Intravenous Immunoglobulin Batches Research Articles

SARS-CoV-2 spike antibody concentration in gamma globulin products from high-prevalence COVID-19 countries are transmitted to X-linked agammaglobulinemia patients.

Patients with X-linked agammaglobulinemia (XLA) are characterized by humoral impairment and are routinely treated with intravenous immunoglobulin (IVIG). In this study, we aimed to investigate the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in IVIG preparations harvested globally and evaluate the transfer of SARS-CoV-2 antibodies to the XLA patient. A single-center, prospective cohort study was conducted in the period of November 2020 to November 2022. Clinical and laboratory data, specifically, SARS-CoV-2 spike IgG levels from the serum of 115 IVIG preparations given to 5 XLA patient were collected. Concurrently, SARS-CoV-2 spike IgG levels from the serum of the 5 XLA was collected monthly. Five XLA patients were evaluated within the study period. All were treated monthly with commercial IVIG preparations. A total of 115 IVIG treatments were given over the study period. The origin country and the date of IVIG harvesting was obtained for 111 (96%) of the treatments. Fifty-four IVIG preparations (49%) were harvested during the COVID-19 pandemic of which 76% were positive (>50AU/mL) for SARS-CoV-2 spike antibodies which were subsequently transmitted to the XLA patients in an approximate 10-fold reduction. SARS-CoV2 spike IgG was first detected in IVIG batches that completed their harvest date by September 2021. Positive products were harvested from origin countries with a documented prevalence over 2,000 per 100,000 population. As the prevalence of COVID-19 infections rises, detection of SARS-CoV-2 spike IgG in commercial IVIG products increases and is then transmitted to the patient. Future studies are needed to investigate the neutralizing capabilities of SARS-CoV-2 IgG and whether titer levels in IVIG remain consistent as the incidence of infection and vaccination rates in the population changes.

High level antibodies to TORCH in the IVIG preparation from Taiwanese.

Congenital TORCH (toxoplasmosis, other viruses [varicella-zoster virus, VZV, etc.], rubella, cytomegalovirus [CMV], Herpes simplex virus [HSV]) infections are major causes of prenatal, perinatal, and postnatal morbidity and mortality. Although treatment or prevention strategies are available for these pathogens, all drugs may not be safe during the pregnancy. The aim of this study is to measure the antibodies (Abs) concentration in the intravenous immunoglobulin (IVIG) preparation to evaluate the therapeutic potential for TORCH infection. We tested the only one commercial IVIG preparation from Taiwanese for the presence of Abs against Toxoplasma gondii, VZV, Epstein-Barr virus (EBV), measles, mumps, rubella, CMV, HSV type 1 (HSV-1), and HSV type 2 (HSV-2) by using enzyme-linked immunosorbent assay or chemiluminescent microparticle immunoassay. In our study, the median level (range) of anti-CMV immunoglobulin G (IgG) is > 250 (All > 250) (arbitrary unit, AU)/mL, anti-EBV > 200 (All > 200) (relative unit, RU)/mL, anti-HSV > 200 (152.75 to >200) RU/mL, anti-VZV > 5000 (All > 5000) IU/L, anti-measles > 5000 (All > 5000) IU/L, anti-mumps > 200 (156.5 to > 200) RU/mL, anti-rubella 209.8 IU/mL (192.7 to 238.5), and anti-Toxoplasma is 14.05 (12.3 to 16) IU/mL. There was not any immunoglobulin M (IgM) against HSV, VZV, mumps, measles, rubella, CMV, EBV, and Toxoplasma in the "Taiwan Blood Services Foundation" IVIG preparations. There was high activity against T. gondii, VZV, EBV, measles, mumps, rubella, CMV, HSV-1, and HSV-2 in all IVIG batches. Further investigation is warranted to confirm the efficacy of IVIG from Taiwanese for congenital TORCH infections.

In vitro evaluation of the biological activities of IgG in seven Chinese intravenous immunoglobulin preparations

The IgG activities of antigen recognition, Fc-mediated complement activation and cellular Fcγ-receptors (FcγRs) binding are critical for intravenous immunoglobulin (IVIg) immunotherapy in a variety of immune deficiency diseases. Further, these activities could be influenced by different plasma sources and the IVIg manufacturing processes of different manufacturers. This study evaluated and compared the biological activities of IgG in 7 IVIg preparations produced by different Chinese manufacturers. By using ELISA and two-dimensional immunoblotting, the binding capacity and antibody repertoire of IVIg against typical pathogenic antigens were investigated. Further, Fc-mediated complement activation and receptor binding activities were measured by the haemolysis method and flow-cytometric assay respectively. The results showed that all of the preparations tested have a broad spectrum of antibodies against the E. coli O157:H7 proteome, and each IVIg has its own distinct antibody repertoire. Compared to the European Pharmacopoeia IgG standard, the mean indices of the pathogenic antigen binding capacity, complement activation activity and FcγRs binding activity in Chinese preparations were 152%, 143% and 87%. The biological activities varied widely among the 7 IVIg preparations, and no significant differences were observed between the different batches of most IVIgs from the same manufacturer. This study will contribute to the improvement of the IVIg product quality evaluation system and an increased understanding of the variety of IgG biological activities in Chinese IVIg preparations.

Reduction of Isoagglutinin in Intravenous Immunoglobulin (IVIG) Using Blood Group A- and B-Specific Immunoaffinity Chromatography: Industry-Scale Assessment.

BackgroundHemolysis, a rare but potentially serious complication of intravenous immunoglobulin (IVIG) therapy, is associated with the presence of antibodies to blood groups A and B (isoagglutinins) in the IVIG product. An immunoaffinity chromatography (IAC) step in the production process could decrease isoagglutinin levels in IVIG.ObjectivesOur objectives were to compare isoagglutinin levels in a large number of IVIG (Privigen®) batches produced with or without IAC and to assess the feasibility of the production process with an IAC step on an industrial scale.MethodsThe IAC column comprised a blend of anti-A and anti-B resins formed by coupling synthetic blood group antigens (A/B-trisaccharides) to a base bead matrix, and was introduced towards the end of the industrial-scale IVIG manufacturing process. Isoagglutinin levels in IVIG were determined by anti-A and anti-B hemagglutinin direct and indirect methods according to the European Pharmacopoeia (Ph. Eur.) and an isoagglutinin flow cytometry assay. IVIG product quality was assessed with respect to the retention of immunoglobulin G (IgG) subclasses, specific antibodies, and removal of IgM using standardized procedures.ResultsThe IAC step reduced isoagglutinins in IVIG by two to three titer steps compared with lots produced without IAC. The median anti-A and anti-B titers with IAC were 1:8 and 1:4, respectively, when measured by the Ph. Eur. direct method, and 1:2 and <1, respectively, when measured by the Ph. Eur. indirect method. The isoagglutinin flow cytometry assay showed an 87–90 % reduction in isoagglutinins in post-IAC versus pre-IAC fractions. IAC alone reduced anti-A and anti-B of the IgMs isotype by 92.5–97.8 % and 95.4–99.2 %, respectively. Other product quality characteristics were similar with and without IAC.ConclusionsIAC is an effective method for reducing isoagglutinin levels in IVIG, and it is feasible on an industrial scale.

Prediction of Protection against Asian Enterovirus 71 Outbreak Strains by Cross-neutralizing Capacity of Serum from Dutch Donors, The Netherlands.

Outbreaks of human enterovirus 71 (EV-71) in Asia are related to high illness and death rates among children. To gain insight into the potential threat for the population of Europe, we determined the neutralizing activity in intravenous immunoglobulin (IVIg) batches and individual serum samples from donors in the Netherlands against EV-71 strains isolated in Europe and in Asia. All IVIg batches and 41%, 79%, and 65% of serum samples from children ≤5 years of age, women of childbearing age, and HIV-positive men, respectively, showed high neutralizing activity against a Dutch C1 strain, confirming widespread circulation of EV-71 in the Netherlands. Asian B3-4 and C4 strains were efficiently cross-neutralized, predicting possible protection against extensive circulation and associated outbreaks of those types in Europe. However, C2 and C5 strains that had few mutations in the capsid region consistently escaped neutralization, emphasizing the importance of monitoring antigenic diversity among circulating EV-71 strains.

Anti-A and anti-B: what are they and where do they come from?

Intravenous immunoglobulin (IVIG) is made from thousands of donors having a variety of blood groups. All of the donors being used for IVIG production, with the exception of group AB donors, have in their plasma antibodies of variable titer commonly known as isohemagglutinins or ABO antibodies. As blood groups O and A are the most commonly found in the world population, most of the plasma used in IVIG production is from donors having these blood groups, with group B and group AB donors being fewer in number. Consequently, all batches of IVIG contain antibodies that are reactive with individuals of group A, group B, and group AB. These antibodies were originally discovered by Dr Karl Landsteiner in the early 1900s and are now known to consist of immunoglobulin (Ig)M, IgG, and IgA classes. As the process for producing IVIG results in almost exclusively IgG, isohemagglutinins contained in IVIG are of this immunoglobulin class. ABO antibodies are highly clinically significant and, because of this, blood bank cross-matching is done to ensure that blood of the correct type is transfused into recipients to avoid a so-called major mismatch or major incompatibility that can cause significant morbidity and often death. Administration of IVIG, which contains ABO antibodies, is often infused into individuals who have the corresponding ABO antigens, commonly called a minor mismatch, and although not as significant as a major mismatch, the isohemagglutinins contained in the IVIG have some risk for a significant transfusion reaction due to the ABO incompatibility. Indeed, currently there is no way to match IVIG to recipients according to blood type, so when IVIG is administered to group A, B, or AB recipients, there is potential for transfusion reactions analogous to a blood transfusion mismatch. For this reason, strict guidelines have been put into place to restrict the titers of the ABO antibodies contained in IVIG. This review will provide background information about the discovery and biochemistry of the ABO antigens and discuss the various isohemagglutinins that are found in plasma of the different ABO blood types and their potential clinical significance. In addition, a brief discussion of the controversial topic of the origins of these antibodies will conclude this review.

The role of isoagglutinins in intravenous immunoglobulin-related hemolysis.

Increased reporting of intravenous immunoglobulin (IVIG)-related hemolytic reactions (HRs) triggered an investigation by the German and Swiss health authorities to identify potential risk factors. From the EudraVigilance database HRs reported between 2008 and 2013 were retrieved for seven IVIG preparations. HRs were classified as mild to moderate (hemoglobin [Hb] decline < 2 g/dL)] or severe (Hb decline > 2 g/dL) and separately analyzed for IVIG doses of less than 2 g/kg body weight and 2 g/kg body weight or more. It was assessed whether HR reporting rates correlate with the isoagglutinin content of the different preparations. Of 569 HR cases retrieved, 103 cases were excluded due to insufficient data, leaving 466 for analysis. Ninety-three cases were classified as mild to moderate and 373 as severe. Approximately 80% of the severe HRs concerned patients with blood group A and only three patients with blood group O. Testing of isoagglutinin titers revealed substantial differences between the seven preparations. IVIG products with high anti-A/anti-B titers (≥32) had elevated HR reporting rates, particularly when cumulative doses at least 2 g/kg were administered. The isoagglutinin content of IVIGs correlates with the risk for HRs. Exclusion of high-titer donations and manufacturing steps that deplete isoagglutinins should be considered for risk mitigation. In patients with blood groups A or AB receiving doses of at least 2 g/kg, the use of IVIG batches with low isoagglutinin titers should be considered to prevent HRs.

Necrotizing Clostridial Soft Tissue Infection: Does IVIG have A Role?

Necrotizing soft tissue infections are fulminant infections associated with a severe systemic inflammatory response. The Center for Disease Control and Prevention reports an annual incidence of 500 to 1000 cases. They are characterized by rapid progression along tissue planes, necrosis, and a fatal course. Early diagnosis, treatment with antimicrobials, and surgical management are the cornerstones of treatment. We report a case of clostridial soft tissue infection of the abdominal wall and thigh that was rapidly spreading despite treatment with antimicrobials and multiple surgical debridements. The patient had chronic medical conditions and severe sepsis requiring vasopressors for hemodynamic support. He showed dramatic improvement after receiving high dose intravenous immunoglobulin (IVIG) for one day. No further spread of gas gangrene was noted, and pressors were weaned off over the next three days. Traditionally, IVIG is reserved for necrotizing soft tissue infections (NSTIs) caused by a group A Streptococcus. However, large batches of pooled IVIG contain antibodies to clostridial exotoxins. Our report highlights the importance of IVIG as an adjunct to conventional treatment under certain circumstances.

Case report: passive transfer of hepatitis B antibodies from intravenous immunoglobulin

BackgroundPrior to initiating immunosuppressive therapy in the treatment of autoimmune inflammatory conditions, it is a requirement to screen for certain viral serology, including hepatitis B (HBV). A positive result may indicate the need for antiviral therapy, or contraindicate immunosuppression all together. An accurate interpretation of serological markers is therefore imperative in order to treat patients appropriately. We present a case of passive anti-HBV antibody transfer following intravenous immunoglobulin (IVIg) infusion, in which misinterpretation of serology results almost led to inappropriate treatment with antiviral therapy and the withholding of immunosuppressive agents. This phenomenon has been previously reported, but awareness remains limited.Case presentationA 50 year old Caucasian gentleman with a history of allogeneic haematopoietic stem cell transplant for transformed follicular lymphoma was admitted to hospital with recurrent respiratory tract infections. Investigation found him to be hypogammaglobulinaemic, and he was thus given 1 g/kg of intravenous immunoglobulin. The patient also disclosed a 3-week history of painful, swollen joints, leading to a diagnosis of seronegative inflammatory polyarthritis. Prior to initiating long term immunosuppression, viral screening found hepatitis B serology suggestive of past infection, with positive results for both anti-HBc and anti-HBs antibody, but negative HBV DNA. In response, prednisolone was weaned and the local hepatology team recommended commencement of lamivudine. Having been unable to identify a source of infection, the case was reported to the local blood centre, who tested a remaining vial from the same batch of IVIg and found it to be anti-HBc and anti-HBs positive. Fortunately the blood products were identified and tested prior to the patient initiating HBV treatment, and the effect of a delay in starting disease-modifying therapy was inconsequential in light of an excellent response to first-line therapies.ConclusionMisinterpretation of serology results following IVIg infusion may lead to significant patient harm, including unnecessary antiviral administration, the withholding of treatments, and psychosocial damage. This is especially pertinent at a time when we have an ever increasing number of patients being treated with IVIg for a wide array of immune-mediated disease. Passive antibody transfer should be considered wherever unexpected serological changes are identified.

Pleconaril Revisited: Clinical Course of Chronic Enteroviral Meningoencephalitis after Treatment Correlates with In Vitro Susceptibility

Human enteroviruses (HEVs) can cause severe infections, especially in patients with a deficient humoral immune response, such as X-linked agammaglobulinemia. In this patient group, chronic enteroviral meningitis (CEMA) is feared because of extensive morbidity and high fatality rate. Treatment options consist of intravenous immunoglobulin (IVIG), with various outcomes. Pleconaril is an antiviral agent with in vitro activity against HEVs that has been used in the treatment of HEV infections. The efficacy of pleconaril and IVIG against HEV isolated from the patients was assessed in vitro in two patients with CEMA. Echovirus 11 was found in the cerebrospinal fluid (CSF) of case 1. Treatment with high-dose IVIG and pleconaril did not provide any clinical improvement and HEV PCR in CSF remained positive. Case 2 (echovirus 13 positive in CSF) was also treated with IVIG and pleconaril. The patient recovered completely and HEV PCR in CSF became negative. Recent IVIG batches contained low titres of neutralizing antibodies against the patient strains. Echovirus 11 (case 1) was resistant to pleconaril in vitro, whereas echovirus 13 (case 2) was susceptible, in accordance with virological response after treatment and subsequent clinical results. This is the first report that evaluates efficacy of antiviral treatment in CEMA patients in relation to in vitro susceptibility of clinical virus isolates. Since pleconaril is no longer available for compassionate use we strongly propagate that new drugs should be developed against these potential life threatening HEV infections.

Different Preparations of Intravenous Immunoglobulin Vary in Their Efficacy to Neutralize Streptococcal Superantigens: Implications for Treatment of Streptococcal Toxic Shock Syndrome

Eight different batches of intravenous immunoglobulin from 3 different manufacturers were tested for neutralizing activities against all currently known streptococcal superantigens. Statistically significant variation among different intravenous immunoglobulin preparations (P<.0001) and between individual streptococcal superantigens (P<.0001) was observed. These results might be helpful for optimizing the type and dose of intravenous immunoglobulin used in adjunctive therapy for severe invasive streptococcal disease.

Treatment of toxic epidermal necrolysis with high-dose intravenous immunoglobulins: multicenter retrospective analysis of 48 consecutive cases.

To evaluate the effect of high-dose intravenous immunoglobulin (IVIG) in toxic epidermal necrolysis (TEN), parameters that may affect response to treatment, and the effect of different IVIG batches on Fas-mediated cell death. Multicenter retrospective analysis of 48 consecutive TEN patients treated with IVIG. Fourteen university hospital dermatology centers in Europe and the United States. Forty-eight patients with TEN (skin detachment >10% of their body surface [mean, 44.8%; range, 10%-95%]). Infusion of IVIG in all patients (range, 0.8-5.8 g/kg), and analysis of the ability of different IVIG batches to inhibit Fas-mediated cell death. Objective response to IVIG treatment, final outcome at day 45, parameters that may affect response to IVIG treatment, and tolerance. Infusion of IVIG (mean total dose, 2.7 g/kg [range, 0.65-5.8 g/kg]; mean consecutive days, 4 [range, 1-5 days]) was associated with a rapid cessation (mean, 2.3 days [range, 1-6 days]) of skin and mucosal detachment in 43 patients (90%) and survival in 42 (88%). Patients who responded to IVIG had received treatment earlier in the course of disease and, on average, higher doses of IVIG. Furthermore, analysis of 35 IVIG batches revealed significant batch-to-batch variations in the capacity of IVIG to inhibit Fas-mediated cell death in vitro. Early infusion of high-dose IVIG is safe, well tolerated, and likely to be effective in improving the survival of patients with TEN. We recommend early treatment with IVIG at a total dose of 3 g/kg over 3 consecutive days (1 g/kg per day for 3 days).

In vitro antiviral and antibacterial activity of commercial intravenous immunoglobulin preparations--a potential role for adjuvant intravenous immunoglobulin therapy in infectious diseases.

The identification of specific antimicrobial activity of intravenous immunoglobulin (IVIG) preparations against particular microbial pathogens can assist in determining their therapeutic potential for specific infectious diseases. We analysed five different commercial IVIG preparations for the presence of antibodies directed against a large panel of viral, bacterial, fungal and parasitic pathogens. All IVIG batches contained high activity against herpesviruses types 1, 2, 6 and 7, as well as against varicella zoster virus, Epstein-Barr virus (EBV), measles, mumps, rubella and parvovirus B19. Some IVIG batches also had a significant activity against adenovirus and Saint Louis encephalitis virus. The IVIGs held high activity against several bacterial pathogens, including Mycoplasma pneumonia, Chlamydia pneumonia, Helicobacter pylori and tetanus. No activity was found against various parasitic and fungal pathogens. Our findings may provide further support for the use of IVIG for the prevention and treatment of infections caused by specific viral and bacterial pathogens.

Anti‐Rh D Activity of Commercial Intravenous Immunoglobulin Preparations

Abstract Background and Objectives: The presence of antibodies against Rh D in intravenous immunoglobulin (IVIG) products has been proposed as causing adverse reactions and blood grouping problems, although data on the incidence and titre of such antibodies is sketchy. This study was conducted to investigate methodology for carrying out haemagglutination tests on IVIG products, and to examine in retrospect 200 IVIG batches for the presence of anti‐D and other haemagglutinins. Materials and Methods: Batches of commercial IVIG products were tested using the low‐ionic‐strength indirect antiglobulin test (LIAT). Positive batches were futher investigated using a typed red cell panel and direct haemagglutination tests. Results: 44 batches of IVIG gave positive LIAT. Of these, 12 contained specific anti‐D. 11 batches had LIAT anti‐D titres of 2–8; a further batch contained anti‐D with a LIAT titre of 64. The remaining 32 batches agglutinated all erythrocyte phenotypes tested with LIAT titres ≤4; 14 of these batches showed positive direct haemagglutination and the presence of rouleaux. Conclusion: 6% of commercial IVIG batches contained specific anti‐D, including one batch (0.5%) showing unusually high titre. 16% of batches contained haemagglutinins of unknown/non‐specificity.

Anti–Rh D Activity of Commercial Intravenous Immunoglobulin Preparations

Background and Objectives: The presence of antibodies against Rh D in intravenous immunoglobulin (IVIG) products has been proposed as causing adverse reactions and blood grouping problems, although data on the incidence and titre of such antibodies is sketchy. This study was conducted to investigate methodology for carrying out haemagglutination tests on IVIG products, and to examine in retrospect 200 IVIG batches for the presence of anti–D and other haemagglutinins. Materials and Methods: Batches of commercial IVIG products were tested using the low–ionic–strength indirect antiglobulin test (LIAT). Positive batches were further investigated using a typed red cell panel and direct haemagglutination tests. Results: 44 batches of IVIG gave positive LIAT. Of these, 12 contained specific anti–D. 11 batches had LIAT anti–D titres of 2–8; a further batch contained anti–D with a LIAT titre of 64. The remaining 32 batches agglutinated all erythrocyte phenotypes tested with LIAT titres ≤4; 14 of these batches showed positive direct haemagglutination and the presence of rouleaux. Conclusion: 6% of commercial IVIG batches contained specific anti–D, including one batch (0.5%) showing unusually high titre. 16% of batches contained haemagglutinins of unknown/non–specificity.

Adverse effects of intravenous immunoglobulin.

The range of diseases in which intravenous immunoglobulin (IVIG) is effective has expanded significantly since its initial use in primary antibody deficiency. There are at present at least 17 preparations of IVIG in use worldwide with similar profiles of adverse effects. Infusion-related effects range in severity. Mild adverse reactions (headache, flushing, low backache, nausea, wheezing) are often associated with a fast infusion rate, and respond rapidly on slowing the infusion. Very rare episodes of life-threatening anaphylaxis may occur, particularly in those IgA-deficient patients with anti-IgA antibodies; such patients should receive an IgA-depleted preparation of IVIG. There are concerns with any blood product about safety in regard to viral transmission. The 4 outbreaks of non-A non-B hepatitis (probably hepatitis C) in the 1980s were associated with the use of particular batches of IVIG. The more recent exclusion of all anti-hepatitis C virus positive individuals from the donor pool, and the introduction of specific antiviral steps in the manufacture of IVIGs, should prevent further outbreaks. The human immunodeficiency virus (HIV) is effectively inactivated during the manufacturing process itself and HIV transmission has not been reported with IVIG. Rarely, haematological (Coombs' test positive haemolysis), neurological (aseptic meningitis) or renal (transient rises in serum creatinine) adverse effects may be seen when high doses of IVIG are used for immunomodulatory purposes. Haemolysis, due to passive transmission of blood group antibodies (anti-A, anti-D), may be prevented by selecting IVIG batches that give a negative cross-match between the recipient's red cells and IVIG.(ABSTRACT TRUNCATED AT 250 WORDS)