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Intravenous Immune Globulin Therapy for the Treatment of Primary Immunodeficiency Disorders


Beginning with the first description of X-linked agammaglobulinemia by Ogden Bruton in 1952, approximately 200 forms of primary immune deficiency disorders (PIDDs) in 8 categories have been clinically characterized.1,2 Broadly speaking, PIDDs may be generally classified as defects in either the innate (e.g., complement deficiencies) or adaptive immune systems (e.g., T-cell defects). While PIDDs typically lead to increased susceptibility to infections, the degree of immune compromise and specific infection types vary widely across specific conditions. Although the prevalence of PIDD varies widely among specific disorders, a survey conducted in 2007 estimates the overall prevalence of PIDD as 1 in 1200 persons in the United States, or approximately 230,000 individuals.3

Immune globulin replacement, by either the intravenous (IVIG) or subcutaneous (SCIG) routes, is the mainstay of treatment for many PIDDs.4,5 The product selection, dosage, and monitoring characteristics of each immune globulin product requires careful consideration on the part of the treatment team involved in the care of the patient. This review aims to summarize the most common PIDD as well as the use of IVIG in their treatment.

Role of the Healthy Immune System

In order to understand PIDD, the role and functions of different portions of the healthy immune system must first be understood. The functioning of the human immune system is dependent on the development and continued function of a number of interconnected and interdependent components.6,7 The first line of defense of the immune system (the innate immune system) does not depend on the development of an immunologic memory and consists of macrophages, dendritic cells, natural killer cells (NK), and others 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.

The innate immune response is dependent on the recognition of a foreign antigen by pattern recognition receptors (PRRs), which are widely conserved throughout evolution and target specific, unique features of infectious organisms, known as pathogen-associated molecular patterns (PAMPs). Following recognition of a PAMP by a PRR, effector cells of the innate immune system, such as macrophages and dendritic cells, are activated and release pro-inflammatory cytokines, such as tumor-necrosis factor (TNF) and interleukin-1β (IL-1β). In turn, these cytokines lead to the activation of the complement system and chemotaxis of neutrophils toward the site of infection.8 Certain PIDDs, such as chronic granulomatous disease (CGD) or terminal complement deficiency are a result of a defect in the innate immune response.9,10

After a dendritic cell (also known as an antigen-presenting cell [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 the T-cell in a processed form attached to a major histocompatibility complex (MHC) molecule on the surface of the APC, with MHC I (expressed by all nucleated cells and expressing intracellular antigens, such as viral proteins) leading to the activation of CD8+, or cytotoxic, T-cells and MHC II (expressed only by dendritic cells, macrophages, and B cells and expressing extracellular antigens, such as bacterial toxins) activating CD4+, or helper, T-cells. This step forms the bridge between the innate and adaptive immune response.11

Following activation, CD8+ T cells undergo clonal expansion, mediated by interleukin-2 (IL-2), and migrate to cells expressing the targeted foreign antigen. Following contact with cells bearing these foreign antigens, CD8+ T-cells release proteins, such as perforin and granzymes, which cause the targeted cell to undergo apoptosis within minutes.12 Additionally, CD8+ T-cells may also release important cytokines, such as interferon-γ (IFN-γ), following activation. In contrast, most CD4+ T cells are not directly cytotoxic, but 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 IFN-γ that, in addition to costimulatory signals, leads to activation of macrophages.13 Macrophages, in turn, are responsible for the phagocytosis and defense against a variety of bacteria, fungi, and parasites, such as Toxoplasma gondii and Pneumocystis jirovecii.14 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. Like T cells, B cells are able to recognize a foreign antigen. However, unlike T cells, B cells recognize free antigen and do not require the presence of MHC molecules.15 This antigen is recognized by a cell-surface immunoglobulin present at the B cell receptor (immunoglobulin M [IgM] in the case of immature B-cells and both IgM and immunoglobulin D [IgD] in mature B cells), which 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 reexpressed on the surface of the B cell bound to an MHC II molecule. This in turn is recognized by TH2 cells, which are activated, undergo clonal expansion, and allow for activation and maturation and differentiation of B cells. In certain cases, this process may occur independent of T-cell stimulation.16

Mature B cells exist in 1 of 2 predominant forms. The first form of mature B cells, memory B cells, may exist for years or decades and are ultimately responsible for the rapid immunologic response on repeat exposure to a foreign antigen.17 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 form, plasma cells, produce massive quantities of secreted, antigen-specific antibodies. Plasma cells typically are short-lived; however, longer-lived subsets may be responsible to some extent for the development of an immunologic memory.18 The activation, expansion, and maturation of B cells and the resultant immunoglobulin production is the humoral arm of the innate immune system.

The final link in the immune system is immunoglobulin itself. Immunoglobulins exist in several forms, including IgA, IgD, IgE, IgG, and IgM. All are produced by plasma cells and all are important in the functioning of the immune system, although IgG plays the most important role in relation to the development of antibody-mediated immunity against pathogenic organisms. Each immunoglobulin consists of an Fc (fragment crystallizable) region, which binds to the Fc receptor on effector cells, and Fab (fragment antibody) region, which recognizes the antigen.19 Following antigen binding by IgG, several key responses occur. The first involves activation of the classical pathway of the complement system through the formation of IgG complexes. This, in turn, allows for the opsonization and phagocytosis of pathogens.20 Additionally, binding of IgG complexes to the FcγR leads to activation of macrophages, forming a link to cell-mediated immunity.21

Linking Defects in the Immune System to Specific Infections

While there is considerable overlap in the functional components of the immune system, defects in specific components may be linked to a predisposition to different types of infections. In the case of PIDD and other immune deficiencies, these predispositions can be used to predict infections that a patient may develop. For example, patients with defects in the complement system or with hypogammaglobulinemia are predisposed to severe infections with the encapsulated bacteria Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis because of defective complement-mediated phagocytosis.10 Defective cell-mediated immunity, such as is seen in patients with AIDS or those taking immunosuppressive medications for the prevention of organ transplant rejection, typically leads to opportunistic infections, such as Pneumocystis jirovecii, severe viral infections, or atypical mycobacteria.22,23 Finally, neutropenia or defective neutrophil function, which may be caused by several factors, including PIDDs and cytotoxic chemotherapy, leads to a predisposition to typical bacterial infections as the result of a defective innate immune response.24


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, and/or IgM. While still uncommon in the overall population, CVID is one of the most commonly encountered PIDD, with a prevalence estimated at between 1 in 25,000 and 1 in 50,000.25 CVID is a diagnosis of exclusion, and is often discovered in patients who present later in life with recurrent sinopulmonary infections and are subsequently found to have hypogammaglobulinemia.26 Current diagnostic criteria supported by the Pan-American Group for Immunodeficiency (PAGID) and the European Society for Immunodeficiencies (ESID) require the following 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 that age; 2) at least 2 years of age; 3) poor vaccine response and/or absence of isohemagglutinins; 4) exclusion of other causes of hypogammaglobulinemia.27 Other, more stringent, criteria have recently been proposed,28 although all require the exclusion of other identified causes of immune deficits.

More than 90% of patients with CVID will present with 1 or more serious infections during a lifetime, in addition to a number of other complications. In one large, prospective cohort of patients with CVID, followed over a 40 year time period, 68% experienced autoimmune or inflammatory conditions, 28.5% developed chronic lung disease, 15.4% had noninfectious gastrointestinal disease, and nearly 20% developed a malignancy.29 Treatment with IVIG, introduced for CVID in the 1970s, has decreased associated mortality from 29.6% to 19.6%,29 primarily the result of a reduction in infectious complications. However, even with IVIG these patients continue to experience a higher incidence of infectious complications when compared with the general population.30

Severe Combined Immunodeficiency (SCID)

SCID is another group of heterogeneous disorders characterized by a complete block of T-cell lymphocyte differentiation. In contrast to CVID, patients with SCID present early in life with severe infections and, without treatment, the majority will die within 1 year of life.31 The prevalence of SCID is estimated at between 1 in 50,000 and 1 in 500,000 live births, although the most common 2 forms, X-linked SCID (X-SCID) and adenosine deaminase deficiency (ADA), account for 45.4% and 14.8% of cases, respectively.32 Patients with X-SCID have defects in the IL-2 receptor γ chain, leading to an almost complete loss of T-cells and NK cells, but retain normal counts of B cells (albeit 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.33,34

Patients with SCID generally present with severe opportunistic infections of the respiratory system (e.g., Pneumocystis jirovecii) and gastrointestinal tract at 3 to 6 months of age.31 Without treatment, all forms of SCID are universally fatal. Some patients with ADA deficiency are able to be maintained on replacement therapy with pegylated (PEG)-ADA35; however, treatment with hematopoietic stem cell transplantation (HSCT) remains the treatment of choice for SCID.36 In addition to a serving as a temporizing measure prior to HSCT, IVIG is a standard treatment option for patients with inadequate B-cell function following engraftment.37

Wiskott - Aldrich Syndrome (WAS)

In contrast to both CVID and SCID, WAS is linked to a single gene and is caused by one of several defects in a gene on the X-chromosome known as the WAS protein (WASp).38 In addition to the recurrent infections as a result of immunodeficiency, patients with WAS characteristically present with thrombocytopenia, eczema, autoimmune disorders, and malignancy.39 WASp is a ubiquitous protein in the cytoplasm of hematopoietic cells, with mutations leading to defective cytoskeleton formation and, ultimately, deficiencies in both B- and T-cell signaling and antigenic response.39 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 and occurs in 1 to 10 out of every 1,000,000 live births.39

Patients with WAS invariably present with thrombocytopenia of varying degrees, with about half having small platelets. Approximately 70% will present with inadequate response to pneumococcal polysaccharide antigens following immunization, although the majority of patients have near-normal levels of IgG.40 The treatment of choice for patients with the most severe phenotypes (i.e., those developing autoimmune complications) of WAS have a poor prognosis and require HSCT,41 although supportive measures including splenectomy, antibiotic prophylaxis, and IVIG improve short- and medium-term survival for patients with WAS.42


In addition to PIDD, IVIG is used, with varying degrees of success, in more than 150 distinct inflammatory, autoimmune, and infectious conditions.43 A summary of the indications for which IVIG is used is presented in Table 1, with only a small proportion being FDA-approved indications. Collectively, off-label uses of IVIG account for more than 75% of the total use of IVIG in the United States.44 The vast majority of these indications have limited strong supporting clinical evidence, with only a minority considered to be definitely beneficial.45

Table 1. Uses for Intravenous Immune Globulin
Immune deficiency Autoimmune/inflammatory disorders Infectious diseases
  • Primary immunodeficiency

    • Congenital agammaglobulinemia
    • Common variable immunodeficiency
    • Wiskott-Aldrich syndrome
    • X-linked agammaglobulinemia
    • Severe combined immunodeficiency

  • Secondary immunodeficiency

    • Chronic lymphocytic leukemia
    • Pediatric HIV infection
    • Allogeneic bone marrow transplantation
  • Kawasaki disease
  • Chronic inflammatory demyelinating polyneuropathy
  • Multifocal motor neuropathy
  • Idiopathic thrombocytopenic purpura
  • Kidney transplantation involving a recipient with a high antibody titer or an ABO-incompatible donor
  • Antibody mediated rejection after solid organ transplantation
  • Alzheimer's disease
  • Guillain-Barré syndrome
  • Relapsing-remitting multiple sclerosis
  • Myasthenia gravis
  • Refractory polymyositis
  • Polyradiculoneuropathy
  • Lambert–Eaton myasthenic syndrome
  • Opsoclonus–myoclonus syndrome
  • Birdshot retinopathy
  • Refractory dermatomyositis
  • Autoimmune hemolytic anemia
  • Autoimmune neutropenia
  • Neonatal alloimmune thrombocytopenia
  • HIV-associated thrombocytopenia
  • Graft-versus-host disease
  • Toxic epidermal necrolysis or Stevens–Johnson syndrome
  • Necrotizing fasciitis
  • Systemic lupus erythematosus
  • Stiff-man syndrome
  • Anemia associated with parvovirus B19
  • Cytomegalovirus
  • Clostridium difficile colitis
  • Neonatal sepsis
  • Severe sepsis
  • BK virus
U.S. Food and Drug Administration (FDA)-approved indications in bold

Secondary Immunodeficiencies

The secondary immunodeficiencies are characterized by an acquired defect in the immune system rather than an innate genetic cause. A number of environmental, infectious, pharmacologic, and metabolic causes may lead to a secondary immunodeficiency with wide-ranging clinical presentations.46 Among infectious causes, the most well-known (and common) is the Acquired Immunodeficiency Syndrome (AIDS) caused by the Human Immunodeficiency Virus (HIV). Infection with HIV leads to depletion of CD4+ T cells and, in its advanced stages, infections with organisms similar to those found in patients with the more severe forms of PIDD.47 Other common examples of secondary immunodeficiency include the hematologic malignancies chronic lymphocytic leukemia (CLL) and multiple myeloma. Patients with these disorders commonly present with hypogammaglobulinemia and increased susceptibility to infections independent of the receipt of cytotoxic chemotherapy and experience decreased risk of both major and clinically documented infections when prophylactically treated with IVIG.48

Autoimmune and Inflammatory Disorders

IVIG has been used to treat a number of autoimmune and inflammatory conditions, either as the primary treatment or in combination with other therapies. While certain conditions, such as idiopathic thrombocytopenic purpura, have large amounts of high-quality clinical data supporting the use of IVIG treatment, other conditions have evidence limited to uncontrolled case series or small, uncontrolled trials.49 In contrast to PIDD or secondary immune deficiencies, where replacement of deficient or defective IgG is the therapeutic goal, the effect of IVIG in many other disorders is reliant on the immunomodulatory effects of IVIG and often requires dosages that are 4-fold higher than those routinely used in the treatment of PIDD.50 The mechanism by which IVIG exerts immunomodulatory effects remains unclear.51 The administration of IVIG at immunomodulatory doses results in the decreased production of pro-inflammatory cytokines, such as TNF-α and IL-1, limits the deposition of complement-containing immune complexes, and suppresses antibody-dependent cell-mediated toxicity.

Due to the differences in dosage and therapeutic endpoints, differentiating autoimmune and inflammatory conditions, which may be treated with IVIG, from PIDD is critically important. In certain cases, the clinical manifestations of these conditions may overlap, making differentiation challenging. For example, Kawasaki Disease (KD) is a relatively common condition of unknown etiology that results in systemic inflammation, vasculitis, fever, and, if left untreated, may result in the development of fatal coronary artery aneurysms. The standard-of-care treatment for KD is the administration of a high-dose of IVIG (i.e., 2 g/kg) in addition to aspirin.52 This dosage reflects the need for the immunomodulatory effects of IVIG, rather than simple antibody replacement. Likewise, various autoimmune diseases lead to the production of antibodies targeting antigens on red blood cells (causing autoimmune hemolytic anemia), platelets (causing idiopathic thrombocytopenic purpura) or neutrophils (causing autoimmune neutropenia).53 These conditions may present with laboratory abnormalities similar to those of PIDD or, in the case of autoimmune neutropenia, may cause a predisposition to infectious diseases. Similar to other autoimmune diseases, IVIG may be used in treatment at a higher, immunomodulatory dose.


Body Weight

The most commonly used initial dose of IVIG used in the United States is 400 mg/kg administered every 4 weeks, with variation in practices among clinicians in the United States and Europe.61 An important consideration when initiating IVIG therapy for the treatment of PIDD is determining the correct body weight for dosing purposes. Currently available pharmacokinetic data indicate that there is significant interpatient variability in serum immunoglobulin levels following the administration of IVIG with low distribution into adipose tissue.54 One study specifically evaluated the effect of body weight in patients who were receiving replacement IVIG therapy for CVID. After adjusting for patient weight, trough immunoglobulin levels had no correlation with either total body weight or body mass index (BMI).55 Together, these data indicate that the use of ideal or an adjusted body weight may be appropriate when IVIG is used in the treatment of obese or overweight patients.

The currently available guidelines in the United States do not provide recommendations about the optimal weight to use when dosing IVIG. The National Blood Authority of Australia states that there is limited evidence to support the use of lean body weight when selecting a dose of IVIG, but stresses that further research is required to determine the optimal dosing weight.56 Certain provinces in Canada, in contrast, require that an adjusted body weight be used for obese patients who are receiving IVIG therapy.57 Due to the paucity of clinical data and differing regulatory guidance regarding the selection of an appropriate weight for IVIG dosing, clinicians should be aware of local policies and standard practices when evaluating IVIG dosage.

Monitoring the Therapeutic Response to IVIG in PIDD

After starting therapy with IVIG, most patients with PIDD will require long-term treatment and monitoring. Elevation of serum IgG levels clearly correlates with a decrease in infectious complications in patients with CVID; however, limited clinical data support a specific goal or monitoring frequency.30 A meta-analysis evaluating the impact of IgG trough concentrations on the rate of pneumonia in patients with PIDD found a substantial decline in the incidence of pneumonia as trough concentrations increased from 5 to 10 g/L, indicating that a threshold of 5 g/L may not be appropriate for all patients.58 In the largest study conducted to date of infections and their relation to trough IgG concentrations, the trough levels required to minimize infections ranged from 5 to 17 g/L, with maintenance dosages of 0.2 to 1.2 g/kg/month.30 Together, these data suggest that a single specific trough target may not be appropriate when using IVIG for the treatment of patients with PIDD.

In light of these and other similar findings, several experts now recommend that the IVIG dosage be adjusted according to a patient’s clinical response, which should be defined according to the incidence and severity of infections rather than a specific trough concentration.59 The practice guidelines for the use of IVIG in the treatment of PIDD issued by the Canadian National Advisory Committee on Blood and Blood Products echo this recommendation, stating that the dose of IVIG should be based on the clinical effectiveness and not to simply increase a trough concentration.60,61 Guidelines recommend the monitoring of trough IgG concentrations every 3 to 6 months for pediatric patients and every 6 to 12 months for adults, with exceptions made based on the clinical scenario (e.g., development of a new, serious infection).60


While the currently marketed IVIG products share similar labeling and clinical use; specific differences in product formulation play an important role in choosing the optimal product for the treatment of a patient with PIDD. Specific product characteristics are listed in Table 2. Although the currently available IVIG products all go through a multistage purification process from pooled human plasma, certain non-IgG components may be present in low concentrations in the final product. These impurities include cytokines, proteolytic enzymes, and other immune globulin fractions, including IgM and IgA.62,63

Table 2. Product Characteristics of Available Intravenous Immune Globulin Formulations
Consideration Gammagard Liquid 10% Gamunex-C 10%
Privigen 10% Flebogamma 10% DIF Bivigam 10% Octagam 5% Carimune NF Gammagard SD Gammaplex 5%
Manufacturer Baxter Healthcare Grifols Therapeutics Inc CSL Behring Grifols Therapeutics Inc Biotest Pharmaceuticals Octapharma USA CSL Behring Baxter Healthcare Bio Products Laboratory
Concentration 10% 10% 10% 10% 10% 5% 6% 5% 5%
Form Liquid Liquid Liquid Liquid Liquid liquid lyophilized lyophilized liquid
Sodium Content Trace Not detectable Trace Trace Trace Not detectable 0.9% 0.85% 2.3 mg/mL
Stabilizer Glycine Glycine Proline Sorbitol Glycine Maltose Sucrose Glucose Sorbitol, glycine, polysorbate 80
Osmolality / Osmolarity 240-300 mOsm/kg 258 mOsm/kg 240-440 mOsm/kg 240-370 mOsm/kg Not disclosed 310-380 mOsm/kg 690 mOsm/kg 636 mOsm/kg 420-500 mOsm/kg
IgA Content 37 mcg/mL 46 mcg/mL ≤ 25 mcg/mL < 6 mcg/mL ≤ 200 mcg/mL ≤ 200 mcg/mL >720 mcg/mL 2.2 mcg/mL < 10 mcg/mL
pH 4.6 – 5.1 4 – 4.5 4.6 – 5 5.5 4 – 4.6 5.1 – 6 6.4 – 6.8 6.4 – 7.2 4.8 – 5
IgA = immunoglobulin A; IV = intravenous; SC = subcutaneous

The Role of IgA

Selective IgA deficiency is considered to be the most common PIDD, occurring in as many as 1 in every 333 healthy blood donors in the United States. Up to 90% of patients with IgA deficiency are asymptomatic, while the remainder may have an increased tendency to develop recurrent infections of the respiratory and gastrointestinal tracts, in addition to having a predisposition toward allergies and autoimmune conditions.64 Among patients with IgA deficiencies, 24% to 32% may have specific anti-IgA IgG antibodies, with percentages ranging from 18% to 22% in patients with hypogammaglobulinemia.65,66 Due to the presence of preexisting antibodies or subsequent immunization following exposure to IgA, patients with IgA deficiency may be more likely to develop anaphylactic reactions following the administration of IVIG. Fortunately, the risk of this event appears to be low given the frequency with which IVIG is administered and the population prevalence of IgA deficiency; therefore, routine screening of patients for IgA deficiency prior to treatment with IVIG is not recommended.63 The IgA content of commercially available IVIG products is included in Table 2.

Differing Pharmaceutical Characteristics

In addition to IVIG and other components remaining from the plasma purification process, various stabilizers, including maltose, glucose, sucrose, sorbitol, and amino acids, are routinely added to IVIG formulations to prevent degradation or aggregation in the final product.44 The specific stabilizer used can play a critical role in a patient’s tolerance of an individual product. Currently used IVIG products have a roughly physiologic osmolarity around 300 mOsm/kg, with the higher osmolarity found in the older products, contributing significantly to the development of venous irritation at the infusion site.

There are 2 specific sugars used as stabilizers in IVIG products that warrant special consideration. The first, maltose, cannot be distinguished from glucose by blood glucose monitoring technologies that use the glucose dehydrogenase pyrolloquinoline quinone (GDH-PQQ) methodology. The presence of maltose in a blood sample being tested will lead to a falsely elevated blood glucose reading and insulin doses selected based on this false reading may be significantly overdosed. Cases of hypoglycemia, coma, and death have been attributed to inappropriate insulin dosing as a result of false readings from GDH-PQQ–based systems; therefore, clinicians using maltose-containing IVIG products should be aware of the glucose monitoring technology that is being use in their institution and by their patients when monitoring at home.67 Maltose is also a disaccharide derived from corn, which may increase the risk for cross reactivity in patients with corn allergy. IVIG products stabilized with sucrose have been linked to the development of acute renal failure, in some cases necessitating temporary hemodialysis. While these reports are limited and nephrotoxicity appears to be reversible, avoiding sucrose-containing IVIG products in patients who are at risk for the development of nephrotoxicity, such as those with preexisting renal disease, is prudent. Further, while the majority of cases reporting acute renal failure associated with the use of IVIG have involved sucrose-stabilized products, all of the product labels contain a warning for the risk of acute renal failure. For patients at risk of acute renal failure (e.g., baseline chronic kidney disease, diabetes, older adults, actively septic, taking nephrotoxic medications), care should be taken to mitigate the risk for renal injury. These steps may include giving the IVIG dose over a longer period of time, ensuring the patient is adequately hydrated, and withholding nephrotoxic medications, if clinically prudent.68


Early-generation immune globulin products had a notably high incidence of infusion-related adverse events, primarily because of the presence of immunoglobulin aggregates capable of activating the complement system. Current manufacturing processes avoid the formation of aggregates and have dramatically lowered the incidence of these adverse events.44 Other adverse events, such as aseptic meningitis, hemolysis, and thrombosis, and the previously discussed anaphylactic reactions and acute renal failure, have since been observed with the widespread use of IVIG. Additionally, as derivatives of human plasma, the transmission of infectious disease is theoretically possible. The remainder of this review discusses adverse reactions that may be seen with IVIG therapy.

Transmission of Infectious Disease

Currently available IVIG products are meticulously screened for transmissible infectious agents, beginning with donor selection and continuing through final plasma preparation. A series of redundant steps are used to minimize this risk, although it must be noted that no process is 100% effective. First, plasma donors are screened for hepatitis B surface antigen, HIV, and hepatitis C and excluded from the pool if any test returns positive. Second, solvents and detergents are applied to the product, followed by nanofiltration, chemical inactivation, polyethylene glycol precipitation, and pasteurization of the IVIG preparation.69 No cases of HIV transmission have ever been reported following use of an IVIG product and hepatitis C transmission has been eliminated since screening of the donor pool for this infection began in the mid-1990s.70

Anaphylactoid Reactions

Anaphylactoid reactions may appear during or immediately following infusion of IVIG and are caused by inflammatory responses to specific components of the IVIG product. These may include IgG complexes or fragments, stabilizers, low molecular weight polypeptides, alloantibodies to blood type A or B, or, as previously mentioned, low levels of IgA in the solution.71 Additionally, the temperature at which the product is infused may play a role. While these reactions occur infrequently overall, the most common reactions are headache, chest tightness, flushing, dyspnea, nausea, back pain, vomiting, and diarrhea.44 Of these, headache is the most commonly reported anaphylactoid reaction and is more common with higher doses of IVIG.

Several more serious reactions may occur in individuals with agammaglobulinemia who have not been previously treated with IVIG. In this case, IgG may lead to complement activation and the production of anaphylatoxins C3a and C5a, which in turn can trigger mast cell and polymorphonuclear cell degranulation with release of histamine and cytokines and subsequent severe hypotension. In individuals not meeting this profile, these events are relatively rare.72

The presence of low molecular weight polypeptides may also contribute to the occurrence of less severe adverse events or, less commonly, they may be caused by a true IgE-mediated allergic reaction to foreign IgG. Should these events occur, the IVIG infusion should be stopped or slowed immediately. In the case of less severe reactions, the infusion may be resumed at a lower rate and continued as tolerated. More severe or persistent reactions should lead to cessation of the infusion until a cause has been identified, often following further analysis of the infusion solution. These events should be reported to the product manufacturer, who can perform an extensive analysis of the solution and comparison with other lots from the same batch of IVIG. Frequently, however, these reactions are idiosyncratic and may be mitigated by the pre-administration of diphenhydramine and/or acetaminophen. Routine corticosteroid use to prevent adverse reactions is not recommended, but it may have a role in the treatment of patients who have a known history of severe reactions to IVIG or to ablate an ongoing severe reaction.

Aseptic Meningitis

The majority of headaches caused by IVIG are infusion-related and are mild and self-limited. Cases of aseptic meningitis, however, have been reported and require special consideration. Common symptoms of aseptic meningitis include severe acute headache, nuchal rigidity, photophobia, lethargy, painful eye movements, fever, nausea, and vomiting.73 While the symptoms of aseptic meningitis mimic those of bacterial meningitis, the 2 can be distinguished by differing cerebrospinal fluid findings and the self-limited nature (persisting for 3 to 5 days following onset).


All plasma products may contain small quantities of preformed antibodies against ABO antigens.74 Manufacturers attempt to remove these preformed antibodies; however, all marketed products do contain these antibodies. These preformed antibodies will lead to hemolysis and, in severe cases, anemia requiring transfusions. Several risk factors for the development of hemolysis have been identified, including non-O blood type, high dose IVIG therapy, and high anti-A/B IgG titers in the product.75 High-risk patients should be carefully monitored for 2 to 3 days following IVIG infusion and, if necessary, a complete hemolytic workup should ensue if the hemoglobin decreases by more than 2 g/dL. If necessary, the manufacturer must be contacted to determine the levels of anti-A/B titers because these may vary by product batch and are not in the labeling information. Patients at risk for hemolysis should also be informed of the appropriate signs and symptoms, such as dark-colored urine and fatigue and report these to a clinician if identified. Notably, the doses if IVIG used to manage immunodeficiency disorders are lower than those implicated in most cases of hemolysis.


Certain thromboembolic complications, including cerebrovascular accident, myocardial infarction, deep vein thrombosis, and pulmonary embolism have been more recently recognized as severe adverse events that may follow IVIG infusion.76 Including thrombophlebitis at the infusion site, the overall rate of thromboembolic events caused by IVIG infusion is estimated at approximately 3%. While the exact mechanism of these events is unclear, hyperviscosity occurring following the rapid infusion of high doses and even the presence of prothrombic proteins, such as Factor XI, in IVIG products have all been reported as potential causes.77,78 Due to heightened awareness of the harms that may be caused by excessive Factor XI, manufacturers now routinely screen products and attempt to minimize the levels present in the final product. Despite these precautionary measures, the risk of thrombosis, particularly in patients with a predisposition to thrombosis, should be considered prior to initiating IVIG therapy. In cases where use cannot be avoided in high-risk patients, measures such as splitting a dose over several days or using a lower rate of infusion may be a prudent way of mitigating this risk.


The use of IVIG is a standard of care for many forms of PIDDs. Differing dosages, monitoring parameters, and therapeutic endpoints make it important to differentiate PIDDs from the myriad other uses of IVIG. Patients receiving maintenance IVIG for the treatment of PIDD require individualization of treatment and do not have a single definitive laboratory parameter to monitor efficacy. Certain product characteristics, such as impurities and stabilizers, allow for the selection of the most appropriate IVIG product for an individual patient.


Immune Deficiency Foundation (IDF) http://www.primaryimmune.org
Primary Immunodeficiency UK (PID UK) – http://www.piduk.org


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