Incidence and risk factors for intravenous immunoglobulin‐related hemolysis: A systematic review of clinical trial and real‐world populations

Abstract

Background: Severe hemolysis rarely occurs in patients receiving intravenous immunoglobulin (IVIG) therapy. A systematic review was performed to assess the incidence of IVIG-related hemolysis and the impact of patient and product risk factors. Study Design and Methods: A systematic literature search for terms related to "IVIG products", "hemolysis," and "adverse events" was conducted in Embase for articles published between January 1, 2015, and May 31, 2021. Studies with no clinical datasets, no IVIG treatment, or where IVIG was used to treat hemolytic conditions were excluded. Of the 430 articles retrieved, 383 were excluded based on titles/abstracts and 14 were excluded after in-depth review.Results: In total, 33 articles were analyzed and separated into observational studies (n = 16), clinical trials (n = 8), and case reports (n = 9). The incidence proportion for IVIG-related hemolysis ranged from 0% to 19% in observational studies and 0%-21% in clinical trials. A higher incidence of IVIG-related hemolysis was consistently reported in patients with blood groups A and AB. Hemolysis occurred more frequently in patients treated with IVIG for some conditions such as Kawasaki disease; however, this may be confounded by the high dose of IVIG therapy. IVIG-related hemolysis incidence was lower in studies using IVIG products citing manufacturing processes to reduce isoagglutinin levels than products that did not. Conclusion:This analysis identified patient and product risk factors including blood group, IVIG dose, and IVIG manufacturing processes associated with elevated IVIG-related hemolysis incidence.

A retrospective analysis of haemolytic reactions to intravenous immunoglobulin using data from the Transfusion‐Transmitted Injuries Surveillance System (Ontario)

“…Risk factors identified in this study (non-O blood group recipients and dose) have been previously reported in numerous prospective and retrospective studies [2]. Patients of blood groups A, B and AB were at greater risk of haemolysis compared with group O patients likely because of the passive transfer of ABO antibodies in the IVIG product.…”

“…The most frequent types of reactions to IVIG included: FNHTR (30.8%), minor allergic 1 Sites that are required to report moderate to severe reactions only. 2 Sites that report all reactions (mild, moderate and severe); the analysis of reaction frequency and rate included only reactions reported between 2014 and 2021 (n = 568/620 reactions). (antipyretics, antihistamines, corticosteroids, diuretics, sedatives and epinephrine) were not administered before transfusion.…”

“…Patient factors can have a contributing role in the risk and onset of IVIG-associated haemolysis as described in the literature. Patient risk factors identified include increased macrophage phagocytic activity, absence of immunosuppressive drugs, patient co-morbidities, underlying health issues, inflammatory status and routine use of medications (non-steroidal anti-inflammatory drugs, broad-spectrum antibiotics and gastrointestinal medications) [2,6,7,17,19].…”

“…Haemolysis (acute or delayed) can be mild to severe reactions that can occur during or following an IVIG infusion [2]. The primary cause of these reactions appears to be ABO antibodies in the IVIG product that can bind to red blood cells of group A, B and/or AB individuals resulting in intravascular and/or extravascular haemolysis [3].…”

“…To decrease the risk of haemolysis some manufacturers have modified the manufacturing process, to reduce ABO antibody concentration in the product [4]. Others have suggested that screening and excluding donors with high anti-A and anti-B titres may be effective [2,5]. Risk factors for IVIG haemolysis appear to be receiving a high dose of IVIG (≥2 g/kg), non-group-O blood type recipients and median anti-A and anti-B titres of 16 and 8, respectively [2,[6][7][8][9].…”