Skin Test Results and Cross-Reactivity Patterns in IgE- and T-Cell-Mediated Allergy

Skin Test Results and Cross-Reactivity Patterns in IgE- and T-Cell-Mediated Allergy to Gadolinium-Based Contrast Agents

Copyright © 2021 The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease

Hans-Peter Grueber,1Arthur Helbling,2 and Lukas Joerg2

1Radiology Division, Spital Region Oberaargau, Spital Langenthal, Langenthal, Switzerland.

2Division of Allergology and Clinical Immunology, Department of Pneumology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.


Allergies to gadolinium-based contrast agents (GBCAs) are rare and manifest usually as an immediate drug hypersensitivity reaction (DHR), compatible with an immunoglobulin E (IgE)-mediated mechanism. Although the molecular structures of GBCA show some similarities and are either linear or macrocyclic, the frequency and pattern of cross-reactivity remain unclear. However, cross-reactivity has been described. The aim of this investigation was to assess cross-reactivity in patients with GBCA allergy based on skin tests and exposure. We retrospectively evaluated a total of 28 cases with a proven allergy to a GBCA, including 11 from the database of the allergy division of the Inselspital, Bern and 17 published cases from the literature, retrieved with a PubMed-MEDLINE search. The majority of cases were immediate DHR, with 8/11 cases from the database (72.7%) and 16/17 published cases (94.1%). In both groups macrocyclic GBCA were most often identified as causative drugs. A cross-reactivity based on skin test results was found in 2 out of 11 database cases (18.2%) and in 6 out of 17 literature cases (35.3%). Cross-reactivity occurred within macrocyclic GBCA in 1/11 database cases and 3/17 literature cases, and included both macrocyclic and linear GBCA in 1/11 and 4/17 subjects. There was no cross sensitization among linear GBCA. Skin test-negative GBCA were well tolerated, even in cases with sensitization to linear and macrocyclic GBCA. Overall, cross-reactivity in GBCA allergy is rare (approximately 29%), and may occur among macrocyclic GBCA or in between macrocyclic and linear GBCA. IgE to linear GBCA seems to be rarely cross-reactive. Skin test is helpful in identifying safe alternatives, as no reaction to skin test-negative GBCA was observed.


Paramagnetic contrast agents containing gadolinium are used worldwide and daily in magnetic resonance imaging. Despite their frequent use, severe adverse events are rare and gadolinium-based contrast agents (GBCAs) are considered to have a good safety profile.1 As GBCAs are used at high intravenous concentrations, hypersensitivity reactions can nevertheless occur.2 It is thought that such reactions are mostly based on a non-immunological mechanism with activation of mast cells, which may result in “anaphylactoid” reactions.3 The majority of these hypersensitivity reactions are immediate. Based on clinical observations as well as results of positive skin and in vitro tests,2 an immunoglobulin E (IgE)-mediated mechanism seems likely in some cases.2 Delayed drug hypersensitivity reaction (DHR) may also occur, but appear to be very rare.4

In patients with GBCA allergy, requiring further magnetic resonance imaging, a question arises which GBCA can be safely used. Based on the structure of the gadolinium-carrying chelates, GBCAs are divided into linear or macrocyclic (ring structure) compounds (Figure). Because allergic reactions to GBCAs are rare, knowledge on possible cross-reactivity among GBCAs is scarce. Some case reports suggest cross-reactivity among GBCAs.5, 6, 7, 8 Currently, it is not known whether cross-reactions only occur within macrocyclic GBCAs alone, linear GBCAs alone, or both. In the study by Chiriac et al.9 a systematic approach not focusing on cross-reactivity was pursued. It has been shown that the intradermal test has a good negative predictive value. This finding implies that, in subjects with suspected GBCA allergy and negative intradermal test to GBCAs, these agents can be administered again.9 However, only 5 out of 27 patients had a positive skin test result in this study: the underlying mechanism of most reactions remained unclear and might have been non-immunological.

The aim of the current study was to evaluate subjects with a skin test documented IgE- or T-cell-mediated allergy to GBCAs with regard to cross-reactivity to other GBCAs.

FIGURE: Molecular structure of macrocyclic and linear GBCAs and cross-reactivity pattern. Possible cross-reactivities between GBCA are indicated with arrows, directed from the given to the cross-reactive compound. Cross-reactions occur mostly within macrocyclic or in between macrocyclic and linear GBCAs.

GBCA, gadolinium-based contrast agent; Gd-DOTA, gadoterate meglumine; Gd-HP-DO3A, gadoteridol; Gd-BT-DO3A, gadobutrol; Gd-BOPTA, gadobenate; Gd-DTPA, dimeglumine gadopentetate; Gd-EOB-DTPA, gadoxetate disodium; Gd-DTPA-BMA, gadodiamide.