Not all IGIV preparations are created equal

April 2004

---Ronald Sacher, MD

Intravenous immune globulins (IGIV) are concentrates of pooled plasma derived from thousands of blood donors containing a high concentration of immunoglobulin G (IgG) antibodies with specificity against a wide spectrum of pathogens. These therapeutic immunoglobulins are polyvalent and are processed to provide a concentration of greater than 90% IgG.

Hyperimmune immunoglobulins have directed specificity toward single antigens or infectious agents. The more recently engineered immunoglobulins with monoclonal specificity are used for more targeted immunotherapy.

The therapeutic use of IGIV is based on two fundamental strategies: replacement therapy for primary or secondary humoral antibody deficiency and immunomodulation for autoimmune or certain infectious
diseases.

IGIV preparations have been a mainstay for the treatment of primary immunodeficiency syndromes where immunoglobulin replacement can prevent or ameliorate bacterial infections. Patients with immunodeficiencies are at significant risk of developing serious and often life-threatening invasive infections. Antibody replacement using IGIV is necessary to minimize complications associated with chronic sinusitis, bronchiectasis and recurrent episodes of pyogenic pneumonia. Replacement therapy aims to maintain an adequate level of serum immunoglobulins and, consequently, humoral immunity.

IGIV use has expanded beyond the simple replacement therapy for immunodeficiency to a number of other arenas including immunomodulation for hematological, infectious and neuroimmunological disorders. The exact mode of action of IGIV in these conditions is likely multidimensional and has not yet been fully determined. Indeed, it is likely that the anti-infective and immunomodulatory mechanisms overlap and are interrelated (see Figure 1).

The use of high-dose IGIV in immunomodulant therapy has an impact on various immunological responses and for neutralization of foreign agents. Infusion of high doses of IGIV elicits and/or attenuates an array of biological and immunological responses. Consequently, it has been used in the management of diverse immune disorders.

In ITP

Immune thrombocytopenic purpura (ITP) is a disorder involving autoantibodies directed against platelets resulting in varying degrees of thrombocytopenia with markedly shortened platelet survival. It was the first syndrome where higher (immunomodulating) doses of IGIV demonstrated therapeutic effectiveness.

In 1981, Imbach et al first used 400 mg/kg/day for 5 days, a dose that has now become standard for immunomodulant therapy. ITP may be acute or chronic (lasting for longer than six months). The acute ITP syndrome, found mostly in children, usually resolves spontaneously without therapy. However, a small number of these patients will require therapy, and IGIV has been shown to be effective in preventing or treating bleeding events.

It can also be used to defer splenectomy in chronic ITP of childhood. IGIV therapy is effective in adults, who more commonly have the chronic disorder. It is effective particularly in patients with severe thrombocytopenia (less than 20,000/µL), those who are at risk of life-threatening bleeding or to prepare patients for surgery when platelet counts are lower than 50,000/µL. It is also useful in preventing peripartum hemorrhage or in increasing platelet counts in pregnant patients with severe ITP who undergo cesarean section.

There are still a number of unresolved issues that remain regarding the use of IGIV in the management of ITP. Specifically, which ITP patients should receive IGIV vs. Rh immunoglobulin vs. steroids or no treatment? The optimal doses and frequency of administration are still under investigation and have changed from the original five-day course to more abbreviated strategies such as one- to two-day courses at lower doses. IGIV’s use in chronic ITP involves individual physician preference, but includes those listed above and patients who have clinically significant bleeding and have had a splenectomy.

Use in children

In the management of acute ITP in children, there continues to be considerable debate on usage. Specifically, since the disorder is self-limiting, 20% to 25% of pediatricians in a recent survey favored no therapy. Others favored therapy only when the platelet count was less than 10,000/µL, and others also favored therapy when there is evidence of “wet thrombocytopenia.”

Chronic lymphocytic leukemia (CLL) is a clonal disorder of usually B lymphocytes and consequently is not uncommonly associated with hypogammaglobulinemia. These patients also may have immunodeficiency and are susceptible to bacterial infections, particularly infections due to encapsulated organisms. The ability of IGIV to prevent recurrent bacterial infections in CLL, complicated by hypogammaglobulinemia, has been demonstrated. In addition, CLL may be complicated by the concurrent presence of ITP. IGIV may also be useful in the treatment of ITP that can occur with CLL.

Although IGIV has been approved by the FDA for the management of immunodeficiency associated with bone marrow transplantation (Table 1), its use has dramatically declined because its effectiveness in ameliorating graft vs. host disease (GVHD) has been marginal, and furthermore its utility in attenuating or preventing cytomegalovirus (CMV) infection has also not conclusively been demonstrated.

More specifically, since newer therapies are now available both for the management of GVHD and the prevention and management of CMV, IGIV’s use in these conditions has declined. It does, however, have a role in provision of humoral antibody replacement therapy after bone marrow or progenitor cell transplantation. Principles of its application in this situation are not unlike those in other immunodeficiency disorders with a maintenance of an optimal level of humoral antibodies in the serum.

Kawasaki disease (KD) is an acute vasculitis of unknown etiology that occurs predominantly in infants and young children. It is associated with a staphylococcal superantigen toxin that is believed to produce the mucocutaneous syndrome. In patients with KD, there is a 25% association with coronary artery aneurysms and a 2.5% fatality rate. The immune-mediated endothelial injury is most effectively treated by a combination of IGIV and aspirin. IGIV administration during the acute phase can reduce the incidence of coronary dilatation to less than 5%.

Although IGIV has also been approved for the management of pediatric HIV infection, with the introduction of highly active antiretroviral replacement therapy (HAART), the use of IGIV in the management of pediatric HIV infection has declined.

Increased off-label use

Despite the declining use of IGIV for the FDA-approved labeled indications, its use has expanded greatly during the past decade. Currently, more than 50% of IGIV therapy is for off-label indications. A number of consensus conferences starting in 1990, including one held at the NIH, recognized the usefulness of IGIV for the management of some autoimmune disorders, including chronic inflammatory demyelinating polyneuropathy (CIDP). In 1995, another consensus conference convened by the University Hospital Consortium evaluated off-label use of polyvalent intravenously administered immunoglobulin preparations and stated its position regarding IGIV use for several diseases.

Although this list is not all-inclusive, a list of the more commonly used off-labeled indications for IGIV is present in Table 2. IGIV efficacy for patients with Guillain-Barré syndrome has been demonstrated in two large controlled trials. Indeed it is also the drug of choice in multifocal motor neuropathy. Furthermore, it is also proven effective in chronic inflammatory demyelinating polyneuropathy, dermatomyositis and Lambert-Eaton myasthenic syndrome. It is probably also effective in myasthenia gravis and polymyositis. In fact, the list continues to expand.

FIGURE 2       Viral Inactivation Methods Differ Among IGIV Products Multiple, complementary steps may be most effective

Product S/D treatment Pasteurization Low pH (4.25) Pepsin/pH4 Trypsin Caprylate Venoglobulin-S           Gammagard S/D           Carimune NF           Iveegam EN           Polygam           Gammar-P I.V.           Gamunex

Source: Ronald Sacher, MD

Efficacy

Regarding IGIV efficacy, there are limited large-scale controlled studies in the disease states where IGIV is used. Comparisons are often made retrospectively using efficacy data in the same indication for different products — so-called “surrogate measures.”

There are few direct comparisons between products produced by different manufacturing methods. Clinical efficacy may be associated with the expected properties, including a high intact monomeric IgG content, normal distribution of IgG subclasses, increased circulating half-life and higher titers and/or functional activity of specific antibodies. In the management of primary immunodeficiency syndromes, only a limited number of trials have used the number of infections as an outcome measure. If one considers IGIV from the early ’50s as a first-generation product, and the newer fourth-generation caprylate-chromatography treated IGIV released in 2003, the number of infections per year has dramatically decreased from 3.54 per year to 0.18 +/- 0.52 infections per year.

These data are from one manufacturer’s product because there has really been no head-to-head comparison of other manufacturers’ products. In two studies looking at efficacy, safety and toxicity of a fourth-generation product (Gamunex, Bayer HealthCare Biological Products) and a third-generation product from the same manufacturer, Gamimune at 10%, this randomized double-blind parallel group controlled trial in the United States and Canada showed that the proportion of patients with at least one validated infection was statistically significantly lower in the fourth-generation preparation compared with the third generation.

This well-controlled trial comparing two IGIVs head-to-head established a new unique proof of principle challenging the perception of therapeutic equivalence. A similar equivalence study designed to compare efficacy, safety and tolerability of the same preparations in adults and children with acute and chronic ITP evaluated the proportion of patients whose platelets counts increased from better than 20,000 mL to greater than 50,000 mL by day 7 after treatment.

This trial was also an equivalence one and showed the preparation to be equivalent with a statistically significantly reduced need for steroids beyond day 7 in the fourth-generation group. There was also a trend to improvement in ecchymoses, petechiae, IGIV doses beyond day 21 and the need for a splenectomy beyond day 7. In other words, they trend to a reduction in bleeding episodes and the need for emergent care.

The expert panel convened by the University Healthcare Consortium’s Technology Assessment Group evaluated off-label IGIV use using evidence-based criteria. Their recommendations were published in 1995 after reviewing the published literature up to that time. The conclusions then were that there was no difference in either the safety or efficacy profiles for the different IGIVs.

Since that time, with the variety of new preparations becoming available and with the recent introduction of a fourth-generation preparation, it is apparent that statement needs to be reevaluated. Clearly the production methodology defines the product and may have implications in safety, efficacy, tolerability and convenience.

There are a multitude of variables in IGIV production where critical product differences are introduced. Starting with the original source plasma, going through the process of fractionation, purification, stabilization, viral inactivation and removal and finally formulation and composition, it is clear that all IGIV preparations are not the same. The current IGIV products are presumed safe, but there are differences in their approach to enhancing safety.

Safety and tolerability issues

Immunoglobulin therapy in general is remarkably safe.

It has been used for more than 50 years. Initially, immunoglobulin concentrates were administered intramuscularly (first generation), and although this was painful, the overall safety profile was well demonstrated. Attempts to inject the same preparation of the immunoglobulins intravenously resulted in serious adverse events including activation of the complement cascade and anaphylaxis. The newer IV preparations were first used in the early 1980s. They were purified, contained fewer aggregates and had a positive safety profile. Newer preparations have evolved since then with an even better safety profile. Most reactions to IGIV, however, are mild, transient, self-limiting and do not require discontinuation of therapy. They are often related to the speed of infusion, but there is a large interpatient variability. Other complications have been reported with certain preparations and include aseptic meningitis, acute renal failure and thrombotic events. Many of the serious reactions appear to be associated with products that contain sucrose. Common and specific adverse events of IGIVs are listed in Table 3.

The potential for infectious disease transmission can occur with any blood product derivative. IGIV, however, has a remarkable safety record with respect to known pathogen transmission. The reasons for this may involve the preproduction donor and plasma screening and testing and post-production virus inactivation and/or viral removal. However, viral inactivation and removal methods differ among IGIV products. Specifically, multiple complementary steps may be the most effective. Figure 2 shows the different methods used for the available products in the United States. Safety is one key element where differences may exist; the other is tolerability.

The right match

Regarding tolerability of the preparations, finding the “right match” for the patient is a critical clinical concern. Issues such as volume load, osmolality, sodium content, sugar content, immunoglobulin A (IgA) content and pH all can be important in specific patients. Preparations are available in concentrations between 3% and 12%. Obviously, those given at higher concentrations can reduce the volume load.

Patients’ considerations regarding concentration and fluid volume are important in those with congestive heart failure, hypertension and vascular disease and renal dysfunction; neonates; the elderly; and also for patients’ convenience relating to infusion time. Larger doses that are used in immunomodulant therapy pose two challenges: increased fluid volume and increased length of time for infusion. Infusion rates may be limited because of poor tolerability and adverse events. The preparations available can be dispensed as lyophilized products that have been reconstituted in either water or as liquid saline or liquid preparations.

The lyophilized products prepared at higher concentrations may result in a hyperosmolar solution. In particular, those that are stabilized with glucose at a 5% solution have an osmolality of 636 mOsm-L, whereas a 10% preparation has an osmolality of 1,250 mOsm-L. Preparations that are stabilized with sucrose at a 6% solution when reconstituted with saline have an osmolality of 636 mOsm-L, whereas those that are reconstituted with saline at a concentration of 12% have a osmolality of 1,074 mOsm-L. When these preparations are reconstituted with water, the osmolality changes and is reduced to 384 mOsm-L and 690 mOsm-L, respectively.

Hyperosmotic states have been implicated in thrombotic complications, and certainly considerations of osmolality are important in patients with congestive heart failure, renal dysfunction, hypertension and vascular disease and in neonates and the elderly. Sodium content is also a variable that is widely different in the available preparations: from trace amounts to 0.9%. Concentrating some preparations from 5% to 10% can create approximately a 2% saline solution with implications on the same patient population. Figure 3 shows the available products in the United States and the comparison of concentration, stabilizer contents, sodium content, osmolality, pH and IgA level. These data were obtained from the manufacturers’ package inserts.

Sugar as stabilizer

The use of sugars as stabilizing agents is widespread, and indeed sugar is added as a stabilizer to most IGIV preparations. As mentioned above, the concentration of sugar affects osmolality, and the type of sugar may affect the occurrence of adverse events. Specifically, 90% of IGIV-induced acute renal failure episodes were associated with sucrose in sugar-containing preparations. Patients with pre-existing renal disorders and those with diabetes are particularly susceptible to the potential of acute renal failure when IGIV is used.

Consequently, finding the “right match” of IGIV with the patient’s profile is important, because from the preceding it is apparent that IGIV patients are not all the same nor are IGIV products. Critical clinical decisions need to be made as to what is the appropriate product selection based on a patient’s risk factors and potential IGIV risk factors as is shown in Figure 4.

From the foregoing discussion it is apparent that there are differences in available IGIV preparations that can influence safety, efficacy and tolerability. Statements that all IGIVs are the same need to be reevaluated. Foremost, decisions regarding the use of one preparation vs. another need to consider the indication for administration and the patient’s profile.

For more information:

• Nydegger UE, Mohacsi PJ. Immunoglobulins in Clinical Medicine. Chapter 24 in: Rossi's Principles of Transfusion Medicine. 3rd ed. Simon TL, et al. Philadelphia, Pa: Williams and Wilkins; 2002;316-332.
• Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Eng J Med. 2001;345(10):747-755.
• Sacher RA. Evaluation and review: Symposium covers indications for the use of intravenous immune globulin. J Allergy Clin Immunol. 2001;108(Suppl ):S1-2.
• Sacher RA. Intravenous immunoglobulin. Consensus statement. J Allergy Clin Immunol. 2001;108(4 Suppl):S139-46.
• Yu Z, Lennon VA. Mechanism of intravenous immune globulin therapy in antibody-mediated autoimmune diseases. N Engl J. Med. 1999;340:227-228.

• Ronald Sacher, MD, is a professor of Internal Medicine and Pathology and the director of the Hoxworth Blood Center at the University of Cincinnati Medical Center.