Immunoglobulins (Igs) aka antibodies are glycoprotein molecules produced by plasma cells in response to a variety of antigenic stimuli involved in diverse physiological and pathological processes. Igs primarily function in the adaptive arm (although “natural Igs” work in the innate arm) of the immune system and are subdivided, on the basis of heavy chains they contain, into various classes i.e., IgM, IgG, IgD, IgA, and IgE.
IgG is further subdivided into various subclasses i.e., IgG1, IgG2, IgG3 and IgG4 (in order of decreasing abundance), and IgA into IgA1 and IgA2. IgG is the most abundant Ig with a plasma concentration range of 700 to 1600 mg/dL and this constitutes about 75 to 80% of the Igs. IgA constitutes about 15% of the Igs at a plasma concentration of 70 to 400 mg/dL, whereas IgM has a range of 40 to 230 mg/dL in the plasma.
Intravenous Immunoglobulin (IVIG) is a concentrate of the pooled immunoglobulins derived from 1000s to 100,000s of healthy donors depending upon the manufacturer. Igs play a pivotal role in the humoral adaptive immunity, ergo IVIG reflects a collective exposure of the donor population to their environment and can be expected to contain antibody repertoire of multiple specificities against a broad spectrum of infectious agents (bacterial, viral and others), self-antigens and anti-idiotype antibodies.
The composition of IVIG products closely corresponds to that of Igs in the normal human plasma especially IgG (along with its subclasses), IgA, traces of other Igs, cytokines and soluble receptors. IVIG products are prepared using Cohn-Oncley procedure, the first step of which is cold ethanol precipitation used to enrich the IgG from the plasma of donors. Any two IVIG product varies with respect to the presence of excipients such as substances used to stabilize proteins and prevent aggregation of IgG (sugars such as glucose, maltose, D-sorbitol or more recently amino acids such as glycine or proline), sodium levels, pH levels, osmolality and other Igs (for example, IgA can vary from 0.06 to 40 mg in different preparations).
IgG comprises more than 90% of the proteins in an IVIG preparation and it is the principal component required for the therapeutic effect of IVIG. Some authors even consider IVIG to stand for Intravenous IgG. Thus the goal of IVIG therapy is to replenish sufficient amounts of IgG antibodies that not only passively neutralizes or opsonizes a broad spectrum of infectious pathogens but could also elicit an active immune response via activation of various immune cells thus conferring protection against diverse diseases.
The indications for IVIG can be classified informally into a few broad categories based on the mechanism of action and the type of conditions they treat. They are as follows:
Different IVIG doses (low vs. high) are administered based on the indicated medical condition because the mechanisms of action differ with different doses. Low-dose Igs serve merely as a passive replacement in immunodeficiencies (category I only). High-dose Igs take an active part and modulate the immune functions with additional anti-inflammatory activity (category II only). Of note, there is considerable overlap between autoimmunity and inflammatory conditions as they almost always co-exist. Category III, hyperimmune therapy does not fall under the purview of dose-differentiation as they are specific antibodies and are given at doses “pro re nata” so that they neutralize the small proportion of specific pathogenic antigens. The actual difference in doses and their plausible differences in mechanisms of action are discussed below in their respective sections.
According to the latest report of American Academy of Allergy, Asthma and Immunology (AAAAI), the indications for IVIG therapy is divided into 4 ordinal groups depending on how the therapy benefits the patients: “Definitely beneficial”, “Probably beneficial”, “May provide benefit” and “Unlikely to provide benefit”. Here we will discuss only the first group as the number of diseases that are included in all the groups are numerous and outside the scope of this paper.
IVIG replacement therapy is the apparent treatment of choice for humoral primary immunodeficiencies, as these patients cannot mount an effective immune response towards pathogens. Humoral primary immunodeficiencies are the most common and comprise the largest patient population of primary immunodeficiency (PI) diseases. Humoral PI has the most number of FDA approved IVIG products than any other condition. These diseases are characterized by absent or low serum concentrations of Igs, recurrent infections and the need for repeated intravenous antibiotics, a lack of normal antibody response to a vaccine challenge or a normal antibody concentration with defective function and an identifiable genetic defect.
Agammaglobulinemia due to lack of B cells is the archetype condition in the group of PIs and was first described Bruton in an 8-year old boy with recurrent pneumococcal infections. He discovered the lack of serum immunoglobulins and treated successfully with subcutaneous Igs. It was discovered later to be a genetic disorder with an X-linked inheritance pattern and the newborns are usually protected by the maternal IgGs to protect the fetus. The disease does not usually manifest until after 6 months of age when the maternal IgG wanes and signs of recurrent bacterial infections become apparent. However, the average age at diagnosis with a positive family history is 2.6 years of age with an average life-span of 15 to 20 years underscoring the need for IVIG therapy for survival. A list of other conditions that “Definitely benefit” from IVIG therapy appears in Table 1.
Secondary humoral immunodeficiencies can be caused by a number of conditions and the most common of those is malnutrition. While malnutrition is manageable and leads to the recuperation of immune defense, there are a number of other conditions for which treatment is unavailable or where secondary immunodeficiency is inevitable. These conditions like PIs require low-dose IVIG therapy to avoid the risk of frequent and deadly infections. Cancers such as B-cell chronic Lymphocytic Leukemia (B-cell CLL) and multiple myeloma (MM) leads to humoral immunosuppression and these conditions definitely benefit from IVIG therapy. Other conditions that also definitely benefit are those with B-cell depleting therapies such as lymphoma and geriatric people with recurrent infections. In addition to the clinical picture, IgG levels in plasma can be used to guide in deciding on IVIG therapy for secondary conditions and values of IgG less than or equal to 150 mg/dL are considered severe hypogammaglobulinemia. For levels that are in the range of 150 to 600 mg/dL additional testing of antibody levels in response to vaccines like tetanus and diphtheria should be considered before starting IVIG therapy. A list of other secondary immunodeficiency conditions that benefit from IVIG therapy appears in Table 1.
In autoimmune and inflammatory conditions, two to four-fold increases in doses of IVIG, when compared to replacement doses, can bring a variety of protective changes . These changes as explained below are complex and various studies have shown the efficacy of high-dose strategy in these conditions. For example, Immune thrombocytopenic purpura (ITP) is an autoimmune condition characterized by isolated thrombocytopenia causing life-threatening bleeding. IVIG therapy has shown to raise the platelet count within 4 days of administration reducing the need for frequent and repeated platelet transfusions. Glucocorticoids along with IVIG are now considered first-line therapy in this condition and have greatly improved the lives of these patients. Other such conditions are given in Table 1.
For specific therapy against infectious pathologies, hyperimmune IVIG that contains high concentrations of specific IVIG targeted against a specific organism or antigen is administered. Hyperimmune IVIG is purified from human donors who were recently vaccinated or are in the convalescent period recovering from an infection. Such hyperimmune IVIG is currently indicated for postexposure prophylaxis of hepatitis A & B, tetanus, rabies, diphtheria, botulism, varicella-zoster, respiratory syncytial virus and cytomegalovirus infections.
However, the US-Food and Drug Administration approved conditions that are indicated for IVIG therapy are dispersed among all the categories described above are only a few and include humoral PIs, ITP, B-cell CLL, Common Variable Immunodeficiency (CVID), Kawasaki disease (KD), Multifocal Motor Neuropathy (MMN), bone marrow transplantation and HIV infection. Along with FDA approved use of IVIG, the off-label uses of this product are growing at a tremendous pace. Other conditions were IVIG therapy demonstrates benefit include toxic epidermal necrolysis and Stevens-Johnson syndrome, neonatal sepsis, Birdshot retinochoroidopathy, Henoch-Schonlein purpura, and toxic shock syndrome. IVIG is used in a multitude of other conditions where it is regarded as beneficial and the list is extensive and the readers are advised to refer to the updates from the most recent guidelines when necessary.
The basic structure of the IgG molecule is made up of polypeptide chains and consists of two identical heavy chains and two identical light chains forming a Y-shaped structure. The protease papain can digest the Ig into two Fab fragments and one Fc fragment. IgG-Fab is the antigen-binding fragment and mediates highly specific interactions with the antigenic epitope. IgG-Fc is the crystallizable region, which mediates the binding to Fc-gamma-receptors (FcgRs) on immune cells and/or complement proteins.
Major functions of the Fab portion of IgG are neutralization of infective pathogens (by interfering with pathogen attachment to host cell receptor or by targeting various steps in their lifecycle) and non-specific opsonization by binding to the surface of microorganisms leading to phagocytosis.
IgG-Fc binds to various FcgRs, which are expressed on almost all the immune cell types and can be either activatory or inhibitory in function. IgG-FcgR interaction results in pleiotropic functional consequences including the activation or inhibition of effector immune response, expansion of regulatory T cell population (inhibits overt immune response), modulation of FcgR expression on B cells and immune cells, phagocytosis, antibody-dependent cellular cytotoxicity (ADCC), immune cell differentiation and maturation, apoptosis regulation, expression of proinflammatory mediators, modulation of antigen-presenting cell and dendritic cell functions.
In humoral immunodeficiencies, IVIG primarily acts by substituting for the lack of IgG and confers passive immunity by neutralizing bacterial toxins and viruses through the Fab portion. They also help activate the complement cascade at low doses by specific interaction with pathogens, a function which reverses in high-doses to complement inactivation by non-specific interactions. Polyvalent IVIG products with a higher number of donors would contain a much larger spectrum of specificities and would be more efficient in immune replacement therapies. The effects of replacement dose IVIG in PIs are observed well beyond the half-life of IgG administered suggesting induction of active immunity. This is exemplified by the activation of cellular immunity, for example, IVIG modulates T cell immunity in PIs and increases CD4 counts in CVID, induces B cell Ig production in CVID patients, and induces dendritic cell (DC) maturation.
Autoimmunity is essentially an overt immune response against the body’s own tissues and IgG autoantibodies are considered the main players in most of the conditions. Self-antigen is recognized by Fab fragment of IgG autoantibody and Fc fragment relays this signal to Fc-gamma-receptors (FcgRs) on various immune cells . IgG autoantibodies cause inflammation  by interacting with FcgRs , neonatal FcR (FcRn) and complement proteins . Autoantibodies cause disruption of a myriad of functions including cellular lysis (as in ITP), triggering micro thrombosis, ADCC, complement-dependent cytotoxicity, uncontrolled neutrophil activation, stimulation of hormonal receptor (Grave’s disease), receptor blockade of neural transmission (MG), induction of inflammation (rheumatoid arthritis) and altered cell signaling .
The immunomodulatory actions of high-dose IVIG in autoimmune and inflammatory conditions are highly complex and differ in different diseases. In general, high-dose IVIG paradoxically leads to a reversal of their effects, as opposed to their actions at replacement doses, resulting in a more immunosuppressive and anti-inflammatory phenotype.
In addition to the above mechanisms, natural autoantibodies present in the IVIG also suppress some of the autoimmune pathophysiological mechanisms. Sialylated IgG antibodies present in IVIG preparations are shown to have an anti-inflammatory property, although this claim is controversial.
Hyperimmune IgG also provides passive immunity to an infectious agent, but unlike replacement therapy, they are active against only one specific pathogen. High-dose IVIG therapy, in contrast, exerts it's action through its non-specific interactions with various immune molecules and cells as seen above. Hyperimmune IgG action is instant and leads to an efficient clearance of specific pathogenic microorganism or toxin mediating the disease.
Different IVIG preparations are used at different doses in diverse diseases in a variety of patients with dissimilar immune statuses and although research so far has shed some light on the various mechanisms of actions, it is very hard to generalize the actions and must be considered separately for each disease in question.
IG is available either as 5% (50 mg/dL) or 10% (100 mg/dL) liquid or as lyophilized preparations. As the name suggests, IVIG administration intravenously, and the half-life of a typical intravenous Ig infusion is about 3 to 4 weeks. The dosage, peak concentrations achieved, and frequency of dosing, as elaborated in the text, appear in summary form in Table 2.
Low-dose replacement therapy: In PIs, IVIG is usually administered at replacement doses of 400 to 600 mg/kg per month, achieving plasma levels of 1200 to 1400 mg/dL. IgG trough levels (defined as the lowest concentration achieved before the next dose) of 500 to 800 mg/dL are achievable with this dosing and are considered to be protective from infectious consequences in immunodeficient patients. IVIGs administered at a frequency of once every month are usually sufficient for PIs through a wear-off effect (increased susceptibility to infection) can occur near the end of their dosing cycle for at-risk patients and should be borne in mind. In cases of acute infections in immunodeficient patients, a short-term course of high-dose IVIG merit considered for treatment as in enteroviral meningoencephalitis.
High-dose immunomodulatory and anti-inflammatory therapy: For immunomodulation, higher doses of IVIG are necessary, ranging from 1000 to 3000 mg/kg of body weight to achieve peak plasma concentrations of 2500 to 3500 mg/dL. The optimal dosage, duration, and frequency are usually determined based upon the indication, response to treatment, adverse effects, relapse rate, infectious episodes, patient preferences, and affordability. In general, a high-dose IVIG protocol, usually but not always, involves an initial dose, maintenance dose, tapering/intensifying, and discontinuation. In general, a protocol of 2 mg/kg/course divides into 400 mg/day for five days is a universally employed administration strategy for autoimmune diseases. It is modifiable in certain conditions; for instance, in the case of ITP, a dose of 1000 mg/kg is given for 1 to 2 days. Weekly regimens may also be employed depending on the clinical situation and the particular patient.
Hyperimmune therapy: The dosage of hyperimmune IVIG varies with every indication, but some generalizations are possible. The most common means of administration is as a single intramuscular dose after the suspected exposure to a particular pathogen, and the earlier it is administered after exposure, the better the outcome. In addition to the intramuscular route, some of these immune sera also are given as IVIG therapy. They may also be administered sometimes in a multi-dose regimen, for example, 750 mg/kg of respiratory syncytial virus (RSV) IVIG is given every month to infants in RSV season. The dosage can also increase in cases of immunocompromised and immunosuppressed patients.
Infusion rate: is another important parameter to consider in IVIG therapy, especially in patients new to IVIG therapy. Infusions are started at a rate of 0.5 to 1 mL/kg/hour for the first 15 to 30 minutes, and if no adverse reaction occurs, then the rate can be increased subsequently every 15 to 30 minutes to a maximum of 3 to 6 mL/kg/hour. Dose fractionation should also be considered to decrease the possibility of any adverse reaction.
Pharmacokinetic profiles of IVIG products show a considerable interindividual variability and also vary in different disease states; for example, in bone marrow recipients, the reported half-life of IVIG is around 2 to 6 days. Due to the presence of FcRn, IVIG preparations have a similar half-life as that of endogenous IgG, which has a median half-life of about 23 days. In immunodeficient patients, the reported half-life of IVIG is 33 to 36 days.
SCIG therapy can be a consideration in the event of any systemic adverse effects and poor venous access. SCIG is usually administered at a lower dose of 100 to 200 mg/kg and is administered much more frequently, i.e., every week or two weeks, and achieves a better nadir (trough level) than IVIG that achieves higher peak levels. SCIG, which typically contains a small transfusion volume on average 20 to 60 mL, also has the advantage that it can be administered at home and has better patient compliance.
Adverse reactions can be either immediate or delayed and can be of different severity. Immediate reactions can be of mild, moderate, and serious types. These occur within 30 to 60 minutes of the start of IVIG infusion and are reported in 5% of patients. Most common generalized side effects are mild in severity and include headache, fever, chills, and fatigue. These effects are attributable to excipients and stabilizer contained in the preparation. Sugar-depleted preparations are now available with only amino acids as a stabilizing agent. Most of these reactions are mild and transient and attributed to a particular IVIG product and its infusion rate. A ten-year retrospective study on adverse effects of IVIG concluded that most of the adverse events are due to the fast infusion rates. Vomiting, chest pain, and headache classify as a moderate reaction. Mild-to-moderate reactions can be mitigated with symptomatic treatment, premedication, slowing the transfusion rate, lowering the dose or withdrawing, and replacing with a different IVIG preparation.
Serious adverse reactions are more common in geriatric patients than any other age group due to the pre-existing co-morbidities. The most common of these include headache, myalgia, back pain, nausea, vomiting, rash, fatigue, malaise, tachycardia, erythema, flushing, fever, hypo- or hypertension, and fluid overload. Severe uncommon side effects include urticaria, severe headaches, dyspnea, pruritus, thromboembolic events, and hemolytic reactions. Serious rare effects are transfusion-related acute lung injury (TRALI), acute renal failure, anaphylaxis to IgE or IgG antibodies to IgA (in IgA deficiency), arrhythmias, aseptic meningitis, arthritis, hepatitis, pleural effusion or other dermatological manifestations.
Less than 1% of patients may have a delayed reaction, which includes renal impairment, transfusion-related infection, hematological, and neurological disorders. Solvent related adverse effects such as the high volume of infusions as needed in some liquid formulations can lead to volume overload in patients with cardiac or renal conditions and require appropriate attention using concentrated IVIG preparations or subcutaneous immunoglobulin (SCIG) therapy. Adverse effects are preventable with certain premedications, including non-steroidal anti-inflammatory drugs, antihistamines, corticosteroids, or saline for pre-hydration.
There are certain reported drawbacks or risks, but due to stringent regulation of IVIG product approval, there are no recently reported cases. These include:
Although there are no absolute contraindications for IVIG products as they are not generic drugs and are not interchangeable, their use in high-risk patients must proceed with caution. Every IVIG product is different, and a patient with a life-threatening reaction to one product may not have any reactions with a different preparation. Thus the contraindications are related to the particular component of the IVIG product.
In general, there are a few noteworthy caveats:
Patients receiving initial (first-time) IVIG infusions and high-risk category should be monitored carefully for any infusion-related reactions or adverse effects. The slowest initial infusion rates are necessary to prevent any untoward situation. The infusion should be carried out in the presence of an expert physician and in a setting well equipped to tackle any adverse reaction swiftly. Concomitant medications of the patients should be reviewed before starting on IVIG therapy, for example, inhibitors of the renin-angiotensin system (RAS).
IgG levels in blood serve as an essential yardstick to guide IVIG therapy. It is also used to assess the effectiveness of the treatment and helps to modify the IVIG course and frequency. Measuring IgG levels at different times to evaluate the peak plasma levels and trough levels can assess response to therapy. Trough levels are particularly important in replacement therapy, as maintaining constant plasma level are necessary for this life-long therapeutic strategy. However, the clinical scenario dictates the true response to IVIG therapy in all circumstances. Clinical response is the most important variable on which to base a course of IVIG treatment, and doses are repeated every month over several months to years (for immunomodulation) or indefinitely (for immunodeficiencies) depending on the condition of the patient and undergo reevaluation as needed.
Patients with blood type A, B, or AB should be monitored carefully for hemolytic transfusion reaction during high-dose therapy as they may contain anti-A or anti-B blood group antibodies. These patients should be followed-up with a hemoglobin workup two days after the therapy.
Various stringent quality-control measures are employed to ensure the safety of a typical IVIG product and include virus inactivation, removal of coagulation factors, and depletion of IgG aggregates. Though IVIG is generally considered to be safe, well-tolerated, and an efficacious therapeutic modality, reports exist in the literature of various toxicities have been reported.
There are reports of renal toxicity with sucrose-containing products and patients greater than or equal to 65 years, patients receiving concomitant nephrotoxic agents, patients with diabetes mellitus, pre-existing renal disease, hypovolemia, and sepsis are at increased risk for acute renal failure and renal insufficiency. Urine output, blood urea nitrogen, and creatinine require assessment in patients with increased risk of developing acute renal failure. There are also reports of cardiac toxicity has been reported after IVIG therapy in a patient with scleromyxedema, where it resulted in myocardial infarction. Hematological toxicities, including various cytopenias and thrombotic complications, have also been reported and should be considered in patients with increased risk of thrombosis.
The onus for IVIG therapy success lies mainly in the treating physician to achieve treatment goals, as every patient needs a unique and tailored infusion regime. The first and primary means of achieving this is by having a correct diagnosis, and this occurs through efficient interprofessional communication between specialists. More often than not, the diagnosis may fall on the category where off-label use of IVIG is required (as evidenced by a large number of such conditions), and assessing the appropriateness of IVIG therapy must be balanced against the morbidity of the condition. Clinicians and other providers can accomplish this by staying up-to-date on the current guidelines from the authorities such as the American Academy of Allergy, Asthma & Immunology, the European Academy of Allergy and Clinical Immunology, and the World Allergy Organization. Recently available scientific evidence of the use of IVIG in specific disease trials or studies should always be used along with clinician's experience to guide the decision on dosage, targeted optimal IgG levels, choice of IVIG product, and course of treatment and should be modified in a patient-centric setting. The choice of IVIG product needs special attention as the products are not generic and only a particular product, but not the other may meet the patient's needs.
IVIG therapy is a consistently evolving practice, and more large-scale clinical trials are needed to assess the efficacy of treatment in specific conditions that may not be feasible in other rare conditions. In such situations, a treating physician has the responsibility to publish individual case studies and be part of a collective framework in establishing guidelines for IVIG therapy. Nurses play an evident role in patient care during IVIG infusion and to promptly report any adverse reaction to the treating physician to be able to tackle the situation immediately. The government and health authorities can influence the type of product approved in the local market and thereby serving a fundamental role. The cost of IVIG and the availability in low and middle-income countries are challenging, and governmental/national measures to reduce the costs will bring the IVIG therapy to the doorstep of the poor. Finally, the hospital authorities must not only be well-equipped to handle the transfusion but also can play a role in establishing standard IVIG protocols for well-established diseases, and the hospital's research office should encourage more projects to address the off-label use in rare conditions.
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