to the donor. Another important difference involved with the production of immune globulin products is that a plasma donor can donate more frequently (i.e., every 2 weeks versus every 8 weeks) than whole blood donors; in addition, the antibody profiles of plasma donors may differ from those of whole blood donors because certain antibody levels take longer to recover than others. Pooling of plasma from these sources and a large overall donor pool, thus, provides a diversity of antibody repertoires and antibody specificities.^4,7 Numerous immune globulin products have been approved by the U.S. Food and Drug Administration (FDA).¹ Other human plasma products used in modern medical practice include the following: albumin, Factor VIII, Alpha 1 Proteinase Inhibitor (alpha1-PI), hyperimmune globulins directed against specific pathogens (e.g., rubella, cytomegalovirus (CMV), rabies, tetanus, hepatitis A, hepatitis B, and measles), and rho (d) immune globulin.

PRODUCT CHARACTERISTICS

The current immune globulin products available in the United States (U.S.) market are considered the third and fourth generations, according to the evolution of the product. The immune globulin products are formulated to have specific quantities of the immunoglobulin G (IgG) subclasses in a similar distribution to that of normal plasma and, also, to have differences in immunoglobulin A (IgA) content, stabilizers, and preservatives. Differences between the products are a result of variations in the manufacturing process that can affect the immune globulin components, the pH, sodium content, osmolality, and stability of the final product (Table 1).^1,7,8 From a practical standpoint, another important difference is the final concentration of the product. Some of the more concentrated products (10% to 20%) can be infused subcutaneously and the more concentrated, intravenously administered, products (10%) can generally be infused over a shorter period of time than the less concentrated products (3% to 6%), thus, potentially freeing infusion space in the ambulatory clinic, reducing nursing time, and also providing convenience to the patient.⁹

Stability of the immune globulin molecules is of the utmost importance to ensuring the product is efficacious and will be well tolerated. Three features that impact the stability of the immune globulin molecules are aggregation, fragmentation, and oxidation. Aggregation and fragmentation are altered by the final immune globulin concentration, the pH, temperature, light exposure, and agitation (during the admixture process, storage, and/or transportation). Oxidation discolors the visual appearance of the final immune globulin product. Disequilibrium between monomer and dimer concentrations can disrupt the integrity of immune globulin formulations and high levels of immune globulin dimers have been associated with a greater incidence of adverse, mostly anaphylactoid, reactions upon infusion of the immune globulin preparation.¹⁰ Dimer formation depends on aspects of the manufacturing process, such as IgG concentration, pH, size of the plasma donor pool, storage time, and temperature. Stabilizers are used to prevent aggregation, fragmentation, oxidation, and dimer formation; sugars, such as maltose, sucrose, glucose, and sorbitol, are used for some products. To help reduce the overall solute load, which can become elevated with sugars, the amino acids glycine and L-proline have been added to the fourth generation formulations.^1,8 The specific stabilizer used can play an important role in an individual product's tolerability.¹¹ Osmolarity can vary widely between some of the products. Hyperosmolar solutions are typically seen with the older lyophilized intravenous immune globulin (IVIG) products, whereas the fourth generation products have a more physiologic osmolarity of around 300 mOsm/kg. Higher osmolarity solutions tend to cause more local venous irritation at the infusion site.

Maltose stabilized immune globulin products can pose an important safety consideration that warrants attention from health care professionals. Certain glucose monitoring technologies, specifically, those using the glucose dehydrogenase pyrroloquinoline quinone (GDH-PQQ) methodology cannot distinguish between glucose and maltose. When maltose is present in a blood sample, using a GDH-PQQ glucose test strip, it will produce a significantly elevated glucose result. This can lead to inappropriate dosing and the administration of insulin, potentially resulting in hypoglycemia, coma, or death.¹² 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. Fortunately, 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, thus, not subject to falsely elevated results from maltose. If a maltose-stabilized immune globulin product is to be used within a health care system, or by a patient, it is prudent to determine which technology is being employed 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 still remain on the market.¹

ADVERSE EVENTS

The earliest immune globulin products were plagued by a relatively high incidence of infusion-related adverse events that were the result of complement-activating aggregated immune globulin.

These adverse effects have been greatly reduced in the last 2 decades through the implementation of manufacturing steps that avoid the formation of aggregates.^1,4-6,8 Subsequently, another series of serious adverse events, such as acute renal failure, aseptic meningitis, hemolysis, and thrombosis, have been observed. Some of these events can be attributed to either certain immune globulin products, to the size of the dose administered for specific indications, the rate of infusion, or to characteristics of the patient receiving the treatment. In general, immune globulin therapy is well-tolerated and much of the risk can be mitigated by considering patient and product characteristics (Table 2).^13,14

For the purposes of this review, the adverse events are divided into the following 3 categories: transmission of infectious disease, anaphylactoid or infusion-related reactions, and serious delayed events, such as acute renal failure, aseptic meningitis, hemolysis, and thrombosis.

Transmission of Infectious Disease

Currently, the risk of transmitting infectious disease with the administration of immune globulin products had essentially been eliminated. Screening against potentially infectious agents begins with the donor selection process and continues throughout plasma collection and plasma preparation. While there is no 100% safe process, manufacturers employ a series of redundant steps to ensure viral elimination. These steps include the following: 1) exclusion of hepatitis B surface antigen, human immunodeficiency virus (HIV), and hepatitis C positive blood and plasma donations; 2) use of solvent/detergent; 3) nanofiltration; 4) pH 4/pepsin inactivation; 5) polyethylene glycol precipitation; and 6) pasteurization (treatment of the immune globulin in a solution at 60°C).^1,8,15

Importantly, no case of HIV transmission has ever been associated with immune globulin products. It is thought that the fractionation process excludes the virus. On the other hand, a number of cases of hepatitis C infection did occur in the 1990s.¹⁶ The transmission of hepatitis C via immune globulin led to the implementation of strict plasma testing requirements for each plasma unit donated, as well as final preparations by highly sensitive nucleic acid testing.

The risk of transmitting spongiform encephalopathies, such as Creutzfeldt-Jakob Disease (CJD), has also been a source of concern for some clinicians and regulatory agencies. Fortunately, no evidence has emerged to show that blood products are capable of transmitting CJD; regulatory bodies continue to maintain aggressive surveillance.¹⁷

Anaphylactoid Reactions

Anaphylactoid reactions typically manifest during, or just after, the immune globulin infusion and result from an inflammatory response elicited by components of the immune globulin product. These components may include one or more of the following: IgG complexes, immune globulin fragments, stabilizers, the temperature of the solution infused, acute complement activation, IgA, low molecular weight polypeptides, and alloantibodies to blood type A/B.¹⁹ The original products developed contained IgG complexes that occurred as a result of the tackiness of the immune globulins that cause aggregation during purification from other plasma proteins. Fortunately, these complexes have been eliminated by modern manufacturing processes. Currently available products can still cause anaphylactoid reactions, however, these severe reactions have become relatively uncommon.⁴ The most common anaphylactoid reactions are headache, flushing, chest tightness, dyspnea, back pain, nausea, vomiting, and diarrhea, as well as a rare case of hypotension.^5,6

Headache is the most frequently reported adverse effect to accompany immune globulin treatment. The incidence of headache does not appear to be related to the indication for the treatment; however, the occurrence of headache is much less common when a low dose is used.

More serious anaphylactoid reactions occur most frequently in previously untreated individuals with agammaglobulinemia. In these individuals, immune globulin 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 events are relatively rare in those who do not meet this profile.¹⁸

Common reactions that are more mild include fever, malaise, myalgia, and headache. These events occur during, or within hours after, finishing the infusion. These symptoms usually resolve with a slowing of the infusion rate and are self-limiting. Immune globulin infusions cause the release of cytokines, such as tumor necrosis factor (TNF), interleukins, and interferon, because of the 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 these events.^4,6

The products currently available may contain varying amounts of contaminating IgA (Table 1). Importantly, IgA can cause the formation of anti-IgA antibodies in patients who are IgA deficient. These anti-IgA antibodies can cause anaphylactoid reactions upon infusion of immune globulin intravenous preparations in some of the patients who are IgA deficient, which would result from the 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 anaphylactoid reaction in these patients is anticipated, but the incidence appears low given the total number of these reactions reported compared with the overall number of patients with IgA deficiency. In fact, screening for IgA deficiency prior to immune globulin intravenous is not routinely recommended.⁴

Low molecular weight polypeptides are also thought to contribute to the occurrence of the less severe adverse effects described above. Moreover, allergic reaction to foreign IgG with a resultant release of IgE may also contribute to these events.⁴ When these events occur or symptoms begin to manifest, the infusion should be slowed or stopped immediately. For less severe reactions, 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 and treatment should only resume when a cause for the reaction is identified. These more severe events should also be reported to the manufacturer. The sample can even be sent to the manufacturer for extensive analysis and comparison to other lots from the same batch. Most often the causes of these events are idiosyncratic and the events resolve without further intervention. Administration of acetaminophen and/or diphenhydramine at the time of the infusion can mitigate some risk of the more minor events occurring. The routine use of corticosteroid injections has not been recommended; but it may have some role in the prevention of future events for those with a history of severe reactions or in treating severe reactions as they occur.^4,6

Acute Renal Failure

Overall, approximately 40 cases of acute renal failure associated with immune globulin intravenous treatments have been reported.^20,21 Most of these patients had existing renal disease prior to treatment. The histological finding identified in most cases is swelling and vacuolization of proximal tubular cells with preservation of brush borders.²¹ The mechanism of this renal injury is caused by the carbohydrates added to stabilize immune globulin preparations. Specifically, sucrose, a stabilizing agent for certain immune globulin intravenous products, has been implicated most often. Keeping this in mind, a high level of vigilance is recommended when using high dose immune globulin intravenous in patients with severe or even moderate renal insufficiency.⁴ It is prudent to exercise caution when treating patients with a sucrose stabilized product who have mild renal impairment, even when the treatment only requires a low dose of immune globulin. 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 1). Renal function (serum creatinine and urine output) should be closely monitored in patients treated with high doses of sucrose-containing immune globulin intravenous formulations, both before and after therapy. It would be prudent to monitor all patients administered immune globulin intravenous products stabilized with carbohydrate products, such as glucose, sorbitol, or maltose, because treatment has the potential to cause renal dysfunction, especially if the product has a high solute load.⁴

Aseptic Meningitis

Headache is the most commonly reported adverse effect associated with immune globulin infusions and the incidence increases with larger doses infused over a shorter period of time. Most of these headaches are mild in nature, self-limiting, and an interruption in therapy is not required.^4,6 Cases of aseptic meningitis requiring discontinuation of immune globulin treatment have been reported over the years and strategies to minimize these neurological adverse effects can be employed. Aseptic meningitis presents initially as severe acute headache, nuchal rigidity, lethargy, fever, photophobia, painful eye movements, nausea, and vomiting.²² 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 and persist for 3 to 5 days.⁴ The overall presentation and symptoms resemble those associated with bacterial meningitis. Notably, patients reporting a history of migraine are more prone to developing an episode of aseptic meningitis, regardless of the commercial preparation administered. Simultaneous treatment with corticosteroids does not appear to have any protective effect.⁴

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 immunoglobulin into the CSF. Some allogeneic IgG does cross the blood-brain barrier and has been verified in the CSF studies involving immune globulin recipients.²³ While rare, the exact frequency of aseptic meningitis has not been established, but the incidence does appear to be related to the dose used.²⁴ Dosages of 1 g/kg or greater, administered during a 24-hour period, may warrant closer monitoring for this adverse event.⁴

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.⁴ Immune globulin preparations are no exception and, thus, contain amounts of anti-A/B antibodies that vary between products and even between 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 (e.g., 2 g/kg), and administration of immune globulin preparations with high titer anti-A/B antibodies.^25,26 Monitoring high-risk patients administered hemoglobin 48 to 72 hours after immune globulin intravenous 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 immune globulin intravenously should also be counseled to report the presence of dark colored urine within the first several days after infusion to a clinician; this symptom could indicate the presence of red blood cell destruction.^4,6

Thrombosis

Thromboembolic complications, such as myocardial or cerebral infarction, deep vein thrombosis, and pulmonary embolism have recently received increased notice as severe events that can be precipitated by immune globulin infusion.^27,28 The overall rate of thromboembolic events is approximately 3% and this estimate includes thrombophlebitis at the infusion site.²⁸ Several mechanisms have been proposed as the cause of these events, including hyperviscosity that may be the result of rapid infusions of high doses into a volume-depleted hyperviscous blood stream or infusions in patients with established arteriolosclerosis and the diminished ability to autoregulate vascular tone.²⁹ Even more importantly, the elevated levels of activated Factor XI in immune globulin products have been shown to increase the risk of thromboembolic events.^30,31 In fact, a recall of Octagam (immune globulin [IGIV]) occurred in 2011 because of a series of reported thrombotic events. The analyses of these batches implicated elevated levels of activated Factor XI as the culprit.³² Manufacturers now 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 immune globulin therapy and clinicians may choose to avoid immune globulin 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.³³ Interestingly, subcutaneous administration of immune globulin has also been associated with a higher risk of thromboembolic complications when compared with intravenous administration.²⁸

Subcutaneous Versus Intravenous Route of Administration

Several immune globulin products are approved for administration via the intravenous or subcutaneous route. One product, marketed in the United States is approved for the subcutaneous route of administration only and the other products are only approved for intravenous administration (Table 1). The subcutaneous route has emerged as an alternative method of administration for diseases requiring lower doses of immune globulin (400 to 600 mg/kg monthly), such as those in the immunodeficiency spectrum.⁹ Advantages of the subcutaneous route of administration include reduction in anaphylactoid reactions, avoidance of the need for vascular access, stable immune globulin a levels, and increased patient autonomy.⁹ The goal is to achieve a systemic serum immune globulin exposure similar to that achieved with the intravenous route of administration.

The more frequent and regular dosing of immune globulin via the subcutaneous route results in flatter pharmacokinetic parameters and reduced catabolism of the immune globulin. The slower absorption from the subcutaneous tissue into the systemic circulation results in an overall reduction in anaphylactoid reactions. The subcutaneous route of administration also helps to encourage self-infusion and at-home infusion. There is an increased incidence of local reactions, such as swelling and redness at the site of the infusion. However, the local reaction usually resolved within a day. Notably, the subcutaneous route has been used by patients with IgA deficiency with antibodies against IgA without inducing hypersensitive reactions.³⁴ While the subcutaneous route of immune globulin administration may not be practical for all patients, this route should be discussed with patients who could benefit.

INDICATIONS

Immune globulin is currently used to treat the following 3 main disease categories: immune deficiency, autoimmune/inflammatory disorders, and infectious diseases (Table 3).^3,35 Within each of these categories, there are a number of associated disease processes that have demonstrated benefit from the utilization of immune globulin therapy, as well as instances where treatment has not proven beneficial. In total, more than 100 different disorders have been treated with immune globulin with varying rates of success.³⁵ In general, when given as antibody replacement therapy, the treatment is administered as a dose of 300 to 600 mg/kg every 3 to 6 weeks.³⁶ Treatment may then be adjusted according to a patient's specific antibody levels or clinical response. Whereas, treatment of autoimmune diseases requires administration of higher immunomodulatory doses (i.e.,1 to 2 g/kg administered over 2 to 5 days).³

All of the currently FDA-approved immune globulin products carry an indication for the treatment of primary immunodeficiency diseases.^1,8 However immune globulin is largely used to treat autoimmune/inflammatory conditions and this accounts for the majority of gram usage in the United States.³ While only a limited number of the estimated 100 possible uses for immune globulin are FDA-approved indications, insurance providers, including Medicare, now recognize immune globulin as the standard of care for a growing number of the off-label indications, as well. Some FDA-approved indications receive little use in current practice (e.g., pediatric HIV). Interestingly, while each product has varying approved indications and the products are not officially recognized as generic, insurance providers typically do not mandate that specific products be used according to their FDA-approved indications. Some of the flexibility has been driven by historical shortages of the immune globulin products and by the lack of comparative studies between the various products. Importantly, each product has a unique national drug code number and billing code, so, it is important to ensure the product administered is the same product billed for because the cost of the products and the reimbursement rates will differ.

Within a given health care system, the utilization of immune globulin will depend on the medical programs that exist within that system and the specific protocols for the treatment of the diseases managed within those programs. For example, heath care systems with pediatric hospitals might utilize a significant amount of immune globulin for the management of Kawasaki disease; whereas a health care system with a transplant center might use more immune globulin for the desensitization of potential transplant recipients with high antibody titers or for the treatment of antibody-mediated rejection.

Treatment of immunodeficiency implies the replacement of polyvalent antibody levels to maintain patients in a normal range that will help prevent a broad range of infectious processes.^36,37 Treatment of active infectious disease occurs when the immune globulin product contains enough antibodies against a specific pathogen to help augment the host immune response against that pathogen (e.g., parvovirus B19 or cytomegalovirus infection). These proinflammatory activities of immune globulin involve complement activation or binding of IgG through the receptor for the crystallizable fragment (Fc) portion of IgG, particularly on innate immune effector cells. Effector-cell functions, including phagocytosis, degranulation, release of proinflammatory cytokines, antibody dependent cell cytotoxicity, and antigen presentation, are all mediated by immune globulin binding to the Fc receptor, which leads to disposal of pathogenic antigens by the immune system.^38,39

The mechanisms by which immune globulin causes immunomodulatory and anti-inflammatory effects have not been as clearly established.³ Several pathways within the immune system may be effected by immune globulin therapy. A number of mechanisms have been proposed and, for certain disease states, several mechanisms may work in tandem to impact the disease process. Use of high-dose immune globulin has established efficacy in treating a number of inflammatory diseases, including Kawasaki disease, inflammatory demyelinating polyneuropathy, idiopathic thrombocytopenia purpura, and antibody-mediated rejection after organ transplantation (Table 3).^3,40,41,42 Known effects from the administration of immune globulin at anti-inflammatory doses includes decreased production of proinflammatory cytokines (e.g., tumor necrosis factor and interleukins), the downregulation of adhesion molecules, a reduction in chemokine and chemokine-receptor expression, and the neutralization of superantigens.^43-47 Since immune globulin contains numerous antibodies with distinct specificities, it is proposed that the anti-inflammatory benefits may be the result of IgG antigen-binding fragments binding to a variety of proteins or cell-surface receptors.⁴⁸ Moreover, immune globulin contains an array of anti-idiotypic antibodies that can bind to specific B lymphocytes, expressing these idiotypes, and downregulate or eliminate autoreactive clones. The Fc fragment of the immune globulin molecule clearly plays a vital role because the Fc-mediated activity results from the effector pathways, receptors, and ligands that interact with the Fc portion of IgG. The most prominent among them include the complement pathway, the neonatal Fc receptor, and the activating and inhibitory Fc receptors for IgG.⁴⁹ The Fc and antigen-binding fragment effects described may play different roles for each of the inflammatory diseases that are treated with immune globulin and, therefore, establishing a uniform mechanism of action across these disease states is not probable.

ROLE OF THE PHARMACIST

The complexities of immune globulin therapy create numerous opportunities for a pharmacist to play an important role in treatment. Pharmacists are well positioned to help prescribers select the best product for the patient being treated, to ensure the appropriate dose is selected for any given disease state, to implement monitoring for adverse events, and to educate patients and providers about the risks associated with immune globulin treatment, as well as to determine the appropriate products to add to a health care system formulary.^1,8 Patients are at an increased risk for adverse events when treatment is changed and they are switched to a new medication. Pharmacists can increase vigilance during these transitions to minimizing adverse events or identify steps to mitigate risk when transitions are necessary.⁵⁰

As a human plasma product, immune globulin is an expensive resource and has a complex and lengthy manufacturing process; therefore, supplies are limited. Approval of new indications may place a major strain on the overall supply in the near future if immune globulin becomes the approved standard of care for a relatively prevalent disease (e.g., Alzheimer's disease). Furthermore, the next product recall creating a global supply deficit could be just around the corner. Pharmacists should continue to work across the continuum of care, along with other health care practitioners, to provide stewardship over immune globulin products to ensure that patients' medical needs are met and patients are able to receive appropriate and safe treatment as necessary.

Summary

The therapeutic role of immune globulin has evolved remarkably during the past several decades and now includes the treatment of inflammatory and autoimmune diseases, in addition to antibody replacement, for which the product was initially developed. The critical differences in the formulation characteristics of the available products, as well as the high cost of these products, the risk of adverse events, and the complicated treatments for which immune globulins are utilized make it imperative that clinicians take an active role in the selection of the most appropriate product for their patients.

References

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