Allergic Signature in Delayed Cross-Hypersensitivity to all Iodinated Contrast Media

Abstract

Delayed hypersensitivity reactions to iodinated contrast media (ICM) occur in 0.5%–23% of exposed patients [1]. These reactions typically present as mild maculopapular exanthema and, in rare cases, may manifest as life-threatening hypersensitivity, such as toxic epidermal necrolysis or DRESS (drug reactions with eosinophilia and systemic symptoms) syndrome. Allergy tests are routinely performed to confirm the allergy and identify safe alternatives within ICM. In certain specific cases, in vitro tests can be helpful. Here, we present the case of a patient with delayed cross-reactivity to all seven available ICM, thoroughly investigated using skin tests, molecular analysis of positive skin tests, and in vitro tests.

A 77-year-old male patient with a history of diabetes, high blood pressure, and prostate cancer and no history of skin conditions underwent coronary angiography with iomeprol. He was previously exposed to ICM (only iomeprol) 3 and 5 years ago. Three days after the infusion, he developed extensive maculopapular exanthema affecting 70% of his body surface (Figure 1A,B). He presented with a fever of 38°C but showed no clinical or biological signs of severity aside from mild liver cytolysis (ALT were at 1.5 times the upper level of normal). There was no hypereosinophilia. Treatment with very potent topical corticosteroids (clobetasol propionate) led to complete resolution within 20 days. The allergy assessment conducted 3 months later included a skin patch test (250 mg/mL) and intradermal testing at 1/10th concentration for iomeprol, both positive at 72 h (++ for patch test). We completed intradermal testing for the following ICM: iodixanol, iobitridol, iopamidol, iohexol, ioversol, and iopromide. All intradermal tests were positive at 72 h with variability in reactivity (Figure 1C,D).

Skin biopsies (3 mm) were performed from positive intradermal reactions to iomeprol (the causative molecule) and iopromide (the less infiltrated positive test) as well as normal skin (as control). Skin samples were analyzed by RT-qPCR to assess the expression of 12 biomarkers distinguishing between allergy and irritation [2] (listed in Figure 2A) as previously described. The analysis revealed a characteristic type IV hypersensitivity signature marked by increased expression of CD8, Granulysin, Interferon gamma, CXCL10 as well as Pleckstrin, HLA-DRA, and GPR183 in positive skin tests compared to healthy skin, supporting cross-delayed reactivity to iopromide and potentially to all ICM tested (Figure 2A). To investigate whether this cross-hypersensitivity could be attributed to the common carbamoyl side chain or a shared excipient (trometamol) present in all ICM, a lymphocyte transformation test (LTT) was performed using various concentrations of three positive ICM including the culprit (iomeprol, iodixanol, iopromide), cefuroxime (which includes a carbamoyloxymethyl chain that is not identical but close to the N-(2,3-dihydroxypropyl)carbamoyl chain found in ICM), trometamol citrate, fosfomycin (containing trometamol as an excipient) and amoxicillin as a control (Figure 2B). The LTT was positive only for the three tested ICM. The patient stimulation/proliferation index increased in a dose-dependent manner and was higher for iomeprol, with a significant proliferation starting at 100 μg/mL.

Based on skin tests alone, we might have hypothesized that both patch tests and intra-dermal skin tests were false positives due to the irritative nature of ICMs. However, the characteristic allergic transcriptomic signature in positive skin tests, combined with the in vitro ICM-specific T cell proliferation, suggests otherwise. Cross-hypersensitivity among ICMs has been suspected to be linked to a common carbamoyl chemical group or a shared excipient (trometamol) [3]. However, the absence of in vitro T cell proliferation following exposure to cefuroxime, trometamol citrate, and fosfomycin argues against this hypothesis, leaving the underlying mechanism for cross-reactivity unexplained. Extended cross-reactivity in delayed ICM allergy, involving monomeric/dimeric as well as ionic/non-ionic ICMs, is rare but particularly challenging for patients requiring ICMs. A case series of 13 ICM-induced DRESS syndrome and 19 acute generalized exanthematous pustulosis (AGEP) reported sensitization to more than one ICM in 77% of patients [4]. While definitive evidence supporting the efficacy of premedication is lacking, some authors have reported that premedication with systemic corticosteroids or ciclosporin [5] may reduce the frequency and severity of reactions in allergic patients re-exposed to ICM [6]. To our knowledge, this is the first thoroughly documented case of delayed hypersensitivity to iomeprol associated with cross-reactivity to the six other ICMs labeled in France.

Concept/Design: F. Hacard, A. Nosbaum, F. Bérard, J.-F. Nicolas, M. Tauber. Data collection or processing: A. Mosnier, A. Facile, N. Poletto, M. Vocanson, M.-A. Lefevre, A. Guironnet-Paquet, M. Tauber. Analysis or Interpretation: A. Mosnier, A. Facile, N. Poletto, M. Vocanson, M.-A. Lefevre, M. Tauber. Literature search: D. Do, L. Bertolotti, M.-A. Lefevre, M. Tauber. Writing: D. Do, L. Bertolotti, M.-A. Lefevre, M. Tauber.

All authors (D. Do, L. Bertolotti, A. Mosnier, A. Facile, V. Bourdenet, N. Poletto, F. Hacard, A. Nosbaum, F. Bérard, J.-F. Nicolas, M. Vocanson, M.-A. Lefevre, M. Tauber) reviewed the results and approved the final version of the manuscript.

Consent was obtained from the participant for the pictures, allergy assessments, and for the article.

The authors declare no conflicts of interest.