Iron is an essential micronutrient and an important element for body function. Iron infusion has been performed with modern formulations to treat iron deficiency (ID) and iron deficiency anemia (IDA) when oral iron becomes intolerant, unresponsive, unsuitable, or nonadherence. ID and IDA are ubiquitous in both developed and developing regions, affecting mostly women of reproductive age, young children, the elderly, and individuals with chronic diseases/inflammation [1]. Can iron infusions rechallenge occur safely in an individual with a history of reactions due to intravenous (IV) iron? This review explores the challenges of providing IV iron therapy in the context of past reactions, where clinically indicated.

Iron has various generic formulations, each of which is unique [2]. Its reaction to a specific product may therefore not necessarily imply that the patient will react to another compound. More importantly, the vast majority of IV iron reactions are minor transfusion-related (e.g., fishbane) and non-immunoglobulin E (IgE)-mediated (complement activated-related pseudo-allergy, CARPA) [3]. There are several non-dextran IV iron formulations, such as iron sucrose, ferric carboxymaltose, ferric derisomaltose (also known as iron isomaltoside), and ferumoxytol. Currently, iron polymaltose and low-molecular-weight dextran, although low-cost, are less utilized because of the requirement for test dosing and a longer infusion duration [1].

Reports of adverse effects (AEs) from IV iron are variable, and depend on the nomenclature used, data source, and study type. Nonetheless, reactions with modern formulations are low, and serious or true anaphylaxis is described as extremely rare [3,4]. Minor or less severe reactions generally occur at a rate of one in 100 infusions [1]. Severe hypersensitivity reactions (SHR) or anaphylaxis for non-dextran have been suggested to occur in 0.024% (24/100,000) and 0.018% (7.5/40,000) of cases, respectively [5,6]. Oregon multi-cohort study, based on two documented epinephrine use among 35,737 infusions, yielded 0.005% [3]. A larger study (2005) described true anaphylaxis as occurring in less than 1:200,000 (after exclusion of old dextran-iron) [4]. Table 1 summarizes the AEs of IV iron use, simplifying with major (SHR or anaphylaxis), and minor/less severe reactions [2,7,8] The Fishbane reaction resulting from free labile iron nanoparticles is described as the most common type, and is usually transient and resolves spontaneously [9,10]. The CARPA reaction is hypothesized to occur with rapid exposure to IV iron, which activates the complement system (C3a and C5a) with anaphylatoxin production, leading to a hypersensitivity reaction with variable intensity [10]. It is recognized that the fishbane reaction and other transfusion reactions are often difficult to distinguish clinically from allergic reactions/anaphylaxis (IgE-mediated) and subsequently heighten the anxiety of professionals and patients, leading to extra or unnecessary interventions [11,12].

The literature search was performed in PubMed, Google Scholar, ResearchGate and ScienceDirect with the search string “intravenous iron reactions” for English articles. Studies without rechallenge, re-exposure, or re-administration with past reactions were excluded. Five studies were identified with a combined total of re-exposure infusion number 1,006. Table 2 lists and analyzes the studies comparing re-exposure to IV iron with past reactions [3,12-15].

The overall results in Table 1 demonstrate a satisfactory sample and outcome, with tolerance, safe, and successful in the majority (>80%) of the rechallenge.

In an Australian study, 69 patients with a history of past reactions (from mild to moderate and few severe types) were rechallenged with the same (9 [13%]) and alternative iron products (60 [87%]); these rechallenges were found to be largely tolerated, safe, and successful (98%) [12]. Though no exact data supplied, a relatively satisfactory outcome without major reactions (SHR or anaphylaxis) was reported in a multi-cohort study in Oregon, in which participants were administered the same (majority, 755 [86%]) and alternative preparations (118 [14%]) in 873 cases [3]. Interestingly, this study exposed reaction rate elevation 68% (same product use) versus 21% (alternative product use) which was compounded by premedication use as well. The other three studies from Europe (the bottom three of Table 1) with small sampling also reported successful re-exposure in 58%–90% participants with past reactions ranging mild to moderate and few severe types [13-15]. Lower satisfactory percentage (58%) in the study by Steveling-Klein et al. [13] was affected by use of same culprit product in majority participants (24/36 [67%]). To note “reactions”, studies number 2 to 5 utilized Ring & Messmer grading scale (grade 1–4), and top number one (Oregon) applied severe adverse events (SAE, defined by the use of epinephrine within 24 hours post-infusion) with the rest as nonSAE; “tolerance, safe and successful” in all these studies seemed to imply no reaction or lesser reaction without major incidents (SHR or anaphylaxis). Those intolerant or unsuccessful cases were reported with aborted/incomplete procedures in the context of non-objectifiable symptoms such as chest tightness, dyspnea, nausea, anxiety, and objectifiable urticaria; notably, none of these five studies reported severe hypersensitivity reactions, anaphylaxis, or fatal reactions in the re-exposure despite the inclusion of previous grade 3–4 reaction cases.

Several other publications with narrative and case report style also reported tolerance without major issues, when rechallenge to IV iron therapy was clinically indicated [11,13-15]. The European Medicines Agency’s 2013 statement [16], “contraindication of IV iron products including alternative product for history of hypersensitivity reactions,” was brought under question by several later studies, indicating a lack of supportive evidence [12-14,17]. Of note, there were a lack of studies on the re-exposure of individuals with prior severe hypersensitivity reactions or anaphylaxis to the same IV iron products; however, the re-exposure of such individuals to alternative preparations was encountered but in small and limited numbers—three cases in Australia (grade 4: two with documented bronchospasm and one with bronchospasm plus multisystem involvement) [12] and three cases in Switzerland (grade 4: two with angioedema, urticaria, and shock, and one with cardiovascular shock) [14]. Encouragingly in the event of simple Fishbane reactions, several studies have consistently reported that resuming the infusion at a slower rate is tolerated and safe even in the same setting, after the infusion has been halted for 10–15 minutes and the symptoms have subsided [9,15,18,19].

Although rechallenge is generally well-tolerated and safe without serious incidents, re-administration with same product seemed to demonstrate increasing reaction incidents, compared with alternativeproduct use group, which was evident in the Oregon multi-cohort study [3] and the study by Steveling-Klein et al. [13]. Furthermore, it is suggested that potential risk factors such as a fast rate of infusion, multiple item/drug allergies, severe atopy/asthma, taking beta blockers or angiotensin converting enzyme inhibitor, mastocytosis, and even the anxiety of professionals be carefully evaluated in every infusion [10,13,19]. Another salient point is that the use of premedication (antihistamine, corticosteroids, or both) for IV iron therapy lacks experts’ consensus due to reports of antihistamines causing vasodilation, hypotension, tachycardia, and sedation, leading to confusion with or worsening of mild reactive symptoms, especially from North America studies where diphenhydramine is primarily used [3,4,11]. The Oregon study highlighted 23-fold rise of associated reactions among cases of premedication in participants in comparison with non-premedicated group (38.6% versus 1.7%) [3]. In contrast, in an Australian study with premedication (42 [61%]), where promethazine is primarily used, negative side-effects from premedication were not reported [12]. Premedication was not employed in three European studies. We were unable to find studies on chlorpheniramine, a commonly used antihistamine in Asia and Europe. Steroid use lacks randomized control data as per Cochrane, but no harmful effects have been reported [20]. Theoretically, steroids are known to be useful for immune-related reactions (IgE or complementmediated).

In conclusion, this study further strengthens the extremely rare occurrence of SHR and anaphylaxis following iron infusion. Rechallenge of IV iron therapy can be considered to have an array of both benefits and risks. Using both the same and different preparations that originally caused a reaction has been found to be tolerated and safe in the case of fishbanes and mild-to-moderate reactions (non-severe hypersensitivity reactions or anaphylaxis). However, rechallenge with alternative compounds appeared to be more favorable. A rechallenge to prior SHR or anaphylaxis with the same product has not been found in this review and is likely to remain unwarranted. Caution is required in patients with a history of severe hypersensitivity reactions or multiple high-risk factors, even when using different products. However, the use of premedication is controversial and requires further investigation.

This review, based on data available to date (October 2022), may be limited by the limited number of rechallenges and a lack of randomized control studies. It may also be marginally constrained by the nonuniform categorization of reactions among institutions/scholars. However, it provides an overall beneficial role for the retrial of iron infusion despite past reactions if indications exist. This study also addresses and counters the long stigma of fear associated with IV iron therapy in the medical community and adds to the growing safety data of modern formulations.