- Email: [email protected]
Adverse reactions during procedures
Journal Pre-proof Adverse reactions during procedures: hypersensitivity to contrast agents and dyes Christine Schönmann, MD, Knut Brockow, MD PII:
S1081-1206(19)31452-8
DOI:
https://doi.org/10.1016/j.anai.2019.11.022
Reference:
ANAI 3082
To appear in:
Annals of Allergy, Asthma and Immunology
Received Date: 16 September 2019 Revised Date:
6 November 2019
Accepted Date: 18 November 2019
Please cite this article as: Schönmann C, Brockow K, Adverse reactions during procedures: hypersensitivity to contrast agents and dyes, Annals of Allergy, Asthma and Immunology (2019), doi: https://doi.org/10.1016/j.anai.2019.11.022. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
1
Adverse reactions during procedures: hypersensitivity to contrast agents and dyes Christine Schönmann, MD, Knut Brockow, MD Department of Dermatology and Allergy Biederstein, School of Medicine, Technical University of Munich, Munich, Germany Corresponding author for proofs and reprints: Knut Brockow, MD Department of Dermatology and Allergy Biederstein Technical University of Munich, Biedersteiner Strasse 29, 80802 Munich, Germany (+49) 89-4140-3182 (+49) 89-4140-3171 (fax) [email protected] (e-mail) No conflict of interest, no funding. Word count: 3749 Keywords: Hypersensitivity, Iodinated contrast media, Gadolinium-based contrast media, Blue dyes, Fluorescein, Diagnosis, Skin test, Management Abbreviations: AGEP Acute generalized exanthematous pustulosis BAT Basophile activation test CM Contrast Media CT Computed tomography DPT Drug provocation test DRESS Drug reaction with eosinophilia and systemic symptoms ELISA Enzyme-linked immunosorbent assay GBCM Gadolinium-based contrast media HLA Human leukocyte antigen ICM Iodinated contrast media IDT Intradermal test IgE Immunoglobulin E IHR Immediate-type hypersensitivity reaction LTT Lymphocyte transformation test MPE Maculopapular exanthem MRI Magnet resonance imaging NIHR Non-immediate hypersensitivity reaction NPV Negative predictive value NSF Nephrogenic systemic fibrosis SDRIFE Symmetric drug-related intertriginous and flexural exanthema SJS Stevens-Johnson-syndrome SPT Skin prick test TEN Toxic epidermal necrolysis Figures and Tables Fig. 1. Clinical pictures of a patient with non-immediate contrast media allergy Fig. 2. Algorithm for skin testing of patients with previous hypersensitivity reactions to iodinated contrast media or gadolinium-based contrast media and skin test result-deduced management of readministration Fig. 3. Molecular structure of blue dyes Fig. 4. Algorithm for management of patients with a history of adverse reactions to iodinated contrast media or gadolinium-based contrast media needing contrasted imaging Tab. 1. Skin test concentrations for contrast agents and dyes
19-09-0461R1
Objective This review provides an overview of the literature on hypersensitivity reactions during procedures to commonly used contrast agents and dyes. A synthesis of current knowledge on clinical symptoms, epidemiology and risk factors, pathomechanism and management of hypersensitivity reactions to these substances is presented. Data Sources A literature search was conducted through Medline. Included were peer-reviewed articles written in English between 2000 and 2019. Study Selections Relevant clinical studies, experimental studies and review articles have been selected. Additionally, case reports have been included, if they carried significant information about rare clinical forms of hypersensitivity reactions, disease mechanisms or therapy. Results An allergological workup is only indicated for patients with a history of immediate (IHR) and non-immediate hypersensitivity reactions (NIHR) but not for toxic or unrelated adverse events. Skin tests +/- experimental cellular laboratory tests in patients with previous reactions can provide evidence for an allergic mechanism. Positive skin tests indicating allergy are more common in severe reactions. If the adverse event was allergic, skin testing of alternatives is helpful for the selection of other contrast agents for future procedures. Premedication alone may be insufficient in these cases and breakthrough reactions occur. For non-allergic reactions, change of contrast agent and premedication is often but not always sufficient to suppress reactions Conclusion Patients with previous NIHR or IHR, especially moderate and severe IHR, needing potential re-administration of contrast agents should be skin tested in order to identify an allergic mechanism as well as alternative agents to be used for future procedures.
1
1
Introduction
2
Contrast media including iodinated contrast media (ICM) for X-ray and CT-scans, gadolinium-based
3
contrast media (GBCM) for MRI-scans and dyes such as patent blue, isoflurane blue, methylene blue
4
and fluorescein for sentinel lymph node detection in breast cancer or melanoma, fluorescence
5
angiography in ophthalmology or evaluation of ureters and bladder during surgery are increasingly
6
used in modern medicine for diagnosis and disease monitoring. More than 70 million doses of ICM
7
and an estimated 50 million doses of GBCM are administered worldwide per year.1,2 There is a risk
8
for adverse reactions to any kind of contrast agents, which in rare cases can be fatal. Consequently,
9
knowledge about treatment and diagnostic workup of adverse events after administration of contrast
10
media is highly relevant.
11
Three different categories of adverse reactions must be discriminated: 1) hypersensitivity reactions
12
(allergic and non-allergic), 2) toxic reactions and 3) events unrelated to exposure to contrast agent.3
13
This review addresses only hypersensitivity reactions.
14
Hypersensitivity reactions can be divided into immediate hypersensitivity reactions (IHR) and non-
15
immediate hypersensitivity reactions (NIHR).4 Symptom onset in IHRs begins immediately up to 1
16
hour after drug administration and present with symptoms of anaphylaxis. NIHRs start more than 1
17
hour up to 10 days after administration of the culprit agent and present with exanthems.4 The most
18
common form is the maculopapular exanthema (ME), but severe forms of NIHR to contrast agents
19
like drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens Johnson syndrome
20
(SJS), toxic epidermal necrolysis (TEN) or acute generalized exanthematous pustulosis (AGEP) have
21
been reported.5
22
Clinical findings in immediate hypersensitivity reactions (IHR)
23
Clinical findings in IHR for all reviewed contrast agents and dyes can range from mild skin symptoms
24
such as urticaria to severe reactions like anaphylactic shock which could be fatal.6 Sometimes it can
25
be difficult to distinguish vasovagal or toxicity-related reactions from anaphylaxis. Toxicity-related
26
reactions often present with pallor, weakness, nausea and vomiting as well as bradycardia, while skin
2
27
reactions (urticarial, pruritus, angioedema), tachycardia, bronchospasm and wheezing are strongly
28
associated with anaphylaxis.2 Clement et al. 7 reported that cardiovascular signs or involvement of
29
three or four different organs are significantly associated with allergic IHR.
30
About 70% of IHRs to ICM present with urticaria/angioedema and pruritus and start within the first 5
31
minutes after administration and nearly all (96%) of severe reactions occur within 20 minutes.8
32
Most commonly seen symptoms of IHRs to GBCM are urticaria (50-90%) and nausea.4 Anaphylaxis
33
is rare and the mortality rate is estimated by the FDA at 8 in 100.000 doses GBCM administered.9
34
Physiologic toxic effects due to hypertonic GBCM (including injection site discomfort,
35
thrombophlebitis, myalgia/arthralgia, paresthesia, headache, dizziness and nausea) occur more
36
frequently than hypersensitivity reactions.10
37
When patent blue or isosulfan blue is the elicitor of IHR, urticaria may occur as pathognomonic blue-
38
green hives.11 Extravasation of dye, which also causes blue-green skin discoloration but no other
39
symptoms such as wheals must be considered as a differential diagnosis to IHR.12 Biphasic reactions
40
have been reported in IHR to patent blue.11 Physicians should be aware of this pattern and carefully
41
monitor the patient after initial treatment for occurrence of a second reaction.
42
Clinical findings in non-immediate hypersensitivity reactions (NIHR)
43
While NIHRs caused by GBCM and dyes are anecdotal, ICM is a common elicitor of NIHR. Typical
44
presentation of an NIHR to ICM is an exanthema, particularly a maculopapular exanthema of mild or
45
moderate severity.13 Figure 1 shows an exemplary picture of maculopapular exanthema in a patient
46
who underwent imaging with iomeprol. Other entities including erythema exsudativum multiforme,
47
bullous fixed drug eruption, pompholyx, drug related eosinophilia with systemic symptoms (DRESS),
48
symmetric drug-related intertriginous and flexural exanthema (SDRIFE) and acute generalized
49
exanthematous pustulosis (AGEP) after intravenous and also after intra-articular ICM-administration
50
have been reported but are exceptional.14–17. Fatal cases of NIHR have been described, especially in
51
patients with vasculitis, Stevens-Johnson syndrome or toxic epidermal necrolysis.18 Severe NIHRs
52
often occur in a complex intensive care unit setting involving more than one potential elicitor of
3
53
NIHR (e.g. antibiotics and contrast CT as search of focus for sepsis). Thus numbers on ICM as
54
elicitor of severe NIHR may be inaccurate.19
55
NIHRs to GBCM are extremely rare, but AGEP has been reported.20 An important non-allergic late
56
reaction to GBCM especially in patients with impaired kidney function is nephrogenic systemic
57
fibrosis (NSF). NSF causes fibrosis mostly of the skin and subcutaneous tissues. However, internal
58
organs, skeletal muscles and joints can be involved, and fatalities have been reported.10 Thus,
59
radiologists must take special care of patients with low glomerulus filtration rate when needing
60
GBCM.
61
NIHRs to dyes have hardly ever been observed and their causality remains unproven.
62
Epidemiology and risk factors
63
Reported data on incidence of IHR and NIHR to contrast media and dyes varies widely between
64
different studies because of different definitions of IHR and NIHR, the difficulty of distinguishing
65
toxicity related from hypersensitivity reactions, different premedication regimes, and generally low
66
incidence-rates requiring large sample sizes to determine incidence accurately.
67
Mild IHR to modern non-ionic ICM may occur in 0.7-3.0% of IV administrations, severe reactions
68
only in 0.02-0.04%.21 Ionic monomeric ICM were approximately 4-fold more likely to elicit adverse
69
drug reactions and therefore have been withdrawn from the market in most countries.4,21 An overview
70
on the different types and names of ICM is given in Figure 2.
71
Estimates of the frequency of NIHR to ICM range from 0.5 to 23% and no significant differences
72
between high- and low osmolar ICM have been found.22 Some reports state a higher incidence of
73
exanthems for dimeric isoosmolar ICM.23
74
Several different risk factors for IHRs and NIHRs to ICM are being discussed. The most important
75
and commonly agreed on risk factor for hypersensitivity reactions is a previous reaction to ICM as
76
risk factor for reoccurrence of the reaction on re-exposure. A previous IHR does not increase the risk
77
for an NIHR and vice versa.24
4
78
IHRs have been reported in approximately 0.04%-0.06% of GBCM administrations in children and
79
0.07% in adults.25–27 Most cases (74%) are mild reactions, 19% moderate reactions and 7% severe
80
ones. Reactions were considered as mild when they were self-limiting and required no treatment
81
(except for antihistamines for cutaneous reaction), moderate when they required immediate medical
82
treatment going beyond antihistamines and severe if the event was life-threatening and typically
83
requiring hospitalization.26 Ionic, macrocyclic GBCM and those with higher protein binding elicit
84
more IHR than linear, non-ionic ones.28 Macrocyclic chelates may elicit more IHRs but are more
85
stable and thus less likely to cause NSF.29
86 87
Risk factors for reactions to GBCM are the same as for ICM. Jung at al. estimated a reoccurrence rate
88
of 30% in patients with previous IHRs27, other authors reported rates of 21-60%.2
89
For all kinds of dyes, the overall incidence of anaphylaxis differs widely between different reports. It
90
most probably lies in the range of 0%-1,1% for isosulfan blue, 0,7-2,7% for patent blue and 0,5%-
91
1,0% for flourescein.11,30,31 Fatal cases have been reported.32
92
Pathophysiology of immediate hypersensitivity reactions
93
The pathophysiology of IHR to contrast agents and dyes is not fully understood yet. Histamine or
94
tryptase release has been demonstrated in many cases, but this just indicates a mechanism of mast cell
95
(or basophil) activation and not necessarily an immunoglobulin E (IgE)-mediated reaction.7 However,
96
in some patients with IHR to ICM, GBCM, PB and IB an “allergic” mechanism is supported by
97
positive skin tests, basophil activation as demonstrated by positive basophil activation test 29,30,33,34.
98
For patent blue presence of specific IgE to patent blue has been described by ELISA supporting an
99
allergic mechanism.35 An allergic mechanism for IHR to ICM has particularly been reported in
100
patients with severe anaphylaxis.36 For GBCM it is speculated that the intact molecule of GBCM is
101
the antigen and not the chelator alone.29 Similarly, the responsible allergen of ICM does not seem to
102
be iodine, since patients rarely react to skin testing with iodine or provocation with Lugol’s solution.37
5
103
It must be highlighted that an allergic mechanism can only be demonstrated in the minority of patients
104
with IHR. Pathophysiology of possible non-allergic mechanisms (e.g. direct mast cell or basophil
105
activation, complement activation, bradykinin formation, etc.) is not fully understood yet.
106
Unlike other allergies, which require previous exposition to the eliciting allergen, Clement et al.7
107
report that 39% of all IHRs (to ICM and GBCM) occurred in patients with no history of previous
108
exposure to the elicitor. It has been discussed, but not proven, that substances in everyday life may be
109
the sensitizing antigen e.g. blue dyes in food coloring for allergies to blue dyes.7,38
110
Pathophysiology of non-immediate hypersensitivity reactions
111
There is strong evidence for a T-cell mediated mechanism of NIHRs to ICM and GBCM: Time of
112
onset and type of skin eruptions, presence of positive patch tests, activated T-cells in positive skin test
113
sites and positive lymphocyte transformation tests (LTT) all support the theory of an underlying type
114
IV allergic mechanism.4,29,39 In addition, the generation of ICM specific T-cell clones has been
115
reported for ICM.40 Alternatively, the p-i concept (pharmacologic interaction of drugs with immune
116
receptors) with direct stimulation of T-cells by diagnostic agents through an HLA- restricted pattern
117
may be involved in eliciting NIHR.41
118
Diagnostic methods
119
Indication for testing
120
To select patients for allergological workup, the clinical presentation and the time interval between
121
contrast media or dye exposure and reaction onset should be consistent with IHR or NIHR. Patients
122
who only experienced one symptom e.g. feeling of warmth or erythema on injection side, nausea,
123
myalgia/arthralgia, paresthesia, headache, or dizziness and/or delayed symptom onset most likely
124
suffered a toxicity related adverse event and do not require further allergy diagnostics. In contrast, in
125
patients with a history of immediately occurring urticaria/angioedema/bronchospasm or anaphylaxis
126
indicating IHR as well as in patients with exanthems after 6 hours to 7 days consistent with NIHR
127
skin testing has been recommended.8,42
6
128
IHRs to diagnostic dyes typically occur in a surgery setting. Thus, in most patients various potential
129
other elicitors of anaphylactic reactions including latex, chlorhexidine, antibiotics, analgesics, and the
130
dye have been administered and should be included in the allergological workup.43
131
Allergological workup should best be performed in an allergy centre experienced in skin testing to
132
drugs +/- laboratory cellular tests, which is able to handle potentially occurring severe reactions in
133
case of provocation tests.42
134
Allergy tests during acute IHR
135
Elevated serum levels of tryptase and/or histamine have been shown in cases of hypersensitivity
136
reactions to ICM, GBCM, fluorescein, patent blue, isosulfan blue and methylene blue.7,30,31,43,44 In the
137
acute phase of an IHR, measurement of serum tryptase levels 1-4 hours after IHR onset and >24h later
138
(for obtaining a baseline level) can be helpful to differentiate anaphylaxis from other forms of
139
adverse events.29 Generally, positive correlation between concentration of tryptase and severity of
140
IHR has been reported, but not every patient with allergic IHR shows an increased tryptase level.7
141
Measurements of increased histamine levels are less practicable, because the assay is not commonly
142
available and half-life time of histamine is only 15-20min, thus requiring blood sample collection only
143
few minutes after reaction onset.
144
Allergy tests in following allergological workup
145
For best sensitivity, patients should be scheduled for allergological workup 2-6 month after the initial
146
reaction,45 although positive skin tests several years after the incident have been described.9
147
IHR to ICM, particularly toxicity-related reactions, were much more common in the past when ionic
148
ICM were in use. Thus, skin testing was usually negative and therefore not recommended. Patients
149
have been managed by ICM avoidance or premedication, which is effective in reducing reoccurrence
150
in the majority of toxic and nonallergic reactions. 46,47 Only after discontinuing use of ionic ICM, it
151
became apparent that severe IHR to non-ionic RCM may sometimes be associated with a positive skin
152
test. It is hypothesized that severe reactions that now occur using nonionic, low- and iso-osmolar ICM
153
are more likely to be immunologic and possibly IgE-mediated. Hence the role of skin testing in the
7
154
evaluation of IHRs to contrast media is envolving, as is the value of changing the ICM for renewed
155
contrast use. Recently, skin testing has increasingly been recommended by experts, particularly in
156
severe IHRs and slowly replaces the traditional practice of avoidance or premedication in an
157
increasing number of institutions.48 Even though less data is available for GBCM, by analogy with
158
RCM skin testing has been recommended particularly in severe reactions.7
159
160
Skin tests
161
Figure 3 shows an algorithm on skin testing and skin-test deducted management of patients. Skin
162
prick tests (SPT) and intradermal tests (IDT) with immediate readings are done for IHR and patch test
163
as well as late readings for SPT and IDT are added in case of an NIHR.49 Skin testing protocols have
164
been investigated in several observational studies for ICM and GBCM, whereas only expert opinions
165
and case series exist for dyes.4,36,50,51 When performing skin tests with dyes there may be a theoretical
166
risk of tattooing, but only temporary discoloration of the skin for 1-2 days has been reported.52
167
After an IHR, SPT and if negative, IDT should be performed with the culprit contrast agent and with a
168
positive (e.g. histamine) and negative control (saline) and read after 20min. If culprit is unknown, it is
169
advisable to test a panel of contrast agents normally used in the hospital/doctors ‘office where the
170
patient first had the procedure causing a reaction. Dilutions of ICM, GBCM and dyes commonly used
171
for skin tests are presented in Table 1, but in case of life-threatening initial reaction, using higher
172
dilutions has been recommended.49 Anaphylaxis after SPT or IDT is exceptional.36 When the culprit is
173
positive, further skin testing with a panel of alternative contrast agents should be performed for
174
selecting an skin test-negative alternative contrast agent for subsequent procedures, which is more
175
likely to be tolerated.8 The panel should be adjusted to agents available in the institution performing
176
the future procedures.
177
After an exanthematous NIHR, a patch test as well as SPT and an IDT with late readings (usually 48h
178
and 72h) are performed.19 It has been reported for ICM and GBCM that IDT showed higher
179
sensitivity than patch test.7,53 The optimal time point for late readings is not well studied and
8
180
additional readings e.g. after 24 hours or after one week may be considered.14 After severe NIHR
181
especially SJS, TEN and vasculitis, skin testing may be of lower value.19 Since re-administration of
182
contrast media is contraindicated in patients with history of life-threatening NIHR, skin tests are only
183
helpful in the case when multiple drugs have been administered to determine the responsible drug for
184
NIHR. In those cases, using higher dilutions of test substances should be considered.49
185
There is no reliable data based on lager patient numbers on skin test sensitivity and specificity for
186
dyes and GBCM. For ICM, sensitivity of skin testing has been shown to depend on the severity of
187
reaction and time between reaction and skin test. A meta-analysis of 21 studies from Yoon et al. 36
188
showed 52% positive skin tests in severe IHRs to ICM but only 17% when also mild and moderate
189
reactions were included. 26% of patients with NIHR had positive skin tests. The specificity of skin-
190
tests for ICM is reported to be 95% for SPT and 91-96% for IDT.53 The negative predictive value
191
(NPV) of skin testing in IHR to ICM has been reported by different authors to be 94% -98% and 68-
192
86% for NIHR.36,45,50,54,55 However, these studies were not only done in patients with positive skin test
193
to the culprit, but also in those (non-allergic) patients with no positive skin test at all. There is no data
194
available on the positive predictive value of skin testing since a re-administration of a skin test
195
positive drug is highly likely to cause a reaction and would thus be unethical.
196
Only little data is available on NPV of skin tests in GBCM, but a case series reported 11 re-
197
administrations of skin test negative GBCM without a single reaction using skin test-negative
198
alternatives.51
199
Cross-reactivity in skin testing of ICM is described by multiple authors and may occur in up to 50%
200
of skin tests, particularly in NIHRs. It has been proposed that cross-reactivity may be more frequent in
201
ICM with N-(2,3-dihydroxypropyl) carbamoyl side chain (iopromide, iomeprol, ioversol, iohexol,
202
iodixanol), but there is inconsistency between different studies and further examination of cross-
203
reactivity patterns is needed.39,45,53 For GBCM, there is in the current state of knowledge insufficient
204
data to validly predict cross-reactivity between different substances. For patent blue and isosulfan
205
blue, a cross-reactivity in skin tests has been shown, which was explained by their similar molecular
9
206
structure, as illustrated in Figure 4.30 Methylene blue is a possible alternative since it has a different
207
molecular structure, it´s lower reported incidence of anaphylaxis.11
208
Laboratory tests
209
Laboratory tests are utilized experimentally to understand the pathomechanism of IHRs and NIHRs
210
and appear to be less sensitive than skin tests, but may also be helpful in confirming the diagnosis in
211
individual patients.8 Basophil activation test (BAT) measures basophil activation, e.g. by CD63
212
expression on basophiles via flow cytometry.56 For patent blue, ICM and GBCM positive BAT could
213
be shown.57–59 For ICM BAT is regularly used, but mostly in small samples sizes and good data on
214
sensitivity are still lacking, but specifity is estimated on 88,4% - 100% and BAT with ICM was
215
suggested to be useful for conformation of IHR to ICM.60 Sensitivity of BAT in GBCM is estimated
216
at 93% but is based on a small number of patients.59 Leukocyte histamine release testing was also
217
described in IHRs to ICM as well as lymphocyte transformation testing in NIHRs.40
218
219
Drug Provocation Test (DPT)
220
Intravenous DPT with a skin test negative contrast agent (ICM or GBCM) has been increasingly
221
described, but is neither part of routine allergological workup yet, nor standardized and
222
validated.39,59,61–64 For fluorescein conjunctival DPT has been reported as additional diagnostical step
223
when all skin tests were negative.65 Severe reactions to DPT have been reported and DPT could cause
224
side effects such as kidney damage when using ICM or nephrogenic systemic fibromatosis when
225
using GBCM.61 Because of its risk of hypersensitivity reactions DPT should be performed in
226
experienced and well-equipped institutions. Performing DPT may be considered especially in patients
227
after severe anaphylaxis with a skin test-negative alternative contrast medium, as DPT has a higher
228
sensitivity than skin testing alone.39
229
10
230
Management of patients with previous hypersensitivity
231
Patients with urgent need of ICM/GBCM without test possibility
232
An algorithm on management of patients with history of hypersensitivity reactions to contrast media
233
and needing a new procedure with contrast media is shown in Figure 5. For patients with a history of
234
ICM or GBCM hypersensitivity with immediate and urgent need of another procedure with contrast
235
media type and severity of initial reaction need to be evaluated. In Patients with mild urticaria or
236
angioedema or uncomplicated maculopapular exanthema, re-administration of a non-culprit contrast
237
medium may be performed using premedication,14 which supresses the majority of non-allergic
238
reactions (Figure 5).66 Several possible premedication protocols have been proposed, with a protocol
239
using a combination of H1-antihistamine (e.g. 50 mg diphenhydramine 1 hour before application) and
240
several doses of corticosteroids (e.g. 50 mg prednisone 13, 7, and 1 hours before application) often
241
cited.48 For NIHR the efficiency of premedication is unknown and likely to be low. Corticosteroids
242
may be used, but one should not rely on them to completely avoid reactions. In IHR allergic reactions
243
might occur despite the use of premedication (breakthrough reactions), but premedication may reduce
244
their severity.2
245
If the patient has suffered a moderate to severe anaphylaxis, another imaging modality should be
246
chosen in order to avoid re-administration of the same substance class (ICM or GBCM) (Figure 5). If
247
imaging with the same substance class is unavoidable and risk benefit analysis justifies the high risk
248
of re-administration, a contrast agent other than the culprit should be selected and premedication as
249
well as anesthesiology stand-by and emergency preparedness should be applied to be able to handle
250
potentially occurring severe reactions. (Figure 5). For these high risk patients, the setting for imaging
251
should be as safe as possible, e.g. by taking place at daytime in hospitals with code teams, with close
252
observation (possibly using pulsoxymetry) especially during the first 20 min since the most severe
253
reactions start quickly.2 Successful desensitization of ICM has been reported for IHR to ICM, but is
254
only used annectodical.67 Patients with a history of life-threatening NIHR re-administration of any
255
contrast agent from the same group (ICM or GBCM) should best be avoided.45
11
256
Management of patients with time for allergological workup
257
For patients without the need for immediate imaging an allergological workup should be performed to
258
classify hypersensitivity mechanism and to select a skin test- or even DPT-negative ICM/GBCM for
259
re-administration (Figure 3). In patients with confirmed IHR by skin test-positive culprit, a skin test-
260
negative alternative can be administered without premedication, but one should still be prepared for
261
emergencies. Applying premedication might still be considered, if the initial hypersensitivity reaction
262
was severe. The positive culprit along with all other skin test-positive contrast agents from the tested
263
panel should be never re-administered.7 In centers, where BAT or LTT is available, they may
264
supplement skin testing and their outcome should be considered to select the agent for
265
readministration. Whether DPT prior to re-administration is advisable must be decided on an
266
individual basis.45
267
If the culprit and test panel is negative in all performed skin tests, further skin tests with a panel of
268
alternative contrast media are not likely to be helpful and a non-culprit agent with premedication and
269
under emergency preparedness can be applied.
270
In cases with severe IHRs a thorough risk benefit analysis is done and re-administering a contrast
271
agent may be contraindicated. In severe bullous or systemic NIHR the culprit along with all other
272
contrast media of the same class (ICM or GBCM) should not be readministered.
273
Management of patients with previous hypersensitivity to dyes
274
There is only scarce literature on managing patients with previous hypersensitivity to dyes but the
275
concepts used in managing patients with hypersensitivity to ICM or GBCM could be transferred to
276
dyes.
277
In IHRs caused by patent blue or isosulfan blue in surgery it should be considered to finish the
278
procedure if the patient can be stabilized reliably, thus avoiding the need of a second procedure with
279
re-administration of dye.30 If re-administration is unavoidable, the safest option would be using
280
methylene blue, indocyanine green or technetium.11,52 For prevention of reactions to patent blue and
281
isosulfan blue, using smaller amount of dye has been proposed, since King et al.68 reported a trend
12
282
towards fewer allergic reactions when less dye was used. However, their findings were not
283
statistically significant.68
284
In patients with a previous reaction to fluorescein, especially severe ones, using an alternative
285
imaging method like indocyanine green angiography or optical choherence tomography angiography
286
to avoid readministration of fluorescein should be considered. If there is no alternative to fluorescein,
287
event-free re-administration of flourescein after desensitization has been described in a case report.69
288
The role of antihistamine and corticosteroid premedication for dyes is still being debated: The
289
efficacy of premedication for fluorescein is unknown and actively being discussed.32,70 For patent blue
290
and isosulfan blue premedication with corticosteroids is thought to reduce severity of reaction but not
291
the occurrence of IHR.4
292
Conclusion
293
Hypersensitivity reactions during procedures to contrast agents and dyes are highly relevant since
294
increasing numbers of applications cause increasing incidence of hypersensitivity reactions, which
295
could possibly end fatal. Radiologists, anaesthetists and surgeons should not rely on premedication,
296
since especially in severe reactions premedication has be reported to be insufficient. They should be
297
well- trained in understanding and managing IHRs and NIHRs and in handling patients with increased
298
risk of hypersensitivity reactions. Since severe hypersensitivity reactions appear to be more likely
299
caused by an allergic mechanism, skin testing in those patients is highly recommended and may help
300
selecting skin-test negative alternatives for use in future procedures. For mild non-allergic reactions
301
changing the contrast medium in combination with premedication is often sufficient. More studies on
302
the mechanism of contrast agent hypersensitivity for ICM, GBCM and dyes and diagnostic value of
303
drug provocation test and BAT would be desirable.
References [1] Christiansen C. X-ray contrast media--an overview. Toxicology 2005;209(2):185–7. [2] Heshmatzadeh Behzadi A, Prince MR. Preventing Allergic Reactions to Gadolinium-Based Contrast Agents. Top Magn Reson Imaging 2016;25(6):275–9. [3] Brockow K, Christiansen C, Kanny G, et al. Management of hypersensitivity reactions to iodinated contrast media. Allergy 2005;60(2):150–8. [4] Brockow K, Sánchez-Borges M. Hypersensitivity to contrast media and dyes. Immunol Allergy Clin North Am 2014;34(3):547-64. [5] Bircher AJ, Brockow K, Grosber M, et al. Late elicitation of maculopapular exanthemas to iodinated contrast media after first exposure. Ann Allergy Asthma Immunol 2013;111(6):576–7. [6] Muraro A, Roberts G, Worm M, et al. Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology. Allergy 2014;69(8):1026–45. [7] Clement O, Dewachter P, Mouton-Faivre C, et al. Immediate Hypersensitivity to Contrast Agents: The French 5-year CIRTACI Study. EClinicalMedicine 2018;1:51–61. [8] Trautmann A, Brockow K, Behle V, et al. Radiocontrast Media Hypersensitivity: Skin Testing Differentiates Allergy From Nonallergic Reactions and Identifies a Safe Alternative as Proven by Intravenous Provocation. J Allergy Clin Immunol Pract 2019;7(7):2218–24. [9] Harr T, Jandus P. Late Diagnosis of Anaphylactic Reaction to Gadolinium-Based Contrast Media by Skin Tests 10 Years After Onset. J Investig Allergol Clin Immunol 2018;28(3):203–5. [10] Carr TF. Pathophysiology of Immediate Reactions to Injectable Gadolinium-based Contrast Agents. Top Magn Reson Imaging 2016;25(6):265–8. [11] Iqbal FM, Basit A, Salem F, et al. Feeling blue, going green and finding other attractive alternatives: a case of biphasic anaphylaxis to patent blue and a literature review of alternative sentinel node localisation methods. BMJ Case Rep 2015;2015:bcr2015213107. [12] Chu JN, Lazar J, Badger J. A postoperative blue rash: indigo carmine dye extravasation. Int J Dermatol 2015;54(9):e371-2. [13] Brockow K, Ardern-Jones MR, Mockenhaupt M, et al. EAACI position paper on how to classify cutaneous manifestations of drug hypersensitivity. Allergy 2019;74(1):14–27. [14] Corbaux C, Seneschal J, Taïeb A, et al. Delayed cutaneous hypersensitivity reactions to iodinated contrast media. Eur J Dermatol 2017;27(2):190–1. [15] Epskamp C, Snels DGCTM, Yo GL, et al. Bullous fixed drug eruption in a patient with metastatic renal cell carcinoma induced by iodinated contrast during pazopanib treatment. Eur J Dermatol 2016;26(2):207–8. [16] Grandvuillemin A, Ripert C, Sgro C, et al. Iodinated contrast media-induced acute generalized exanthematous pustulosis confirmed by delayed skin tests. J Allergy Clin Immunol Pract 2014;2(6):805–6. [17] Velter C, Schissler C, Moulinas C, et al. Acute generalized exanthematous pustulosis caused by an iodinated contrast radiocontrast medium for computed tomography arthrography of the knee. Contact Derm 2017;76(6):371–3. [18] Yang SS, Aw DC, Chandran NS. Severe Cutaneous Adverse Reactions Following Intravenous Contrast: A Report of 2 Cases. Ann Acad Med Singap 2015;44(12):561–4.
[19] Tasker F, Fleming H, McNeill G, et al. Contrast media and cutaneous reactions. Part 2: Delayed hypersensitivity reactions to iodinated contrast media. Clin Exp Dermatol 2019. (Epub ahead of print) [20] Bordel Gómez MT, Martín García C, Meseguer Yebra C, et al. First case report of acute generalized exanthematous pustulosis (AGEP) caused by gadolinium confirmed by patch testing. Contact Derm 2018;78(2):166–8. [21] Katayama H, Yamaguchi K, Kozuka T, et al. Adverse reactions to ionic and nonionic contrast media. A report from the Japanese Committee on the Safety of Contrast Media. Radiology 1990;175(3):621–8. [22] Webb JAW, Stacul F, Thomsen HS, et al. Late adverse reactions to intravascular iodinated contrast media. Eur Radiol 2003;13(1):181–4. [23] Sutton AG, Finn P, Grech ED, et al. Early and late reactions after the use of iopamidol 340, ioxaglate 320, and iodixanol 320 in cardiac catheterization. Am Heart J 2001;141(4):677–83. [24] Brockow K. Immediate and delayed cutaneous reactions to radiocontrast media. Chem Immunol Allergy 2012;97:180–90. [25] Forbes-Amrhein MM, Dillman JR, Trout AT, et al. Frequency and Severity of Acute AllergicLike Reactions to Intravenously Administered Gadolinium-Based Contrast Media in Children. Invest Radiol 2018;53(5):313–8. [26] Dillman JR, Ellis JH, Cohan RH, et al. Frequency and Severity of Acute Allergic-Like Reactions to Gadolinium-Containing IV Contrast Media in Children and Adults. American Journal of Roentgenology 2007;189(6):1533–8. [27] Jung J-W, Kang H-R, Kim M-H, et al. Immediate hypersensitivity reaction to gadolinium-based MR contrast media. Radiology 2012;264(2):414–22. [28] Behzadi AH, Zhao Y, Farooq Z, et al. Immediate Allergic Reactions to Gadolinium-based Contrast Agents: A Systematic Review and Meta-Analysis. Radiology 2018;286(2):471–82. [29] Fok JS, Smith WB. Hypersensitivity reactions to gadolinium-based contrast agents. Curr Opin Allergy Clin Immunol 2017;17(4):241–6. [30] Hunting AS, Nopp A, Johansson SGO, et al. Anaphylaxis to Patent Blue V. I. Clinical aspects. Allergy 2010;65(1):117–23. [31] Lee T, Sanderson D, Doyle P, et al. Anaphylactic Shock After Intravenous Fluorescein Administration for Intraoperative Cystoscopy. Obstet Gynecol 2018;131(4):727–9. [32] Kornblau IS, El-Annan JF. Adverse reactions to fluorescein angiography: A comprehensive review of the literature. Surv Ophthalmol 2019;64(5):679–93. [33] Laroche D, Aimone-Gastin I, Dubois F, et al. Mechanisms of severe, immediate reactions to iodinated contrast material. Radiology 1998;209(1):183–90. [34] Yannuzzi LA, Rohrer KT, Tindel LJ, et al. Fluorescein Angiography Complication Survey. Ophthalmology 1986;93(5):611–7. [35] Wöhrl S, Focke M, Hinterhuber G, et al. Near-fatal anaphylaxis to patent blue V. Br J Dermatol 2004;150(5):1037–8. [36] Yoon SH, Lee S-Y, Kang H-R, et al. Skin tests in patients with hypersensitivity reaction to iodinated contrast media: a meta-analysis. Allergy 2015;70(6):625–37.
[37] Scherer K, Harr T, Bach S, et al. The role of iodine in hypersensitivity reactions to radio contrast media. Clin Exp Allergy 2010;40(3):468–75. [38] Haque RA, Wagner A, Whisken JA, et al. Anaphylaxis to patent blue V: a case series and proposed diagnostic protocol. Allergy 2010;65(3):396–400. [39] Torres MJ, Gomez F, Doña I, et al. Diagnostic evaluation of patients with nonimmediate cutaneous hypersensitivity reactions to iodinated contrast media. Allergy 2012;67(7):929–35. [40] Lerch M, Keller M, Britschgi M, et al. Cross-reactivity patterns of T cells specific for iodinated contrast media. J Allergy Clin Immunol 2007;119(6):1529–36. [41] Pichler WJ, Naisbitt DJ, Park BK. Immune pathomechanism of drug hypersensitivity reactions. J Allergy Clin Immunol 2011;127(3 Suppl):S74-81. [42] Rosado Ingelmo A, Doña Diaz I, Cabañas Moreno R, et al. Clinical Practice Guidelines for Diagnosis and Management of Hypersensitivity Reactions to Contrast Media. J Investig Allergol Clin Immunol 2016;26(3):144-55. [43] Dewachter P, Mouton-Faivre C, Tréchot P, et al. Severe anaphylactic shock with methylene blue instillation. Anesth Analg 2005;101(1):149-50. [44] Sandhu S, Farag E, Argalious M. Anaphylaxis to isosulfan blue dye during sentinel lymph node biopsy. J Clin Anesth 2005;17(8):633–5. [45] Schrijvers R, Breynaert C, Ahmedali Y, et al. Skin Testing for Suspected Iodinated Contrast Media Hypersensitivity. J Allergy Clin Immunol Pract 2018;6(4):1246–54. [46] American Academy of Allergy, Asthma, American College of Allergy, Asthma, Joint Council of Allergy, Asthma, et al. Drug allergy: an updated practice parameter. Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 2010;105(4):259. [47] Greenberger PA, Patterson R. The prevention of immediate generalized reactions to radiocontrast media in high-risk patients. Journal of Allergy and Clinical Immunology 1991;87(4):867–72. [48] Sánchez-Borges M, Aberer W, Brockow K, et al. Controversies in Drug Allergy: Radiographic Contrast Media. J Allergy Clin Immunol Pract 2019;7(1):61–5. [49] Brockow K, Romano A, Blanca M, et al. General considerations for skin test procedures in the diagnosis of drug hypersensitivity. Allergy 2002;57(1):45–51. [50] Soyyigit S, Goksel O, Aydin O, et al. What is the clinical value of negative predictive values of skin tests to iodinated contrast media? Allergy Asthma Proc 2016;37(6):482–8. [51] Chiriac A-M, Audurier Y, Bousquet P-J, et al. Clinical value of negative skin tests to gadolinium contrast agents. Allergy 2011;66(11):1504–6. [52] Baker MG, Cronin JA, Borish L, et al. Evaluation of a skin testing protocol for diagnosing perioperative anaphylaxis due to isosulfan blue allergy. Ann Allergy Asthma Immunol 2014;113(3):330–1. [53] Brockow K, Romano A, Aberer W, et al. Skin testing in patients with hypersensitivity reactions to iodinated contrast media - a European multicenter study. Allergy 2009;64(2):234–41. [54] Caimmi S, Benyahia B, Suau D, et al. Clinical value of negative skin tests to iodinated contrast media. Clin Exp Allergy 2010;40(5):805–10.
[55] Kwon OY, Lee J-H, Park S-Y, et al. Novel Strategy for the Prevention of Recurrent Hypersensitivity Reactions to Radiocontrast Media Based on Skin Testing. J Allergy Clin Immunol Pract 2019. (Epub ahead of print) [56] Mayorga C, Celik G, Rouzaire P, et al. In vitro tests for drug hypersensitivity reactions: an ENDA/EAACI Drug Allergy Interest Group position paper. Allergy 2016;71(8):1103–34. [57] Boita M, Mietta S, Bommarito L, et al. Basophil activation test in the diagnosis of patent blue V anaphylaxis. Ann Allergy Asthma Immunol 2015;115(1):78–9. [58] Trcka J, Schmidt C, Seitz CS, et al. Anaphylaxis to iodinated contrast material: nonallergic hypersensitivity or IgE-mediated allergy? AJR Am J Roentgenol 2008;190(3):666–70. [59] Kolenda C, Dubost R, Hacard F, et al. Evaluation of basophil activation test in the management of immediate hypersensitivity reactions to gadolinium-based contrast agents: a five-year experience. J Allergy Clin Immunol Pract 2017;5(3):846–9. [60] Pinnobphun P, Buranapraditkun S, Kampitak T, et al. The diagnostic value of basophil activation test in patients with an immediate hypersensitivity reaction to radiocontrast media. Ann Allergy Asthma Immunol 2011;106(5):387–93. [61] Soria A, Masson N, Vial-Dupuy A, et al. Allergological workup with half-dose challenge in iodinated contrast media hypersensitivity. Allergy 2019;74(2):414–7. [62] Seta V, Gaouar H, Badaoui A, et al. Low-dose provocation and skin tests in patients with hypersensitivity to gadolinium-based contrast agents. Clin Exp Allergy 2019;49(5):724–8. [63] Sesé L, Gaouar H, Autegarden J-E, et al. Immediate hypersensitivity to iodinated contrast media: diagnostic accuracy of skin tests and intravenous provocation test with low dose. Clin Exp Allergy 2016;46(3):472–8. [64] Lerondeau B, Trechot P, Waton J, et al. Analysis of cross-reactivity among radiocontrast media in 97 hypersensitivity reactions. J Allergy Clin Immunol 2016;137(2):633-635.e4. [65] Trindade-Porto C, Alonso-Llamazares A, Robledo T, et al. Fluorescein-induced adverse reaction. Allergy 1999;54(11):1230. [66] American College of Radiology Commitee. ACR Manual on Contrast Media Version 10.3 2018;2018:1–125. https://www.acr.org › ACR › Files › Clinical-Resources [67] Gandhi S, Litt D, Chandy M, et al. Successful rapid intravenous desensitization for radioiodine contrast allergy in a patient requiring urgent coronary angiography. J Allergy Clin Immunol Pract 2014;2(1):101–2. [68] King TA, Fey JV, van Zee KJ, et al. A prospective analysis of the effect of blue-dye volume on sentinel lymph node mapping success and incidence of allergic reaction in patients with breast cancer. Ann Surg Oncol 2004;11(5):535–41. [69] Nucera E, Schiavino D, Merendino E, et al. Successful fluorescein desensitization. Allergy 2003;58(5):458. [70] Knowles SR, Weber EA, Berbrayer CS. Allergic reaction to fluorescein dye: successful one-day desensitization. Can J Ophthalmol 2007;42(2):329–30.
1
Captions Fig. 1 Clinical pictures of a patient with non-immediate contrast media allergy. A) Maculopapular exanthem after Imeron (Iomeprol) despite premedication with corticosteroid and H1- and H2-antihistamins. B) In the patch test after 48 hours positive reaction to Imeron (Iomeprol) (arrow) with cross-reactivity to other contrast media. Fig. 2 Overview over the different chemical properties of iodinated contrast media (ICM). In ionic ICM, the contrast agent consists of a 1,3,5-tri-iodobenzene core including an acid-group (COO¯ group) as anion and sodium or meglumine as cation, whereas non-ionic products don´t carry acid groups. Fig. 3 Algorithm for skin testing of patients with previous hypersensitivity reactions to iodinated contrast media or gadolinium-based contrast media and skin test result-deduced management of re-administration. This algorithm is based on skin testing, but further allergological tests could be added e.g. basophil activation test, lymphocyte transformation test or drug provocation test, as described in the review. CM contrast media, DRESS drug reaction with eosinophilia and systemic symptoms, IDT intradermal test, ME maculopapular exanthem, SJS Steven-Johnson Syndrome, SPT skin prick test, TEN toxic epidermal necrolysis.
Fig. 4 Molecular structure of blue dyes. Patent blue and isosulfan blue have partially identical structures (marked in blue) whereas methylene blue has a completely different structure.
Fig. 5 Algorithm for management of patients with a history of adverse reactions to iodinated contrast media or gadolinium-based contrast media needing contrasted imaging. Management according to outcome of skin testing is described in Figure 2.
2
CM Contrast media, DRESS drug reaction with eosinophilia and systemic symptoms, ICM iodinated contrast media, GBCM gadolinium-based contrast media, IHR immediate hypersensitivity reaction, NIHR non-immediate hypersensitivity reaction, SJS StevenJohnson Syndrome, TEN toxic epidermal necrolysis.
Table 1. Skin test concentrations for contrast agents and dyes Name of contrast agent or dye Iodinated contrast media (ICM) Gadolinium based contrast media (GBCM) Dyes Fluorescein
Skin prick test (SPT) Undiluted (300-320 mg/ml) Undiluted
Intradermal Patch test test (IDT) (PT) 1:10* Undiluted
1:10
Additional information on skin tests see EACCI/ENDA Guidelines 41
Undiluted
Reading times: Immediate hypersensitivity reaction: SPT and IDT after 20min Non-immediate exanthems**: SPT and IDT after 20min, 48h, 72h PT after 48h, 72h
1:10
Undiluted
1:100
No data
Isosulfan blue
Undiluted (200mg/ml) Undiluted (25mg/ml) Undiluted
1:10
No data
Methylene blue
Undiluted
1:100
No data
Patent blue
Comments
*1:10 is recommended by EACCI/ENDA Guidelines, but IDT with undiluted ICM may be performed in non-severe nonimmediate hypersensitivity reactions. There is inconclusive data, if undiluted ICM can cause irritative reactions in the immediate reading of IDT **Timepoints for late readings are standardized, but not well studied. Additional readings (e.g. 24h, 1week) may be added.
History of adverse reaction to CM
Type of reaction based on chronology and symptoms
Immediate type hypersensitivity (urticaria, anaphylaxis)
Toxic/physiologic reaction or unrelated event
Non-immediate hypersensitivity (exanthems)
SPT and, if negative, IDT with immediate reading of culprit CM
No allergological workup
Severity of reaction
Positive
Negative
Patch test, SPT and IDT with late readings of culprit + panel of alternatives
Perform SPT and IDT with alternative CM
Use skin-test negative CM
Suggestions for re-administration
Severe (e.g. SJS, TEN, DRESS)
Mild (e.g. ME)
Use CM other than culprit with premedication under emergency preparedness. When initial reaction was life-threatening consider a different imaging modality to avoid re-administration
Positive
Negative
Use skin-test negative CM
Use non-culprit CM + corticoid premedication
Skin test possible for confirmation of diagnosis. Initial use of higher dilutions No re-administration
CH3CH2
N+
CH2CH3
CH3CH2
N+
CH2CH3
N
–
SO3
H3C
HO HO3S
SO3H
N CH3CH2
Isosulfan Blue
CH2CH3
N NaO3S
CH2CH3
N H3C
S
N+
H3C
CH3CH2
Patent Blue
CH3
Methylene Blue
CI
–
When is the next radiological examination needed? Elective
Urgent/emergency Imaging/procedure with another method possible and sufficient?
Yes
Use that method
No Type and severity of initial reaction? Perform allergological workup prior to re-administration
Urticaria/angioedema or mild maculopapular exanthema
Severe IHR/anaphylaxis
Severe NIHR (SJS, TEN, DRESS)
Risk/benefit analysis for re-administration?
Manage patient according to outcome of allergy testing
Re-administer other than culprit with premedication and emergency preparedness
Avoid or re-administer non-culprit alternative with premedication, emergancy preparedness and anesthesiology stand-by
Avoid all CM of the same class (all ICM or GBCM)
Chemical properties of Iodinated Contrast Media IONIC
NONIONIC
Monomeric:*
Monomeric:
Iothalamate Iopanoic acid Iotroxic acid Diatrizoate Metrizoate
Iohexol Iopamidol Iopromide Ioversol Ioxilan Iomeprol Iobitridol
Dimeric:*
Ioxaglate
* Mostly used as a meglumin or sodium salt
Dimeric:
Iodixanol
S1081-1206(19)31452-8
DOI:
https://doi.org/10.1016/j.anai.2019.11.022
Reference:
ANAI 3082
To appear in:
Annals of Allergy, Asthma and Immunology
Received Date: 16 September 2019 Revised Date:
6 November 2019
Accepted Date: 18 November 2019
Please cite this article as: Schönmann C, Brockow K, Adverse reactions during procedures: hypersensitivity to contrast agents and dyes, Annals of Allergy, Asthma and Immunology (2019), doi: https://doi.org/10.1016/j.anai.2019.11.022. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
1
Adverse reactions during procedures: hypersensitivity to contrast agents and dyes Christine Schönmann, MD, Knut Brockow, MD Department of Dermatology and Allergy Biederstein, School of Medicine, Technical University of Munich, Munich, Germany Corresponding author for proofs and reprints: Knut Brockow, MD Department of Dermatology and Allergy Biederstein Technical University of Munich, Biedersteiner Strasse 29, 80802 Munich, Germany (+49) 89-4140-3182 (+49) 89-4140-3171 (fax) [email protected] (e-mail) No conflict of interest, no funding. Word count: 3749 Keywords: Hypersensitivity, Iodinated contrast media, Gadolinium-based contrast media, Blue dyes, Fluorescein, Diagnosis, Skin test, Management Abbreviations: AGEP Acute generalized exanthematous pustulosis BAT Basophile activation test CM Contrast Media CT Computed tomography DPT Drug provocation test DRESS Drug reaction with eosinophilia and systemic symptoms ELISA Enzyme-linked immunosorbent assay GBCM Gadolinium-based contrast media HLA Human leukocyte antigen ICM Iodinated contrast media IDT Intradermal test IgE Immunoglobulin E IHR Immediate-type hypersensitivity reaction LTT Lymphocyte transformation test MPE Maculopapular exanthem MRI Magnet resonance imaging NIHR Non-immediate hypersensitivity reaction NPV Negative predictive value NSF Nephrogenic systemic fibrosis SDRIFE Symmetric drug-related intertriginous and flexural exanthema SJS Stevens-Johnson-syndrome SPT Skin prick test TEN Toxic epidermal necrolysis Figures and Tables Fig. 1. Clinical pictures of a patient with non-immediate contrast media allergy Fig. 2. Algorithm for skin testing of patients with previous hypersensitivity reactions to iodinated contrast media or gadolinium-based contrast media and skin test result-deduced management of readministration Fig. 3. Molecular structure of blue dyes Fig. 4. Algorithm for management of patients with a history of adverse reactions to iodinated contrast media or gadolinium-based contrast media needing contrasted imaging Tab. 1. Skin test concentrations for contrast agents and dyes
19-09-0461R1
Objective This review provides an overview of the literature on hypersensitivity reactions during procedures to commonly used contrast agents and dyes. A synthesis of current knowledge on clinical symptoms, epidemiology and risk factors, pathomechanism and management of hypersensitivity reactions to these substances is presented. Data Sources A literature search was conducted through Medline. Included were peer-reviewed articles written in English between 2000 and 2019. Study Selections Relevant clinical studies, experimental studies and review articles have been selected. Additionally, case reports have been included, if they carried significant information about rare clinical forms of hypersensitivity reactions, disease mechanisms or therapy. Results An allergological workup is only indicated for patients with a history of immediate (IHR) and non-immediate hypersensitivity reactions (NIHR) but not for toxic or unrelated adverse events. Skin tests +/- experimental cellular laboratory tests in patients with previous reactions can provide evidence for an allergic mechanism. Positive skin tests indicating allergy are more common in severe reactions. If the adverse event was allergic, skin testing of alternatives is helpful for the selection of other contrast agents for future procedures. Premedication alone may be insufficient in these cases and breakthrough reactions occur. For non-allergic reactions, change of contrast agent and premedication is often but not always sufficient to suppress reactions Conclusion Patients with previous NIHR or IHR, especially moderate and severe IHR, needing potential re-administration of contrast agents should be skin tested in order to identify an allergic mechanism as well as alternative agents to be used for future procedures.
1
1
Introduction
2
Contrast media including iodinated contrast media (ICM) for X-ray and CT-scans, gadolinium-based
3
contrast media (GBCM) for MRI-scans and dyes such as patent blue, isoflurane blue, methylene blue
4
and fluorescein for sentinel lymph node detection in breast cancer or melanoma, fluorescence
5
angiography in ophthalmology or evaluation of ureters and bladder during surgery are increasingly
6
used in modern medicine for diagnosis and disease monitoring. More than 70 million doses of ICM
7
and an estimated 50 million doses of GBCM are administered worldwide per year.1,2 There is a risk
8
for adverse reactions to any kind of contrast agents, which in rare cases can be fatal. Consequently,
9
knowledge about treatment and diagnostic workup of adverse events after administration of contrast
10
media is highly relevant.
11
Three different categories of adverse reactions must be discriminated: 1) hypersensitivity reactions
12
(allergic and non-allergic), 2) toxic reactions and 3) events unrelated to exposure to contrast agent.3
13
This review addresses only hypersensitivity reactions.
14
Hypersensitivity reactions can be divided into immediate hypersensitivity reactions (IHR) and non-
15
immediate hypersensitivity reactions (NIHR).4 Symptom onset in IHRs begins immediately up to 1
16
hour after drug administration and present with symptoms of anaphylaxis. NIHRs start more than 1
17
hour up to 10 days after administration of the culprit agent and present with exanthems.4 The most
18
common form is the maculopapular exanthema (ME), but severe forms of NIHR to contrast agents
19
like drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens Johnson syndrome
20
(SJS), toxic epidermal necrolysis (TEN) or acute generalized exanthematous pustulosis (AGEP) have
21
been reported.5
22
Clinical findings in immediate hypersensitivity reactions (IHR)
23
Clinical findings in IHR for all reviewed contrast agents and dyes can range from mild skin symptoms
24
such as urticaria to severe reactions like anaphylactic shock which could be fatal.6 Sometimes it can
25
be difficult to distinguish vasovagal or toxicity-related reactions from anaphylaxis. Toxicity-related
26
reactions often present with pallor, weakness, nausea and vomiting as well as bradycardia, while skin
2
27
reactions (urticarial, pruritus, angioedema), tachycardia, bronchospasm and wheezing are strongly
28
associated with anaphylaxis.2 Clement et al. 7 reported that cardiovascular signs or involvement of
29
three or four different organs are significantly associated with allergic IHR.
30
About 70% of IHRs to ICM present with urticaria/angioedema and pruritus and start within the first 5
31
minutes after administration and nearly all (96%) of severe reactions occur within 20 minutes.8
32
Most commonly seen symptoms of IHRs to GBCM are urticaria (50-90%) and nausea.4 Anaphylaxis
33
is rare and the mortality rate is estimated by the FDA at 8 in 100.000 doses GBCM administered.9
34
Physiologic toxic effects due to hypertonic GBCM (including injection site discomfort,
35
thrombophlebitis, myalgia/arthralgia, paresthesia, headache, dizziness and nausea) occur more
36
frequently than hypersensitivity reactions.10
37
When patent blue or isosulfan blue is the elicitor of IHR, urticaria may occur as pathognomonic blue-
38
green hives.11 Extravasation of dye, which also causes blue-green skin discoloration but no other
39
symptoms such as wheals must be considered as a differential diagnosis to IHR.12 Biphasic reactions
40
have been reported in IHR to patent blue.11 Physicians should be aware of this pattern and carefully
41
monitor the patient after initial treatment for occurrence of a second reaction.
42
Clinical findings in non-immediate hypersensitivity reactions (NIHR)
43
While NIHRs caused by GBCM and dyes are anecdotal, ICM is a common elicitor of NIHR. Typical
44
presentation of an NIHR to ICM is an exanthema, particularly a maculopapular exanthema of mild or
45
moderate severity.13 Figure 1 shows an exemplary picture of maculopapular exanthema in a patient
46
who underwent imaging with iomeprol. Other entities including erythema exsudativum multiforme,
47
bullous fixed drug eruption, pompholyx, drug related eosinophilia with systemic symptoms (DRESS),
48
symmetric drug-related intertriginous and flexural exanthema (SDRIFE) and acute generalized
49
exanthematous pustulosis (AGEP) after intravenous and also after intra-articular ICM-administration
50
have been reported but are exceptional.14–17. Fatal cases of NIHR have been described, especially in
51
patients with vasculitis, Stevens-Johnson syndrome or toxic epidermal necrolysis.18 Severe NIHRs
52
often occur in a complex intensive care unit setting involving more than one potential elicitor of
3
53
NIHR (e.g. antibiotics and contrast CT as search of focus for sepsis). Thus numbers on ICM as
54
elicitor of severe NIHR may be inaccurate.19
55
NIHRs to GBCM are extremely rare, but AGEP has been reported.20 An important non-allergic late
56
reaction to GBCM especially in patients with impaired kidney function is nephrogenic systemic
57
fibrosis (NSF). NSF causes fibrosis mostly of the skin and subcutaneous tissues. However, internal
58
organs, skeletal muscles and joints can be involved, and fatalities have been reported.10 Thus,
59
radiologists must take special care of patients with low glomerulus filtration rate when needing
60
GBCM.
61
NIHRs to dyes have hardly ever been observed and their causality remains unproven.
62
Epidemiology and risk factors
63
Reported data on incidence of IHR and NIHR to contrast media and dyes varies widely between
64
different studies because of different definitions of IHR and NIHR, the difficulty of distinguishing
65
toxicity related from hypersensitivity reactions, different premedication regimes, and generally low
66
incidence-rates requiring large sample sizes to determine incidence accurately.
67
Mild IHR to modern non-ionic ICM may occur in 0.7-3.0% of IV administrations, severe reactions
68
only in 0.02-0.04%.21 Ionic monomeric ICM were approximately 4-fold more likely to elicit adverse
69
drug reactions and therefore have been withdrawn from the market in most countries.4,21 An overview
70
on the different types and names of ICM is given in Figure 2.
71
Estimates of the frequency of NIHR to ICM range from 0.5 to 23% and no significant differences
72
between high- and low osmolar ICM have been found.22 Some reports state a higher incidence of
73
exanthems for dimeric isoosmolar ICM.23
74
Several different risk factors for IHRs and NIHRs to ICM are being discussed. The most important
75
and commonly agreed on risk factor for hypersensitivity reactions is a previous reaction to ICM as
76
risk factor for reoccurrence of the reaction on re-exposure. A previous IHR does not increase the risk
77
for an NIHR and vice versa.24
4
78
IHRs have been reported in approximately 0.04%-0.06% of GBCM administrations in children and
79
0.07% in adults.25–27 Most cases (74%) are mild reactions, 19% moderate reactions and 7% severe
80
ones. Reactions were considered as mild when they were self-limiting and required no treatment
81
(except for antihistamines for cutaneous reaction), moderate when they required immediate medical
82
treatment going beyond antihistamines and severe if the event was life-threatening and typically
83
requiring hospitalization.26 Ionic, macrocyclic GBCM and those with higher protein binding elicit
84
more IHR than linear, non-ionic ones.28 Macrocyclic chelates may elicit more IHRs but are more
85
stable and thus less likely to cause NSF.29
86 87
Risk factors for reactions to GBCM are the same as for ICM. Jung at al. estimated a reoccurrence rate
88
of 30% in patients with previous IHRs27, other authors reported rates of 21-60%.2
89
For all kinds of dyes, the overall incidence of anaphylaxis differs widely between different reports. It
90
most probably lies in the range of 0%-1,1% for isosulfan blue, 0,7-2,7% for patent blue and 0,5%-
91
1,0% for flourescein.11,30,31 Fatal cases have been reported.32
92
Pathophysiology of immediate hypersensitivity reactions
93
The pathophysiology of IHR to contrast agents and dyes is not fully understood yet. Histamine or
94
tryptase release has been demonstrated in many cases, but this just indicates a mechanism of mast cell
95
(or basophil) activation and not necessarily an immunoglobulin E (IgE)-mediated reaction.7 However,
96
in some patients with IHR to ICM, GBCM, PB and IB an “allergic” mechanism is supported by
97
positive skin tests, basophil activation as demonstrated by positive basophil activation test 29,30,33,34.
98
For patent blue presence of specific IgE to patent blue has been described by ELISA supporting an
99
allergic mechanism.35 An allergic mechanism for IHR to ICM has particularly been reported in
100
patients with severe anaphylaxis.36 For GBCM it is speculated that the intact molecule of GBCM is
101
the antigen and not the chelator alone.29 Similarly, the responsible allergen of ICM does not seem to
102
be iodine, since patients rarely react to skin testing with iodine or provocation with Lugol’s solution.37
5
103
It must be highlighted that an allergic mechanism can only be demonstrated in the minority of patients
104
with IHR. Pathophysiology of possible non-allergic mechanisms (e.g. direct mast cell or basophil
105
activation, complement activation, bradykinin formation, etc.) is not fully understood yet.
106
Unlike other allergies, which require previous exposition to the eliciting allergen, Clement et al.7
107
report that 39% of all IHRs (to ICM and GBCM) occurred in patients with no history of previous
108
exposure to the elicitor. It has been discussed, but not proven, that substances in everyday life may be
109
the sensitizing antigen e.g. blue dyes in food coloring for allergies to blue dyes.7,38
110
Pathophysiology of non-immediate hypersensitivity reactions
111
There is strong evidence for a T-cell mediated mechanism of NIHRs to ICM and GBCM: Time of
112
onset and type of skin eruptions, presence of positive patch tests, activated T-cells in positive skin test
113
sites and positive lymphocyte transformation tests (LTT) all support the theory of an underlying type
114
IV allergic mechanism.4,29,39 In addition, the generation of ICM specific T-cell clones has been
115
reported for ICM.40 Alternatively, the p-i concept (pharmacologic interaction of drugs with immune
116
receptors) with direct stimulation of T-cells by diagnostic agents through an HLA- restricted pattern
117
may be involved in eliciting NIHR.41
118
Diagnostic methods
119
Indication for testing
120
To select patients for allergological workup, the clinical presentation and the time interval between
121
contrast media or dye exposure and reaction onset should be consistent with IHR or NIHR. Patients
122
who only experienced one symptom e.g. feeling of warmth or erythema on injection side, nausea,
123
myalgia/arthralgia, paresthesia, headache, or dizziness and/or delayed symptom onset most likely
124
suffered a toxicity related adverse event and do not require further allergy diagnostics. In contrast, in
125
patients with a history of immediately occurring urticaria/angioedema/bronchospasm or anaphylaxis
126
indicating IHR as well as in patients with exanthems after 6 hours to 7 days consistent with NIHR
127
skin testing has been recommended.8,42
6
128
IHRs to diagnostic dyes typically occur in a surgery setting. Thus, in most patients various potential
129
other elicitors of anaphylactic reactions including latex, chlorhexidine, antibiotics, analgesics, and the
130
dye have been administered and should be included in the allergological workup.43
131
Allergological workup should best be performed in an allergy centre experienced in skin testing to
132
drugs +/- laboratory cellular tests, which is able to handle potentially occurring severe reactions in
133
case of provocation tests.42
134
Allergy tests during acute IHR
135
Elevated serum levels of tryptase and/or histamine have been shown in cases of hypersensitivity
136
reactions to ICM, GBCM, fluorescein, patent blue, isosulfan blue and methylene blue.7,30,31,43,44 In the
137
acute phase of an IHR, measurement of serum tryptase levels 1-4 hours after IHR onset and >24h later
138
(for obtaining a baseline level) can be helpful to differentiate anaphylaxis from other forms of
139
adverse events.29 Generally, positive correlation between concentration of tryptase and severity of
140
IHR has been reported, but not every patient with allergic IHR shows an increased tryptase level.7
141
Measurements of increased histamine levels are less practicable, because the assay is not commonly
142
available and half-life time of histamine is only 15-20min, thus requiring blood sample collection only
143
few minutes after reaction onset.
144
Allergy tests in following allergological workup
145
For best sensitivity, patients should be scheduled for allergological workup 2-6 month after the initial
146
reaction,45 although positive skin tests several years after the incident have been described.9
147
IHR to ICM, particularly toxicity-related reactions, were much more common in the past when ionic
148
ICM were in use. Thus, skin testing was usually negative and therefore not recommended. Patients
149
have been managed by ICM avoidance or premedication, which is effective in reducing reoccurrence
150
in the majority of toxic and nonallergic reactions. 46,47 Only after discontinuing use of ionic ICM, it
151
became apparent that severe IHR to non-ionic RCM may sometimes be associated with a positive skin
152
test. It is hypothesized that severe reactions that now occur using nonionic, low- and iso-osmolar ICM
153
are more likely to be immunologic and possibly IgE-mediated. Hence the role of skin testing in the
7
154
evaluation of IHRs to contrast media is envolving, as is the value of changing the ICM for renewed
155
contrast use. Recently, skin testing has increasingly been recommended by experts, particularly in
156
severe IHRs and slowly replaces the traditional practice of avoidance or premedication in an
157
increasing number of institutions.48 Even though less data is available for GBCM, by analogy with
158
RCM skin testing has been recommended particularly in severe reactions.7
159
160
Skin tests
161
Figure 3 shows an algorithm on skin testing and skin-test deducted management of patients. Skin
162
prick tests (SPT) and intradermal tests (IDT) with immediate readings are done for IHR and patch test
163
as well as late readings for SPT and IDT are added in case of an NIHR.49 Skin testing protocols have
164
been investigated in several observational studies for ICM and GBCM, whereas only expert opinions
165
and case series exist for dyes.4,36,50,51 When performing skin tests with dyes there may be a theoretical
166
risk of tattooing, but only temporary discoloration of the skin for 1-2 days has been reported.52
167
After an IHR, SPT and if negative, IDT should be performed with the culprit contrast agent and with a
168
positive (e.g. histamine) and negative control (saline) and read after 20min. If culprit is unknown, it is
169
advisable to test a panel of contrast agents normally used in the hospital/doctors ‘office where the
170
patient first had the procedure causing a reaction. Dilutions of ICM, GBCM and dyes commonly used
171
for skin tests are presented in Table 1, but in case of life-threatening initial reaction, using higher
172
dilutions has been recommended.49 Anaphylaxis after SPT or IDT is exceptional.36 When the culprit is
173
positive, further skin testing with a panel of alternative contrast agents should be performed for
174
selecting an skin test-negative alternative contrast agent for subsequent procedures, which is more
175
likely to be tolerated.8 The panel should be adjusted to agents available in the institution performing
176
the future procedures.
177
After an exanthematous NIHR, a patch test as well as SPT and an IDT with late readings (usually 48h
178
and 72h) are performed.19 It has been reported for ICM and GBCM that IDT showed higher
179
sensitivity than patch test.7,53 The optimal time point for late readings is not well studied and
8
180
additional readings e.g. after 24 hours or after one week may be considered.14 After severe NIHR
181
especially SJS, TEN and vasculitis, skin testing may be of lower value.19 Since re-administration of
182
contrast media is contraindicated in patients with history of life-threatening NIHR, skin tests are only
183
helpful in the case when multiple drugs have been administered to determine the responsible drug for
184
NIHR. In those cases, using higher dilutions of test substances should be considered.49
185
There is no reliable data based on lager patient numbers on skin test sensitivity and specificity for
186
dyes and GBCM. For ICM, sensitivity of skin testing has been shown to depend on the severity of
187
reaction and time between reaction and skin test. A meta-analysis of 21 studies from Yoon et al. 36
188
showed 52% positive skin tests in severe IHRs to ICM but only 17% when also mild and moderate
189
reactions were included. 26% of patients with NIHR had positive skin tests. The specificity of skin-
190
tests for ICM is reported to be 95% for SPT and 91-96% for IDT.53 The negative predictive value
191
(NPV) of skin testing in IHR to ICM has been reported by different authors to be 94% -98% and 68-
192
86% for NIHR.36,45,50,54,55 However, these studies were not only done in patients with positive skin test
193
to the culprit, but also in those (non-allergic) patients with no positive skin test at all. There is no data
194
available on the positive predictive value of skin testing since a re-administration of a skin test
195
positive drug is highly likely to cause a reaction and would thus be unethical.
196
Only little data is available on NPV of skin tests in GBCM, but a case series reported 11 re-
197
administrations of skin test negative GBCM without a single reaction using skin test-negative
198
alternatives.51
199
Cross-reactivity in skin testing of ICM is described by multiple authors and may occur in up to 50%
200
of skin tests, particularly in NIHRs. It has been proposed that cross-reactivity may be more frequent in
201
ICM with N-(2,3-dihydroxypropyl) carbamoyl side chain (iopromide, iomeprol, ioversol, iohexol,
202
iodixanol), but there is inconsistency between different studies and further examination of cross-
203
reactivity patterns is needed.39,45,53 For GBCM, there is in the current state of knowledge insufficient
204
data to validly predict cross-reactivity between different substances. For patent blue and isosulfan
205
blue, a cross-reactivity in skin tests has been shown, which was explained by their similar molecular
9
206
structure, as illustrated in Figure 4.30 Methylene blue is a possible alternative since it has a different
207
molecular structure, it´s lower reported incidence of anaphylaxis.11
208
Laboratory tests
209
Laboratory tests are utilized experimentally to understand the pathomechanism of IHRs and NIHRs
210
and appear to be less sensitive than skin tests, but may also be helpful in confirming the diagnosis in
211
individual patients.8 Basophil activation test (BAT) measures basophil activation, e.g. by CD63
212
expression on basophiles via flow cytometry.56 For patent blue, ICM and GBCM positive BAT could
213
be shown.57–59 For ICM BAT is regularly used, but mostly in small samples sizes and good data on
214
sensitivity are still lacking, but specifity is estimated on 88,4% - 100% and BAT with ICM was
215
suggested to be useful for conformation of IHR to ICM.60 Sensitivity of BAT in GBCM is estimated
216
at 93% but is based on a small number of patients.59 Leukocyte histamine release testing was also
217
described in IHRs to ICM as well as lymphocyte transformation testing in NIHRs.40
218
219
Drug Provocation Test (DPT)
220
Intravenous DPT with a skin test negative contrast agent (ICM or GBCM) has been increasingly
221
described, but is neither part of routine allergological workup yet, nor standardized and
222
validated.39,59,61–64 For fluorescein conjunctival DPT has been reported as additional diagnostical step
223
when all skin tests were negative.65 Severe reactions to DPT have been reported and DPT could cause
224
side effects such as kidney damage when using ICM or nephrogenic systemic fibromatosis when
225
using GBCM.61 Because of its risk of hypersensitivity reactions DPT should be performed in
226
experienced and well-equipped institutions. Performing DPT may be considered especially in patients
227
after severe anaphylaxis with a skin test-negative alternative contrast medium, as DPT has a higher
228
sensitivity than skin testing alone.39
229
10
230
Management of patients with previous hypersensitivity
231
Patients with urgent need of ICM/GBCM without test possibility
232
An algorithm on management of patients with history of hypersensitivity reactions to contrast media
233
and needing a new procedure with contrast media is shown in Figure 5. For patients with a history of
234
ICM or GBCM hypersensitivity with immediate and urgent need of another procedure with contrast
235
media type and severity of initial reaction need to be evaluated. In Patients with mild urticaria or
236
angioedema or uncomplicated maculopapular exanthema, re-administration of a non-culprit contrast
237
medium may be performed using premedication,14 which supresses the majority of non-allergic
238
reactions (Figure 5).66 Several possible premedication protocols have been proposed, with a protocol
239
using a combination of H1-antihistamine (e.g. 50 mg diphenhydramine 1 hour before application) and
240
several doses of corticosteroids (e.g. 50 mg prednisone 13, 7, and 1 hours before application) often
241
cited.48 For NIHR the efficiency of premedication is unknown and likely to be low. Corticosteroids
242
may be used, but one should not rely on them to completely avoid reactions. In IHR allergic reactions
243
might occur despite the use of premedication (breakthrough reactions), but premedication may reduce
244
their severity.2
245
If the patient has suffered a moderate to severe anaphylaxis, another imaging modality should be
246
chosen in order to avoid re-administration of the same substance class (ICM or GBCM) (Figure 5). If
247
imaging with the same substance class is unavoidable and risk benefit analysis justifies the high risk
248
of re-administration, a contrast agent other than the culprit should be selected and premedication as
249
well as anesthesiology stand-by and emergency preparedness should be applied to be able to handle
250
potentially occurring severe reactions. (Figure 5). For these high risk patients, the setting for imaging
251
should be as safe as possible, e.g. by taking place at daytime in hospitals with code teams, with close
252
observation (possibly using pulsoxymetry) especially during the first 20 min since the most severe
253
reactions start quickly.2 Successful desensitization of ICM has been reported for IHR to ICM, but is
254
only used annectodical.67 Patients with a history of life-threatening NIHR re-administration of any
255
contrast agent from the same group (ICM or GBCM) should best be avoided.45
11
256
Management of patients with time for allergological workup
257
For patients without the need for immediate imaging an allergological workup should be performed to
258
classify hypersensitivity mechanism and to select a skin test- or even DPT-negative ICM/GBCM for
259
re-administration (Figure 3). In patients with confirmed IHR by skin test-positive culprit, a skin test-
260
negative alternative can be administered without premedication, but one should still be prepared for
261
emergencies. Applying premedication might still be considered, if the initial hypersensitivity reaction
262
was severe. The positive culprit along with all other skin test-positive contrast agents from the tested
263
panel should be never re-administered.7 In centers, where BAT or LTT is available, they may
264
supplement skin testing and their outcome should be considered to select the agent for
265
readministration. Whether DPT prior to re-administration is advisable must be decided on an
266
individual basis.45
267
If the culprit and test panel is negative in all performed skin tests, further skin tests with a panel of
268
alternative contrast media are not likely to be helpful and a non-culprit agent with premedication and
269
under emergency preparedness can be applied.
270
In cases with severe IHRs a thorough risk benefit analysis is done and re-administering a contrast
271
agent may be contraindicated. In severe bullous or systemic NIHR the culprit along with all other
272
contrast media of the same class (ICM or GBCM) should not be readministered.
273
Management of patients with previous hypersensitivity to dyes
274
There is only scarce literature on managing patients with previous hypersensitivity to dyes but the
275
concepts used in managing patients with hypersensitivity to ICM or GBCM could be transferred to
276
dyes.
277
In IHRs caused by patent blue or isosulfan blue in surgery it should be considered to finish the
278
procedure if the patient can be stabilized reliably, thus avoiding the need of a second procedure with
279
re-administration of dye.30 If re-administration is unavoidable, the safest option would be using
280
methylene blue, indocyanine green or technetium.11,52 For prevention of reactions to patent blue and
281
isosulfan blue, using smaller amount of dye has been proposed, since King et al.68 reported a trend
12
282
towards fewer allergic reactions when less dye was used. However, their findings were not
283
statistically significant.68
284
In patients with a previous reaction to fluorescein, especially severe ones, using an alternative
285
imaging method like indocyanine green angiography or optical choherence tomography angiography
286
to avoid readministration of fluorescein should be considered. If there is no alternative to fluorescein,
287
event-free re-administration of flourescein after desensitization has been described in a case report.69
288
The role of antihistamine and corticosteroid premedication for dyes is still being debated: The
289
efficacy of premedication for fluorescein is unknown and actively being discussed.32,70 For patent blue
290
and isosulfan blue premedication with corticosteroids is thought to reduce severity of reaction but not
291
the occurrence of IHR.4
292
Conclusion
293
Hypersensitivity reactions during procedures to contrast agents and dyes are highly relevant since
294
increasing numbers of applications cause increasing incidence of hypersensitivity reactions, which
295
could possibly end fatal. Radiologists, anaesthetists and surgeons should not rely on premedication,
296
since especially in severe reactions premedication has be reported to be insufficient. They should be
297
well- trained in understanding and managing IHRs and NIHRs and in handling patients with increased
298
risk of hypersensitivity reactions. Since severe hypersensitivity reactions appear to be more likely
299
caused by an allergic mechanism, skin testing in those patients is highly recommended and may help
300
selecting skin-test negative alternatives for use in future procedures. For mild non-allergic reactions
301
changing the contrast medium in combination with premedication is often sufficient. More studies on
302
the mechanism of contrast agent hypersensitivity for ICM, GBCM and dyes and diagnostic value of
303
drug provocation test and BAT would be desirable.
References [1] Christiansen C. X-ray contrast media--an overview. Toxicology 2005;209(2):185–7. [2] Heshmatzadeh Behzadi A, Prince MR. Preventing Allergic Reactions to Gadolinium-Based Contrast Agents. Top Magn Reson Imaging 2016;25(6):275–9. [3] Brockow K, Christiansen C, Kanny G, et al. Management of hypersensitivity reactions to iodinated contrast media. Allergy 2005;60(2):150–8. [4] Brockow K, Sánchez-Borges M. Hypersensitivity to contrast media and dyes. Immunol Allergy Clin North Am 2014;34(3):547-64. [5] Bircher AJ, Brockow K, Grosber M, et al. Late elicitation of maculopapular exanthemas to iodinated contrast media after first exposure. Ann Allergy Asthma Immunol 2013;111(6):576–7. [6] Muraro A, Roberts G, Worm M, et al. Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology. Allergy 2014;69(8):1026–45. [7] Clement O, Dewachter P, Mouton-Faivre C, et al. Immediate Hypersensitivity to Contrast Agents: The French 5-year CIRTACI Study. EClinicalMedicine 2018;1:51–61. [8] Trautmann A, Brockow K, Behle V, et al. Radiocontrast Media Hypersensitivity: Skin Testing Differentiates Allergy From Nonallergic Reactions and Identifies a Safe Alternative as Proven by Intravenous Provocation. J Allergy Clin Immunol Pract 2019;7(7):2218–24. [9] Harr T, Jandus P. Late Diagnosis of Anaphylactic Reaction to Gadolinium-Based Contrast Media by Skin Tests 10 Years After Onset. J Investig Allergol Clin Immunol 2018;28(3):203–5. [10] Carr TF. Pathophysiology of Immediate Reactions to Injectable Gadolinium-based Contrast Agents. Top Magn Reson Imaging 2016;25(6):265–8. [11] Iqbal FM, Basit A, Salem F, et al. Feeling blue, going green and finding other attractive alternatives: a case of biphasic anaphylaxis to patent blue and a literature review of alternative sentinel node localisation methods. BMJ Case Rep 2015;2015:bcr2015213107. [12] Chu JN, Lazar J, Badger J. A postoperative blue rash: indigo carmine dye extravasation. Int J Dermatol 2015;54(9):e371-2. [13] Brockow K, Ardern-Jones MR, Mockenhaupt M, et al. EAACI position paper on how to classify cutaneous manifestations of drug hypersensitivity. Allergy 2019;74(1):14–27. [14] Corbaux C, Seneschal J, Taïeb A, et al. Delayed cutaneous hypersensitivity reactions to iodinated contrast media. Eur J Dermatol 2017;27(2):190–1. [15] Epskamp C, Snels DGCTM, Yo GL, et al. Bullous fixed drug eruption in a patient with metastatic renal cell carcinoma induced by iodinated contrast during pazopanib treatment. Eur J Dermatol 2016;26(2):207–8. [16] Grandvuillemin A, Ripert C, Sgro C, et al. Iodinated contrast media-induced acute generalized exanthematous pustulosis confirmed by delayed skin tests. J Allergy Clin Immunol Pract 2014;2(6):805–6. [17] Velter C, Schissler C, Moulinas C, et al. Acute generalized exanthematous pustulosis caused by an iodinated contrast radiocontrast medium for computed tomography arthrography of the knee. Contact Derm 2017;76(6):371–3. [18] Yang SS, Aw DC, Chandran NS. Severe Cutaneous Adverse Reactions Following Intravenous Contrast: A Report of 2 Cases. Ann Acad Med Singap 2015;44(12):561–4.
[19] Tasker F, Fleming H, McNeill G, et al. Contrast media and cutaneous reactions. Part 2: Delayed hypersensitivity reactions to iodinated contrast media. Clin Exp Dermatol 2019. (Epub ahead of print) [20] Bordel Gómez MT, Martín García C, Meseguer Yebra C, et al. First case report of acute generalized exanthematous pustulosis (AGEP) caused by gadolinium confirmed by patch testing. Contact Derm 2018;78(2):166–8. [21] Katayama H, Yamaguchi K, Kozuka T, et al. Adverse reactions to ionic and nonionic contrast media. A report from the Japanese Committee on the Safety of Contrast Media. Radiology 1990;175(3):621–8. [22] Webb JAW, Stacul F, Thomsen HS, et al. Late adverse reactions to intravascular iodinated contrast media. Eur Radiol 2003;13(1):181–4. [23] Sutton AG, Finn P, Grech ED, et al. Early and late reactions after the use of iopamidol 340, ioxaglate 320, and iodixanol 320 in cardiac catheterization. Am Heart J 2001;141(4):677–83. [24] Brockow K. Immediate and delayed cutaneous reactions to radiocontrast media. Chem Immunol Allergy 2012;97:180–90. [25] Forbes-Amrhein MM, Dillman JR, Trout AT, et al. Frequency and Severity of Acute AllergicLike Reactions to Intravenously Administered Gadolinium-Based Contrast Media in Children. Invest Radiol 2018;53(5):313–8. [26] Dillman JR, Ellis JH, Cohan RH, et al. Frequency and Severity of Acute Allergic-Like Reactions to Gadolinium-Containing IV Contrast Media in Children and Adults. American Journal of Roentgenology 2007;189(6):1533–8. [27] Jung J-W, Kang H-R, Kim M-H, et al. Immediate hypersensitivity reaction to gadolinium-based MR contrast media. Radiology 2012;264(2):414–22. [28] Behzadi AH, Zhao Y, Farooq Z, et al. Immediate Allergic Reactions to Gadolinium-based Contrast Agents: A Systematic Review and Meta-Analysis. Radiology 2018;286(2):471–82. [29] Fok JS, Smith WB. Hypersensitivity reactions to gadolinium-based contrast agents. Curr Opin Allergy Clin Immunol 2017;17(4):241–6. [30] Hunting AS, Nopp A, Johansson SGO, et al. Anaphylaxis to Patent Blue V. I. Clinical aspects. Allergy 2010;65(1):117–23. [31] Lee T, Sanderson D, Doyle P, et al. Anaphylactic Shock After Intravenous Fluorescein Administration for Intraoperative Cystoscopy. Obstet Gynecol 2018;131(4):727–9. [32] Kornblau IS, El-Annan JF. Adverse reactions to fluorescein angiography: A comprehensive review of the literature. Surv Ophthalmol 2019;64(5):679–93. [33] Laroche D, Aimone-Gastin I, Dubois F, et al. Mechanisms of severe, immediate reactions to iodinated contrast material. Radiology 1998;209(1):183–90. [34] Yannuzzi LA, Rohrer KT, Tindel LJ, et al. Fluorescein Angiography Complication Survey. Ophthalmology 1986;93(5):611–7. [35] Wöhrl S, Focke M, Hinterhuber G, et al. Near-fatal anaphylaxis to patent blue V. Br J Dermatol 2004;150(5):1037–8. [36] Yoon SH, Lee S-Y, Kang H-R, et al. Skin tests in patients with hypersensitivity reaction to iodinated contrast media: a meta-analysis. Allergy 2015;70(6):625–37.
[37] Scherer K, Harr T, Bach S, et al. The role of iodine in hypersensitivity reactions to radio contrast media. Clin Exp Allergy 2010;40(3):468–75. [38] Haque RA, Wagner A, Whisken JA, et al. Anaphylaxis to patent blue V: a case series and proposed diagnostic protocol. Allergy 2010;65(3):396–400. [39] Torres MJ, Gomez F, Doña I, et al. Diagnostic evaluation of patients with nonimmediate cutaneous hypersensitivity reactions to iodinated contrast media. Allergy 2012;67(7):929–35. [40] Lerch M, Keller M, Britschgi M, et al. Cross-reactivity patterns of T cells specific for iodinated contrast media. J Allergy Clin Immunol 2007;119(6):1529–36. [41] Pichler WJ, Naisbitt DJ, Park BK. Immune pathomechanism of drug hypersensitivity reactions. J Allergy Clin Immunol 2011;127(3 Suppl):S74-81. [42] Rosado Ingelmo A, Doña Diaz I, Cabañas Moreno R, et al. Clinical Practice Guidelines for Diagnosis and Management of Hypersensitivity Reactions to Contrast Media. J Investig Allergol Clin Immunol 2016;26(3):144-55. [43] Dewachter P, Mouton-Faivre C, Tréchot P, et al. Severe anaphylactic shock with methylene blue instillation. Anesth Analg 2005;101(1):149-50. [44] Sandhu S, Farag E, Argalious M. Anaphylaxis to isosulfan blue dye during sentinel lymph node biopsy. J Clin Anesth 2005;17(8):633–5. [45] Schrijvers R, Breynaert C, Ahmedali Y, et al. Skin Testing for Suspected Iodinated Contrast Media Hypersensitivity. J Allergy Clin Immunol Pract 2018;6(4):1246–54. [46] American Academy of Allergy, Asthma, American College of Allergy, Asthma, Joint Council of Allergy, Asthma, et al. Drug allergy: an updated practice parameter. Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 2010;105(4):259. [47] Greenberger PA, Patterson R. The prevention of immediate generalized reactions to radiocontrast media in high-risk patients. Journal of Allergy and Clinical Immunology 1991;87(4):867–72. [48] Sánchez-Borges M, Aberer W, Brockow K, et al. Controversies in Drug Allergy: Radiographic Contrast Media. J Allergy Clin Immunol Pract 2019;7(1):61–5. [49] Brockow K, Romano A, Blanca M, et al. General considerations for skin test procedures in the diagnosis of drug hypersensitivity. Allergy 2002;57(1):45–51. [50] Soyyigit S, Goksel O, Aydin O, et al. What is the clinical value of negative predictive values of skin tests to iodinated contrast media? Allergy Asthma Proc 2016;37(6):482–8. [51] Chiriac A-M, Audurier Y, Bousquet P-J, et al. Clinical value of negative skin tests to gadolinium contrast agents. Allergy 2011;66(11):1504–6. [52] Baker MG, Cronin JA, Borish L, et al. Evaluation of a skin testing protocol for diagnosing perioperative anaphylaxis due to isosulfan blue allergy. Ann Allergy Asthma Immunol 2014;113(3):330–1. [53] Brockow K, Romano A, Aberer W, et al. Skin testing in patients with hypersensitivity reactions to iodinated contrast media - a European multicenter study. Allergy 2009;64(2):234–41. [54] Caimmi S, Benyahia B, Suau D, et al. Clinical value of negative skin tests to iodinated contrast media. Clin Exp Allergy 2010;40(5):805–10.
[55] Kwon OY, Lee J-H, Park S-Y, et al. Novel Strategy for the Prevention of Recurrent Hypersensitivity Reactions to Radiocontrast Media Based on Skin Testing. J Allergy Clin Immunol Pract 2019. (Epub ahead of print) [56] Mayorga C, Celik G, Rouzaire P, et al. In vitro tests for drug hypersensitivity reactions: an ENDA/EAACI Drug Allergy Interest Group position paper. Allergy 2016;71(8):1103–34. [57] Boita M, Mietta S, Bommarito L, et al. Basophil activation test in the diagnosis of patent blue V anaphylaxis. Ann Allergy Asthma Immunol 2015;115(1):78–9. [58] Trcka J, Schmidt C, Seitz CS, et al. Anaphylaxis to iodinated contrast material: nonallergic hypersensitivity or IgE-mediated allergy? AJR Am J Roentgenol 2008;190(3):666–70. [59] Kolenda C, Dubost R, Hacard F, et al. Evaluation of basophil activation test in the management of immediate hypersensitivity reactions to gadolinium-based contrast agents: a five-year experience. J Allergy Clin Immunol Pract 2017;5(3):846–9. [60] Pinnobphun P, Buranapraditkun S, Kampitak T, et al. The diagnostic value of basophil activation test in patients with an immediate hypersensitivity reaction to radiocontrast media. Ann Allergy Asthma Immunol 2011;106(5):387–93. [61] Soria A, Masson N, Vial-Dupuy A, et al. Allergological workup with half-dose challenge in iodinated contrast media hypersensitivity. Allergy 2019;74(2):414–7. [62] Seta V, Gaouar H, Badaoui A, et al. Low-dose provocation and skin tests in patients with hypersensitivity to gadolinium-based contrast agents. Clin Exp Allergy 2019;49(5):724–8. [63] Sesé L, Gaouar H, Autegarden J-E, et al. Immediate hypersensitivity to iodinated contrast media: diagnostic accuracy of skin tests and intravenous provocation test with low dose. Clin Exp Allergy 2016;46(3):472–8. [64] Lerondeau B, Trechot P, Waton J, et al. Analysis of cross-reactivity among radiocontrast media in 97 hypersensitivity reactions. J Allergy Clin Immunol 2016;137(2):633-635.e4. [65] Trindade-Porto C, Alonso-Llamazares A, Robledo T, et al. Fluorescein-induced adverse reaction. Allergy 1999;54(11):1230. [66] American College of Radiology Commitee. ACR Manual on Contrast Media Version 10.3 2018;2018:1–125. https://www.acr.org › ACR › Files › Clinical-Resources [67] Gandhi S, Litt D, Chandy M, et al. Successful rapid intravenous desensitization for radioiodine contrast allergy in a patient requiring urgent coronary angiography. J Allergy Clin Immunol Pract 2014;2(1):101–2. [68] King TA, Fey JV, van Zee KJ, et al. A prospective analysis of the effect of blue-dye volume on sentinel lymph node mapping success and incidence of allergic reaction in patients with breast cancer. Ann Surg Oncol 2004;11(5):535–41. [69] Nucera E, Schiavino D, Merendino E, et al. Successful fluorescein desensitization. Allergy 2003;58(5):458. [70] Knowles SR, Weber EA, Berbrayer CS. Allergic reaction to fluorescein dye: successful one-day desensitization. Can J Ophthalmol 2007;42(2):329–30.
1
Captions Fig. 1 Clinical pictures of a patient with non-immediate contrast media allergy. A) Maculopapular exanthem after Imeron (Iomeprol) despite premedication with corticosteroid and H1- and H2-antihistamins. B) In the patch test after 48 hours positive reaction to Imeron (Iomeprol) (arrow) with cross-reactivity to other contrast media. Fig. 2 Overview over the different chemical properties of iodinated contrast media (ICM). In ionic ICM, the contrast agent consists of a 1,3,5-tri-iodobenzene core including an acid-group (COO¯ group) as anion and sodium or meglumine as cation, whereas non-ionic products don´t carry acid groups. Fig. 3 Algorithm for skin testing of patients with previous hypersensitivity reactions to iodinated contrast media or gadolinium-based contrast media and skin test result-deduced management of re-administration. This algorithm is based on skin testing, but further allergological tests could be added e.g. basophil activation test, lymphocyte transformation test or drug provocation test, as described in the review. CM contrast media, DRESS drug reaction with eosinophilia and systemic symptoms, IDT intradermal test, ME maculopapular exanthem, SJS Steven-Johnson Syndrome, SPT skin prick test, TEN toxic epidermal necrolysis.
Fig. 4 Molecular structure of blue dyes. Patent blue and isosulfan blue have partially identical structures (marked in blue) whereas methylene blue has a completely different structure.
Fig. 5 Algorithm for management of patients with a history of adverse reactions to iodinated contrast media or gadolinium-based contrast media needing contrasted imaging. Management according to outcome of skin testing is described in Figure 2.
2
CM Contrast media, DRESS drug reaction with eosinophilia and systemic symptoms, ICM iodinated contrast media, GBCM gadolinium-based contrast media, IHR immediate hypersensitivity reaction, NIHR non-immediate hypersensitivity reaction, SJS StevenJohnson Syndrome, TEN toxic epidermal necrolysis.
Table 1. Skin test concentrations for contrast agents and dyes Name of contrast agent or dye Iodinated contrast media (ICM) Gadolinium based contrast media (GBCM) Dyes Fluorescein
Skin prick test (SPT) Undiluted (300-320 mg/ml) Undiluted
Intradermal Patch test test (IDT) (PT) 1:10* Undiluted
1:10
Additional information on skin tests see EACCI/ENDA Guidelines 41
Undiluted
Reading times: Immediate hypersensitivity reaction: SPT and IDT after 20min Non-immediate exanthems**: SPT and IDT after 20min, 48h, 72h PT after 48h, 72h
1:10
Undiluted
1:100
No data
Isosulfan blue
Undiluted (200mg/ml) Undiluted (25mg/ml) Undiluted
1:10
No data
Methylene blue
Undiluted
1:100
No data
Patent blue
Comments
*1:10 is recommended by EACCI/ENDA Guidelines, but IDT with undiluted ICM may be performed in non-severe nonimmediate hypersensitivity reactions. There is inconclusive data, if undiluted ICM can cause irritative reactions in the immediate reading of IDT **Timepoints for late readings are standardized, but not well studied. Additional readings (e.g. 24h, 1week) may be added.
History of adverse reaction to CM
Type of reaction based on chronology and symptoms
Immediate type hypersensitivity (urticaria, anaphylaxis)
Toxic/physiologic reaction or unrelated event
Non-immediate hypersensitivity (exanthems)
SPT and, if negative, IDT with immediate reading of culprit CM
No allergological workup
Severity of reaction
Positive
Negative
Patch test, SPT and IDT with late readings of culprit + panel of alternatives
Perform SPT and IDT with alternative CM
Use skin-test negative CM
Suggestions for re-administration
Severe (e.g. SJS, TEN, DRESS)
Mild (e.g. ME)
Use CM other than culprit with premedication under emergency preparedness. When initial reaction was life-threatening consider a different imaging modality to avoid re-administration
Positive
Negative
Use skin-test negative CM
Use non-culprit CM + corticoid premedication
Skin test possible for confirmation of diagnosis. Initial use of higher dilutions No re-administration
CH3CH2
N+
CH2CH3
CH3CH2
N+
CH2CH3
N
–
SO3
H3C
HO HO3S
SO3H
N CH3CH2
Isosulfan Blue
CH2CH3
N NaO3S
CH2CH3
N H3C
S
N+
H3C
CH3CH2
Patent Blue
CH3
Methylene Blue
CI
–
When is the next radiological examination needed? Elective
Urgent/emergency Imaging/procedure with another method possible and sufficient?
Yes
Use that method
No Type and severity of initial reaction? Perform allergological workup prior to re-administration
Urticaria/angioedema or mild maculopapular exanthema
Severe IHR/anaphylaxis
Severe NIHR (SJS, TEN, DRESS)
Risk/benefit analysis for re-administration?
Manage patient according to outcome of allergy testing
Re-administer other than culprit with premedication and emergency preparedness
Avoid or re-administer non-culprit alternative with premedication, emergancy preparedness and anesthesiology stand-by
Avoid all CM of the same class (all ICM or GBCM)
Chemical properties of Iodinated Contrast Media IONIC
NONIONIC
Monomeric:*
Monomeric:
Iothalamate Iopanoic acid Iotroxic acid Diatrizoate Metrizoate
Iohexol Iopamidol Iopromide Ioversol Ioxilan Iomeprol Iobitridol
Dimeric:*
Ioxaglate
* Mostly used as a meglumin or sodium salt
Dimeric:
Iodixanol