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Risks for Anaphylaxis With Intravenous Iron Formulations

TO THE EDITOR:We read with interest Dave and colleagues' article (1) on the risk for anaphylaxis with intravenous (IV) iron and would like to highlight several concerns. First, the most important flaw of this study is the inferential definition of anaphylaxis from administrative data. Dave and colleagues employed an algorithm that used surrogates for true anaphylaxis, such as administration of epinephrine (rather than such clinically accurate objective definitions as the presence of wheezing, stridor, shock, and/or increased serum tryptase levels). This algorithm almost certainly overestimates the incidence of anaphylaxis after IV iron administration. Infusion reactions to IV iron occur on a spectrum. Most are minor, non–IgEmediated, and not life-threatening; these are characterized by transient flushing and truncal myalgia likely due to labile free iron in the formulation (known as the “Fishbane reaction”) (2). These reactions can be managed by slowing the infusion rate; however, a combination of unproductive panic, poor understanding, and algorithmic/indiscriminate approaches to managing infusion reactions routinely leads to inappropriate administration of antihistamines and epinephrine. Therefore, we cannot reliably conclude that the cases identified are anaphylaxis; instead, they probably mostly represent unnecessary reactive action to minor labile iron reactions. No amount of covariate adjustment or statistical weighting can remedy this foundational flaw. Second, this study did not consider variations in dose or administration, which reduces applicability to current practice. This also indicates that the previously mentioned overestimation of the incidence of anaphylaxis most likely affected each formulation to a different degree. For example, the study period (2013 to 2018) included a time when more rapid administration of ferumoxytol (510 mg in 17 s) was recommended compared with current, updated administration recommendations (510 mg over 15 min) (3). Administration of 510 mg of ferumoxytol in 17 seconds resulted in a high rate of nonanaphylaxis infusion reactions. The authors' algorithm probably erroneously considered many such reactions to be anaphylaxis, artificially inflating the rate of this adverse effect for ferumoxytol to an even greater degree than for other formulations. Third, this study excluded most patients in whom IV iron is used (including those who are pregnant or have heavy uterine bleeding, most patients with inflammatory bowel disease or who had gastric bypass, and all patients who require dialysis). Given that the risk for anaphylaxis varies considerably by population (2), this raises additional concerns about generalizability even if some cases identified did represent true anaphylaxis. Finally, the authors' interpretations of unreliable conclusions may be harmful. The authors accurately conclude that the risk for anaphylaxis is low with all IV iron formulations. However, they then implicate iron dextran and ferumoxytol as having higher risk than the other formulations. Furthermore, they interpret their findings as “reassuring” for the safety of ferric carboxymaltose, a newer product already barred from many institutional formularies because of unacceptably high rates of hypophosphatemia (75% in 2 recent randomized trials) (4). A single administration of ferric carboxymaltose can cause symptomatic hypophosphatemia lasting weeks to months, and repeated administration can cause osteomalacia and bone deformity or fracture (5). An increase in the frequency of hypophosphatemic complications from more frequent use of ferric carboxymaltose in lieu of iron dextran or ferumoxytol due to conclusions formulated from unreliable results is just 1 example of potential harm that might result from this analysis.