Anaphylaxis to radiographic contrast media.

PURPOSE OF REVIEW: Radiographic contrast media (RCM) are increasingly used in modern diagnostic medicine. Hypersensitivity reactions to nonionic RCM still occur in a significant number of exposed patients, because of the increased use of contrasted radiological investigations. Hypersensitivity reactions may be divided into immediate (<1  h of administration) and nonimmediate responses (>1  h). Immediate reactions present with anaphylaxis. RECENT FINDINGS: Although described less commonly, anaphylaxis to gadolinium contrast media have been increasingly reported in recent literature. In most patients, immunoglobulin (IgE)-mediated allergy cannot be demonstrated and the underlying mechanism remains unknown. In some patients, positive skin tests, specific IgE antibodies or specific cellular tests have been demonstrated. It may be speculated that more allergic reactions could be described, if more adequate methods were developed. Skin prick tests and intradermal tests with 1 : 10 diluted RCM are specific and confirm the diagnosis of RCM hypersensitivity. SUMMARY: There are not enough data yet about the value of skin tests for the selection of a 'well tolerated' RCM. Premedication of previous reactors is common among radiologists. However, breakthrough reactions are a concern and physicians should not rely on the efficacy of pharmacological premedication. Instead, radiologists should be prepared to treat severe RCM-induced allergic reactions in their practice.

Recognition of iodixanol by dendritic cells increases the cellular response in delayed allergic reactions to contrast media.

BACKGROUND: Delayed reactions to iodine contrast media (CM) account for 1-3% of patients with adverse reactions to iodine CM. The cellular and molecular mechanisms of these reactions remain poorly documented. Although most of these reactions are T cell mediated, the involvement of dendritic cells (DC) has not been investigated sufficiently. OBJECTIVE: To determine whether the T cell response to iodixanol requires DC as antigen-presenting cell and, more particularly, to evaluate the changes induced by iodixanol on DC maturation and in vitro production of cytokines after drug stimulation in patients with maculopapular exanthema. METHODS: Peripheral blood lymphocytes, immature monocyte-derived DC (imDC) and skin biopsies were obtained from patients with delayed reactions to iodixanol and tolerant subjects. We studied the consequences of the interaction between DC, lymphocytes and iodixanol by phenotype analysis, proliferation and cytokine production. RESULTS: A T-cell-mediated reaction was evidenced in patient biopsies, with a lymphocyte-rich, peri-vascular infiltrate. Iodixanol induced maturation of imDC from patients but not from controls, with expression of the co-stimulatory markers CD83, CD86 and CD40 and an increase in mean fluorescence intensity of CD80, CD86 and HLA-DR. In the absence of DC, positive cell proliferation to iodixanol was detected in only one patient while the addition of DC produced a positive test in five of the six patients. Similarly, the increase in cytokines (IFN-γ, IL-2, IL-6, IL-1b and TNF-α) was higher when imDC were introduced into the culture together with the culprit drug. CONCLUSION AND CLINICAL RELEVANCE: These results provide evidence for a DC-mediated mechanism in delayed allergic reactions to CM, influencing T cell proliferation and cytokine production. These new insights will be helpful for designing immunotherapeutic strategies and in vitro diagnostic tests of CM-delayed reactions.

Iosimenol, a new non-ionic dimeric contrast medium, does not induce immunoreactivity in the popliteal lymph node assay.

Animal studies in mice were conducted to determine the potential immunoreactivity of the new non-ionic dimeric contrast medium (CM) iosimenol using the PLNA and flow cytometric analyses. Comparative studies were performed with iodixanol. The known immune-reactive substance strepozotocin (STZ) and vehicle injections served as positive and negative controls, respectively. Our experiments did not show any immunological effect of iosimenol, concluding that the new CM iosimenol may be beneficial for use in high-risk patients.

Cross-reactivity patterns of T cells specific for iodinated contrast media.

BACKGROUND: Approximately 3% of patients exposed to iodinated contrast media develop delayed hypersensitivity reactions. OBJECTIVE: We wanted to better understand the molecular basis of contrast media cross-reactivity. METHODS: Cross-reactivity was assessed by skin testing and measurement of T-cell activation (CD69 upregulation) and proliferation ((3)H-thymidine uptake, 5,6-carboxyfluorescein diacetate succinimidyl ester staining) of PBMCs, T-cell lines, and T-cell clones of 2 patients with delayed hypersensitivity reactions to iohexol and iomeprol, respectively. Thirteen different contrast media and potassium iodide were compared. RESULTS: Skin testing and analyses of PBMCs, T-cell lines, and clones showed broad cross-reactivity in both patients. Broad as well as more restricted cross-reactivity patterns were found in iohexol-specific and iomeprol-specific CD4(+) T-cell clones, whereas 1 iomeprol-specific CD8(+) T-cell clone showed no cross-reactivity at all. The reactivity to equimolar concentrations of iohexol and its dimer iodixanol was very similar, suggesting that the dimer was not more stimulatory than its monomer. Consistently low reactivity to iobitridol was found in both patients, but never to iodide. A frequency analysis of contrast medium-specific peripheral T cells gave values between 0.6 % (iomeprol) and 0.05 % (iobitridol). CONCLUSION: Clinically observed cross-reactivity between different contrast media is a result of the presence of contrast media-specific T cells, some of which show a broad cross-reactivity pattern. Iodide ions, known to be present at low concentration in contrast media solutions, do not seem to be the causative moiety. CLINICAL IMPLICATIONS: Detailed in vitro analysis might help identify noncross-reactive contrast media.

Iosimenol, a low-viscosity nonionic dimer: preclinical physicochemistry, pharmacology, and pharmacokinetics.

RATIONALE AND OBJECTIVES: Newer radiologic techniques require fast bolus injections and thus low-viscosity, high-concentration, well-tolerated contrast media (CM), especially in vulnerable patients. To this end, we designed and developed iosimenol, a novel isotonic nonionic dimer, and have conducted tests to enable its clinical evaluation. METHODS: Standard physicochemical methods were used. Effects on erythrocyte morphology and coagulation were investigated in human and rat blood. Neural tolerance was assessed by behavioral tests in rats after intracisternal injection. Immunosensitizing potential was evaluated by the skin sensitization test in guinea pigs and by the popliteal lymph node assay in rats. Pharmacokinetics and biotransformation were investigated in rats and dogs. RESULTS: Iosimenol is extremely hydrophilic, it is less viscous than any other isotonic CM, has little effect on erythrocytes and blood coagulation, and has good neural tolerance. No immunosensitizing effect was found in validated animal models. Pharmacokinetics are identical with other angio- and urographic CM. CONCLUSIONS: Iosimenol is the only CM which, although isotonic, affords, unlike current nonionic dimers, at the same iodine concentration the low viscosity of monomeric, nonionic agents, which are all hypertonic. Iosimenol's pharmacologic characteristics closely resemble those of iotrolan and iodixanol.

The multipotential pseudoantigenicity of X-ray contrast media. Pseudoantigen excess may downregulate the release of hypotensive mediators.

BACKGROUND: X-ray contrast media (CM) toxicity resembles IgE-antigen-based anaphylaxis, and CM-related histamine release has been demonstrated in vitro and in vivo. While nobody has succeeded in producing antibodies against injections of neat CM, the ability of CM to compete with a series of antigens against their respective antibodies has recently been demonstrated. However, there is a paradox, since the CM with the strongest antibody binding are nevertheless the least likely to provoke antigen-antibody-related mast cell/basophil release. METHODS: Two strains of rats were subjected to (a) passive cutaneous anaphylaxis (PCA) studies in the presence of various concentrations of CM, (b) blood pressure (BP) tracings following bolus administrations of various prototypical CM and (c) BP tracings in ovalbumin (OVA)-sensitized rats, challenged with OVA plus CM, vs. OVA plus CM-equivalent saline. RESULTS: In the PCA studies, and the OVA challenge studies, the CM appear to act in an antigen excess mode, limiting the potential of the OVA to elicit anaphylactic changes, as demonstrated by permeability studies or by BP levels. The bolus CM studies demonstrate that the more potent CM 'antigens' actually produce an increase in BP and the less potent CM 'antigens', a drop in BP. These changes can be related to the CM acting in an 'antigen' excess mode vs. an 'antigen' equivalent mode. CONCLUSIONS: The CM have the potential to act in an 'antigen' excess or 'antigen'-equivalent mode. The potential to express an 'antigen'-excess mode in vivo, may be unique to CM because of the high concentrations injected.

[Antigenicity study of iodixanol, a new non-ionic contrast medium].

Antigenic potential of iodixanol, a new non-ionic contrast agent, was evaluated by systemic anaphylaxis (SA) test and homologous passive cutaneous anaphylaxis (Homo-PCA) test using guinea pigs and IgE mediated heterologous PCA (Hetero-PCA) test using rats passively sensitized with mouse sera. SA test was conducted in guinea pigs sensitized with iodixanol at dose levels of 32 or 320 mgI/kg emulsified with Freund's complete adjuvant, followed by challenge with iodixanol (320 mgI/kg). Four- or 24-hr Homo-PCA test was performed with sera from the sensitized animals. Neither positive SA nor Homo-PCA reaction was observed. Hetero-PCA test was performed with the sera from the mice which were sensitized with iodixanol (32 or 320 mgI/kg) with aluminum hydroxide gel. No positive Hetero-PCA reaction was detected in the sera, followed by challenge with iodixanol (320 mgI/kg). Thus, it is concluded that iodixanol possesses no antigenic potential under the present experimental conditions.

The lack of immunogenicity of iotrolan.

RATIONALE AND OBJECTIVES: To test whether it would be possible to raise antibodies against iotrolan in rabbits and, if possible, to develop a radioimmunoassay for iotrolan. METHODS: A "half-molecular" analogue of iotrolan was synthesized, which contained a carboxylic group. This moiety was coupled via a link to bovine serum albumin. The resultant hapten was suspended in Freund's complete adjuvant and used to immunize rabbits by two subcutaneous and two intramuscular injections followed by monthly booster injections. After bleeding of the animals, the antibodies formed were tested. RESULTS: The rabbits successfully developed antibodies against the hapten. These antibodies were tested for cross-reactivity with iotrolan, the iotrolan half-molecule, and the hapten. Minimal cross-reactivity (below 0.5%) was found for iotrolan and the half-molecule. Only the hapten was found to bind to the antibody. CONCLUSIONS: In the current test setting using a half-molecular analogue, it could be shown that iotrolan is probably not immunogenic. The formation of an antibody against the half-molecule coupled to bovine serum albumin can be explained only by immunogenicity of that part of the molecule, which constitutes the bridge or link to the albumin. This part of the hapten, however, is not representative of iotrolan itself.

Preclinical pharmacokinetics and general toxicology of iodixanol.

To document the safety of iodixanol and to assess its pharmacokinetic properties, extensive tests have been performed. Iodixanol was rapidly excreted, mainly via the kidneys, with a plasma half-life in rats and monkeys of 25 and 76 mins, respectively. The pharmacokinetic data were consistent with an extracelleular distribution of iodixanol. During the 24 hours post-dosing, the urinary excretion was from 72 to 100% in rats, and 78% in monkeys. Biliary excretion was 1.5% during the first 4 hours in rats. Fecal excretion was about 7% in rats and 0.8% in monkeys over the first 24 hours after injection. Approximately 0.5 and 1% of the dose was found in the kidneys of rats and monkeys, respectively, 24 hours after dosing. Acute toxicity of iodixanol in rats was low, with an LD(50) greater than 21 g I/kg. In mice the LD(50) was 21 g I/kg and the approximated median lethal dose (ADL(50)) was found to range from 15 to 21 g I/kg. A single dose of 1 and 3 g I/kg was well tolerated in monkeys. As for the other roentgen contrast media, a reversible, dose-related, vacuolation of the proximal tubules in the kidneys was seen in the acute and subacute studies in rats and monkeys. No relationship was seen between the vacuolation and kidney function. Local tolerance studies demonstrated a low irritation potential for iodixanol when injected by a variety of intravascular and extravascular routes. The reproductive capacity of male and female rats was unaffected by iodixanol when administered daily at doses up to 2 g I/kg/day. No teratogenic potential in rats and rabbits of iodixanol was observed. Further, no toxic effects on pups were seen when rats were dosed during the lactation period. Each of 4 standard genotoxicity tests was negative. No antigenic potential of iodixanol was observed when assessed by the passive cutaneous anaphylaxis test and the active systemic anaphylaxis test in guinea pigs. The intravascular tolerability of iodixanol is high, and therefore, iodixanol should be considered as a safe roentgen contrast medium for intravascular use.

Development of polyclonal and monoclonal antibodies to iodinated contrast media.

Two independent systems were developed to produce antibodies to diatrizoate. In the rabbit model polyclonal antibodies were produced that showed cross-reactivity to certain other contrast agents, analogues and serum proteins. In the mouse model monoclonal antibodies were produced that reacted only with diatrizoate, metrizamide, and ovalbumin. These studies demonstrated the potential antigenicity of contrast medium.