Intravenous iron reactions: Insights from an allergy and immunology perspective

Abstract

Background: Diagnosis and management of intravenous iron reactions is often challenging, as skin testing has unproven utility and most reactions are non-IgE-mediated.

Objective: We aimed to identify clinical patterns and tolerability predictors in patients with reactions to intravenous iron.

Methods: We conducted a retrospective cohort study of patients with reactions to intravenous iron who were referred to the Vanderbilt University Medical Center Drug Allergy Clinic from April 2014 through January 2025 and administered a follow-up survey via RedCap to evaluate patient outcomes with future intravenous iron administration.

Results: Of the 51 patients presenting for adverse reactions to intravenous iron, 48 had skin testing performed. The skin testing results were deemed negative in all 48 cases (100%). Notable laboratory test results within 1 year of reaction were low vitamin D level (47%), high parathyroid hormone level (46%), and low phosphorus level (10%). Many patients (56%) were dermatographic, and their drug alert labels included opioids (31%), fluoroquinolones (14%), and radiocontrast dye (8%). Following assessment, 31 patients received intravenous iron (61%) using formulations that were the same as (n = 15 [48%]) and/or different from (n = 17 [55%]) the forumlation initially implicated, with the various modifications including antihistamines, slower infusion rate, and intravenous fluid pretreatment. Of these 31 patients, 27 (87%) tolerated the infusions. Additionally, following evaluation, the patients were surveyed regarding subsequent intravenous iron administrations, eliciting a 29% response rate (n = 15). Of the responders, 7 patients (47%) reported receiving intravenous iron after evaluation; all 7 reported tolerance.

Conclusion: Most reactions to intravenous iron are non-IgE-mediated; however, our study introduces 2 novel observations, namely, a high frequency of dermatographism (56%) and common colabeling of these patients with drug alerts to Mas-related G protein-coupled receptor X2 (MRGPRX2)-activating drugs, suggesting a possible shared pathophysiologic mechanism.

Keywords: Adverse reactions; drug allergy; intravenous iron.