Intravenous Immunoglobulin Products Research Articles

Predicting Factors for the Pattern of Intravenous Immunoglobulin Utilization in a Middle Eastern University Hospital.

Objective:The dramatic increase in the consumption of intravenous immunoglobulin (IVIG) products in nonapproved indications, its high cost, and the severe shortage has developed the concerns of its irrational utilization, especially in the Middle East countries. Therefore, this clinical study attempts to describe the pattern of IVIG administration in one of the largest hospitals in Iran and find the variables associated with inappropriate IVIG utilization.Methods:This cross-sectional medication utilization study was conducted in one of the largest referral hospitals in Iran. Random IVIG administrations were assessed from different wards for 9 months. Different data were collected to evaluate the pattern of IVIG administration and find variables, which could predict this behavior.Findings:IVIG was prescribed for approved indications in 72% of 201 patients recruited in our study. Although, the rate of drug administration was appropriate in most of the study population, hydration and pre-medication were unsuitable in more than one-third of the patients. Among the variables analyzed to find the factors affecting the misuse of IVIG, female gender, older age of patients, and longer time to start IVIG administration due to hospital admission were statistically significant in the multivariate model.Conclusion:Despite the fact that inappropriate use of IVIG was confirmed in less than 30 % of its utilization for the studied patients, it caused a potential risk of treatment complications and a notable and unjustifiable burden of unnecessary costs for this University hospital.

Effect of intravenous immunoglobulin administration on erythrocyte and leucocyte parameters.

Intravenous immunoglobulins (IVIG) are an attractive therapeutic tool for therapy of toxic epidermal necrolysis and severe forms of certain autoimmune diseases, including dermatomyositis, autoimmune blistering diseases, systemic vasculitis and lupus erythematodes. Prompted by a case of IVIG-associated haemolytic anaemia, the effects of IVIG administrations on haematological parameters in patients with dermatological conditions were investigated. Erythrocyte and leucocyte parameters were retrospectively analysed in 16 patients who had received IVIG at doses from 1 to 3 g/kg bodyweight (n = 35 cycles). The influence of IVIG on leucocyte survival was determined in vitro. Decreased absolute erythrocyte numbers, haemoglobin and haematocrit levels and a case of haemolytic anaemia were linked to transfusion of high-, but not low-dose IVIG. In contrast, leucopenia post-IVIG occurred in the vast majority of the recipients, unrelated to the administered IVIG amounts. In vitro investigations revealed a dose-dependent impairment of cell survival by IVIG in the neutrophil and monocyte, but not in the lymphocyte subpopulations. In several IVIG preparations, substantial amounts of blood group anti-A/anti-B antibodies were detected which could have accounted for the observed changes in the haematological parameters in our study cohort. IVIG products should be administered strictly according to indications. Commercially available IVIG products can contain blood group-specific antibodies that may induce haemolysis in some recipients. Monitoring of blood counts during applied IVIG therapy, especially when high doses are administered, is recommended.

High-resolution physicochemical characterization of different intravenous immunoglobulin products.

Intravenous immunoglobulin (IVIg) is a complex mixture drug comprising diverse immunoglobulins and non–IgG proteins purified from the plasma of thousands of healthy donors. Approved IVIg products on the market differ regarding source of plasma, isolation process, and formulation. These products are used widely, and often interchangeably, for the treatment of immunodeficiency and autoimmune and inflammatory diseases, but their mechanisms of action in different indications are not well understood. A primary limitation to understanding the therapeutic relevance of specific components within IVIg has been the limited resolution of analytics historically implemented to characterize its complex mixture. In this study, high-resolution analytics were applied to better understand the composition of IVIg and product variations. We characterized three approved IVIg products: Gammagard®, Privigen®, and Octagam®. Differences in the distribution of molecular weight species, IgG sequence variants, isoforms, glycoforms, and the repertoire of previously reported antibody specificities were identified. We also compared the effect of aging on these products to identify changes in size distribution and posttranslational modifications. This type of characterization may provide insights into the specific factors and components of IVIg that may influence its activity and ultimately lead to optimization of IVIg products for use in autoimmune diseases.

Evaluation of the Safety, Tolerability, and Pharmacokinetics of Gammaplex\xae 10% Versus Gammaplex\xae 5% in Subjects with Primary Immunodeficiency

PurposeThis phase 3, multicenter, open-label, randomized, two-period, crossover bioequivalence trial evaluated the safety, tolerability, and pharmacokinetics of intravenous immunoglobulins (IVIGs) Gammaplex 5% and Gammaplex 10% in 33 adults and 15 children with primary immunodeficiency diseases (PIDs).MethodsEligible adults received five Gammaplex 5% infusions followed by five Gammaplex 10% infusions, or vice versa, stratified by a 21- or 28-day dosing regimen. Pediatric subjects received five Gammaplex 10% infusions only.ResultsThe primary objective, to demonstrate the bioequivalence of Gammaplex 10% and Gammaplex 5% at the 28-day dosing interval, was met based on the Gammaplex 10%/Gammaplex 5% ratio of area under the concentration versus time curve (AUC0–28) values. Throughout the study, total immunoglobulin G trough levels were well maintained, with total values generally ≥600 mg/dL (minimum level for study inclusion). At the dosing schedules and infusion rates used in this study, safety and tolerability were comparable and acceptable in adult and pediatric PID subjects treated with Gammaplex 10% and 5%.ConclusionsIn this study, the first direct comparison of 5% IVIG and 10% IVIG products in PID subjects, the pharmacokinetic analysis demonstrated bioequivalence of Gammaplex 10% and Gammaplex 5% at the 28-day dosing interval. The Gammaplex 10% formulation was safe and well tolerated in pediatric and adult PID subjects. Based on the results from this bridging study in PID subjects, Gammaplex 10% could be expected to have a therapeutic effect similar to the licensed Gammaplex 5%, which has demonstrated efficacy and tolerability in patients with PID and idiopathic thrombocytopenic purpura.

Concentrations of antibodies against β-amyloid 40/42 monomer and oligomers in Chinese intravenous immunoglobulins

Intravenous immunoglobulin (IVIg) preparations are being investigated as a potential agent for treatment or prevention of Alzheimer’s disease (AD). Antibodies towards soluble β-amyloid (Aβ) contained in IVIg were considered to be the major component contributing to the beneficial effect of the preparations in pilot studies. This study compared the antibody concentrations against Aβ in Octagam® IVIg (Octapharma) and 9 IVIg preparations from different Chinese manufacturers by ELISA, using Aβ40 monomer, Aβ40 soluble oligomers, Aβ42 monomer and Aβ42 soluble oligomers as the antigens. The results showed that each preparation contained different antibody levels against the four Aβ forms. The median values of the four antibody concentrations in Chinese IVIg preparations were 16.53, 8.47, 24.36 and 33.25μg/mL, which were remarkably higher than that in Octagam® IVIg (1.66, 2.07, 4.61 and 4.64μg/mL). Moreover, the anti-Aβ42 oligomer antibody levels in almost all IVIg preparations were higher than the anti-Aβ42 monomer antibody, and the concentrations of anti-Aβ42 antibodies in most of the IVIg preparations were significantly higher than that of anti-Aβ40 antibodies. These findings will contribute to an increased understanding of the uniqueness of Chinese IVIg preparations, and could provide support for a trial of a Chinese IVIg product in AD patients.

Establishment of a reference material for standardization of the anti-complementary activity test in intravenous immunoglobulin products used in Japan: A collaborative study

Aggregates of human plasma-derived intravenous immunoglobulins (IVIGs) carries a risk of severe adverse events after nonspecific complement activation induced in humans administrated. Therefore, the anti-complementary activity (ACA) test is legally required in every batch of IVIGs in Japan. However, due to the intrinsic nature of this bioassay, there might be large differences in the results of ACA tests from laboratories, even when the same batch of IVIGs was measured. Our six laboratories evaluated whether there were such differences and argued for establishment of a reference material (RM) for standardization of the ACA test. Our results revealed inter-laboratory differences in ACA values, indicating a need to establish an RM. Therefore, after ACA values in candidate RMs were measured collaboratively, one RM was selected from two candidates and unit value-assigned. The RM in fact normalized the ACA test values for samples measured in parallel at almost all the laboratories, when the values were calculated relative to the assigned unit value of the RM. Thus, we established a first RM to standardize the ACA test in Japan, which enabled each laboratory to normalize ACA values constantly for IVIGs. This indicates that the establishment of an RM can contribute to quality control of IVIGs.

Opsonophagocytic Antibodies to Serotype Ia, Ib, and III Group B Streptococcus among Korean Infants and in Intravenous Immunoglobulin Products.

Group B streptococcus (GBS) infection is a leading cause of sepsis and meningitis among infants, and is associated with high rates of morbidity and mortality in many countries. Protection against GBS typically involves antibody-mediated opsonization by phagocytes and complement components. The present study evaluated serotype-specific functional antibodies to GBS among Korean infants and in intravenous immunoglobulin (IVIG) products. An opsonophagocytic killing assay (OPA) was used to calculate the opsonization indices (OIs) of functional antibodies to serotypes Ia, Ib, and III in 19 IVIG products from 5 international manufacturers and among 98 Korean infants (age: 0–11 months). The GBS Ia, Ib, and III serotypes were selected because they are included in a trivalent GBS vaccine formulation that is being developed. The OI values for the IVIG products were 635–5,706 (serotype Ia), 488–1,421 (serotype Ib), and 962–3,315 (serotype III), and none of the IVIG lots exhibited undetectable OI values (< 4). The geometric mean OI values were similar for all 3 serotypes when we compared the Korean manufacturers. The seropositive rate among infants was significantly lower for serotype Ia (18.4%), compared to serotype Ib and serotype III (both, 38.8%). Infant age of ≥ 3 months was positively correlated with the seropositive rates for each serotype. Therefore, only a limited proportion of infants exhibited protective immunity against serotype Ia, Ib, and III GBS infections. IVIG products that exhibit high antibody titers may be a useful therapeutic or preventive measure for infants. Further studies are needed to evaluate additional serotypes and age groups.

Immunogenicity of murine mPEG-red blood cells and the risk of anti-PEG antibodies in human blood donors.

The immunocamouflage of non-ABO blood group antigens by membrane-grafted methoxypoly(ethylene glycol) (mPEG) may attenuate the risk of red blood cell (RBC) alloimmunization. However, concerns have been raised over the immunogenic risk of PEG and PEG-RBCs. To assess this risk, murine and human studies were performed. Mice were exposed to soluble PEG prior to, or between, multiple transfusions (∼60-day intervals) of control or mPEG-RBCs, and cell survival was determined by flow cytometry. In some studies, the control and mPEG-RBC groups were reversed after one or more transfusions. Furthermore, human blood donors and commercial intravenous immunoglobulin products were examined to detect anti-PEG antibodies and to assess the risk for false positives. Naïve mice receiving chronic mPEG-RBC transfusions had normal RBC survival curves with no evidence of anti-PEG antibodies. Similarly, challenge with soluble PEG did not elicit anti-PEG antibodies in mice. Studies in humans revealed no evidence of a high prevalence of anti-PEG antibodies in either blood donors or commercial intravenous immunoglobulin. However, by use of the methods employed by studies identifying high levels of anti-PEG antibodies, a significant level (∼15%) of "false positives" were detected in commercial antibodies of known (non-PEG) specificities. These findings suggest that methodologic problems yielded a high rate of false positives in these earlier studies. These data continue to support the clinical utility of cellular PEGylation and the low immunogenic risk of grafted mPEG.

BK polyomavirus‐neutralizing activity of intravenous immunoglobulin products derived from donated blood in Japan

Background and ObjectivesBK polyomavirus (BKV) causes BKV‐associated nephropathy and haemorrhagic cystitis, subsequent to BKV reactivation. Intravenous immunoglobulin products (IVIg), manufactured from the plasma of over ten thousand donors, may contain antibodies against BKV. However, the antibody titres and batch‐to‐batch variations in IVIg across the manufacturing year are unknown. This study aims to determine the BKV‐neutralizing activity of IVIg from donated blood in Japan and its trend over the past several years.Materials and MethodsA reliable measurement method was established to quantitatively determine neutralizing activity using the human lung (carcinoma) cell line, A549 and the Gardner strain of BKV. Six lots of IVIg and four lots of pooled plasma were used as the source material for this study.ResultsThe mean neutralizing titre against BKV in pooled plasma was 3·4 ± 0·1 log10 and that in IVIg was 4·1 ± 0·1 log10. The titres of IVIg lots manufactured from 1999 to 2010 were stable.ConclusionIVIg derived from donated blood in Japan demonstrated high neutralizing activity against BKV, and its titre was maintained over the duration of 10 years, suggesting high prevalence of BKV among the donor population in Japan. Further studies are required to clarify the clinical implications of this neutralizing activity in IVIg.

Intravenous immunoglobulin-associated hemolysis: risk factors, challenges, and solutions

Intravenous immunoglobulin-associated hemolysis: risk factors, challenges, and solutions Muhajir Mohamed1,2 1Department of Haematology, Launceston General Hospital, 2Launceston Clinical School, University of Tasmania, Launceston, Tasmania, Australia Abstract: Clinically significant hemolysis associated with intravenous immunoglobulin (IVIG) administration has recently been identified as a major problem requiring special attention, after increased incidence has been documented by US FDA since 2011. IVIG-associated hemolysis remains an under-recognized complication of IVIG therapy, and hence the exact incidence of hemolytic anemia induced by high dose IVIG is not clear. Patients at high risk of IVIG-associated hemolysis are non-O blood group recipients who receive high-dose IVIG for inflammatory or autoimmune disorder. Due to the immunomodulatory potential of high-dose IVIG, the clinical indications have increased over time. The objective of this article is to discuss the epidemiology, risk factors, and challenges of IVIG-associated hemolysis. Strategies to reduce the incidence of clinically significant hemolysis in patients treated with IVIG products and potential avenues for further research in this field are also discussed. Keywords: IVIG, immunoglobulins, hemolysis, ABO, isoagglutinins, hemolytic anemia

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.

The prophylactic effects of human IgG derived from sera containing high anti-PcrV titers against pneumonia-causing Pseudomonas aeruginosa

ABSTRACTThe PcrV cap structure of the type III secretory apparatus of Pseudomonas aeruginosa is a vaccine target. Human immunoglobulin G (IgG) molecules extracted from sera containing high or low anti-PcrV titers were tested for their effects against P. aeruginosa pneumonia in a mouse model. Among 198 volunteers, we selected the top 10 high anti-PcrV titer sera and the bottom 10 low anti-PcrV titer sera and extracted the IgG fraction from each serum sample. First, we examined the effects of the IgG against virulent P. aeruginosa. A lethal dose of P. aeruginosa premixed with saline, low titer human IgG, high titer human IgG, or rabbit-derived polyclonal anti-PcrV IgG was intratracheally administered into the lungs of mice, and their survival and lung inflammation were evaluated for 24 h. The high anti-PcrV titer human IgG had a prophylactic effect. Next, the prophylactic effects of intravenous administration of extracted and pooled high or low anti-PcrV titer human IgG were examined. Here, prophylactic intravenous administration of pooled high anti-PcrV titer human IgG, which showed binding capacity to P. aeruginosa PcrV, was more effective than the administration of its low titer pooled equivalent, and the measured physiological and inflammatory parameters correlated with the anti-PcrV titer levels. This result indirectly implies that high anti-PcrV titers in blood can help to protect against virulent P. aeruginosa infections. In addition, the IgG fractions from such high titer sera have potential to be a source of specific intravenous immunoglobulin products for passive vaccination against virulent P. aeruginosa infections.

Neutralizing activities of human immunoglobulin derived from donors in Japan against mosquito-borne flaviviruses, Japanese encephalitis virus, West Nile virus, and dengue virus.

Japanese encephalitis virus (JEV), West Nile virus (WNV), and dengue virus (DenV) are causal agents of Japanese encephalitis, West Nile fever, and dengue fever, respectively. JEV is considered to be indigenized and widespread in Japan, whereas WNV and DenV are not indigenized in Japan. Globulin products seem to reflect the status of the donor population according to antivirus neutralization activity. However, the anti-JEV, -WNV, and -DenV neutralization activities of globulin products derived from donors in Japan have not been clarified. Furthermore, potential candidates for the development of an effective immunotherapeutic drug for encephalitis caused by JEV, WNV, or DenV have also not been identified. Therefore, the aim of this study was to determine the overall status of the donor population in Japan based on globulin products by evaluating anti-JEV, -WNV, and -DenV neutralizing activities of intravenous immunoglobulin. Overall, intravenous immunoglobulin products showed stable neutralizing activity against JEV but showed no or only weak activity against WNV or DenV. These results suggest that the epidemiological level against WNV and DenV in the donor population of Japan is still low, suggesting that these viruses are not yet indigenized. In addition, JEV vaccinations and/or infections in the donor population do not induce a cross-reactive antibody against WNV.

Inactivated pepsin inhibits neutrophil activation by Fcgamma-receptor-dependent and independent stimuli

Pepsin is widely used to produce F(ab′)2 fragments of immunoglobulin G (IgG). In many cases, at least part of the pepsin will remain present in the F(ab′)2 preparation, albeit in (irreversibly) inactivated form. Here we report on a potent immunomodulatory effect of irreversibly inactivated pepsin on activated human neutrophils. Degranulation, induced by coated IgG or via cytochalasin B/N-formyl-Met-Leu-Phe, was measured by quantifying elastase release, and was found to be inhibited in a dose-dependent manner by inactivated pepsin. Since a number of intravenous immunoglobulin (IVIg) products are also treated by limited digestion with pepsin, we investigated if pepsin would be present in quantities large enough to inhibit neutrophil activation. The amounts of pepsin detected in three different pepsin-treated IVIg products were found to be too low to induce an effect, at least in an in vitro setting.

A clinical trial protocol for the study of intravenous immunoglobulin in patients with primary antibody immunodeficiency disorders

This protocol has been excerpted from protocols recently used to study the safety, efficacy, and pharmacokinetics of 2 new intravenous immunoglobulins (IVIG). It incorporates the safety and efficacy parameters provided by the United States Food and Drug Administration in in a Guidance for Industry that contains recommendations for Investigational New Drug Application sponsors and Biologic License applicants for testing IVIG products as replacement therapy in primary humoral immunodeficiency. The format and contents of the protocol are generally the same as described in the ICH Guideline for Good Clinical Practice. We describe here the topics found in the main body of the protocol. We have omitted items that will be included in a formal protocol such as the title page, identifying number, name and contact information of the sponsor, names and contact information of the persons authorized to sign the protocol and amendments, etc. The success of a study of IVIG in patients with primary humoral immunodeficiency is very much dependent on the care in which patients are selected. It is extremely important to enroll patients who have been verified to be antibody deficient. Therefore, patient selection criteria should involve a thorough review of each patient’s infection history, serum IgG level prior to immunoglobulin therapy, and antibody responses to polysaccharide and protein vaccines. Statement of novelty: This protocol is designed to select study subjects with well-documented antibody deficiencies and therefore will benefit from immunoglobulin therapy.

Transmission of Hepatitis B Core Antibody and Galactomannan Enzyme Immunoassay Positivity via Immunoglobulin Products: A Comprehensive Analysis.

Therapeutic immunoglobulins are used as replacement or immunomodulatory therapy, but can transmit clinically important molecules. We investigated hepatitis B virus (HBV) antibodies and galactomannan enzyme immunoassay (GM-EIA) positivity. Detection of HBV core antibody may prompt antiviral prophylaxis when commencing therapy such as rituximab; a positive GM-EIA result prompts investigation or treatment for invasive fungal disease. We performed a cross-sectional analysis of HBV serology in 80 patients established (>6 months) on immunoglobulin therapy; prospective analysis of HBV serology in 16 patients commencing intravenous immunoglobulin (IVIG); and pre- and post-infusion analysis of GM-EIA in 37 patients receiving IVIG. Pre-IVIG, 9 of 80 patients tested positive for HBV surface antibody and 1 of 80 tested equivocal for HBV core antibody. On IVIG, 79 of 79 tested positive for surface antibody, 37 of 80 tested positive for core antibody, and 10 of 80 tested equivocal for core antibody. There were significant differences by product, but among patients receiving products that appear to transmit core antibody, negative results correlated with lower surface antibody titers and longer time since infusion, suggesting a simple concentration effect. There was a progressive increase with each infusion in the percentage of patients testing positive for HBV core antibody among patients newly commencing IVIG. Some patients "seroreverted" to negative during therapy. Certain IVIG products tested positive for GM-EIA and there were rises in index values in corresponding patient samples from pre- to post-infusion. Overall, 5 of 37 patient samples pre-infusion and 15 of 37 samples post-infusion tested positive for GM-EIA. HBV antibodies and GM-EIA positivity are common in patients receiving IVIG and confound diagnostic results.

Use of Intravenous Anti-RhD Immunoglobulin (RhIG) in the Treatment of Primary Immune Thrombocytopenia

Commercialized intravenous immunoglobulin (IVIG) products have been used since the early 1980s for various patient treatment options, specifically to induce an immunomodulatory and therapeutic effect. IVIG, a pooled immunoglobulin G (IgG) preparation, is used for patients with immune deficiencies, inflammatory conditions, and autoimmune disorders such as primary immune thrombocytopenia (ITP). Front-line therapies for ITP include corticosteroids, IVIG, or anti-RhD immune globulin (RhIG). WinRho SDF (Cangene Corporation, Winnipeg, Manitoba, Canada), a RhIG preparation, was FDA-approved for use in 2005 and is used for treatment of patients with ITP through what is called a Fc blockade mechanism. After intravenous WinRho administration, patient platelets are spared from clearance by the spleen and with a good response to treatment, the patient9s platelet count increases. WinRho is not without potential side effects and also impacts the transfusion service pre-transfusion testing in the event that the patient undergoing treatment requires red cell transfusion. In 2010, a work group of experts reviewed the warnings associated with RhIG and concluded that assuming that patients are appropriate candidates for RhIG, monitored in a clinical setting for 8 hours after administration, RhIG products such as WinRho are considered a very effective front-line therapy for ITP.1 Effective first line therapies can circumvent the necessity for less-desirable second line therapies such as an invasive splenectomy or life-long treatment with thrombopoietin-receptor agonists (TPO-RAs) to increase platelet counts. ABBREVIATIONS:IVIG – intravenous immunoglobulin, ITP – primary immune thrombocytopenia, RhIG – Rh immune globulin, TPO-RAs – thrombopoietin-receptor agonists, MPV – mean platelet volume, RBC – red blood cell, HUS – hemolytic uremic syndrome, TTP – thrombotic thrombocytopenic purpura, DIC – disseminated intravascular coagulation, CBC – complete blood count, PT – prothrombin time, APTT – activated partial thromboplastin time, FDA – Food and Drug Administration

Antibodies against Hepatitis A and Hepatitis B Virus in Intravenous Immunoglobulin Products.

The worldwide seroprevalence of hepatitis A virus (HAV) and hepatitis B virus (HBV) has changed over the last two decades, indicating a declining incidence of HAV and HBV infections. Therefore, vaccinations against HAV and HBV are recommended for unimmunized people before traveling to an endemic area. Unfortunately, primary antibody deficiency (PAD) patients can only obtain humoral immunity through intravenous immunoglobulin G (IVIG) replacement and not from vaccination because of a defect in antibody production. However, few studies have analyzed the titers of antibodies against HAV or HBV in IVIG products. In this study, the titers of anti-HAV and anti-HBs antibodies were measured in nineteen lots of IVIG products from five manufacturers from three countries (A, B from Korea; C, D from Japan; and E from the USA), and trough titers in plasma were estimated. Concentrations of anti-HAV antibody ranged from 1,888–8,927 mIU/mL and estimated trough titers exceeded the minimal protective value in all evaluated IVIG products. Concentrations of anti-HBs antibody ranged from 438–965 mIU/mL in products A and B and were 157, 123, and 1,945 mIU/mL in products C, D, and E, respectively. Estimated trough titers in products A, B, and E exceeded the minimal protective value but those in products C and D did not reach this threshold. These data demonstrated that available IVIG products generally provide sufficient antibodies against HAV and HBV to protect patients with PAD, although the trough concentrations of anti-HBs antibody in two IVIG products did not reach the minimum protective value.

Immune Hemolysis and Aseptic Meningitis after Intravenous Immunoglobulin

INTRODUCTIONHuman intravenous immunoglobulin (IVIG) products are generally considered safe and are used for the treatment of a variety of autoimmune and pro-inflammatory states. However, controlled trials involving IVIG have been of small size with limited power and described only the most common adverse effects [1]. IVIG related hemolysis is a rare adverse effect and is usually self-limited, rarely requiring blood transfusions. A few case reports have also described aseptic meningitis after IVIG use. We describe a patient who developed severe hemolytic anemia and aseptic meningitis after IVIG use.CASE PRESENTATIONA 54 year old woman was admitted with severe head ache, dark colored urine and shortness of breath twenty four hours after receiving IVIG. She was diagnosed with chronic inflammatory demyelinating polyneuropathy (CIDP) a month ago and was started on IVIG. Physical exam was unremarkable. Laboratory tests showed severe anemia with a hemoglobin of 6.1 g/dl (baseline 13 g/dl), indirect hyper-bilirubinemia, low haptoglobin, elevated LDH and hemoglobinuria confirming hemolysis. Hematological testing revealed a positive direct antiglobulin test (DAT), DAT IgG, DAT CD3 and eluate testing were also positive. A lumbar puncture showed neutrophil pleocytosis but no bacteria. A diagnosis of IVIG induced hemolysis and aseptic meningitis was made. O negative packed red blood cells were transfused for severe symptomatic anemia and non-steroidal anti-inflammatory drugs were given for headache. Steroids were deferred since the source of antibodies causing hemolysis was extrinsic. She improved clinically and blood counts returned to baseline in three weeks.DISCUSSIONPooled IVIG is extracted from at least 1000 individuals and contains highly purified polyvalent IgG [2]. Hemolysis after IVIG is thought to be secondary to donor antibodies against host red blood cell antigens and resolves once IVIG is stopped. Risk factors for hemolysis include non-O blood types and the use of high dose IVIG. The patient described was of AB Rh positive blood type but did not receive high dose IVIG. Aseptic meningitis is another rare adverse effect that has been postulated to be related to antibodies in the IVIG that mimic antineutophil cytoplasmic antibodies (ANCA) which activate neutrophils causing neutrophilic pleocytosis [3]. One must be aware of these two rare complications of a commonly used drug.REFERENCES[1] Risks associated with the use of intravenous immunoglobulin. Pierce LR et al. Transfus Med Rev. 2003 Oct;17(4):241-51.[2] Appropriate uses of human immunoglobulin in clinical practice: memorandum from an IUIS/WHO meeting. Bull World Health Organ. 1982;60(1):43.[3] Intravenous immunoglobulins contain naturally occurring antibodies that mimic antineutrophil cytoplasmic antibodies and activate neutrophils in a TNF alpha-dependent and Fc-receptor-independent way. Jarius et al. Blood. 2007;109(10):4376. DisclosuresNo relevant conflicts of interest to declare.

Identification and characterization of natural antibodies against tau protein in an intravenous immunoglobulin product

The latest therapeutic approaches to Alzheimer disease are using intravenous immunoglobulin (IVIG) products. Therefore, the detailed characterization of target-specific antibodies naturally occurring in IVIG products is beneficial. We have focused on characterization of antibodies isolated against tau protein, a biomarker of Alzheimer's disease, from Flebogamma IVIG product. The analysis of IgG subclass distribution indicated skewing toward IgG3 in anti-tau-enriched IgG fraction. The evaluation of their reactivity and avidity with several recombinant tau forms was performed by ELISA and blotting techniques. Truncated non-phosphorylated tau protein (amino acids 155–421) demonstrated the highest reactivity and avidity index. We provide the first detailed insight into the reactivity of isolated natural antibodies against tau protein.