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Introduction

The challenges of treating people with immunodeficiencies reached most people’s awareness in 1971 through the experiences of David Vetter, “the boy in the bubble” who was born with severe combined immune deficiency (SCID). Because of his immediate risk of death from infection caused by even low levels of microbes, David lived in a sterile cocoon environment during the several years he stayed at Texas Childrens Hospital in Houston. Eventually able to live at home but still inside a bubble, David died after a bone marrow transplant at age 12 resulted in his acquiring Epstein–Barr virus and developing fatal lymphoma.

Today, a variety of immunoglobulin G (IgG) products are available and beneficial in patients with both primary immunodeficiencies like the one David had and the more common secondary immune deficiencies that place people at risk of infections. This article will highlight the use of IgG products in secondary immunodeficiencies (SIDs), detail how these products can best be used based on patient comorbidities, and introduce contemporary concepts about intravenous (IV) and subcutaneous (SC) routes of administration.

Types of Immunodeficiencies

The human immune system is complex. Some components provide innate immunity in which the body reacts nonspecifically and immediately to pathogens through processes such as phagocytosis (chemotaxis, migration, ingestion, and microbial killing). The stronger and more specific components of the immune system provide adaptive immunity. On a second or subsequent exposure of an antigen through antigen-presenting cells, the body mounts an antibody-mediated immune response involving memory B cells and many other immune cytokines, other factors, and cells.¹

Antibodies (Figure 1) are immunoglobulins (Ig), and the light chain types are categorized as IgG, IgM, IgA, IgD, and IgE (Figure 2).² Of these types, IgG makes up about 80% of total body immunoglobulins and thus is considered the most important contributor to the specific immune response to previously encountered antigens. IgG antibodies are also involved in immunomodulation, increasing the immune response to foreign antigens and suppressing the body’s reactions to its own proteins.³

Functions of the two Fab arms can include a wide variety of immunomodulatory effects, such as modulation of apoptosis and cell cycle; antiproliferative effects; effects on cell adhesion and cytokine levels; and importantly, antibodies to pathogens, superantigens, and immunoregulatory molecules (e.g., cytokines, T-cell receptors, CD4, and CD5). Fc region functions can include inhibition of phagocytosis, deposition of activated complement, and antibody-dependent cellular cytotoxicity; effects on glucocorticoid receptor binding affinity and dendritic cell maturation; and blockade of access of immune complexes to Fc receptors.

Figure 1. Structure of immunoglobulins. The various parts of the immunoglobulin serve different immunomodulatory functions. Commercially available immunoglobulin products also contain other components, including cytokines, cytokine receptors, CD4, MHC Class II and stabilizing agents, and sugars. Source: Shutterstock and Reference 2.

Figure 2. Classifications of human antibodies. Source: Shutterstock.

Primary immunodeficiencies (PIDs) comprise disorders in which intrinsic defects in the human immune system prevent a person from mounting an immunologic response to microorganisms and other foreign matter. These genetic conditions result from an inability to produce components of the immune system, such as antibodies or B-cells (quantity defects), or deficiencies in function of antibodies, cells, phagocytic cells, complement, or other immunologic components (quality defects).

Classifications of Antibodies

Examples of PIDs illustrate the potential defects in the body’s systems. In common variable immune deficiency (CVID), B cells are present to produce antibodies, but both the amount and quality of IgG produced is low. In X-linked or autosomal recessive agammaglobulinemia, B-cell production by the bone marrow is low, and IgG quantity and quality are very low. In people with deficiencies of specific antibodies, IgG quantity and B-cell counts are normal, but IgG quality is low for specific antigens.⁴

Secondary immunodeficiencies (SIDs; serum IgG concentrations <5 g/L) can be caused by infectious, malignant, or iatrogenic insults to an innately functional immune system. These can result in general or specific antibody deficiencies, depending on the cause. There is a relationship between serum IgG trough levels and the risk for infection; one evaluation found a 5-fold increased rate of pneumonia in patients with levels below 5 g/L compared with those whose levels were 10 g/L or higher.⁵ British and American guidelines state that serum IgG levels below 5 g/L in combination with infection should warrant IgG replacement therapy.^6,7

Epidemiology and Etiology

Despite the extent and nature of the effects that immunodeficiencies can have on people’s lives, a surprising number of cases are not diagnosed. About 10% of people with immunodeficiencies have the primary condition. While there are more than 300 different disorders described as PIDs, most people have either common variable, severe combined, or specific antibody deficiencies.

A 2007 Immune Deficiency Foundation survey of 10,000 U.S. households showed a prevalence of PID of 83 per 100,000 people. An estimated 250,000 people have been diagnosed with PID in the United States, but more than 500,000 people are not diagnosed.⁸ Some 37% of patients with PID reported impairment as a result of infections prior to diagnosis, 23% reported permanent loss of lung function prior to diagnosis, and 11% reported loss of hearing.⁹

Secondary immunodeficiencies can result from a host of other conditions or infections (Table 1).^10–12 They are much more common than PIDs — on the order of 10-fold higher — but prevalence can change based on the prevalence of cancers that affect the immune system, the emergence of pathogens such as the human immunodeficiency virus (HIV) and associated conditions such as the acquired immunodeficiency syndrome (AIDS), and the use of immunosuppressant medications. Normally when the production of antibodies is low, the end result is chronic respiratory infections such as otitis media, bronchitis, and pneumonia, or gastrointestinal infections resulting in chronic diarrhea. Other sequelae include autoimmune disorders, allergies, skin conditions, and even meningitis.

Malignancy-Related Causes

Hematologic malignancies and certain agents used to treat various oncologic and autoimmune disorders are common causes of SID (Table 1).^10–12 Some insults to the immune system are specific and can be countered with specific treatments, as with a low neutrophil count that is improved by colony-stimulating factors. Cancers or cytotoxic drugs that kill B lymphocytes or produce hypogammaglobulinemia are central to this discussion of IgG and immunoglobulin therapies; some of these cytotoxic drugs are also used for immune-mediated disorders such as rheumatoid arthritis and multiple sclerosis (e.g., rituximab, alemtuzumab).

A condition very relevant to the use of immunoglobulin replacement therapy is chronic lymphocytic leukemia (CLL). The most common cause of death in patients with CLL is infection and infective complications. The disease itself produces immune defects, with hypogammaglobulinemia in up to 70% of patients with CLL, and chemotherapy exacerbates the problem. The damage to the immune system is irreversible in most patients, including many of those who achieve complete disease remission. Low levels of IgG are directly proportional to the frequency and severity of infections.¹²

Another oncologic condition in which infections are the primary cause of death is multiple myeloma. As with CLL, effects of the disease and chemotherapy are involved in the increased susceptibility to infections. Susceptibility is greatest in the early stages of the disease and during the first months of induction chemotherapy; early infections involve the respiratory tract, including bronchitis and pneumonia. Involved pathogens are most frequently Haemophilus influenzae and Streptococcus pneumoniae, suggesting hypogammaglobulinemia as a contributing etiologic factor.¹²

Nonmalignancy-Related Causes

The immunosuppression needed in patients undergoing bone-marrow or solid-organ transplantation presents unique challenges in infection prevention and control.

Often used for hematologic malignancies, allogeneic bone-marrow transplantation can produce persistent immune defects. Hypogammaglobulinemia is a common feature of this clinical scenario, creating a need for long-term replacement immunoglobulins regardless of the success of treatment for the underlying malignancy.¹²

The HIV makes its hosts susceptible to a variety of opportunistic infections, but its actions are on T rather than B cells. Infection causes hypergammaglobulinemia but also a defect involving a failure to mount specific antibody responses to T-cell-dependent antigens. Effects differ between children and adults, resulting in different pathogens creating infections in the two groups. Recurrent bacterial infections are more common in children, while opportunistic infections and cancers tend to occur in infected adults.¹²

Other secondary causes of immunodeficiency with hypogammaglobulinemia are shown in Table 1.^10–12These include diseases with Ig loss such as burns, renal, and intestinal diseases, and Good’s syndrome (thymoma, carcinoma cells on the outside of the thymus—the gland that produces lymphocytes).¹²

Drug-Induced Secondary Immunodeficiency

Medications are a common cause of iatrogenic immunodeficiency. As listed in Table 1, these include agents used for treatment of oncologic disorders but also therapies for rheumatoid arthritis, other conditions with autoimmune features, and anticonvulsants.^10–12 For some patients, discontinuation of the offending drug may be sufficient to correct the SID; for others, damage to the immune system could be permanent and require lifelong support for prevention or treatment of infections.

Rituximab in particular has been identified as routine agent used in both combination chemotherapy and nonmalignant therapies that may lead to profound immune depression. The agent binds to the CD-20 antigen of normal and malignant B cells and pre-B cells, initiating a cascade that reduces the number and function of B cells, which can lead to hypogammaglobulinemia. In addition, neutropenia occurs more frequently, adding to the risk of infection. These effects are especially problematic when rituximab is used for maintenance therapy of oncologic or autoimmune diseases, and in patients who receive several courses of therapy; the risk of symptomatic hypogammaglobulinemia has been noteworthy with rituximab, occurring in 6.6% of patients with lymphoma in one report who were treated with the monoclonal antibody.^13,14

Immune Globulins

Originally developed in the 1970s and marketed in the 1980s to meet the needs of patients such as David, the “bubble boy,” intravenous immunoglobulins (IVIG) have been refined pharmaceutically and studied extensively in the intervening years. The products approved by FDA in the 1980s for patients with PID would today not be considered acceptable. Considerable cleavage of the Fc moiety occurred during the manufacturing process, and contaminating viruses – including hepatitis C – were recognized and removed in the 1990s. In 2002, thrombosis was recognized as an adverse effect of IVIG use.¹⁵

Mechanisms of Action

Pharmaceutical products containing IgG have complex effects when administered as replacement therapy to patients with PIDs and SIDs or as immunotherapy in other conditions. Derived from sera of thousands of patients, the products contain antibodies against many diseases and have immense immunologic power of potential benefit to recipients with hypogammaglobulinemia, regardless of cause. These effects and secondary indications of the products derive from the structure of the IgG molecule as depicted in Figure 1.²

While a given unit of an IgG product represents the antibodies produced by many different people, the biologic origin also means there is substantial batch-to-batch variation in specific antibody content. This variation is most important in the F(ab')₂ moiety, as the two “arms” of the IgG molecule carry the specific segments that recognize pathogens and superpathogens. Several IgG actions result from presence of intact and specific F(ab')₂ moieties: antiproliferative effects, modulation of apoptosis (cell death) and cell cycle, activation of specific cells, and effects on cell adhesion.²

IgG products also contain natural antibodies that are hard-coded into the human genome. Multiparous women contain many more anti-idiotype human HLA antigens; these components may be responsible for the efficacy of IgG products in patients with autoimmune diseases.²

The Fc moiety, while less specific for pathogens than the F(ab')₂ arms, is important in the general responses of the immune system to diseases. The general response happens first and protects the body while it reacts to previously encountered antigens by producing specific antibodies. As shown in Figure 1, the Fc fragment has numerous effects on the immunologic response to bacteria and fungi.²

IgG products also contain numerous other substances. These include soluble cytokine inhibitors, soluble CD4, and major histocompatibility complex (MHC) class II. Maltose, sucrose, and other sugars present in the products as stabilizing agents can have immunologic effects.²

Use in Secondary Immunodeficiencies

In the 1980s, HIV was identified as the etiologic agent in the most severe type of SID identified to date, AIDS. Patients died of a multitude of infections as their immune system was compromised by this retrovirus. IVIG was found to be effective for prophylaxis against other infections in children with HIV.¹In addition, high-dose IVIG therapy (1–2 g/kg over 2–5 days) was found to produce increased platelet counts in patients with idiopathic thrombocytopenic purpura (ITP) associated with HIV infection. Researchers also recognized that IVIG therapy could benefit patients living with HIV who developed severe parvovirus B19 or measles infection and in those with autoimmune disorders, in whom high-dose IVIG therapy was efficacious. Products were also developed with high quantities of Ig directed against specific viruses such as hepatitis B or CMV.¹⁶

The currently available IVIG products are licensed by FDA as replacement therapy in patients with PID, adjunctive treatments of patients with certain infections, and/or a limited number of SIDs (Table 2). Medical researchers and clinicians have found the products useful in more than 100 other SIDs, as listed in Table 3. Patients with these conditions have a high risk for infection, and administration of IgG products has been shown to reduce this risk in a wide variety of situations, from specific diseases (e.g., diabetes, uremia, cirrhosis, malnutrition, and disorders of protein loss) to treatments with immunosuppressive drugs, chemotherapy, or radiation.

The burden of SID in these patients is considerable. Up to 85% of patients with CLL can develop SID, and death from subsequent infections is estimated to account for up to 50% of deaths related to CLL and 22% of deaths related to multiple myeloma.^12,17

None of the commercially available IVIG products is approved for all indications, and the products differ considerably in their methods of production. Because of these differences, IVIG products should not be considered commodities that can interchanged freely, as clinicians need to match products with patients based on indications, other evidence of efficacy and safety for specific conditions, and comorbidities; pharmacists must consider these important differences in selecting the optimal products to make available in health systems and managed care organizations.^15,18

When selecting an IgG product for treatment, both the product characteristics and the patient comorbidities need to be considered. The IgG products are not all the same and should not be considered generic equivalents. Patients’ comorbidities — especially renal function, diabetes, cardiac status, weight, and age — are important factors in the selection of the best IgG product, dose, and rate of administration.

Intravenous vs Subcutaneous Administration

Over the past two decades, further refinements in manufacturing and pharmaceutical elegance of IVIG products led researchers to explore additional ways to make immunoglobulin products more useful in practice. This led to development of subcutaneous immunoglobulins (SCIG), which many patients could self-administer and thereby avoid the need for frequent medical appointments to receive IVIG infusions. This route of administration has improved patient quality of life and also proved useful in patients with limited IV access. The SCIG products were more effective in some situations, as they provide a depot release of immunoglobulins over time that simulates the body’s natural functions more closely than the relatively rapid infusion of these agents intravenously (Table 4).¹⁹

Currently, all of the FDA-licensed SCIG products are indicated only for PID (Table 5). As with IVIGs, considerable off-label use occurs, with SCIGs beneficial in patients with chronic neuropathies such as chronic inflammatory demyelinating polyradiculoneuropathy and multifocal motor neuropathy.¹⁶ SCIG products have also been used in SID disorders, such as hypogammaglobinemia in patients with CLL, living with HIV, or undergoing bone marrow transplantation.¹²

Safety Concerns Related to IgG Product Characteristics

The many potential uses of immunoglobulin products combined with two very different routes of administration makes knowledge of product characteristics important for pharmacists.²⁰ In addition to the mechanisms of action and efficacy of IVIG and SCIG products in patients with SID disorders, the products have differing safety concerns based on production methods, viral inactivation, fractionation, purification, and factors such as osmolality, pH, stabilizers, and the relative amounts of IgA, sodium, and sugars.

Production Methods

Available IgG products are derived from whole blood plasma or plasmapheresis obtained from donors at U.S. sites, most of them registered with FDA. A variety of techniques are used to separate the IgG from other plasma components, including cold ethanol fractionation (Cohn-Oncley is the original method; Kistler–Nitschmann is an alternative method used by one manufacturer), nanofiltration, ultrafiltration, ion-exchange chromatography, anion-exchange chromatography, and low pH incubation. Products differ in their finished forms (liquid or lyophilized) and whether they have been solvent/detergent (S/D) treated.¹⁸

While the amount of IgG in finished products is stated on product labeling (e.g., 5%, 10%) the amounts of subclasses of IgG (i.e., IgG1, IgG2, IgG3, IgG4) is different among the various brands. Amounts of other plasma components also differ (e.g., IgA, IgM, albumin, sodium); these variances can be important based on patient factors and diseases being treated.¹⁸

Some IgG brands must be refrigerated, others can be stored at ambient temperatures up to 30° C, and expiratory dates of some products differ based on whether they were stored under refrigeration or at ambient room temperatures. These factors can be important considerations for pharmacies with limited refrigerated space. None of the products should be frozen.¹⁸

Viral inactivation and removal of transmissible spongiform encephalopathies (TSEs, or prions) is another very important step in IgG product manufacturing. In the 1990s, the transmission of hepatitis C virus through the administration of IVIG was noted with some products.²¹ The immediate withdrawal of these products was warranted, and they were replaced with new formulations that are safe from transmission of this virus.

Since the 1990s, many different methods of viral inactivation/removal and TSE removal have been used, including solvent/detergent treatment, inactivation of the viruses with lipid coats through use of fatty acids or enzymes, heat treatment, acid treatment, nanofiltration, depth filtration, and alcohol precipitation (Tables 6 and 7).^22–24 No one method has been deemed superior over the others, and there have not been any other reports of transmission of microbial infections by IVIG since these processes were put in place. Of interest, there has never been a report of transmission of HIV with the administration of any IVIG product.

Because of the possibility of viral mutations and identification of new viruses or prions, use of multiple methods of inactivation and screening of donors is imperative in IgG production.

Patient Risk Factors: Product Osmolarity, pH, and Stabilizer, IgA, and Sodium Content

When considering product selection for the individual patient, both comorbidities and IVIG product characteristics should be considered. Table 8 lists some of the most important characteristics to consider in product selection for patients with risk factors.^25,26

Volume load for the patient is a very important factor for patients who have cardiac impairment, renal dysfunction, or any type of thrombotic risk, in those patients who have diabetes or prediabetes, and those at the ends of the lifespan (neonates and those aged 65 years or older). For these patients, IVIG products at the 10% concentration and those that are also iso-osmolar should be used to minimize the risk of fluid overload.

Stabilizers are used in IVIG products to decrease the formation of end-to-end dimers between IgG molecules. Stabilizers also limit fragments, polymers, and discoloration of the protein solution; only when such problems were solved through the use of stabilizers was the development of stable IgG solutions possible.

Products that use sugars instead of amino acids as stabilizers present greater risk to patients of advanced age and those with diabetes or renal disease (Table 9). Low- or no-sodium IVIG products are better choices for patients with cardiac, renal, or thrombotic risk factors and in neonates and older adults so that complications related to hyperosmolality are avoided.

Product IgA content is a concern only in patients with anti-IgA antibodies. Low IgA levels can indicate such antibodies, but many other causes could be involved. When patients have anti-IgA antibodies, severe adverse reactions or anaphylaxis can result from treatment with IgG products containing IgA. IVIG products that are IgA-depleted are available for such patients.

Establishing Dosing and Monitoring Regimens

Dosing and administration of IVIG and SCIG products is specified in product labeling for approved indications of the commercially available products. These should be followed when IgG products are used for replacement therapy as either IVIG or SCIG except in patients with morbid obesity, as detailed below. When used as immunotherapy, IVIG/SCIG products often need to be titrated to achieve the desired clinical effects or changes in monitoring parameters (e.g., serum IgG levels).

While actual body weight has historically been used for dosing of IgG products, the optimal dose in patients with obesity is poorly studied and has long been controversial. IVIG has very little distribution into fat, but patients with obesity have an increased volume of distribution because of extra body fluids. One approach to dosing IVIG developed at The Ohio State University that accounts for the extra body fluids uses actual body weight (ABW) for patients weighing 100 kg or less and an adjusted body weight for those weighing more than 100 kg. Thus, for patients weighing less than 100 kg, the ABW is multiplied times the per-kg dose recommended in product labeling. For patients weighing more than 100 kg, the dosing weight is calculated using the ideal body weight (IBW) as follows²⁷:

Dosing weight (in kg) = [(ABW – IBW)/2] + IBW

For this equation, the IBW is calculated as it is for the Cockcroft-Gault equation [50 kg for men or 45 kgfor women + 2.3 X (height in inches – 60)].

Other authors have proposed using the Cockcroft-Gault IBW for dosing IgG, but this approach does not account for the increased volume of distribution in patients with obesity. It is an effective cost-saving measure. In one institution, use of IBW lowered the usage of IgG products by 20%, and pharmacist-driven stewardship efforts have ensured prescriber compliance with such guidelines.^28,29 However, the clinical impact of this approach remains unknown.

For IVIG products on the U.S. market (with concentrations of 5% or 10%), refer to the manufacturers’ guidelines for infusion, but note that the dosing guidelines are written in mg/kg/min. The infusion pumps are set in mL/h. Start with an initial rate that allows for observation and monitoring over a 15–30 minute period. Increase the rate as specified and then successively escalate the rate by one third to determine the patient’s maximum tolerated rate. Adverse events can occur at any time; the rate should be slowed until they subside. If the symptoms do not subside, the IVIG infusion should be stopped and symptomatic treatments administered if warranted. For subsequent infusions in patients who have had adverse reactions, premedications (e.g., acetaminophen, steroids, oral or intravenous antihistamines) can be be administered to improve tolerability.

The comorbidities of patients must be taken into consideration when determining the rate of administration. Rapid infusion rates are not recommended in those with renal dysfunction or a history of thromboembolic events, other cardiac impairment, or other serious adverse events to IVIG therapy.

While most IVIG infusions require 2–4 hours for administration (given every 2 to 4 weeks), doses of SCIG are commonly infused weekly in a 1- to 2-hour period. The rapid infusion creates prominent “goose bumps” in the subcutaneous tissue that go down in a few hours. Injection site swelling and mild inflammation are normal reactions to SCIG administration. Headache, vomiting, and pain can also occur and can be managed symptomatically; premedication is not usually used before SCIG infusions.

More serious adverse events have been reported rarely with SCIG. These include allergic, neurologic (e.g., more severe headaches accompanied by other symptoms), renal or circulatory, urinary, and cardiologic adverse effects, as listed in product labeling.

When converting patients from IVIG to SCIG therapy, a 1.37:1 dose conversion is used for most products; for Cuvitru, the conversion is 1.30:1, and for Hyqvia, the conversion is 1:1. For example, for a patient receiving IVIG 40 g monthly, the conversion would be 1.37 X 40 = 54.8 g divided weekly, which would be about 14 g weekly of a standard SCIG product, 13 g of Cuvitru weekly or 26 grams biweekly, or 40 grams of Hyqvia monthly. Remember to round doses to the nearest vial size and adjust the number of injection sites to the patient’s body type and level of tolerance. Administered subcutaneously, these amounts provide a relatively constant serum IgG level with a low peak and higher trough over a dosing interval; doses administered intravenously yield more of a peak-and-trough effect in serum concentrations.

Monitoring of IgG therapy differs based on the condition being treated. Serum IgG levels can be measured just before the next doses to determine the trough concentration, with doses and frequency adjusted as needed. Clinical response is the most important monitoring parameter for most conditions, with avoidance of infections and improvement in target symptoms the best indicators of IgG efficacy.

Summary

The use of Ig for prevention of infections dates back to the 1940s and for agammaglobulinemia to 1951. IVIG was not available until 1979 when carbohydrate and amino acid stabilizers were used to decrease dimerization and aggregate formation. This innovation allowed for larger dose administration and therapeutic levels to effectively treat primary immune deficiencies.

The use of IVIG in a patient with ITP led to the serendipitous discovery that IVIG modulated the immune system to block the attack of antibodies on platelets by blocking the Fc receptor sites. This discovery led to the use of IgG products as immunotherapy for neurologic disorders. Before development of antiretroviral products in the 1990s, IVIG products were important interventions in patients with HIV, especially children. For patients with CLL or multiple myeloma, the protection from pathogens provided by IgG products is critical, as most deaths from these conditions are associated with infections. Similarly, immunodeficiencies induced by medications such as rituximab can be managed with IVIG or SCIG treatment.

SIDs differ from PIDs in the fact that the cause of the deficiency may be temporary and therefore the IVIG treatment may be short term as well. Often the cause of the SID is iatrogenic and could resolve spontaneously. The approach to SID should start with identification of the most likely cause (Table 1).^10–12 Independent of the cause, the treatment plan is similar to PID and monitoring IgG levels can improve the reduction of infections related to the SID.

SCIG products were developed over the past two decades to provide IgG therapies on a more convenient basis for patients. They also have the advantage of ensuring a more consistent blood level of IgG over each weekly dosing interval.

By applying the information provided in this article, pharmacists can contribute to the health care team during management of patients with PID or any of the numerous SID conditions that occur commonly. IgG products are complex, but with the requisite knowledge and skills, they can be used effectively and safely to improve the lives of millions of patients.

Resources

American Academy of Allergy, Asthma & Immunology: Provides consumers with information about primary and secondary immunodeficiencies. https://www.aaaai.org/conditions-and-treatments

IG Living: magazine for the immune globulin community, including patients with Ig-treatable chronic illness and their caregivers. www.igliving.com

Immune Deficiency Foundation: Organization providing information and advocacy for those with primary immunodeficiencies. https://primaryimmune.org

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