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Anti-A/B isoagglutinin reduction in an intravenous immunoglobulin product and risk of hemolytic anemia: a hospital-based cohort study.

ABSTRACT: BACKGROUND:Intravenous immunoglobulins (IVIG) are derived from large human plasma pools. IVIG-associated hemolytic anemia (HA) is a known class effect, likely attributed to dose-dependent passive transfer of anti-A/B isoagglutinins. Two isoagglutinin reduction steps were implemented in the manufacturing process of Privigen (human 10% liquid IVIG): exclusion of high-anti-A-titer donors in 2013, replaced by specific immunoaffinity chromatography in 2015. We aim to estimate the clinical effectiveness of both measures. STUDY DESIGN AND METHODS:Using the US hospital-based Premier Healthcare Database, three Privigen cohorts were generated based on calendar periods indicative of manufacturing changes: Period 1 (baseline) January 2008 to December 2012, Period 2 (high-anti-A-titer donor exclusion) October 2013 to December 2015, and Period 3 (immunoaffinity chromatography) October 2016 to April 2019. HA within a 10-day at-risk period after Privigen administrations was identified from review of patient record summaries. Incidence rate ratios (IRRs) were estimated from Poisson regression (Period 1 reference) adjusting for hospital setting, sex, age, Privigen indication, dose, and first use. RESULTS:Crude incidence rates of HA were 1.49 per 10,000 person-days in Period 1 (38 HA, 9439 patients), 1.01 in Period 2 (20 HA, 7710 patients), and 0.14 in Period 3 (3 HA, 7759 patients). Adjusted IRR for HA in Period 2 was 0.71 (95% confidence interval [CI], 0.41-1.23), and in Period 3 was 0.10 (0.03-0.33) compared with Period 1. The IRR for HA in Period 3 compared with Period 2 was 0.14 (95% CI, 0.04-0.47). CONCLUSION:Implementation of immunoaffinity chromatography in Privigen manufacturing resulted in a significant 90% reduction of HA risk. HA has become a rare event in association with Privigen use.

SUBMITTER: Wallenhorst C

PROVIDER: S-EPMC7496198 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Anti-A/B isoagglutinin reduction in an intravenous immunoglobulin product and risk of hemolytic anemia: a hospital-based cohort study.

Wallenhorst Christopher C Patel Ami A Shebl Amgad A Hubsch Alphonse A Simon Toby L TL Martinez Carlos C

Transfusion 20200602 7

<h4>Background</h4>Intravenous immunoglobulins (IVIG) are derived from large human plasma pools. IVIG-associated hemolytic anemia (HA) is a known class effect, likely attributed to dose-dependent passive transfer of anti-A/B isoagglutinins. Two isoagglutinin reduction steps were implemented in the manufacturing process of Privigen (human 10% liquid IVIG): exclusion of high-anti-A-titer donors in 2013, replaced by specific immunoaffinity chromatography in 2015. We aim to estimate the clinical eff ...[more]

PMID: 32488887

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Project description:IntroductionHemolysis is considered a class effect and a rare adverse event that can occur following therapy with human normal immunoglobulin for intravenous administration [i.e., intravenous immunoglobulin (IVIG)]. Anti-A/B isoagglutinins (also referred to as isohemagglutinins) originating from donor plasma are present in polyvalent immunoglobulin G (IgG) products and are considered a probable risk factor for hemolysis. We hypothesized that, by excluding plasma from donors with high isoagglutinin titers, the final IVIG product would have a meaningful reduction in anti-A/B isoagglutinin titers.MethodsA method for screening donor plasma for anti-A isoagglutinins using an automated indirect agglutination test (IAT) was developed. A cut-off for donor plasma exclusion was defined. Industry-scale donor plasma pools and final IVIG product were prepared according to the manufacturing process of Privigen(®) (CSL Behring, Berne, Switzerland; human 10% liquid IVIG). Anti-A/B isoagglutinin content in pooled plasma and final IVIG product was measured by IAT, direct agglutination test, and a flow cytometry-based assay [fluorescence-activated cell sorting (FACS) anti-A].ResultsScreening of plasma from 705 donors identified 48 (6.8%) donors with high anti-A isoagglutinin titers in plasma (IAT agglutination score ≥2+ in a 1:200 pre-dilution). Exclusion of plasma from these donors resulted in a one-titer-step reduction of anti-A isoagglutinin in pooled plasma, confirmed by a twofold anti-A isoagglutinin concentration reduction measured by FACS anti-A (1,352 vs. 2,467 µg/g IgG). When the same screening and exclusion were applied to industrial-scale plasma pools (resulting in the exclusion of plasma from 5% of donors), anti-A isoagglutinins were reduced by one titer step in the final IVIG product. Anti-B isoagglutinins were also reduced by one titer step, as many donors with high anti-A isoagglutinins also have high anti-B.ConclusionReduction of anti-A/B isoagglutinin titers in IVIG products on an industrial scale is feasible through implementation of anti-A donor screening, which may reduce the risk of hemolysis following IVIG therapy.

Dataset Information

Anti-A/B isoagglutinin reduction in an intravenous immunoglobulin product and risk of hemolytic anemia: a hospital-based cohort study.

Publications

Anti-A/B isoagglutinin reduction in an intravenous immunoglobulin product and risk of hemolytic anemia: a hospital-based cohort study.

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