Hypersensitivity reactions to intravenous iron: guidance for risk minimization and management

Abstract

Intravenous iron is widely used for the treatment of iron deficiency anemia when oral iron is inappropriate, ineffective or poorly tolerated. Acute hypersensitivity reactions during iron infusions are very rare but can be life-threatening. This paper reviews their frequency, pathogenesis and risk factors, and provides recommendations about their management and prevention. Complement activation-related pseudo-allergy triggered by iron nanoparticles is probably a more frequent pathogenetic mechanism in acute reactions to current formulations of intravenous iron than is an immunological IgE-mediated response. Major risk factors for hypersensitivity reactions include a previous reaction to an iron infusion, a fast iron infusion rate, multiple drug allergies, severe atopy, and possibly systemic inflammatory diseases. Early pregnancy is a contraindication to iron infusions, while old age and serious co-morbidity may worsen the impact of acute reactions if they occur. Management of iron infusions requires meticulous observation, and, in the event of an adverse reaction, prompt recognition and severity-related interventions by well-trained medical and nursing staff.

Introduction

Intravenous (IV) iron is increasingly used for the treatment of iron deficiency anemia (IDA) when oral iron is ineffective or poorly tolerated and when it or blood transfusion is inappropriate.21 It is also indicated in combination with erythropoiesis-stimulating agents in chronic kidney disease and chemotherapy-induced anemia. While acute reactions during iron infusions are very infrequent, they can be life threatening.

In 2013, the European Medicines Agency (EMA) published a report of their 2-year investigation of the adverse drug reactions to all IV iron drugs available in Europe3 (Table 1). The formulations considered were sodium ferric gluconate, iron sucrose, iron (III)-hydroxide dextran complex, ferric carboxymaltose, and iron (III) isomaltoside 1000.

Table 1.Summary of conclusions of the 2013 EMA report3 on IV iron products.

The aims of the present article are:

• to outline the frequency and outcomes of reactions to IV iron;
• to summarize current views about the pathogenesis of such reactions;
• to indicate the risk factors for reactions to IV iron; and
• to provide detailed guidance on risk minimization and management of iron infusions and acute reactions to them.

We are unaware of any existing guidance on how to prevent and manage hypersensitivity reactions (HSRs) to this increasingly used treatment, and intend this paper primarily for healthcare professionals, whether they be doctors or nurses, who prescribe and administer IV iron. Our aim is to offer advice that has been developed from a comprehensive literature search and iterative expert review about best practice before, during and after administration of IV iron to patients with IDA.

Terminology

Current nomenclature relating to acute adverse reactions to IV drugs is confusing, inconsistent and sometimes contradictory. In this report, we refer to all acute reactions to IV iron as hypersensitivity reactions (HSRs), sub-dividing them into mild, moderate or severe/life-threatening, depending on their clinical presentation. We have adopted the World Allergy Organisation proposal that the term “anaphylaxis” is reserved for severe HSRs,4 irrespective of pathogenesis, and avoid the term “anaphylactoid”, which historically has been used loosely to denote either non-immunological or even mild HSRs.

Methods

We undertook literature searches in PUBMED and EMBASE using the search terms “intravenous”, “anaphylaxis”, “anaphylactic”, “anaphylactoid”, “iron” as major subject headings or occurring in the title/abstract. These searches were supplemented by refined drug-class specific searches with the term “infusion reactions”. Secondary searches were made manually by screening articles retrieved by the online searches. Articles giving experimental data on adverse reactions to IV drugs were selected along with major anaphylaxis guidelines.

We concluded from these searches that: a) no existing anaphylaxis treatment guideline is strictly evidence-based, since the very rare occurrence of severe acute infusion reactions precludes randomized clinical trials as to how they should be managed; and b) there is so little information specifically relating to IV iron reactions that indirect evidence relating to acute reactions to other intravenous drugs had to be considered in preparing the present guidance.

We, therefore, assembled a panel of experienced clinicians from fields of medicine in which IDA is common (gastroenterology, hematology, immunology, internal medicine, nephrology, obstetrics and gynecology), as well as experts in the pharmacology of drug reactions and IV iron. Our recommendations result from development of a consensus in which the working group went through an iterative process of literature review and discussion of current clinical practice about each measure proposed.

Preparation of paper and declaration of interests

One of the authors (DSR) initiated this review but considered that it could not be undertaken without administrative and financial support to assemble the necessary international clinical expertise. The pharmaceutical company Pharmacosmos funded two one-day meetings in Copenhagen for the initial preparation of the paper. All available IV iron drugs were considered and no distinctions have been made between them in terms of safety or efficacy (see below). The pharmaceutical company had no editorial influence on the study and were not invited to approve the manuscript. No medical writer or unacknowledged authors were involved.

Frequency and outcomes of hypersensitivity reactions to intravenous iron infusions

Unlike previous authors, who had used a range of methodologies and assessed products that included poorly-tolerated high molecular weight dextran preparations which are no longer available,85 the EMA were unable to differentiate between current IV iron products in relation to the risk of severe HSRs. In this context, Wysowski et al.9 also concluded, from US data, that “because of under-reporting, possible differential reporting, absence of iron dextran brand names, and incomplete use (denominator) data, incidence rate and relative risk estimates cannot be calculated”. Death and other severe long-term sequelae arising from use of IV iron are very rare. In the largest such study to date, death certificate data from the US National Center for Health Statistics between 1979–2005 showed that there were around 3 deaths/year ascribed to iron infusions in the US, approximating 1 for every 5 million doses of IV iron sold.109

Pathogenesis of hypersensitivity reactions to intravenous iron

Mechanisms by which iron infusions induce adverse reactions may vary with the iron preparation used and with the pre-existing morbidity of the recipient. They cannot be distinguished by their clinical presentation. The two main possibilities are immunological IgE-mediated responses, for example, to the dextran component of IV iron preparations containing this molecule, and complement activation-related pseudo-allergy (CARPA).11 There are, however, no data to support the concept that IgE-mediated hypersensitivity commonly accounts for reactions to current formulations of IV iron.1312 CARPA may be the most common mechanism of acute HSRs provoked by any infusion containing nanoparticles, of which all existing IV iron preparations consist.14 The final common pathway of these processes is likely to include activation of mast cells and basophils, either directly, or via anaphylatoxins (C3a and C5a) that increase in blood as a consequence of complement activation. The secretion products of these cells, which include histamine, thromboxanes, leukotrienes and platelet-activating factor,11 trigger smooth muscle contraction, increased capillary permeability and loss of fluid from the intravascular space. Subsequent bronchospasm, laryngeal edema, tachycardia, hypo- or hypertension, hypoxia and reduced tissue perfusion can culminate, in severe HSRs, in loss of consciousness, circulatory collapse (shock), and cardiac and respiratory arrest.15

A fast iron infusion rate is a well-recognized risk factor, one possible explanation being the rapid increase in labile free iron observed in this situation.16 However, prevention of HSRs by reducing the speed of infusion is an effective practice not only with IV iron but also with other reactogenic drugs, so the phenomenon is unlikely to be solely due to higher levels of free iron. For example, it is also possible that, after rapid injection of IV iron, the clearance rate from the blood of anaphylatoxins by carboxypeptidase N and by uptake by blood and other cells is exceeded by their rate of production, leading to exacerbation of the CARPA pathogenic sequences described above.1511

Risk factors for hypersensitivity reactions to intravenous iron

Several factors have been suggested, on an evidence base of varying robustness, as predisposing to, on the one hand, an increased risk of an HSR occurring in patients given IV iron, and on the other, to a reaction, which if it occurs, has a worse outcome in the iron recipient. These factors have recently been re-stated by the EMA3 and represent a relative contraindication to the administration of IV iron to patients presenting them (Table 2). If IV iron is to be given to individuals with any of these risk factors, an extremely slow infusion rate and meticulous observation is recommended (see below).

Table 2.Factors increasing risk and/or severity of hypersensitivity reactions (HSRs) in patients given iron infusions.

Some of the factors, such as a previous adverse reaction to IV iron or other drugs, a fast iron infusion rate (see above), a history of severe atopy and systemic mastocytosis, appear to increase both the incidence and severity of HSRs.113

In contrast, pre-existing severe respiratory or cardiac disease, old age and the use of beta-blockers or ACE inhibitors, may worsen the outcome of an HSR if it occurs.17 In pregnancy, IV iron is contraindicated in the first trimester183 since there are no trials confirming its safety during this time: existing data suggest that its use should be confined to the second or third trimester of pregnancy if the benefit is judged to outweigh the risks for both mother and fetus.1918 While earlier anecdotal reports suggested that iron dextran may worsen disease activity in patients with rheumatoid arthritis and lupus erythematosus,20 more recent data indicate that IV iron could even have a beneficial effect on the underlying disease.21

Lastly, it has been suggested that anxiety on the part of healthcare professionals giving IV drugs increases the risk of HSRs.22

Management of intravenous iron infusions and hypersensitivity reactions

Figure 1.Algorithm outlining grading and management of acute hypersensitivity reactions to intravenous iron infusions. Details are given in the text.

Table 3.Information to be recorded in patients’ case records immediately after any IV iron-related hypersensitivity reaction (HSR) (adapted from Vogel29). This information helps to determine future treatment strategies.

Conclusions

There is a paucity of evidence about how to manage HSRs to iron infusions. The rarity of HSRs means that there will never be a formal clinical trial to assess optimal therapeutic measures. Areas in which further research is needed and could be productive, however, include clarification of the pathogenesis of HSRs, risk definition in individual patients and in different diseases, and the role of pre-medication and risk reduction protocols in high-risk patients.

Hypersensitivity reactions to IV iron are rare but potentially life-threatening. They are at least partly preventable by implementation of risk minimization measures. Their management requires prompt recognition and grading of severity, together with meticulous monitoring and immediate treatment. All staff involved in giving iron infusions need regular training to ensure that when these rare events develop they are dealt with calmly and expeditiously.

Footnotes

• Authorship and Disclosures Information on authorship, contributions, and financial & other disclosures was provided by the authors and is available with the online version of this article at www.haematologica.org.

• Received June 11, 2014.
• Accepted August 5, 2014.