A prospective observational study of the incidence, natural history, and risk factors for intravenous immunoglobulin‐mediated hemolysis

Abstract

Background Intravenous Immune Globulin (IVIG) is used to treat numerous immune‐mediated and inflammatory conditions. There is growing awareness of hemolysis, occasionally severe, as a side‐effect of this therapy. While most cases are associated with anti‐A and/or anti‐B isoagglutinins, the frequency and mechanism of hemolysis remain poorly characterized. Study Design and Methods A prospective observational study was conducted to determine incidence, natural history and risk factors for IVIG‐mediated hemolysis. A total of 99 infusions of high‐dose IVIG (2 g/kg or higher) administered to 78 non‐group O patients were monitored and graded according to Canadian IVIG Hemolysis Pharmacovigilance Group. Serum ferritin and C3/C4 levels were monitored as indicators of macrophage activation and complement consumption, respectively. Supplementary investigations included assessment for ABO zygosity, Secretor status, FcR polymorphisms, eluate IgG subclass, monocyte monolayer assay, and a panel of cytokines. Results Hemolysis was observed in 32 of 99 (32%) of infusions, with 19 of 99 (19%) grade 2 or higher. Hemolysis was only apparent 5‐10 days after a completed IVIG infusion in 84% of cases and was associated with increases in serum ferritin without complement‐consumption. In univariate analysis, increased risk was observed in group AB patients, first‐time IVIG recipients, those not taking immuosuppressive medications, or patients treated with a specific IVIG brand; however, in multivariate analysis, product association was no longer observed. No other patient‐ or practice‐related risk factors were identified. Conclusion IVIG‐mediated hemolysis is common and frequently severe. Monitoring for 5‐10 days following an infusion should be considered in non‐O patients receiving high‐dose IVIG with known risk factors.

2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Kawasaki Disease

“…Repeated doses of IVIG may put patients at risk of hemolytic anemia, and the results of ongoing studies may alter this recommendation in the future (45–47). In patients with risk factors for hemolytic anemia with IVIG, such as non–type O blood groups, alternative therapies, such as glucocorticoids or nonglucocorticoid immunomodulatory therapy, should be considered (45,48). Combination therapy (i.e., multiple anticytokine agents) is not recommended for routine care and generally should only be considered in patients with extremely severe disease.…”

Suspected human intravenous immunoglobulin‐induced acute haemolytic anaemia in a dog

“…hIVIG is a transfusion product comprising plasma‐derived immunoglobulins from numerous human donors (Pendergrast et al . 2021). Several hIVIG‐associated adverse effects have been reported in humans and animals (Spurlock & Prittie 2011,Desborough et al .…”

“…Immunoglobulins are used for treating inflammatory conditions and immune-mediated diseases in humans and animals (Marsella 2000, Byrne & Giger 2002, Nuttall & Malham 2004, Trotman et al 2006, Bianco et al 2007, Grozdanic et al 2008, Abelson et al 2009, Bianco & Hardy 2009, Spurlock & Prittie 2011, 2020, Shemer et al 2018. hIVIG is a transfusion product comprising plasmaderived immunoglobulins from numerous human donors (Pendergrast et al 2021). Several hIVIG-associated adverse effects have been reported in humans and animals (Spurlock & Prittie 2011,Desborough et al 2014, Taylor et al 2015, Guo et al 2018.…”

In favour of combining more than one alternate strategy

“…Third, for the sake of safety, donors at higher risk of developing antibodies could still be screened, even if their plasma was derived for the plasma fractioning industry and not destined for transfusion. Of note, the reported haemolytic reactions with plasma derivatives have been caused by anti-A or -B haemagglutinins but not red cell irregular antibodies [4].…”