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Pathophysiology of contrast media anaphylactoid reactions: new perspectives on an old problem

Since its first use in 1929 (1), the administration of iodinated-organic radiocontrast media (RCM) has become an increasingly indispensable tool in diagnostic radiology. The number of radiologic examinations requiring RCM exceeds 15 million per year in the USA alone (2). Mild adverse reactions, mostly attributable to vasodilatiotr, occur in up to 3% of intravenous RCM infusions (3), but it is the idiosyncratic anphylactoid reactions which may be fatal, and which cause the greatest clinical concern. Acute anaphylactoid reactions occur in 12% of intravenous studies with the older or "firstgeneration" RCM materials (4), and fatality rates ranging from O.(X)2% to 0.009% have been reported (5). Risk factors for fatal outcome include atopy, prior sensitivity, and intravenous as opposed to intra-arterial injection (4). With the advent of "second-generation" RCM in the past two decades (4), low-osmolar or isoosmolar compounds have significantly decreased the occurrence of adverse reactions by about threefold compared with the previous hyperosmolar agents (6, 7). Severe anaphylactoid reactions stiil oecur with the iso-osmolar second-generation compounds. Data collected by the US Food and Drug Administration between 1990 and 1994 (2) indicated that, while the use of lower osmolar RCM significantly reduced the incidence of total reactions, the incidences of severe and fatal reactions are similar to those for hyperosmolar RCM. The same observations were seen in a similar study in the UK (reported in [2]). It is important to note, however, that prior to 1990 the incidence of both severe and fatal reactions was higher, suggesting that in 1990-4 high-risk patients were more likely to have received low-osmolar agents (2). This substantial reduction of toxicity, including anaphylactoid and fatal reactions, since the introduction of low-osmolar RCM suggests that the hypertonicity of the first-generation RCM was itself responsible for much of the morbidity and at least some of the deaths. Despite intense research efforts, the pathogenesis of serious, sometimes life-threatening anaphylactoid reactions to RCM has not yet been fully elucidated. Substantial data in vitro indicate that activation of peripheral blood basophils and tissue mast cells by hypertonic RCM plays a crucial role in some reactions (4). Other inflammatory pathways such as the complement, coagulation, and fibrinolytic cascades may be activated during RCM infusions, but the correlation with clinical reactivity has generally been poor (3, 4). Clearly, other mechanisms appear to be at work in some cases. Early on, the possibility that these immediate, life-threatening anaphylactoid reactions were "allergic" or immunologic in origin was postulated. The identification of atopy and seafood allergy as associated risk factors (8^10) was interpreted as supportive of this hypothesis, although a common "releasability" factor in all three conditions is an equally plausible explanation (11). For the first generation of RCM, there are experimental and theoretic considerations which argue against the immunologic hypothesis. First, there are the clinical features of RCM reactions: they often occur on first administration, are relatively doseindependent, and do not always recur in previous reactors (3). Second, the original RCM consisted of single, iodinated benzene rings, many of which lack the chemical reactive groups required to haptenate micromolecules and render them immunogenic. Efforts to raise antisera to RCM generally have confirmed its very weak immunogenicity (12). However, the lack of immunogenicity has been recently reported also for a nonionic dimer, iotrolan (13). And third, there is a large body of in vitro data indicating that RCM can activate human basophils and mast cells by an igEindependent mechanism which is not always predictable by the osmolarity of the compounds (11, 14; for review, see 4).