Discussion
In order to reduce the likelihood of an HSR recurrence, a change of LOCM is currently recommended during subsequent re-exposure for patients who experienced a prior allergy-like immediate-onset HSR. Additionally, selecting the appropriate premedication may have further reduction effect.21,22 However, there is no failsafe way to determine which LOCM is the best alternative for these patients. This study suggests that performing skin tests combined with grouping LOCMs based on the presence of N-(2,3-dihydropoxypropyl) carbamoyl side-chains might help physicians choose safe alternatives that will not be reactive on subsequent systemic re-exposure. LOCM cross-reactivity was assessed based on skin test reactivity and the presence of a shared N-(2,3-dihydroxypropyl) carbamoyl side chain. Our study results demonstrate that switching from the culprit LOCM to an alternative without identical side chains helps to reduce the risk of recurrent HSR, especially in cases of severe index HSR. Based on our findings, we suggest using a clinical algorithm that involves skin testing and switching the LOCM based on its side chain as the approach for re-administration in patients who have experienced a previous immediate HSR (Figure 4).
Risk factors for the recurrence of LOCM-induced HSR include a previous history of contrast media hypersensitivity, the presence of an allergic disease, hyperthyroidism, and a family history of contrast media hypersensitivity.23 Although high doses of steroids in combination with antihistamines are widely used to prevent HSR in high-risk groups, this strategy was originally conceived to prevent infusion reactions related to high osmolar contrast media injections.5,24,25 Therefore, its efficacy has not been fully validated for the prevention of recurrent HSR to LOCM.21 It must be highlighted that despite premedication and changing the culprit LOCM, 14.3% (11/77) of the patients with previous HSR to LOCM still had recurrent BTR including anaphylaxis, although most cases were mild HSR, in our previous study.21 Therefore, premedication and change of culprit LOCM may not be sufficient enough to prevent the recurrence of immediate HSRs, particularly in those cases in which the patient experienced a severe index HSR.
A previous study demonstrated that using skin tests as a screening tool for primary prevention in the general population is of little value.15 Although skin tests do not elucidate a primary preventive effect on HSR, the question of whether or not they will aid in the diagnosis and therapeutic decision-making for patients who had a previous HSR still remains . In the present study, the rate of recurrent HSR to LOCM following a contrast media change based on a skin test was 11.9% in patients with a history of moderate and severe HSR. This is much lower than that reported in previous studies by the same group who had premedication and a change of LOCM that was independent of a skin test (14.3%).21 In a recent study based on skin tests conducted on 69 patients who had a previous HSR, it was found that a change in LOCM following the skin test was helpful only in cases in which the patient showed skin test positivity to the culprit LOCM and skin tests were not beneficial if there was no skin test reactivity to the culprit LOCMs.26In our study, the recurrence of HSR did not change based on whether the patient showed skin test positivity to the culprit LOCM (positive to culprit LOCM: 10.3% vs. negative to culprit LOCM: 12.0%). Moreover, changing the LOCM to one that does not have an identical side chain to the culprit was helpful for reducing the recurrence of HSR in patients who had severe index HSRs, regardless of culprit LOCM positivity.
Compared to previous work,19,26 the current study investigated the effects of changing LOCM based on its N-(2,3-dihydroxypropyl) carbamoyl side chain. Since, in our study, we conducted skin tests on 186 patients who had severe immediate HSRs and 75.5% of the initial culprit LOCMs were clearly validated, our study provides enough data to analyze the results according to alternative LOCMs. We found that the cross-reactivity rate of the skin tests varied based on the presence of the common side chain. Furthermore, the outcome of re-exposure to those alternate LOCMs that were selected based on their side chain was favorable, especially in those with severe index HSRs who were more likely to have an allergic reaction. Two other studies investigated the cross-reactivity between LOCMs and alternatives LOCMs that were suggested as safe based on presence of the N-(2,3-dihydroxypropyl) carbamoyl side chain.17,18However, in these studies, either the data representing the outcomes of re-exposure to LOCM was absent or there was no information on the culprit and/or re-exposed contrast media in cases that had immediate HSRs.19 Our study presents the results of re-exposure to LOCMs according to the presence or absence of the common side chain and we used a larger sample size. As a result, we are able to draw a more definitive conclusion.
The present study also showed that the use of non-reactive LOCMs in skin test and common side chain change were not fully preventive to recurrent HSR. Although all preventive measures (e.g., premedication and the change of LOCM based on side chain) were taken, 7.8% of patients still experienced a recurrence of HSR when re-exposed to LOCM. For these vulnerable patients, further safety protocols, such as an intravenous challenge or desensitization, should be considered. There is only a small number of research investigating the effect of intravenous challenges of LOCMs performed on high-risk patients before re-exposure. A recent study suggests that intravenous provocation tests with a skin test-negative LOCM is safe in both immediate and delayed HSR.27 The provocation protocol started at 0.05 mL and following this, patients received 0.5, 1.0, 5.0, 7.5, 10.0, and 25.0 mL every 30 minutes (total 49.05 mL). Further studies involving re-challenges based on the common side chain are needed to confirm the optimal alternative for immediate hypersensitivity to LOCMs.
This study has some limitations to be considered. First, when an alternative LOCM was selected based on whether or not it had an identical side chain to the culprit, the study did not employ enough differing culprit LOCM-alternative LOCM pairs. This might be affected by some unknown bias in the selection of LOCMs as the process of switching to an alternative LOCM was not ideally randomized. Second, since this study was conducted only on patients who had skin tests performed, it is difficult to clarify the role of the skin test, itself, on choosing a safe alternative. Nevertheless, this study has valuable and immediate clinical implications and provides practical information for selecting safe LOCM alternatives.
In conclusion, our study demonstrates that skin test-negative LOCMs still induce HSR. Furthermore, we demonstrated that selecting an LOCM based on the presence of a common side chain will give additional safety benefits upon re-exposure to LOCM in those patients who experienced severe index HSRs.