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Administration of IV\u2010iron is considered a safe procedure, but severe hypersensitivity reactions (HSRs) can occur at a very low frequency. Recently, new guidelines have been published by the European Medicines Agency with the intention of making IV\u2010iron therapy safer; however, the current protocols are still non\u2010specific, non\u2010evidence\u2010based empirical measures which neglect the fact that the majority of IV\u2010iron reactions are not IgE\u2010mediated anaphylactic reactions. The field would benefit from new specific and effective methods for the prevention and treatment of these HSRs, and the main goal of this review was to highlight a possible new approach based on the assumption that IV\u2010iron reactions represent complement activation\u2010related pseudo\u2010allergy (CARPA), at least in part. The review compares the features of IV\u2010iron reactions to those of immune and non\u2010immune HSRs caused by a variety of other infused drugs and thus make indirect inferences on IV\u2010iron reactions. The process of comparison highlights many unresolved issues in allergy research, such as the unsettled terminology, multiple redundant classifications and a lack of validated animal models and <jats:italic>lege artis<\/jats:italic> clinical studies. Facts and arguments are listed in support of the involvement of CARPA in IV\u2010iron reactions, and the review addresses the mechanism of low reactogenic administration protocols (LRPs) based on slow infusion. It is suggested that consideration of CARPA and the use of LRPs might lead to useful new additions to the management of high\u2010risk IV\u2010iron patients.<\/jats:p>","DOI":"10.1111\/bph.13268","type":"journal-article","created":{"date-parts":[[2015,8,12]],"date-time":"2015-08-12T09:19:01Z","timestamp":1439371141000},"page":"5025-5036","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":146,"title":["Hypersensitivity to intravenous iron: classification, terminology, mechanisms and management"],"prefix":"10.1111","volume":"172","author":[{"given":"J","family":"Szebeni","sequence":"first","affiliation":[{"name":"Nanomedicine Research and Education Center Semmelweis University  Budapest Hungary"},{"name":"Department of Nanobiotechnology and Regenerative Medicine Miskolc University  Miskolc Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Fishbane","sequence":"additional","affiliation":[{"name":"Hofstra North Shore\u2010LIJ School of Medicine  New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Hedenus","sequence":"additional","affiliation":[{"name":"Department for Internal Medicine Sundsvalls Hospital  Sundsvall Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Howaldt","sequence":"additional","affiliation":[{"name":"Research Institute for IBD HaFCED GmbH &amp; Co. 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