DISCUSION
The use of ICM in radiological examinations can be challenging when a patient has a history of HSR. Recommending an alternative ICM is difficult due to high CR among them32. Additionally, the efficacy of premedication has been debated, and there is increasing support for conducting an allergy study to identify a safe ICM for allergic patients 21,23. Additionally, the efficacy of premedication remains controversial, and there is growing support for considering a more effective approach, such as recommending the switch to an ICM, especially with a targeted selection based on an allergy work-up to identify a safe ICM for allergic patients21,23.
In this study, we employed a protocol to evaluate both the safety and efficacy of rapid DPT for identifying a safe alternative ICM for 130 patients with a previous HSR to ICM. This population exhibited diverse characteristics and varying severity of symptoms, enhancing the robustness of the results. Notably, there was a significant proportion of patients with anaphylaxis (13%), which supports the safety of rapid DPT even in high-risk populations. Furthermore, a higher percentage of patients with delayed HSR was included compared to previous studies2,13,23,27,43,44. Enrolling such patients is challenging because their symptoms often manifest outside of healthcare settings and are frequently unrecognized19,45–47.
In our population, the occurrence of HSR upon first contact with ICM was 53.8%, higher than previously reported19,26,30,48–51, which reported percentages around 30%. This phenomenon has been classically attributed to the nonspecific release of mast cell mediators. However, the fact that 33% of patients demonstrated positive ST upon first contact with ICM suggests the possibility of sensitization mechanisms. These may include sensitization to the carbamoyl side chain of ICM, potentially induced by prior contact with other molecules sharing this chain, such as the antibiotic cefuroxime, or that sensitization may have occurred through inadvertent exposure to ICM via drinking water52,53.
The results regarding the ICM involved in HSR can vary depending on the availability of ICM at each center, making direct comparisons among studies challenging. For example, some publications have reported a higher incidence of HSR, particularly immediate reactions, with iopromide and iomeprol compared to iohexol, ioversol, and iopamidol54–56. Conversely, other studies have identified iohexol57 or iodixanol58as the most frequently implicated ICM, and a meta-analysis found no significant differences between various hypoosmolar ICM59. In our population, the most used ICMs were iohexol and iodixanol. Then, it is not surprising that they were also responsible for the majority of HSR that occurred.
A significant association was observed both with the type of HSR (immediate or delayed) (p<0.001) and with the symptoms presented (p<0.05) in our population. Iodixanol was more closely associated with delayed cutaneous symptoms and was not related to any episodes of anaphylaxis, which is consistent with previously reported results60–63. In contrast, iohexol was associated with mild symptoms, with no significant difference between immediate and delayed reactions. Unknown ICM was significantly associated with more severe symptoms, which may be related to the fact that, with such a prolonged delay, the involved ICM was of the hyperosmolar type. The ICM was unknown for a large proportion of subjects (40.7%), similar to findings in previous studies (49, 64), with a significantly longer delay in initiating the study (median of 168 months). This delay may contribute to recall bias due to the difficulty in remembering the specific ICM involved
Both the percentage of ST and the NPV in our study were comparable to those reported in previous research26,36,47,64, underscoring the necessity of completing the allergy study with DPT. The main objective of the current study was to evaluate the safety and usefulness of rapid DPT in a large population, including patients with severe symptoms. The safety of the protocol was well-established as all positive DPT results were mild, even among patients with a history of anaphylaxis. In terms of usefulness, we were able to successfully recommend an alternative ICM to 94% of patients by the end of the study. Additionally, 50 of these patients required a new radiological examination, which could be performed using the recommended ICM without premedication, with good tolerance observed in all cases.
A previous retrospective study has reported clinical phenotyping of patients with HSR to ICM (65), based on patient characteristics, clinical history, and ST results. This study identified different risks for developing an ICM allergy, but it did not report on the risk associated with the administration of new ICM. In contrast, our study conducted a statistical analysis phenotyping patients with HSR to ICM into three distinct clusters, each associated with different risks for developing a DPT when administering an alternative ICM. According to our results, by grouping our patients into three clusters, the safety of DPT could be enhanced. An expected limitation of our approach could be that the proposed clusters may only be implemented in similar populations and where the ICM used for the allergy study overlaps with ours. Consequently, it may be complex to apply our results to populations with different attributes.
Higher risk of a positive ST has been associated with immediate HSR, anaphylactic shock, and a shorter delay in initiating the allergy evaluation10,64. However, the only identified risk factor for a positive ST was the involvement of iopromide. History of oncological pathology was found to increase the risk of developing a positive DPT.
In the mathematical model designed to predict the positivity of ST and DPT, the ROC curves showed an acceptable AUC, although the predictive statistical power was limited due to a low goodness-of-fit. This suggest that the model lacked the ability to generalize to other populations. We think that the regression analysis was limited by the number of patients included, and more specifically, by an insufficient number of patients with positive ST or DPT results. This limitation may be attributed to the selected variables lacking sufficient discriminatory power.
In any case, we consider that predictive mathematical models represent a valuable tool for improving the safety of high-risk tests, such as DPT. Further research with larger sample sizes, potentially through multicentre studies, is needed to achieve more statistically significant results.
Another limitation of our study was that the median age of the patients was higher compared to previous studies, which could influence the type of comorbidities, the radiological examinations performed, and the ICM used. Therefore, our results should be cautiously extrapolated to younger populations.
Additionally, the high percentage with unknown ICM involvement increased the likelihood that the implicated ICM was not included in the panel used for the allergy study. As a result, we could not be certain whether the DPT were performed with an alternative or the implicated ICM. However, this situation reflects daily practice in Allergy Units, where DPT are often conducted without knowing the specific suspected drug.
In conclusion, we successfully evaluated the tolerability of a protocol using rapid DPT in a prospective allergy study to identify alternative ICM for patients with immediate or delayed HSR to ICM, with varying degrees of severity, ranging from mild episodes to anaphylaxis. We also characterized our population into three clusters with different risk profiles for DPT outcomes. Finally, we have developed a predictive model for allergic test results. Larger studies are needed to confirm our findings and improve the predictive accuracy of the proposed regression model.
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