Intravenous Immunoglobulin Products Research Articles

Outbreak of Hepatitis C Associated With Intravenous Immunoglobulin Administration— United States, October 1993-June 1994

On February 21, 1994, the Food and Drug Administration (FDA) was notified of 14 possible cases from three different countries of acute hepatitis C among persons who had received Gammagard, an intravenous immunoglobulin (IGIV) product manufactured by Baxter Healthcare Corporation (Glendale, California). The company removed Gammagard from the worldwide market on February 23, 1994. The American Red Cross removed Polygam (IGIV manufactured by Baxter Healthcare from American Red Cross plasma) from the market on the same date. This report presents preliminary findings of an evaluation of transmission of hepatitis C virus (HCV) infection from these products and guidelines for monitoring patients who may have received them.

Long-term use of IgA-depleted intravenous immunoglobulin in immunodeficient subjects with anti-IgA antibodies.

The use of intravenous immunoglobulin is standard practice for antibody replacement in the humoral immunodeficiency diseases. Most infusions proceed uneventfully, but a proportion of infusions (5-8%) produces some degree of an infusion reaction. While the cause of most of these infusion reactions is unknown, an established, but rare cause of reactions is IgA antibodies in the serum of the patient, which apparently forms an immune complex with the traces of IgA in the infused immunoglobulin. This article describes our studies of five immunodeficient patients who had high-titered anti-IgA antibodies and a history of severe infusion reactions to intravenous immunoglobulin products not depleted of IgA (IgA content, 270-720 micrograms/ml). Over a 6-year period we gave these patients IgA-depleted intravenous immunoglobulin for a total of 170 infusions. These infusions were generally well tolerated; however, mild to moderate infusion reactions did occur in 9 of the 170 infusions (5.3%). These reactions were not related to the IgA content of the immunoglobulin solutions used--ascertained to vary between 0.4 and 2.9 micrograms/ml of IgA. Levels of plasma C3a and C4a increased after immunoglobulin infusions but the appearance of these components was not accompanied by any infusion reaction. We conclude that the long-term infusions of IgA-depleted intravenous immunoglobulin, within the range of IgA concentrations investigated, into patients with even very high-titered antibodies to IgA, is a safe practice.

Virus inactivation during production of intravenous immunoglobulin.

The effect of pepsin treatment at pH 4 on the infectivity of several enveloped viruses was assessed under the conditions used during the production of intravenous immunoglobulins. It was shown that the prototypes of four virus families--human immunodeficiency virus (Lentivirinae), herpes simplex virus type 1 and human cytomegalovirus (Herpesviridae), Semliki Forest virus (Togaviridae), and vesicular stomatitis virus (Rhabdoviridae)--were inactivated by this procedure. With vesicular stomatitis virus as a model, the contributions of both low pH and pepsin were demonstrated, and pepsin had a synergistic or additive action.

Production and Characterization of a Human Hyperimmune Intravenous Immunoglobulin against Pseudomonas aeruginosa and Klebsiella Species

A hyperimmune globulin for intravenous use (H-IVIG) was prepared from the plasma of donors immunized with Pseudomonas aeruginosa and Klebsiella vaccines. H-IVIG preparations contained substantially higher IgG antibody levels to all nine P. aeruginosa vaccine antigens and to 22 of the 24 Klebsiella vaccine antigens than did commercial IVIG. The H-IVIG was more effective at promoting the opsonophagocytic killing of P. aeruginosa and Klebsiella vaccine serotype strains than normal IVIG. The H-IVIG neutralized greater than 20 times more toxin A than commercial IVIG. Only the H-IVIG offered significant protection against Klebsiella K2 sepsis. The H-IVIG provided significantly better protection against six of the eight P. aeruginosa vaccine serotypes than normal IVIG when compared in a murine burn wound sepsis model. The H-IVIG also protected mice against an Enterobacter aerogenes challenge, whereas normal IVIG was ineffective.

Screening Plasma Donors for High‐Titre Antibody to Cytomegalovirus Using a Latex Agglutination Test

Cytomegalovirus (CMV) can cause severe morbidity in immunosuppressed patients. Regional transfusion centres in the UK are required to supply high-titre anti-CMV plasma to the Blood Products Laboratory (BPL), now called 'Bio-Products Laboratory', for the production of specific intravenous immunoglobulin at the Protein Fractionation Centre in Scotland. For this purpose, 703 plasmapheresis donors were screened by a modified latex agglutination test to assess their suitability as donors with high-titre anti-CMV. CMV antibodies were found in 48% of the donors. Seropositivity increased with age ranging from 33% in the 20- to 29-year age group to 57% in the 40-49 age group, although the 50-59 age group showed a slight decline to 53%. In all age ranges except the 40-49 group, seropositivity was highest in the female population. With the latex test, 14% of the total donors screened had a titre greater than or equal to 1 in 64, 7% greater than or equal to 1 in 128 and 4.2% greater than or equal to 1 in 256. Samples from 18 donors with titres greater than or equal to 1 in 128 were sent to BPL and all samples were found to have a sufficiently high titre for the production of CMV immune plasma. For BPL the 'cut-off' level for CMV immune plasma is a titre greater than or equal to 1 in 64 by complement fixation. Since the establishment of a panel of donors with high-titre anti-CMV plasma, more than 10 kg of plasma are dispatched monthly from our centre to BPL.

Factors affecting the production of intravenous immunoglobulin

Factors affecting the production of intravenous immunoglobulin

Screening Plasma Donors for High-Titre Antibody to Cytomegalovirus Using a Latex Agglutination Test

Cytomegalovirus (CMV) can cause severe morbidity in immunosuppressed patients. Regional transfusion centres in the UK are required to supply high-titre anti-CMV plasma to the Blood Products Laboratory (BPL), now called ‘Bio-Products Laboratory’, for the production of specific intravenous immunoglobulin at the Protein Fractionation Centre in Scotland. For this purpose, 703 plasmapheresis donors were screened by a modified latex agglutination test to assess their suitability as donors with high-titre anti-CMV. CMV antibodies were found in 48% of the donors. Seropositivity increased with age ranging from 33% in the 20- to 29-year age group to 57% in the 40-49 age group, although the 50-59 age group showed a slight decline to 53%. In all age ranges except the 40-49 group, seropositivity was highest in the female population. With the latex test, 14% of the total donors screened had a titre ≥ 1 in 64, 7% ≥ 1 in 128 and 4.2% ≥ 1 in 256. Samples from 18 donors with titres ≥ 1 in 128 were sent to BPL and all samples were found to have a sufficiently high titre for the production of CMV immune plasma. For BPL the ‘cut-off’ level for CMV immune plasma is a titre ≥ 1 in 64 by complement fixation. Since the establishment of a panel of donors with high-titre anti-CMV plasma, more than 10 kg of plasma are despatched monthly from our centre to BPL.

Potential contribution of mild pepsin treatment at pH4 to the viral safety of human immunoglobulin products.

Different manufacturers use several different processes for the production of intravenous immunoglobulin. Several manufacturers include a production step where the immunoglobulin is treated with low levels of pepsin at pH 4. A series of experiments were undertaken to assess whether or not pH 4/pepsin treatment could inactivate a range of test viruses. Acid-labile viruses such as vaccinia, herpes simplex, mumps and Semliki Forest virus were found to be susceptible to pH 4/pepsin treatment whereas poliovirus type 2, an acid-stable virus, was completely resistant to this treatment. In immunoglobulin preparations, viral contaminants are likely to be present as antibody/virus complexes and such complexing was found to help protect the test viruses from inactivation by pH 4/pepsin treatment. Despite this protection, at least 99% of the test inoculum of two susceptible viruses (vaccinia and herpes simplex) was found to be inactivated after treatment and the subsequent dissociation of virus/antibody complexes. It is concluded that pH 4/pepsin treatment may contribute to the safety of intravenous IgG by inactivating potential viral contaminants.

Potential Contribution of Mild Pepsin Treatment at pH4 to the Viral Safety of Human Immunoglobulin Products

Different manufacturers use several different processes for the production of intravenous immunoglobulin. Several manufacturers include a production step where the immunoglobulin is treated with low levels of pepsin at pH 4. A series of experiments were undertaken to assess whether or not pH 4/pepsin treatment could inactivate a range of test viruses. Acid-labile viruses such as vaccinia, herpes simplex, mumps and Semliki Forest virus were found to be susceptible to pH 4/pepsin treatment whereas poliovirus type 2, an acid-stable virus, was completely resistant to this treatment. In immunoglobulin preparations, viral contaminants are likely to be present as antibody/ virus complexes and such complexing was found to help protect the test viruses from inactivation by pH 4/pepsin treatment. Despite this protection, at least 99% of the test inoculum of two susceptible viruses (vaccinia and herpes simplex) was found to be inactivated after treatment and the subsequent dissociation of virus/antibody complexes. It is concluded that pH 4/pepsin treatment may contribute to the safety of intravenous IgG by inactivating potential viral contaminants.

Safety of intravenous immunoglobulin treatment.

In a prospective clinical and biochemical study of 16 patients treated with high doses of an immunoglobulin product that had been modified for intravenous use by mild pepsin treatment at pH 4 no evidence of hepatitis could be found. This contrasts with recent reports that intravenous immunoglobulin products can apparently transmit non-A, non-B hepatitis.

1040 Prophylactic infusions with an unmodified intravenous immunoglobulin product causing few side-effects in patients with antibody deficiency syndromes

Thirty-two patients with common variable immunodeficiency (CVID) and two patients with IgA and IgG subclass deficiency received a total of 1,040 intravenous (i.v.) infusions during 60 patient years with 7,575 g of a new immunoglobulin (Ig) preparation. The content of prekallikrein activators and the anti-complementary activity in the tested Ig preparation was low and, in comparison to seven other commercial i.v. Igs, so was the proportion of IgG polymers and fragments. The IgA content was always less than or equal to 0.02 g/l, often less than 0.004 g/l, and it was possible to continuously give the Ig prophylactically to four patients with anti-IgA antibodies, i.e. three with CVID and one with combined IgA-IgG2 deficiency. Adverse reactions were only noted in 4.7% of the 1,040 infusions and in 12 out of the 34 patients. None of the reactions were of the anaphylactic type, but two patients had moderate reactions and one had anuria, probably not caused by the Ig. A simultaneous infection seemed to increase the risk of phlogistic reactions, as five out of six patients who reacted with temperature rise and chills had a simultaneous upper respiratory tract infection. A substudy of various dosage schedules was performed with 11 patients receiving 203 infusions over 10.8 patient years. On 25 mg/kg/week of Ig given i.v. every five weeks, a mean increase in the preinfusion serum IgG level of 0.3 g/l was observed, as compared to earlier i.m. prophylaxis with the same dose. Only 1/4 of the patients on 25 mg/kg/week every five or three weeks reached a preinfusion IgG level greater than or equal to 3 g/l.(ABSTRACT TRUNCATED AT 250 WORDS)