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.