Intravenous Iron and Infection Risk—Still an Unanswered Question

The study by Shah et al¹ reports the results of a meta-analysis of approximately 40 000 individuals who received intravenous (IV) iron in 162 clinical trials, including 154 randomized clinical trials (RCTs). Their findings suggest that IV iron was associated with an increase in the risk of infections (relative risk, 1.17; 95% CI, 1.04-1.31). These findings raise 3 important questions. First: why is this study important; second, why is the evidence to date inconclusive; and third, what is the best way to answer this complex question?

Iron is an essential nutrient for both humans and pathogenic microorganisms.² Regulation of iron distribution in the body functions as part of an innate immune response against invading pathogens.² Infusion of large amounts of iron can potentially subvert the body’s protective iron sequestering response. Extracellularly, iron is bound to transferrin, with nontransferrin bound iron only found in the circulation in pathological states. Administration of IV iron is known to generate nontransferrin bound iron, which, in animal studies, has been shown to enhance the growth of siderophilic bacteria.³ This is the biological basis for concern about infectious complications of IV iron, a drug that has been increasing in use. Thus, it is important to determine whether IV iron increases infection risk.

The study by Shah et al¹ attempts to answer this question using the tool of meta-analysis of a very large amount of data. However, the authors note that much of the data on which they based their analysis were potentially biased.

In contrast to the evidence on IV iron, there is well-documented evidence that oral iron supplementation is associated detrimental infection outcomes. This has been demonstrated in studies from tropical areas and Africa, particularly in relationship to malaria and diarrheal diseases.² What accounts for this disparity? First, the characteristics of the individuals in whom the studies of oral iron were performed vastly differ from the individuals who received IV iron in studies conducted in resource-rich countries. Second, the different routes and timing of administration: oral (continuous) and IV iron (intermittent), may have divergent biological effects regarding pathogens. IV iron preparations are complex nanodrugs that are first processed by macrophages before becoming available to body tissues, whereas oral iron is absorbed directly. Oral iron adversely alters the gut microbiome, supporting pathogenic organisms, which has not yet been demonstrated in humans for IV iron.⁴ Thus, extrapolation of the known risk of oral to IV iron may not be warranted.

Most studies of IV iron were performed for efficacy (ie, increase in hemoglobin levels or reduction in transfusions), with careful documentation of allergic adverse effects. However, as seen from the study of Shah et al,¹ infections were often poorly documented. Furthermore, the existing literature has led to conflicting conclusions partly by comparing the adverse events of oral and IV iron, among other biases.⁵ This implies that this issue can be resolved by a prospective RCT of IV iron, with infection as a well-defined end point.

The best example of such a prospective RCT was performed by MacDougall and colleagues in more than 2000 patients undergoing hemodialysis.⁶ They found no difference in infection rates according to IV iron administration. However in that study, although infection was well defined, both study groups received iron, albeit in varying doses (1.8-fold difference in amount). It could be argued that the use of a placebo group would have yielded a more convincing conclusion, but for ethical reasons, this could not be done in patients undergoing hemodialysis. A prospective, placebo-controlled RCT of IV iron in a different patient group could be equally problematic. For ethical reasons, administration of placebo instead of IV iron to patients who require iron treatment is not acceptable, nor is it customary to give IV iron to iron-replete individuals.

It is also possible that the investigation of infection risk from IV iron needs to be focused on distinct patient populations, since previous studies mainly focused on patients with chronic kidney disease. Another adverse event from IV iron, hypophosphatemia, was not recognized in patients with chronic kidney disease because their metabolism of fibroblast growth factor 23 differs from that of individuals with healthy kidney function.⁷ Therefore, various patient subgroups (eg, individuals with inflammatory bowel disease or women with menorrhagia) may need to be studied separately regarding the infection risk of IV iron. Ultimately, to define the biological mechanisms of infection risk, the use of animal models may be more informative.³

In summary, the issue of infection risk from IV iron is not simple to unravel. For the present, clinicians should be cautious and defer IV iron therapy during acute infections, as has been suggested.⁶ More conclusive evidence is required to guide us on the use of this important therapeutic modality.

Published: November 12, 2021. doi:10.1001/jamanetworkopen.2021.34453

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Rund D. JAMA Network Open.

Corresponding Author: Deborah Rund, MD, Haematology Department, Hebrew University-Hadassah Medical Organization, Ein Kerem, Jerusalem, Israel 91120 (Deborah.rund@mail.huji.ac.il).

Conflict of Interest Disclosures: None reported.