Hypersensitivity to intravenous iron: classification, terminology, mechanisms and management

Abstract

Intravenous (IV) iron therapy is widely used in iron deficiency anaemias when oral iron is not tolerated or ineffective. Administration of IV-iron is considered a safe procedure, but severe hypersensitivity reactions (HSRs) can occur at a very low frequency. Recently, new guidelines have been published by the European Medicines Agency with the intention of making IV-iron therapy safer; however, the current protocols are still non-specific, non-evidence-based empirical measures which neglect the fact that the majority of IV-iron reactions are not IgE-mediated anaphylactic reactions. The field would benefit from new specific and effective methods for the prevention and treatment of these HSRs, and the main goal of this review was to highlight a possible new approach based on the assumption that IV-iron reactions represent complement activation-related pseudo-allergy (CARPA), at least in part. The review compares the features of IV-iron reactions to those of immune and non-immune HSRs caused by a variety of other infused drugs and thus make indirect inferences on IV-iron reactions. The process of comparison highlights many unresolved issues in allergy research, such as the unsettled terminology, multiple redundant classifications and a lack of validated animal models and lege artis clinical studies. Facts and arguments are listed in support of the involvement of CARPA in IV-iron reactions, and the review addresses the mechanism of low reactogenic administration protocols (LRPs) based on slow infusion. It is suggested that consideration of CARPA and the use of LRPs might lead to useful new additions to the management of high-risk IV-iron patients. AbbreviationsADRs, adverse drug reactions; API, active pharmaceutical ingredient; CARPA, complement activation-related pseudoallergy; CHMP, Committee for Medicinal Products for Human Use; EMA, European Medicinal Agency; HMW-ID, high molecular weight iron dextran; HSRs, hypersensitivity reactions; ID, intravenous dextran; IV-iron, intravenous iron; LMW-ID, low molecular weight iron dextran; LRP, low reactogenic administration protocol; Mab, monoclonal antibody; MBL, mannose binding lectin; MRI, magnetic resonance imaging; SPIO, superparamagnetic iron oxide; WAO, World Allergy Organisation BJP British Journal of Pharmacology

Two case reports of desensitization in patients with hypersensitivity to iron

“…[6,10,11] However, several authors have suggested that these antihistamines should not be administered because they could cause adverse effects that could be misinterpreted as DHRs, such as a slight urticariform reaction [12][13][14][15]. Moreover, some authors suggest that corticosteroids have a greater influence on anaphylaxis than on DHRs; therefore, their usefulness in the initial part of the protocol should be reassessed [12]. Other authors have suggested that premedication should be omitted completely, although such modifications to the protocol are still being investigated [7].…”

Safety of Oral and Intravenous Iron

“…However, this is now off the market and has been replaced by new iron preparations such as low-molecular-weight iron dextran, ferum­oxytol, ferric carboxymaltose, and iron isomaltoside. Studies have shown all iron products have a good safety record, with a lower rate of reactions than rituximab or penicillin [28]. Modern iron formulations are associated with a low risk of reactions, and they have fewer adverse effects than oral iron in several studies.…”

Modern iron replacement therapy: clinical and pathophysiological insights

“…More serious "anaphylactoid" reactions, including hemodynamic and respiratory changes, can also occur with virtually all IV iron preparations, including the newer ones (see below), but appear exceedingly rare (see below). At variance with serious AEs with old compound like iron-HMWD, for whom in some cases a IgE-mediated mechanisms could be demonstrated [104,105], such reactions are now increasingly attributed to complement activation-related pseudo-allergy (CARPA) [106]. This mechanism is thought to be activated by iron nanoparticles [106], thus, again, the stability of the carbohydrate shell and the different physicochemical properties of the various compounds are likely critical.…”

“…At variance with serious AEs with old compound like iron-HMWD, for whom in some cases a IgE-mediated mechanisms could be demonstrated [104,105], such reactions are now increasingly attributed to complement activation-related pseudo-allergy (CARPA) [106]. This mechanism is thought to be activated by iron nanoparticles [106], thus, again, the stability of the carbohydrate shell and the different physicochemical properties of the various compounds are likely critical. Anyway, a recent systematic meta-analysis of 103 trials including more than 10,000 patients treated with various IV iron preparations and more than 7000 patients treated with different comparators (oral iron, placebo) found serious AEs with IV iron extremely rare (< 1,200,000 doses), and no more frequent than comparators [107].…”