Intravenous Immune Globulin Products Research Articles

Neutralizing activity of intravenous immune globulin products against enterovirus D68 strains isolated in Japan

BackgroundEnterovirus D68 (EV-D68), belonging to Enterovirus D, is a unique human enterovirus mainly associated with common respiratory diseases. However, EV-D68 can cause severe respiratory diseases, and EV-D68 endemic is epidemiologically linked to current global epidemic of acute flaccid myelitis.MethodsIn this study, we measured neutralizing antibody titers against six clinical EV-D68 isolates in nine intravenous immune globulin (IVIG) products commercially available in Japan to assess their potential as therapeutic options for severe EV-D68 infection.ResultsSeven IVIG products manufactured from Japanese donors contained high neutralizing antibody titers (IC50 = 0.22–85.01 µg/mL) against all six EV-D68 strains. Apparent differences in neutralizing titers among the six EV-D68 strains were observed for all IVIG products derived from Japanese and non-Japanese blood donors.ConclusionsHigh levels of EV-D68–neutralizing antibodies in IVIG products manufactured from Japanese donors suggest that anti-EV-D68 antibodies are maintained in the Japanese donor population similarly as found in foreign blood donors. Apparent differences in neutralizing antibody titers against the six EV-D68 strains suggest distinct antigenicity among the strains used in this study regardless of the genetic similarity of EV-D68.

SARS-COV-2 ANTIBODY LEVELS CONTINUE TO RISE IN IMMUNE GLOBULIN PREPARATIONS

<h3>Introduction</h3> We previously published data on SARS-CoV-2 antibody levels in commercial intravenous immune globulin (IVIG) products that were prepared between August 2019 to September 2021 and showed a dramatic increase in antibody levels corresponding with increase in COVID-19 cases and vaccine availability. We continue to report on the longitudinal analysis of SARS-CoV-2 antibody levels in IVIG preparations and have updated data through March 2022. <h3>Methods</h3> IVIG samples are collected from our infusion clinic. IVIG product name, lot number and manufacturing date were recorded. SARS-CoV-2 antibody levels and total immunoglobulin levels were measured using commercially available assays. <h3>Results</h3> No IVIG products manufactured on or before January 2020 had detectable SARS-CoV-2 antibodies. We observed a dramatic increase in SARS-CoV-2 antibody levels that coincided after the availability of COVID-19 vaccines with many levels increasing beyond the upper limit threshold of 2,500 U/mL after February 2021. The commercial laboratory has now expanded the reporting range to an upper limit threshold of 25,000 U/mL. Under the new reporting range, we tested older samples that had exceeded the previous reporting range as well as newer samples. We see a continued rise in SARS-CoV-2 antibodies with levels quickly reaching >25,000 U/mL by October 2021 as the COVID-19 pandemic continues. <h3>Conclusion</h3> SARS-CoV-2 antibody levels in IVIG preparations continue to increase exponentially with case prevalence and increased vaccinations. We are planning to dilute samples to further trend levels beyond the current reporting range. It remains undetermined what level of SARS-CoV-2 antibody correlates to immunity against developing symptomatic disease.

Intravenous Immune Globulin (IVIG) for Treatment of Autoimmune Heparin-Induced Thrombocytopenia: A Systematic Review.

To evaluate intravenous immune globulin (IVIG) for autoimmune heparin-induced thrombocytopenia (aHIT), including platelet recovery, IVIG dose, dosing weight, IVIG product used, and complications reported. PubMed and EMBASE were searched from inception through June 21, 2020. Search terms included heparin-induced thrombocytopenia, HIT, intravenous immune globulin, IVIG, autoimmune HIT, aHIT, and immune globulin. Patients administered IVIG for HIT and diagnosed by immunoassay (optical density ≥2) or positive activation assay were included. Twenty-four cases were reviewed; 92% had persistent aHIT. Time to IVIG administration post-nonheparin anticoagulant initiation was 9 days (median). Most common IVIG cumulative dose was 2 g/kg (dosed as 1 g/kg/d for 2 consecutive days); 75% had a favorable platelet increase (≥50 × 109/L) within 5 days of initial IVIG dosing. aHIT is characterized by critically low platelets, thrombosis, and a persistent delay in platelet recovery despite treatment with a nonheparin anticoagulant. An immunoassay and subsequent confirmatory activation assay (at low, high, and 0 IU/mL unfractionated heparin levels) is recommended to confirm diagnosis. Patients nonresponsive to nonheparin anticoagulants within 5 days of initiation should be evaluated for IVIG treatment (2 g/kg cumulative dose). More data are needed to clarify appropriate IVIG dosing weight, although based on current published literature, it is recommended to use actual body weight. Data reported support use of IVIG as adjunctive therapy for patients with aHIT. Judicious IVIG use based on key clinical and laboratory findings is critical.

Clinical Experience with Octagam® 10%, a solvent detergent virus inactivated intravenous immunoglobulin: a Canadian retrospective review of utilization.

In Canada, intravenous immune globulin (IVIg) products are licensed for six disease indications, however it has been demonstrated that patients with a number of other conditions also benefit from IVIg. Here we report the routine clinical use of Octagam® 10 % across three Canadian institutions. A total of 135 patients were treated with Octagam®, for conditions represented by five distinct indication groups. The results of this review indicate that Octagam® has been well adopted and is prescribed to Canadian patients similar to other IVIg products. In alignment with current practices, 85 % of Octagam’s utilization was classified as appropriate based on Canadian IVIg guidelines.

Intravenous immune globulin and thromboembolic adverse events in patients with hematologic malignancy

AbstractIn patients with hypogammaglobulinemia secondary to chronic lymphocytic leukemia (CLL) or multiple myeloma (MM), intravenous immune globulin (IVIg) may be administered to reduce the risk of infection. Since 2013, IVIg products have carried a boxed safety warning about the risk of thromboembolic events (TEEs), with TEEs reported in 0.5% to 15% of patients treated with IVIg. In this retrospective cohort study of older patients with CLL or MM identified from the Surveillance, Epidemiology, and End Results-Medicare Linked Database, we assessed rates of clinically serious TEEs in 2724 new users of IVIg and a propensity-matched comparison group of 8035 nonusers. For the primary end point, arterial TEE, we observed a transient increased risk of TEE during the day of an IVIg infusion and the day afterward (hazard ration = 3.40; 95% confidence interval [CI]: 1.25, 9.25); this risk declined over the remainder of the 30-day treatment cycle. When considered in terms of absolute risk averaged over a 1-year treatment period, the increase in risk attributable to IVIg was estimated to be 0.7% (95% CI: −0.2%, 2.0%) compared with a baseline risk of 1.8% for the arterial TEE end point. A statistically nonsignificant risk increase of 0.3% (95% CI: −0.4%, 1.5%) compared with a baseline risk of 1.1% was observed for the venous TEE end point. Further research is needed to establish the generalizability of these results to patients receiving higher doses of IVIg for other indications.

Retrospective Analysis of Clinical Response in Children with Severe Immune Thrombocytopenia Undergoing Treatment with Intravenous Immune Globulin

Background:Childhood immune thrombocytopenia (ITP) is a common bleeding disorder characterized by an isolated thrombocytopenia resulting from unknown causes, commonly presenting between 1 to 10 years of age. Nearly one child in 20,000 will experience ITP each year in the United States. The American Society of Hematology recommends that children with platelet counts of <20,000/μL and significant mucous membrane bleeding, or with platelet counts of <10,000/μL and minor purpura, should receive treatment with intravenous immune globulin (IVIg), IV RhIG, or corticosteroids.Objective:The objectives of this retrospective analysis was to determine if pediatric patients with severe ITP are responding to IVIg treatment with or without concomitant corticosteroids and if different IVIg products have any difference in response. We evaluated mean platelet counts at initial presentation and following IVIg therapy. The endpoints of this study were rate, degree, and rapidity of the platelet count response, cost of treatment, adverse effects and comparison of these with different IVIg products.Methods:This study was a single center, retrospective analysis of patients undergoing IVIg treatment for severe ITP. After institutional IRB approval, subjects were identified through Intermountain's Enterprise Data Warehouse. Subjects were pediatric patients aged ≤18 years of age with immune thrombocytopenia that received treatment with IVIg from January 2009 through April 2015. Patients were eligible for inclusion if they had an initial platelet level of <20,000/mm3 drawn within 48 hours prior to starting IVIg therapy and at least one platelet level within seven days following IVIg administration. Patients were excluded if they received a platelet transfusion prior to IVIg therapy. Platelet increase was assessed by analyzing the mean difference in platelet increase between initial values preceding IVIg administration compared to the highest drawn platelet level within a 7 day period post-IVIg therapy. Three different IVIg products were used which included Gammagard, Gammagard S/D and Gamunex. Response was defined as a platelet rise to at least 20,000/mm3. Cost-effectiveness was also evaluated.Results:At Primary Children's Hospital between January 2009 and April 2015, approximately 150 patients were diagnosed with ITP, the majority of whom were either observed without treatment or received corticosteroid therapy. Forty six patients were identified as having severe ITP requiring IVIg therapy, of which 72% were males. Median age of ITP patients receiving IVIg was 8 years. Twelve patients were excluded, as eight patients received platelet transfusions, three patients had initial platelet levels above 20,000/mm3, and one patient did not have a documented follow-up platelet level. This left 34 eligible patients for data analysis. Twelve patients (35%) received both IVIg and steroids. Twenty two patients (65%) had an appropriate platelet response within the 7 day period. The mean platelet increase was 76,000/mm3 in patients who received IVIg. Mean platelet increase of 88,000/mm3 was observed in patients receiving only IVIg therapy, compared to 53,000/mm3 in patients receiving both IVIg and corticosteroids. Seventy-six percent of patients received Gammagard with an average platelet response of 88,000/mm3, of which 69% responded by day 7. Twelve percent of patients received Gamunex with an average platelet response of 89,000/mm3, of which 75% responded by day 7. Twelve percent of patients received Gammagard S/D with an average platelet response of 10,000/mm3, of which 25% responded by day 7. Average IVIg cost per patient was $2,736 with a mean expense of $36 per 1000/mm3 increase in platelet counts.Conclusion: Similar to other published reports, patients with severe ITP responded well to IVIg therapy. Patients who failed to respond to initial steroid treatment experienced a platelet response with concomitant corticosteroid and IVIg therapy. Though the numbers are small, our study suggests for the first time that IVIg product with >98% IgG levels (i.e. Gammagard, Gamunex) have better response rates than Gammagard S/D which has 90% IgG level. Further analysis needs to be completed evaluating duration of therapeutic effect from IVIg. This information will be used to help detect a clinically meaningful response to IVIg therapy directed at increasing platelet counts and preventing ITP complications. DisclosuresNo relevant conflicts of interest to declare.

Hemolytic events associated with intravenous immune globulin therapy: a qualitative analysis of 263 cases reported to four manufacturers between 2003 and 2012.

Objectives of this study were to identify possible patient and product risk factors for intravenous immune globulin (IVIG)-associated hemolysis, a recognized side effect of IG therapy; analyze IVIG indications; and examine dose levels (g/kg body weight) and total IVIG dose administered. Reports of IVIG-associated hemolysis for 10 years (2003-2012) for four participating IG manufacturers were identified using a uniform case definition (Standardized MedDRA Query "Hemolytic disorders," Broad Scope, Version 16.0) and analyzed. IVIG-associated hemolysis appears to occur predominantly at dose levels exceeding 0.5 g/kg, with 72% of cases with known dose information having dose levels between 1 and 2.5, and can affect patients at any age, without a clear gender preference. No association was found between hemagglutinin exposure and development of hemolysis, nor between dose levels and odds of receiving a transfusion to treat hemolysis. Patients with blood group AB may be at higher risk of hemolysis than those with group A or B. Data examined confirm that IVIG-associated hemolysis predominantly occurs following infusion of high IVIG doses, and can affect patients at every age of both genders. While presence of hemagglutinins appears to play a major role in pathogenesis of hemolytic disorders, high hemagglutinin titers of IVIG products themselves seem to be of less relevance, indicating that the pathomechanism of IVIG-associated hemolysis may be related to the presence, but not the absolute amount, of hemagglutinins. Patients with hemolysis had additional hemolytic risks such as multiple comorbidities and medication use. IG-treated patients with multiple risks should be closely monitored for hemolysis.

Neutralization of Enterovirus D68 isolated from the 2014 US outbreak by commercial intravenous immune globulin products

BackgroundIn 2014, an outbreak of Enterovirus D68 (EV-D68) was recorded as the largest in the US with cases confirmed in 49 states. Intravenous immune globulin (IVIG) has been used to treat enterovirus infections in neonates and is an accepted replacement therapy for immunodeficient patients. ObjectivesThis study aimed to detect the presence of neutralizing antibodies to EV-D68 viruses from the 2014 outbreak in commercially available IVIG products. Study designCommercially available lots of IVIG preparations were obtained from five different manufacturers (2–10 preparations per manufacturer) and tested for neutralizing antibodies against the prototype EV-D68 virus and three EV-D68 isolates representing strains circulating during the 2014 outbreak. ResultsAll lots of IVIG tested were positive for EV-D68 neutralizing antibodies, with high titers ranging from 9.5log2 to 17.5log2, and with comparable median titers to all four EV-D68 viruses. Conclusions and discussionAmino acid sequence differences in the regions of the predicted antigenic sites on the viral capsid may explain some of the differences in neutralization among the different strains. The neutralization titers suggests that the 2014 outbreak EV-D68 viruses share some antigenic sites with the prototype virus and also present some unique antigenic sites distinct from the prototype. However, the commercial IVIG lots tested all contained high levels of neutralizing antibodies against EV-D68.

One IVIG mystery solved, another demands vigilance

The mysterious link between one manufacturer’s intravenous immune globulin (IVIG) product and an unusual rate of thrombotic and thromboembolic events is now known—too much coagulation factor XIa. But the company’s resolution of that issue does not mean pharmacists can relax their efforts to minimize the risk of adverse events related to the manufacture of IVIG products, said two experts. “Manufacturers are always trying to make a cleaner product,” said Jerry Siegel, a clinical associate professor at The Ohio State University College of Pharmacy in Columbus. But in trying to eliminate an undesirable, natural plasma constituent such as immunoglobulin A and produce a purer mixture of immunoglobulin G, a manufacturer can introduce a problem, Siegel said. Ashley A. Vo, director of transplant immunotherapy at Cedars-Sinai Medical Center in Los Angeles, can attest to that. Vo said the manufacturing processes for 10% liquid IVIG products involve chromatography, which improves the overall purity.

Passive Transfer of Hepatitis B Core Antibody by Intravenous Immune Globulin in Patients with Immune Thrombocytopenic Purpura.

Abstract 2418Poster Board II-395 Background:Rituximab may reactivate remote hepatitis B infection. Thus, hepatitis B core antibody (HBcAb) seropositivity was an exclusion for a randomized trial of rituximab in patients with immune thrombocytopenic purpura (ITP) in Canada. During screening for this trial, we observed a high rate of HBcAb seropositivity at our centre. We investigated passive antibody transfer by intravenous immune globulin (IVIg) as a potential explanation. Methods:We performed a case-control study of consecutive ITP patients screened for eligibility for a randomized trial of rituximab. We compared the frequency of prior IVIg use and the IVIg product administered to patients who tested positive (n=11) and negative (n=13) for HBcAb. Total (IgG and IgM) HBcAb was tested using a microparticle enzyme immunoassay (MEIA) that measures the rate of inhibition compared with an internal cut-off value (AxSYM®, Abbott Laboratories, IL, USA). We calculated the odds ratio (OR) and 95% confidence interval (CI) for IVIg exposure. We also tested different lots of 2 IVIg products directly for HBcAb in the MEIA. Results:Of 24 consecutive patients with ITP screened, 11 (45.8%) were positive for HBcAb and thus were excluded from the randomized trial. The observed rate of HBcAb seropositivity in this cohort was 35 times higher than the expected seroprevalence in Canada of 1.3% (O'Brien Transfusion 2009). Of 11 HBcAb-positive patients, 10 (90.9%) had received prior IVIg [OR, 16 (95% CI, 1.54, 166.05)]. Of the 10 patients who received IVIg, 8 (80.0%) received Gamunex (10% human immune globulin, Talecris Biotherapeutics, Clayton, NC). HBcAb was repeated in 8 seropositive patients, of whom 4 were negative on repeat testing 7 to 104 weeks after the last dose of IVIg. Of the 13 HBcAb-negative patients, 5 (38.5%) had received prior IVIg; none were Gamunex. Seroconversion was documented in one patient serially tested after receiving Gamunex; MEIA rates decreased (became positive) rapidly, then gradually increased to normal after 7 weeks. Samples from 4 lots of Gamunex were reactive in the MEIA; whereas 3 lots of IGIVnex (Talecris Biotherapeutics) were non-reactive. Conclusions:False positive HBcAb results may occur due to the passive transfer of HBcAb from Gamunex, an IVIg product manufactured from donors who are not screened for HBcAb. HBcAb should be interpreted cautiously in any patient who received IVIg. We recommend HBcAb testing before IVIg administration so that treatments such as rituximab are not withheld unnecessarily. Disclosures:Arnold:Hoffman-LaRoche: Research Funding; Amgen: Consultancy, Honoraria. Meyer:The NCIC CTG is a clinical trials cooperative group. It receives its base grant support from the Canadian Cancer Society Research Institute. Many of its clinical trials include research support from industry. : Research Funding.

Cost-Minimization Analysis of Anti-D Immune Globulin Versus Intravenous Immune Globulin for the Initial Treatment of Immune Thrombocytopenic Purpura.

Immune Thrombocytopenic Purpura (ITP) is an autoimmune disorder in which opsonized platelets are prematurely destroyed within the spleen. At this time both anti-D immune globulin (anti-D) and intravenous immune globulin (IVIG) are established treatment options for the management of ITP in children and adults. Due to the tremendous increase in demand for IVIG products in the past decade and the subsequent lack of sufficient production a national shortage has emerged. As a consequence, the direct cost and resulting burden on the healthcare payer has risen dramatically for this treatment option. We performed a cost-minimization analysis (CMA) to compare the cost of using anti-D versus IVIG for the initial treatment of non emergent ITP in appropriate patients. A CMA was employed for this economic evaluation because clinical evidence supports the supposition that the efficacies of the treatment options in question are similar. The perspective used for this study was that of the healthcare payer. The study population includes children and adults with non emergent forms of ITP who are both Rh positive and nonsplenectomized. This CMA did not include the cost to the healthcare payer for treatment administration or the incidence and cost of subsequent treatments for each product. The incidence of severe adverse events when using IVIG or anti-D are rare and therefore were not included in this CMA. In this analysis the cost for the non emergent initial treatment of ITP using [Immune Globulin Intravenous (Human)] 10% (Gammagard Liquid 10%) 1gm/kg × 2 days was compared to anti-D (WinRho® SDF Liquid) 50μg/kg × 1 day respectively. We performed a CMA using the same initial dose and duration of IVIG and anti-D dosed at 75μg/kg. And finally we performed a CMA using one day of treatment for both IVIG and anti-D dosed at 75μg/kg. An average patient weight of 75kg was used for initial dose calculations for each product. The average wholesale price (AWP) for each product was used for cost calculations. Gammagard Liquid 10% was selected as the product for IVIG therapy because this product currently holds a large portion of market share for IVIG products in the US. An example CMA calculation was; Gammagard Liquid 10% 1g/kg × 75kg × 2 days × $101.25 – WinRho® SDF 50μg/kg × 75kg × $1.10/μg. The results of these three CMAs when using anti-D versus IVIG for the initial treatment of ITP yielded a cost savings of $11,063.00, $9,000.50 and $1,406.25 respectively. When the CMA calculations were adjusted to use the actual number of vials needed to dispense the final dose of IVIG and anti-D dosed at 75μg/kg, the savings realized was $1,213.75 per dose dispensed. These CMAs have demonstrated the cost benefit of using anti-D for the initial treatment of non emergent ITP in appropriate patients.

Acute Renal Failure and Intravenous Immune Globulin: Occurs with Sucrose-Stabilized, but Not with D-Sorbitol–Stabilized, Formulation

To report 2 cases of acute renal failure (ARF) following administration of sucrose-stabilized intravenous immune globulin (IVIG), one of which did not recur following subsequent doses of d-sorbitol-stabilized formulation, and review the relevant literature. A 44-year-old white man awaiting heart transplantation developed ARF requiring hemodialysis following administration of sucrose-stabilized IVIG for high alloreactivity to population human leukocyte antigens. Following a return of renal function to baseline, subsequent doses of d-sorbitol-stabilized IVIG were administered without incident. A 90-year-old white man developed ARF after administration of sucrose-stabilized IVIG for monoclonal gammopathy. Renal function returned to baseline, and no subsequent IVIG doses were administered. An objective causality assessment revealed that sucrose-stabilized IVIG was the probable cause of the adverse drug event for both cases. Several case reports of ARF secondary to IVIG have been published. Recent publications note that sucrose-stabilized IVIG products have a disproportionately high rate of ARF occurrence (approximately 88%) versus non-sucrose-stabilized formulations. Recent market data for IVIG products indicate that sucrose-stabilized products account for approximately 40% of the total IVIG market. When administered intravenously, sucrose is excreted unchanged in the urine. ARF has been reported in patients receiving large doses of intravenous sucrose. ARF secondary to IVIG may be more likely to occur with sucrose-stabilized formulations. Before prescribing IVIG, clinicians should consider other nephrotoxic medications, preexisting renal function, age, diabetes mellitus, and rate of infusion. In patients at risk, it may be best to avoid sucrose-stabilized formulations.

Interferon Content of Intravenous Immunoglobulin: Variation Between Preparations

The use of intravenous immune globulin (IVIG) has presented many confusing questions as to the diverse usefulness in various unrelated disease states. Approved for the primary immunodeficiencies, IVIG as a therapeutic modality has proven benefit in disease states such as Kawasaki's disease, Guillain-Barre syndrome, idiopathic thrombocytopenic purpura, and recently relapsing multiple sclerosis. Evidence has surfaced about the ability of IVIG to reverse the immune responses, much like steroids, through such modalities as Fc receptor blockade and cytokine regulation. We present further evidence of the as yet unknown array of cytokines present in commercial IVIG preparations. The cocktail-like availability of these cytokines have the potential to influence immune mechanisms; specifically, levels of the interferons present in commercial IVIG products vary from source to source. Without knowing the cytokine profile present in the products, the usefulness of these IVIG preparations in altering immune function may be misleading to researchers and clinicians.

Assessment of microbial growth in intravenous immune globulin preparations

The ability of intravenous immune globulin (IVIG) products to support bacterial and yeast growth was studied. Microtiter plates containing preparations of eight commercially available IVIG products were inoculated with 10(5) colony-forming units (CFUs) of bacteria per milliliter or 10(3) CFUs of yeast cells per milliliter. The organisms used were Candida albicans, Torulopsis glabrata, Pseudomonas aeruginosa, Staphylococcus epidermidis, and Klebsiella pneumoniae. The plates were incubated at 3, 25, or 37 degrees C for seven days. For each organism and each temperature, a total of 16 identical wells were studied per preparation. Optical density was measured at 24-hour intervals to determine bacterial growth; yeast growth was determined visually. None of the IVIG preparations supported bacterial growth at any temperature over the seven-day period. No preparation supported visible yeast growth at 3 degrees C; however, most of the preparations did support yeast growth at 25 and 37 degrees C. The failure of the IVIG preparations to support bacterial growth at all temperatures and yeast growth at 3 degrees C suggests that a reconsideration of recommended expiration dates for IVIG products may be warranted.