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.

Hemolysis after high‐dose intravenous immunoglobulin: An under‐appreciated sequelae

“…One manufacturer changed their IVIG processing to lower isoagglutinin titers, which resulted in less hemolysis. 8,9 E184 CORRESPONDENCE…”

“…3,4 Additional studies identified a direct association between anti-A and anti-B titers in IVIG and hemolysis in patients. 7,8 In one study, only group A recipients receiving IVIG underwent hemolysis and those receiving IVIG 1 g/kg/wk had less hemolysis than those randomized to 2 g/kg/wk. 3 A prospective study showed that 32% of IVIG infusions resulted in hemolysis with 19% clinically-significant, occasionally severe hemolysis.…”

“…[3][4][5] Many such examples suggesting the role of isoagglutinins to induce hemolysis exist. [3][4][5]7,8 Overall, cases of hemolysis have increased substantially, 3,4 apparently directly attributable to the 2007 change in manufacturing.…”

“…One mildly successful approach to reducing recipient hemolysis was removing donors with high titer isoagglutinins. 8 However, making certain donors ineligible to donate was counter-productive at a time of IVIG shortage. Subsequent study demonstrated that immunoaffinity removal of anti-A/anti-B was more effective at reducing isoagglutinin titers; using this technique, certain manufacturers were able to reduce the final titers of isoagglutinins in their products 9 and this had a greater effect in reducing recipient hemolysis.…”

Intravenous immunoglobulin and the current risk of moderate and severe anaphylactic events, a cohort study

“…This was a retrospective observational cohort study, derived from a convenience cohort of an IvIg IgPro10 cohort, originally sampled to study the risk of hematological anemia in association with IvIg IgPro10 [18]. The cohort comprised patients who were treated with intravenous Ig.…”