Intravenous Immunoglobulin Preparations Research Articles

Anti-Neuronal Antibodies Within the IVIg Preparations: Importance in Clinical Practice.

Our study objective was testing for anti-neuronal autoantibodies within commercially available intravenous immunoglobulin (IVIg) preparations. Sixteen samples from 5 different commercially available IVIg preparations were tested with cell-based assays (CBA) and enzyme-linked immunosorbent assay (ELISA) to detect and characterize common neuronal autoantibodies, and with immunohistochemistry on teased fibers from mouse sciatic nerve and on mouse brain sections to screen for nodal and not yet identified neuronal antigens. In 15/16 IVIg preparations, anti-GAD antibodies were detected in titers ranging from 40 to 1507 IU/mL, as typically seen in type 1 diabetes, but not in the range (> 2000 IU/mL) seen in GAD-positive neurological patients. None of the preparations was however positive with anti-GAD CBA. Antibodies to AQP4 were also detected by ELISA in 15/16 IVIg preparations with titers comparable to those seen in AQP4-seropositive NMO patients; with CBA, however, all IVIg samples were AQP4-negative. IVIg preparations contained IgG-anti-MAG antibodies by ELISA at statistically significant higher titers compared to controls. Two of the 16 IVIg samples were positive for human 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies. All IVIg preparations were negative for antibodies to MOG, NMDAR, anti-nodal, and other neuronal-specific proteins. IVIg preparations contain antibodies against GAD and AQP4 in titers comparable to those seen in autoimmune patients when tested by ELISA, but not by CBA or tissue immunohistochemistry, suggesting that the autoantibodies within the IVIg are against linear rather than structural epitopes, as part of the natural antibody immune repertoire. The information is clinically important for diagnosis when testing patients' sera after they have received therapy with IVIg to avoid false interpretation.

Peculiarities of treatment of primary immune thrombocytopenia

The article describes the experience of treating primary immune thrombocytopenia (ITP) in the hematology department of the Amur Regional Clinical Hospital. In the presence of indications for ITP treatment, the fi rst stage in most cases was the administration of prednisone (1–2 mg/kg body weight per day in tablets, for 1 month), if it has been ineff ective, splenectomy was performed or thrombopoietin receptor antagonists were administered. In case of recurring ITP after splenectomy, rituximab was used, that contributed to the achievement of stable remission in such situations. In pregnant patients with ITPs who require treatment, intravenous immunoglobulin preparations were used for up to 20 weeks, after 20 weeks therapy, glucocorticoids were added (usually pulp therapy with methylprednisolone or dexamethasone). With the timely diagnostics of the disease and adequate therapy administration in the majority of cases, the prognosis of the disease was favorable.

Intravenous immunoglobulin for adjunctive treatment of severe infections in ICUs.

This review focuses on the emerging literature regarding the use of intravenous immunoglobulins (IVIg) in critically ill patients with severe infections. The aim is to provide an accessible summary of the most recent evidence of IVIg use in sepsis and septic shock and to help clinicians to understand why there is still equipoise regarding the potential benefit of this adjunctive therapy in this setting. Observational studies with propensity score matching analyses and investigating the effect of IVIg in severe infections including necrotizing soft tissue infection have been recently published. These studies suffer important flaws precluding robust conclusion to be drawn. Some recent randomized controlled trials raised interesting findings supportive of personalized medicine but are likely to be underpowered or confounded. Insufficient evidence is available to support IVIg use in sepsis and septic shock, apart from the specific case of streptococcal toxic shock syndrome. Current literature suggests that IVIg efficacy in sepsis or septic shock could depend on the IVIg preparation (IgM-enriched or minimal IgM), time of administration (<24 h), dose, and the inflammatory/immunomodulation profile of the patients. Investigator-initiated research, incorporating these parameters, is warranted to determine whether IVIg benefits critically ill patients with severe infection.

Czech Hizentra Noninterventional Study With Rapid Push: Efficacy, Safety, Tolerability, and Convenience of Therapy With 20% Subcutaneous Immunoglobulin

PurposeImmunoglobulin substitution therapy is an essential therapeutic approach for patients with primary antibody deficiencies. Different methods of administration, including intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG) preparations, provide effective and tolerable treatment and enable the adjustment of therapy to patients’ needs. A new 20% SCIG represents a new therapeutic option and a new route of administration using rapid-push application. The aim of the Czech Hizentra Noninterventional Study With Rapid Push (CHHINSTRAP) is to evaluate patient satisfaction with as well as the tolerability and efficacy of nonmedical switch to 20% SCIG from previous treatment with IVIG or SCIG and rapid push as a new way to administer SCIG. CHHINSTRAP is the first Phase IV, noninterventional, open-label, prospective, multicentric study of this type conducted in Central and Eastern Europe. MethodsPrimary end points, including efficacy, adverse effects, convenience of use, and overall satisfaction, were evaluated by Treatment Satisfaction Questionnaire for Medication version II. Secondary end points, such as serum IgG trough levels, infusion duration, number of application sites, frequency of infections, related hospital admissions, and antibiotic consumption, were obtained from patients at each follow-up visit. FindingsTogether, 50 eligible patients with primary antibody deficiency were switched from SCIG or IVIG to an equivalent dose of 20% SCIG and were followed up for 12 months during 5 consecutive visits. The results indicate that patients switched from previous IVIG or SCIG preparations had significantly higher serum trough IgG levels and a lower incidence of infections and related events, such as hospital admissions or consumption of antibiotics. These findings were also reflected in gradually increasing convenience of use and overall satisfaction reported by patients. Apart from duration of application, no differences were found between patients previously receiving SCIG or IVIG. Moreover, our study found a high level of safety of 20% SCIG rapid push, which was comparable to other preparations and application methods. ImplicationsOn the basis of the results of CHHINSTRAP study, we conclude that 20% SCIG is a tolerable and effective immunoglobulin preparation, representing a new therapeutic approach in patients with primary antibody deficiencies. Its efficacy and tolerability have been found in patients on nonmedical switch from previous treatment with IVIG or SCIG.

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.

Anti-inflammatory activity of intravenous immunoglobulin through scavenging of heme

Therapeutic intravenous immunoglobulin preparations (IVIg) are used for treatment of wide range of autoimmune and inflammatory diseases. Versatile mechanisms have been reported to contribute to the immunomodulatory effects of IVIg. Here we demonstrate that IVIg has a strong potential to inhibit pro-inflammatory effect of extracellular heme. Indeed, the presence of immunoglobulins reduced the potential of heme to activate the complement system on the surface of human endothelial cells. Since extracellular heme is considered as one of the principal pathogenic factors in hemolytic disorders, its therapeutic scavenging by IVIg may have significant clinical repercussions.

Differential Recognition of Diet-Derived Neu5Gc-Neoantigens on Glycan Microarrays by Carbohydrate-Specific Pooled Human IgG and IgA Antibodies.

Sialic acids (Sias) cover vertebrate cell surface glycans. N-Acetylneuraminic acid (Neu5Ac) and its hydroxylated form N-glycolylneuraminic acid (Neu5Gc) are common Sia in mammals. Humans cannot synthesize Neu5Gc but accumulate it on cells through red-meat rich diets, generating numerous immunogenic Neu5Gc-neoantigens. Consequently, humans have diverse anti-Neu5Gc antibodies affecting xenotransplantation, cancer, atherosclerosis, and infertility. Anti-Neu5Gc antibodies circulate as IgG, IgM, and IgA isotypes; however, repertoires of the different isotypes in a large population have not been studied yet. Here, we used glycan microarrays to investigate anti-Neu5Gc IgGs and IgAs in intravenous immunoglobulin (IVIG) or pooled human IgA, respectively. Binding patterns on microarrays fabricated with Neu5Gc- and Neu5Ac-glycans, together with inhibition assays, revealed that different IVIG preparations have highly specific anti-Neu5Gc IgG reactivity with closely related repertoires, while IgAs show cross-reactivity against several Neu5Ac-glycans. Such different anti-Neu5Gc IgG/IgA repertoires in individuals could possibly mediate distinctive effects on human diseases.

Analysis of sialic acid levels in Chinese intravenous immunoglobulins by high-performance liquid chromatography with fluorescence detection.

Intravenous immunoglobulin (IVIg) is increasingly used for the treatment of autoimmune and systemic inflammatory diseases with both licensed and off-label indications. Recent studies indicated that IVIg-mediated immunomodulation and anti-inflammation are closely associated with the IgG sialylation, especially with IgG crystallizable fragment (Fc) sialylation. The sialic acid levels of the IgG molecules and Fc fragments in 12 IVIg preparations from six Chinese manufacturers were evaluated. The Fc fragments were derived from the papain digestion of IVIg, followed by affinity and size exclusion chromatography. The sialic acid levels in Fc fragments and IVIg preparations were determined by high-performance liquid chromatography with fluorescence detection, after the sialic acid residues were released from the proteins. The results showed that the sialic acid levels in Chinese IVIg preparations ranged from 0.875 (mol/mol IgG) to 1.085 (mol/mol IgG), and the sialic acid levels in Fc fragments were from 0.321 (mol/mol Fc) to 0.361 (mol/mol Fc). Furthermore, the sialic acid levels of IVIg preparations and Fc fragments from different Chinese manufactures were significantly different. These findings will contribute to an increased understanding of Chinese IVIg preparations and the relationship between the sialic acid levels in IVIg preparations and their clinical efficacy in future clinical studies.

Synergistic convergence of microbiota-specific systemic IgG and secretory IgA

Commensals induce local IgA responses essential to the induction of tolerance to gut microbiota, but it remains unclear whether antimicrobiota responses remain confined to the gut. The aim of this study was to investigate systemic and intestinal responses against the whole microbiota under homeostatic conditions and in the absence of IgA. We analyzed blood and feces from healthy donors, patients with selective IgA deficiency (SIgAd), and patients with common variable immunodeficiency (CVID). Immunoglobulin-coated bacterial repertoires were analyzed by using combined bacterial fluorescence-activated cell sorting and 16S rRNA sequencing. Bacterial lysates were probed by using Western blot analysis with healthy donor sera. Although absent from the healthy gut, serum antimicrobiota IgG are present in healthy subjects and increased in patients with SIgAd. IgG converges with nonoverlapping secretory IgA specificities to target the same bacteria. Each individual subject targets a diverse microbiota repertoire with a proportion that correlates inversely with systemic inflammation. Finally, intravenous immunoglobulin preparations target CVID gut microbiota much less efficiently than healthy microbiota. Secretory IgA and systemic IgG converge to target gut microbiota at the cellular level. SIgAd-associated inflammation is inversely correlated with systemic anticommensal IgG responses, which might serve as a second line of defense. We speculate that patients with SIgAd could benefit from oral IgA supplementation. Our data also suggest that intravenous immunoglobulin preparations can be supplemented with IgG from IgA-deficient patient pools to offer better protection against gut bacterial translocations in patients with CVID.

Hemolysis induced cross-matching difficulty with intravenous immunoglobulin: a case report

BackgroundIntravenous immunoglobulin is one of the most common modalities of treatment for Guillain–Barré syndrome. Although minor complications are easily preventable with pre-medications, rare complications like hemolysis occur at unexpected times and carry risks of repeated transfusions. A complication like difficulties in cross-matching blood is an uncommon event and is often not anticipated. We present one such rare case.Case presentationA 56-year-old man of Asian origin had presented to our hospital with rapidly progressive weakness of bilateral upper and lower limbs over 4 days. Guillain–Barré syndrome was diagnosed by nerve conduction velocity testing and lumbar puncture examination. On the third day of admission in hospital he was intubated because of respiratory failure. Intravenous immunoglobulin at 0.4 mg/kg per day for 5 days was planned and started. Our patient was scheduled for tracheostomy on a routine basis anticipating prolonged requirement of ventilator support. As the blood was being arranged, the blood bank facilities informed us about difficulties in cross-matching of the blood. Repeated samples and attempts at cross-matching were futile. After reviewing the available literature and diagnosing a case of hemolysis, relevant tests were performed and they were positive.ConclusionsAnti-A and anti-B antibody present in intravenous immunoglobulin preparations sensitize the red blood cells to hemolysis and this occurrence is often incriminated as a cause of cross-matching and sometimes blood grouping difficulty. Although a high dose of intravenous immunoglobulin or repeated courses are often cited as reasons for hemolysis, individual variability in responses is common and it is not surprising to see one like we had in our case.

Abstract 104: AAV-Exosomes: A Novel Platform for Myocardial Gene Delivery for Cardioprotection

Introduction: Adeno-associated viruses (AAVs) are viral vectors of choice for delivering genes for long-term expression due to their safety in clinics. However, pre-existing immunity to AAVs from naturally present neutralizing antibodies (NAbs, present in between 60% and 90% of population) poses a significant challenge for AAV-mediated gene delivery. NAbs prevent AAVs from infecting target cells, greatly reducing transduction efficiency and, therefore, the clinical efficacy. Thus, it is essential to develop novel AAV-based vectors that circumvent the effect of NAbs. Objectives: We aimed to investigate the ability of exosome-encapsulated AAVs (AAVExo) to evade NAbs and serve as a highly efficient gene transfer tool for cardiovascular therapeutics. Methods and Results: We developed a multi-step purification strategy using iodixanol density gradient to isolate AAVExo with minimal contamination from free AAVs (AAV1, 6 or 9). Biochemical assays, flow cytometry, IVIS Spectrum in vivo optical imaging and echocardiography were used to detect AAV-mediated gene delivery and evaluate cardiac function. AAV6Exo-mCherry and AAV9Exo-FLuc were resistant to NAbs and significantly improved expression of mCherry and firefly luciferase (FLuc) both in mouse and human (iPSC-derived) cardiomyocytes in vitro , and in murine hearts in vivo (in nude mice preinjected with NAbs), compared to free AAVs. To test the therapeutic efficacy of AAVExo-mediated gene delivery in the presence of NAbs, we injected AAV9-SERCA2a or AAV9Exo-SERCA2a into post-MI hearts of nude mice preinjected with IVIg (human intravenous immunoglobulin) preparation. Hearts treated with AAV9Exo-SERCA2a had significantly improved cardiac function compared to those treated with free AAV9-SERCA2a (%EF 62.6 ± 9.8 vs. 28.4 ± 5.3, respectively; 2 weeks after surgery). Conclusion: Delivery of AAVs protected by carrier exosomes is a promising approach to circumvent the issue of NAbs in AAV-based gene therapy, which can be used in the entire population of patients and may result in higher gene delivery efficacy.

Subcutaneous Immunoglobulin Replacement Therapy Experience with Intravenous Preparation

Objective: Intravenous immunoglobulin preparations have been used in the treatment of primary immunodeficiency for many years. Recently, immunoglobulin administration via the subcutaneous route has become popular. Subcutaneously administered immunoglobulin provides more stable serum immunoglobulin levels and has a lower incidence of systemic adverse effects than the intravenous route. This method increases the quality of the patient’s life by self administration or parental administration at home. Immunoglobulin preparations designed for subcutaneous administration have been available in Europe and the US since 2006. Although subcutaneous immunoglobulin preparations are not available in Turkey, the subcutaneous administration route has recently been included in the instructions of the three intravenous products with 10% concentration. Our aim was to use one of these intravenous immunoglobulin preparations via the subcutaneous route and describe its advantages and disadvantages. Materials and Methods: Six primary immunodeficiency patients were selected from our clinic. The procedure was described and informed consent obtained. They had been treated with intravenous immunoglobulin for the last few years. Their monthly immunoglobulin dosage was calculated and roughly divided into weekly doses. The first few administrations took place under medical supervision at the hospital until the patients and/or their family learned the procedure. Results: They were encouraging with fewer side effects, better life quality and lower infection rates in our small sample of patients. Conclusion: In this article, we describe our experience with 6 primary immunodeficiency patients of our clinic in whom we successfully used intravenous immunoglobulin preparation via the subcutaneous route.

A Protein Microarray Assay for Serological Determination of Antigen-specific Antibody Responses Following Clostridium difficile Infection.

We provide a detailed overview of a novel high-throughput protein microarray assay for the determination of anti-Clostridium difficile antibody levels in human sera and in separate preparations of polyclonal intravenous immunoglobulin (IVIg). The protocol describes the methodological steps involved in sample preparation, printing of arrays, assay procedure, and data analysis. In addition, this protocol could be further developed to incorporate diverse clinical samples including plasma and cell culture supernatants. We show how protein microarray can be used to determine a combination of isotype (IgG, IgA, IgM), subclass (IgG1, IgG2, IgG3, IgG4, IgA1, IgA2), and strain-specific antibodies to highly purified whole C. difficile toxins A and B (toxinotype 0, strain VPI 10463, ribotype 087), toxin B from a C. difficile toxin-B-only expressing strain (CCUG 20309), a precursor form of a B fragment of binary toxin, pCDTb, ribotype-specific whole surface layer proteins (SLPs; 001, 002, 027), and control proteins (tetanus toxoid and Candida albicans). During the experiment, microarrays are probed with sera from individuals with C. difficile infection (CDI), individuals with cystic fibrosis (CF) without diarrhea, healthy controls (HC), and from individuals pre- and post-IVIg therapy for the treatment of CDI, combined immunodeficiency disorder, and chronic inflammatory demyelinating polyradiculopathy. We encounter significant differences in toxin neutralization efficacies and multi-isotype specific antibody levels between patient groups, commercial preparations of IVIg, and sera before and following IVIg administration. Also, there is a significant correlation between microarray and enzyme-linked immunosorbent assay (ELISA) for antitoxin IgG levels in serum samples. These results suggest that microarray could become a promising tool for profiling antibody responses to C.difficile antigens in vaccinated or infected humans. With further refinement of antigen panels and a reduction in production costs, we anticipate that microarray technology may help optimize and select the most clinically useful immunotherapies for C. difficile infection in a patient-specific manner.

Intravenous Immunoglobulin Preparations: Quality Assurance Measures and Proposed Strategies for Improving its Safe and Judicious use in India

Intravenous Immunoglobulin Preparations: Quality Assurance Measures and Proposed Strategies for Improving its Safe and Judicious use in India

Naturally occurring antibodies against serum amyloid A reduce IL-6 release from peripheral blood mononuclear cells.

Serum amyloid A (SAA) is a sensitive inflammatory marker rapidly increased in response to infection, injury or trauma during the acute phase. Resolution of the acute phase and SAA reduction are well documented, however the exact mechanism remains elusive. Two inducible SAA proteins, SAA1 and SAA2, with their variants could contribute to systemic inflammation. While unconjugated human variant SAA1α is already commercially available, the variants of SAA2 are not. Antibodies against SAA have been identified in apparently healthy blood donors (HBDs) in smaller, preliminary studies. So, our objective was to detect anti-SAA and anti-SAA1α autoantibodies in the sera of 300 HBDs using ELISA, characterize their specificity and avidity. Additionally, we aimed to determine the presence of anti-SAA and anti-SAA1α autoantibodies in intravenous immunoglobulin (IVIg) preparations and examine their effects on released IL-6 from SAA/SAA1α-treated peripheral blood mononuclear cells (PBMCs). Autoantibodies against SAA and SAA1α had a median (IQR) absorbance OD (A450) of 0.655 (0.262–1.293) and 0.493 (0.284–0.713), respectively. Both anti-SAA and anti-SAA1α exhibited heterogeneous to high avidity and reached peak levels between 41–50 years, then diminished with age in the oldest group (51–67 years). Women consistently exhibited significantly higher levels than men. Good positive correlation was observed between anti-SAA and anti-SAA1α. Both anti-SAA and anti-SAA1α were detected in IVIg, their fractions subsequently isolated, and shown to decrease IL-6 protein levels released from SAA/SAA1α-treated PBMCs. In conclusion, naturally occurring antibodies against SAA and anti-SAA1α could play a physiological role in down-regulating their antigen and proinflammatory cytokines leading to the resolution of the acute phase and could be an important therapeutic option in patients with chronic inflammatory diseases.

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.

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.

False positive serum levels of (1–3)-ß-D-Glucan after infusion of intravenous immunoglobulins and time to normalisation

(1-3)-ß-D-Glucan (BDG) is a marker for invasive fungal diseases (IFD). Administration of intravenous immunoglobulin preparations (IVIG) has been reported to lead to false positive BDG serum levels >80pg/ml. The aim of the study was to determine the time interval between IVIG infusion and normalisation of BDG serum levels. In 22 paediatric haemato-/oncologic patients, we analysed 92 BDG serum levels obtained within 4 weeks after IVIG administration (0.5 to 1g/kg body weight), correlated them to 54 IVIG episodes and compared them to 76 BDG levels obtained in 29 patients without IVIG administration in the 4 weeks prior to BDG analyses (control group). BDG peak levels within 3 days after IVIG ranged from 21.47 to 660.38 (median 201.4) pg/ml. BDG serum levels at 7, 14 and 21 days (+/-1 day each) after IVIG infusion were significantly higher than BDG serum levels in the control group (p<0.001 each). By days 7, 14, and 21 (+/-1 day each) after IVIG infusion, BDG serum levels have normalized (<80pg/ml) in 64.0%, 76.5% and 100%, respectively. IVIG administration leads to false positive BDG levels in the vast majority of patients. Elevated BDG levels may be detectable for more than two weeks after IVIG administration, while BDG levels normalized within 3 weeks in all patients. Therefore, BDG should not be used to diagnose IFD within three weeks after IVIG administration.

A multicentre, prospective, non-randomized, sequential, open-label trial to demonstrate the bioequivalence between intravenous immunoglobulin new generation (IGNG) and standard IV immunoglobulin (IVIG) in adult patients with primary immunodeficiency (PID)

ObjectivesTo demonstrate the bioequivalence between 2 intravenous immunoglobulin (IVIG) preparations, TEGELINE® and ClairYg®, a ready-to-use 5% IVIG, in primary immunodeficiency (PID). Secondary objectives were to assess the efficacy, safety and pharmacokinetics of ClairYg®. MethodsTwenty-two adult PID patients receiving stable doses of TEGELINE® (5% lyophilized IVIG) were switched to ClairYg® for 6 months. ClairYg® was administered under the same conditions as TEGELINE®, either every 3 or 4 weeks. The primary endpoint was mean average total IgG trough level at steady state with ClairYg® versus TEGELINE®. Clinical efficacy was also assessed in terms of infections and associated events. ResultsBioequivalence was established with a mean average total IgG trough level at steady state being 8.05g/L with TEGELINE® and 9.17g/L with ClairYg® (i.e. geometric mean for the difference between ClairYg® and TEGELINE® was 1.136; [90% CI: 1.092–1.181] P<0.001), within the pre-specified margin to establish bioequivalence (0.80–1.25). Total IgG trough levels remained clinically adequate (>4–6g/L) throughout the study. No patient was hospitalized for infection or had serious bacterial infections while receiving ClairYg®. The median annualized infections rate per patient was similar for both products: 4.35 [0; 21.8] for TEGELINE® and 4.30 [0; 15.1] for ClairYg®. Infections were less common with higher IgG trough levels (>8.16g/L). ClairYg® showed good safety, in particular good hepatic and renal tolerance, and did not induce hemolysis. ClairYg® pharmacokinetics profile was comparable to that of TEGELINE®. ConclusionClairYg® is safe and effective in the treatment of adult PID.

Biological Safety of a Highly Purified 10% Liquid Intravenous Immunoglobulin Preparation from Human Plasma.

BackgroundA highly purified 10% liquid intravenous immunoglobulin, IQYMUNE®, has been developed using an innovative manufacturing process including an affinity chromatography step for the removal of anti-A and anti-B hemagglutinins.ObjectivesThe pathogen (viruses and prions) clearance efficacy of the manufacturing process and its robustness for critical steps were investigated.MethodsThe manufacturing process of IQYMUNE® includes two dedicated complementary virus reduction steps: solvent/detergent (S/D) treatment and 20 nm nanofiltration as well as two contributing steps, namely caprylic acid fractionation and anion-exchange chromatography. The clearance capacity and robustness of these steps were evaluated with a wide range of viruses (enveloped and non-enveloped) and with a model of human transmissible spongiform encephalopathies (TSEs).ResultsThe IQYMUNE® manufacturing process demonstrated a high and robust virus removal capacity with global reduction factors (RFs) of relevant and model viruses: ≥14.8 log10 for human immunodeficiency virus type 1 (HIV-1), ≥16.9 log10 for bovine viral diarrhoea virus (BVDV)/Sindbis virus, ≥15.7 log10 for pseudorabies virus (PRV), ≥12.8 log10 for encephalomyocarditis virus (EMCV) and 11.0 log10 for porcine parvovirus (PPV). The process also exhibited a high removal capacity for the TSE agent with an overall RF of ≥12.9 log10 due to the complementary actions of the caprylic acid fractionation, anion-exchange chromatography and nanofiltration steps.ConclusionData from virus and prion clearance studies fully support the high safety profile of IQYMUNE®, with a minimal reduction of 11 log10 for the smallest and most resistant non-enveloped virus, PPV, and more than 12 log10 for the TSE agent.