Iodinated contrast media hypersensitivity.pdf

Iodinated contrast
media Hypersensitivity
F1 Pongsawat Rodsaward

Outline
•Radiocontrast media
•Epidemiology and Risk factor
•Pathophysiology
•Clinical manifestation
•Investigation
•Management

Radiocontrast media
•Iodinated contrast media (ICM) were introduced into clinical practice in the
early twentieth century.
•In the 1950s, ICM were increasingly used thanks to new formulations with
higher resolution and lower toxicity.
•In the 1970s, nonionic dimeric ICM and derivatives with higher
physiological osmolality were developed.
J Investig Allergol Clin Immunol 2016; Vol. 26(3): 144-155

Radiocontrast media
•ICM are iodine salts whose basic chemical structure comprises a benzene
ring with at least 3 iodine atoms (triiodobenzene).
•The number of iodine atoms in each molecule is responsible for producing
radiopacity.
•An ICM is ionic if it transforms into ions or charged particles in aqueous
solution or nonionic if it does not form ions, remaining instead an
electrically neutral particle in solution.

Radiocontrast media classification
1950s 1980s 1980-present
1990-present

Name Type OSM Osmolality
Ionic
Ioxaglate (Hexabrix) Dimer 580 LOCM
Diatrizoate (Hypaque 50, Renografin) Monomer 1,550 HOCM
Iothalamate (Conray) Monomer 1843 HOCM
Metrizoate (Isopaque 370) Monomer 2,100 HOCM
Nonionic
Iodixanol (Visipaque 320) Dimer 290 IOCM
Iotrolan (Isovist) Dimer 320 IOCM
Iomeprol (Iomeron 350) Monomer 618 LOCM
Ioversol (Optiray 300) Monomer 651 LOCM
Ioxilan (Oxilan 350) Monomer 695 LOCM
Iobitridol (Xenetix 300) Monomer 695 LOCM
Iopromide (Ultravist 370) Monomer 774 LOCM
Iopamidol (Iopamiro, Isovue-370) Monomer 796 LOCM
Iohexol (Omnipaque 350) Monomer 884 LOCM
isoosmolar contrast media
osmolality of approximately
290 mOsm/kg
high-osmolar contrast media
osmolality of 1500 to 1800
mOsm/kg
low-osmolar contrast media
osmolality of 600 to 850
mOsm/kg
Advances in Nephrology, vol. 2014, Article ID 691623, 11 pages

J Allergy Clin Immunol. 2016 Feb;137(2):633-635.
Radiocontrast media classification
Omnipaque 350
Xenetix 300
Omnipaque 350
Iopamiro 370
Visipaque 320
Iopamiro 370
Visipaque 320
ionic tri-iodized monomers (IMs)
ionic hexa-iodized dimers (IDs)
nonionic tri-iodized monomers (NIMs)
nonionic hexaiodized dimers (NIDs)
Xenetix 300

Epidemiology
•Worldwide more than 75 million X-ray examinations are performed per year
using radiographic contrast media (RCM).
•Currently nonionic RCMs are preferred more in clinical practice owing to
their lower hypersensitivity profile.
•The prevalence of immediate hypersensitivity reactions
• Monomeric ionic RCM: 3.8% - 12.7%
• Nonionic RCM: 0.7% - 3%
J Allergy Clin Immunol Pract 2019;7:61-5
Br J Radiol. 2017 Feb;90(1070):20160729.

Epidemiology and Risk factor
ADR profile of non-ionic iodinated contrast media
from 120,822 cases who underwent enhanced CT
examination in Daping hospital (China) from January
2014 to March 2016
Br J Radiol. 2017 Feb;90(1070):20160729.
Characteristics
Number of patients
(%) ADR (%)
Characteristics Number of
patients (%) ADR (%)
Characteristics Number
of patients (%) ADR (%)
Total 120,822 506 (0.42)
Male 66,753 (55.25) 256 (0.38)
Female 54,069 (44.75) 250 (0.46)
Age range (years) 0–104 4-90
<10 485 (0.40) 2 (0.41)
10–19 1146 (0.95) 4 (0.35)
20–29 3382 (2.80) 25 (0.74)
30–39 6874 (5.69) 41 (0.60)
40–49 21,751 (18) 140 (0.64)
50–59 27,853 (23.05) 140 (0.50)
60–69 33,263 (27.53) 103 (0.31)
70–79 19,681 (16.29) 41 (0.21)
>80 6387 (5.29) 10 (0.16)
Types of NICMs
Iso-osmolar 18,614 (15.41) 129 (0.69)
Hypo-osmolar 102208 (84.59) 377 (0.37)

ADRs are more common in patients at high injection dose
(>=100 ml) and speed (>=5 ml/sec )
The incidence was the highest in patients with
previous ADRs to ICMs and the lowest in those with
a history of ICM usage but no prior reactions.
Br J Radiol. 2017 Feb;90(1070):20160729.

J Investig Allergol Clin Immunol. 2019;29(6):444-450.
Included all patients who underwent an LOCMenhanced
computed tomography (CT) examination from July 2012
through June 2014 at Seoul National University Hospital,
Seoul, Korea.
total of 205,726 exposures to LOCM in 86,328 patients,
2004 immediate HSRs during the study period (incidence
of 0.97%)
The incidence of HSR did not differ significantly across the 5
LOCM assessed in the study.

number of previous exposures
J Investig Allergol Clin Immunol. 2019;29(6):444-450.
The incidence of immediate hypersensitivity to LOCM was
higher in patients with comorbid allergic diseases such as
asthma, allergic rhinitis and chronic urticaria and in patients
with cancer and chronic liver disease.
Gradually increasing trend in the incidence of
hypersensitivity to iodinated contrast media
as the number of previous exposures
increased

Asian Pac J Allergy Immunol. 2013 Dec;31(4):299-306.
The retrospective case-control study was
conducted between 2008 and 2010 in Siriraj
Hospital, access to the medical records of all
patients exposed to iodinated CM
The prevalence of CM adverse reactions was
as low as 1.05%
555 reactions (95.9%) Adult
24 reactions (4.1%) Ped

Asian Pac J Allergy Immunol. 2013 Dec;31(4):299-306.
Risk factors consist of a history of previous CM
reactions, female gender and seafood allergy.
Nevertheless, serious immediate reactions could
occur particularly in patients with asthma.

Risk factor
Data of 407 patients investigated in 9
Italian Allergy Centers for suspected
HRs to ICM were analyzed and
compared with a control group of 152
subjects that tolerated one or more
ICM-enhanced examinations
Eur Ann Allergy Clin Immunol . 2022 Mar;54(2):60-67.

Pathophysiology - immediate
• Immediate nonallergic reactions
• Osmolality - direct membrane effect
• Hyperosmolality >> stimulation of histamine release from basophils and mast cells
• low-osmolality nonionic monomers produce the lowest levels of histamine release from basophils
compared with others
• Activation of the complement system
• C3a, C4a and C5a
• Activation of factor XII
• leading to activation of the kinin system and the production of bradykinin
• MRGPRX2
• MRGPRX2-related anaphylactic reactions induced by Iopamidol
• IgE mediated reaction
The British Journal of Radiology, 78(2005), 686–693
Int Immunopharmacol. 2019 Oct;75:105800.

Pathophysiology - immediate
•Immediate nonallergic reactions
•IgE mediated reaction
• Positive skin test results with RCM
• It has been demonstrate ionic RCM -specific IgE
• assays for the modern non-ionic RCM have not been described
Ring J (ed): Anaphylaxis. Chem Immunol Allergy. Basel, Karger, 2010, vol 95, pp 157–169

Pathophysiology - delayed
•T cell–mediated mechanism
• Positive skin test site biopsies show a perivascular infiltrate consisting mainly of
CD4+ and CD8+ T cells
• RCM-related T-cell activity may be assessed in vitro by lymphocyte
transformation test
Ring J (ed): Anaphylaxis. Chem Immunol Allergy. Basel, Karger, 2010, vol 95, pp 157–169

Pathophysiology - delayed
• case of a patient who developed
Stevens-Johnson syndrome (SJS)
to a previously tolerated iodinated
contrast medium, amidotrizoate,
after the use of atezolizumab, a
PD-L1 blocker.
Hammond S, et al. J Immunother Cancer 2021;9:e002521.

Pathophysiology - HLA
5.06%
6.77%
6.36%
1.55%
0.82%
6.77%
Korean population
Transl Clin Pharmacol. 2021 Jun;29(2):107-116
Associations between HLA alleles and iodinated
contrast media– induced hypersensitivity in Koreans

Clinical manifestation
Hypersensitivity
reaction
Immediate
(Within 1 hr)
Non-immediate
(More than 1 hr)

Immediate hypersensitivity
American Colleague of Radiology, Manual on Contrast Media 2021
IH reactions occur within 1 h of CM
and clinically present as pruritis
and urticaria plus or minus
angioedema in approximately 70%
of cases
Clinical and Experimental Dermatology (2019) 44, pp839–843

Immediate hypersensitivity

Anaphylaxis
Extracted all the cases of RCM induced hypersensitivity from
January 2005 to December 2012 at Seoul National University
Hospital, in Seoul, Korea
A total number of contrast-enhanced CT scans during the study
period was 632,513. A total of 104 cases of RCM related
anaphylaxis were monitored during the study period. The
incidence of contrast-induced anaphylaxis was 0.016%.
PLoS One. 2014 Jun 16;9(6):e100154.

34.6% of patients, developed anaphylaxis on their
first exposure to RCM.
Anaphylactic patients presenting with shock had a
history of more frequently exposure to RCM)
compared to those without hypotension.
PLoS One. 2014 Jun 16;9(6):e100154.
Anaphylaxis

PLoS One. 2014 Jun 16;9(6):e100154.
Skin tests were performed in 51
patients after development of
RCM induced anaphylaxis.
Overall skin test positivity to RCM
was 64.7% and 81.8% in patients
with anaphylactic shock.
Among hypersensitivity symptoms
present in patients with
anaphylaxis, cardiovascular
symptoms were the most common
(88/104, 84.6%), followed by skin
symptoms (69/104, 66.3%) and
respiratory symptoms (50/104,
48.1%)

Delayed hypersensitivity
• The majority of late skin reactions occur within 3
days of contrast medium administration
• DHRs occur in 0.5–23% of people receiving ICM
and often present as a maculopapular exanthem.
• Other reactions include urticaria, angioedema and
scaling eruptions.
• They are usually self-limiting and resolve within 7
days.
Clin Exp Dermatol. 2019 Dec;44(8):844-860.
Eur Radiol (2011) 21:2305–2310

Disease N Onset ICM Remark
FDE 10 within 24 h over half of cases was a nonionic
monomeric medium
AGEP 16 2 h and 3 days 7/16 being triggered by
iodixanol
DRESS 6 within 1 h to 3 days - The majority (5/6) of
patients had multiple
exposures to ICM before
developing DRESS
SJS/TEN 11 30 min to 3 days Nonionic monomeric ICM was
the most frequent culprit
SDRIFE 4 6 h to 2 days -
Vasculitis 5 8 to 48 h -
Iododerma 17 2- 3 days - The majority of cases
(13/17) had renal
insufficiency

Ioderma
• a type of halogenoderma
• is a rare neutrophilic dermatosis occurring after exposure
to iodine including ICM, irrigation of wounds with
povidine iodine, ingestion of iodide supplements and the
use of amiodorone.
• Lesions most commonly appeared on the face and upper
body with satellite lesions on the extremities,
characterized by an acneiform, pustular and
haemorrhagic bullous or nodular vegetative eruption.
• The majority of cases had renal insufficiency, which likely
caused impaired iodine clearance.
AACE CLINICAL CASE REPORTS Vol 4 No. 2 March/April 2018

Outline
•Radiocontrast media
•Epidemiology and Risk factor
•Pathophysiology
•Clinical manifestation
•Investigation
•Management
Outline

Investigation
•Immediate
• Indication
• Skin test
• Tryptase
• Basophil activation test
• Drug provocation test
•Delayed
• Indication
• Skin test
• Lymphocyte transformation test
• Drug provocation test
Practice parameter - Allergy. 2021 May;76(5):1325-1339.

Indications for testing (immediate)
•To perform allergy work-up in patients with a history of ICM-induced
anaphylaxis (strong/moderate).
•To perform it in patients with a history of ICM-induced isolated urticaria,
angioedema, or bronchospasm (weak/ low).

•Skin testing for RCM immediate hypersensitivity may potentially identify
safe alternative(s) for re-exposure.
• However, this still needs to be confirmed with additional prospective studies.
• The opinion of most members of the expert panel is that the evaluation of patients
with RCM-induced anaphylaxis or exanthema should always include appropriate
skin tests ensuring that patients with IgE-mediated or delayed-type allergy are not
missed.
• Allergy testing may also identify alternative RCM that could be tolerated in future
radiologic investigations
Indications for testing
International Drug Allergy Symposium held at the Joint Congress of the American Academy of Allergy, Asthma & Immunology/World
Allergy Organization on March 1, 2018
Indications for testing

Skin tests (immediate)
• When to test:
• STs are preferably performed within 2-6 months after the reaction (weak/low).
• What to test:
• STs should be performed with the ICM involved in the reaction if known (strong/high).
• If the result is positive or if the culprit ICM is unknown, STs should be performed with
the broadest possible panel of ICM (strong/moderate).
• How to test:
• ICM should be used undiluted at 300- 320 mg/mL for SPT and diluted at 1:10 for IDT
(strong/ moderate).
• STs should start by performing SPT and, if negative, continue with IDT
(strong/moderate).

Skin tests (immediate)
• Skin testing for RCM immediate hypersensitivity may potentially identify safe
alternative(s) for re-exposure.
• However, this still needs to be confirmed with additional prospective studies.
• The opinion of most members of the expert panel is that the evaluation of patients
with RCM-induced anaphylaxis or exanthema should always include appropriate
skin tests ensuring that patients with IgE-mediated or delayed-type allergy are not
missed.
• Allergy testing may also identify alternative RCM that could be tolerated in future
radiologic investigations

12%
19%
42%
25%
1.25%
25%
50%
17%
100%
4%
Biomedicines 2022, 10, 759.
Retrospective study of patients who were
referred from January 2016 to April 2021
to the Allergy Unit of the Fondazione
Policlinico Universitario A. Gemelli IRCCS
in Rome (Italy)

Cross reactivity (immediate)
Allergy. 2009 Feb;64(2):234-41.
Skin prick, intradermal and patch tests with a series of
contrast media were conducted in 220 patients with either
immediate or nonimmediate reaction
Positive skin tests were observed in 32 of 122 patients
with immediate reaction (26%)
Xenetix
Omnipaque
Iopamiro
Ultravist
Visipaque

Allergy. 2015 Jun;70(6):625-37.
Xenetix
Omnipaque
Iopamiro
Ultravist
Visipaque
Xenetix Omnipaque Iopamiro Ultravist Visipaque

Cross reactivity (immediate)
J Allergy Clin Immunol Pract. Jul-Aug 2018;6(4):1246-1254.
Xenetix
Omnipaque
Ultravist
Visipaque
Iopamiro
Visipaque Ultravist Omnipaque Iopamiro Xenetix

Cross reactivity (delayed)
Allergy. 2009 Feb;64(2):234-41.
Xenetix
Omnipaque
Iopamiro
Ultravist
Visipaque

Cross reactivity (delayed)
J Allergy Clin Immunol Pract. Jul-Aug 2018;6(4):1246-1254.
Omnipaque
Ultravist
Visipaque
Iopamiro
Xenetix
Visipaque Ultravist Omnipaque Iopamiro Xenetix

Skin test – NPV
Nine studies reported various
modalities and doses for ICM
challenge (10-120 mL), with
negative predictive value (NPV)
of skin tests vs challenge
ranging from 37.5% to 100%
Allergy. 2019 Feb;74(2):414-417.

In cases allergic to more than
one ICM, DPT with negative-
ST ICM was positive in more
than 60% (24/36) of cases
Front Pharmacol. 2020 Sep 23;11:575437.
For IRs, ICM was administered
intravenously in saline at 45-min
intervals using 5, 15, 30, and 50 cc
(cumulative dose 100 cc).
For, NIR in the first run, 5, 10,
and 15 cc of ICM at 1-h intervals
were administered, and if no
reaction occurred, in the second
run, 20, 30, and 50 cc
(cumulative dose of 100 cc)

• Prospectively recruited patients
who were scheduled to undergo
contrast enhanced CT
• all subjects underwent IDT with
the iodinated contrast agent
that was planned for use at the
time of the scheduled CT
examination. The skin test was
performed about 30 minutes
before CT scanning
Intradermal skin test before performing computed tomography
has no clinical value for prediction of a hypersensitivity reaction
and should not be performed routinely.
J Allergy Clin Immunol Pract. 2020 Jan;8(1):267-272.
IDT before performing computed tomography

Tryptase
•Tryptase determination at the acute phase is useful for confirming IHR to
ICM, if a transient increase is detectable (strong/moderate).

Basophil activation test
•BAT can be a complementary tool to diagnose IHR to ICM, showing good
correlation with ST and DPT results.
•It may be especially useful in cases with severe reaction and
contraindications for ST or DPT.
•BAT can be an additional tool for diagnosing patients with IHR with severe
reactions or those with high risk (weak/low).

Drug provocation test (immediate)
•Either re-exposition or DPT can be performed to confirm tolerance to a skin
test-negative ICM; the decision is based on availability of DPT and risk-
benefit analysis (strong/high).
•DPT with ICM can be done as a diagnostic test either with the culprit or
with an alternative ICM (strong/high).
•Available protocols should be standardized and validated (strong/high).
•Renal function needs to be carefully monitored (strong/ high).

•As in any DPT, the decision needs to be taken based on a risk-benefit
analysis of each patient and should be done only in well-equipped centers
and by trained personnel in immediate emergency treatment (strong/low).
•The possibility to perform the DPT together with the radiological
examination should be considered (strong/low).
•DPT is not indicated in patients at risk (renal complaints, hyperthyroidism,
radioactive iodine therapy, pregnant and breastfeeding women,
nephrotoxic medication, etc) (strong/high).

•Considering that DPT involves the risk of severe reactions, the expert group
recommends that this is performed only in selected cases using a skin
teste negative RCM to identify alternative RCMs for further radiologic
investigations.
Drug provocation test

Indications for testing (delayed)
•To identify patients with T–cell-mediated reactions to ICM and to provide
guidance on tolerability of alternatives, all patients with a suspicion of ICM-
induced exanthema should be tested (strong/moderate).
•Delayed-appearing urticaria and angioedema are usually ST-negative
(weak/low).

Skin test (delayed)
•When to test: ideally within the first 6 months after the clinical reaction and
more than 6 months in case of DRESS (weak/low).
•What to test: ideally the suspected culprit and several commonly used
alternatives due to the extended crossreactivity in NIHR (strong/moderate).
In DRESS and FDE, patch tests can be useful and SPT and IDT should
not be used (weak/low).

Skin test (delayed)
• How to test:
• IDT with 1:10 dilution of the standard concentration of ICM or undiluted on the upper
arm or upper back with delayed reading after 48 and 72 hours (weak/ low).
• PT on the upper back with undiluted standard solution of ICM with reading at 48 hours
and a delayed reading (72-120 hours) (strong/low).
• Patients should be instructed to return for additional readings in case of any later
appearing skin reaction at the test site (weak/low).
• Using both tests may enhance sensitivity (weak/low).
• If all tests are negative: Consider IDT and/or PT with undiluted ICM in local testing,
especially in FDE (weak/low)

Lymphocyte Transformation Test
•The LTT can be done as an additional diagnostic tool in selected cases
with contraindications for STs (weak/ low).
•It should only be performed by experienced physicians (weak/low).

Drug provocation test (delayed)
•DPT with ICM can be necessary to confirm the diagnosis or to identify a
safe alternative ICM (weak/low).
•The ICM chosen for DPT may be the culprit in patients with nonsevere
reactions and negative ST, and a ST negative alternative in patients with
confirmed NIHR or with severe reactions (weak/low).
•Renal function need to be carefully monitored (strong/ high).
•Available protocols should be standardized (strong/ high).

Int J Immunopathol Pharmacol. Jan-Dec 2021;35:20587384211015061.

Management
•Premedication
•Changing Contrast Media Within the Same Class
•Flow of management
•Desensitization

Premedication
• 50 mg prednisone administered 13 and 7 hours
and 1 hour before CT (total, 150 mg prednisone)
• 50 mg diphenhydramine administered 1 hour
before CT
• 32 mg methylprednisolone by mouth 12 hours and 2
hours before contrast medium administration.
• 50 mg diphenhydramine may be added as in option 1
JACI 1991
• 200 mg of IV hydrocortisone administered at 5
hours and 1 hour before CT (total, 400 mg of
hydrocortisone administered by means of IV)
• 50 mg of IV diphenhydramine administered 1
hour before CT

Premedication
• Premedication is not a general recommended approach (high/strong).
• In cases where the culprit ICM is unknown and ICM administration is needed, premedication
could be an option (weak/low).
• There is no evidence to prove the efficacy of premedication in patients with NIHR to ICM
(high/strong).
• Given that premedication
• does not prevent all reactions
• has not been confirmed to reduce the incidence of moderate or severe reactions or reaction-related
deaths
• has limited supporting efficacy in high-risk patients, and is accompanied by direct and indirect harms
• the utility of premedication in high- risk patients is uncertain.
Practice parameter- Allergy. 2021 May;76(5):1325-1339.

Premedication
•Its use can be reserved to decrease reaction frequency or severity in high-
risk patients (eg, those who have experienced previous anaphylactic
reactions to RCM, mastocytosis) including those who experienced severe
immediatetype reactions without evidence of an IgE-mediated mechanism.
•For patients who have suffered DRESS or SJS/TEN associated with RCM,
the contrast media is contraindicated and a non-crossreactive alternative
will need careful evaluation.
•Premedication is contraindicated in these patients and further exposure to
the same contrast can be lethal. J Allergy Clin Immunol Pract 2019;7:61-5

Rates of Breakthrough Reactions in Inpatients
at High Risk Receiving Premedication Before
Contrast-Enhanced CT
• Inpatients (n = 1051) completing a 13-hour corticosteroid and diphenhydramine
premedication regimen before LOCM-enhanced CT
• 60% (626/1051) of premedicated patients had had a previous reaction to iodinated
contrast material.
• 40% (425/1051) were premedicated for other reasons.
• The overall breakthrough reaction rates were 1.2% (13/1051), 2.1% (13/626) for
those with a previous iodinated contrast reaction, and 0% (0/425) for those
premedicated for other reasons
• The estimated NNTs were 69 (95% CI, 39–304) to prevent a reaction of any
severity 569 (95% CI, 389– 1083) to prevent a severe reaction.
• 50 mg prednisone administered 13 and 7 hours
and 1 hour before CT (total, 150 mg prednisone)
• 50 mg diphenhydramine administered 1 hour
before CT
AJR Am J Roentgenol . 2015 Jul;205(1):77-84.

Summary of Observed Indirect Harm Associated with
Premedication in the Inpatient Study Cohort
Radiology. 2016 May;279(2):492-501
• Premedicated inpatients had a
• significantly longer median length of
stay (+25 hours; 158 vs 133 hours, P
< .001)
• significantly longer median time to
CT (+25 hours, 42 vs 17 hours,
respectively; P < .001)
• significantly greater risk of hospital
acquired infection.

Changing Contrast Media Within the Same Class
•In patients with a prior allergic-like or unknown-type contrast reaction to a
known contrast medium, changing contrast media within the same class
(e.g., one iodinated medium for another) may help reduce the likelihood of
a subsequent contrast reaction.

Eur Radiol. 2016 Jul;26(7):2148-54.
Adverse reaction
61 (27.7%) 47 (17.3%) 3 (5.2%) 6 (2.7%)
Premedication prior to contrast for patients
with previous ARs may be protective, however,
changing CM was more effective.
• Iopamidol was used for the CT studies
throughout the entire period.
• iohexol were administered only to the
patients with the breakthrough reactions to
iopamidol.

Eur Radiol. 2016 Jul;26(7):2148-54.
Premedication prior to contrast for patients
with previous ARs may be protective, however,
changing CM was more effective.

Eur Radiol. 2017 Jul;27(7):2886-2893.
• included all patients who had previously experienced
a moderate or severe initial HSR to LOCM and in
whom the subsequent exposure occurred between 1
January 2014 and 31 December 2014
• 150 moderate to severe initial HSRs (328 re-
exposure)
• the independent risk factors for recurrence of HSR were
• Diabetes
• chronic urticaria
• drug allergy other than to iodinated contrast media
(ICM)
• severe initial HSR
• The risk of recurrent HSR was 67.1% lower in cases where
the implicated ICM was changed to another one (odds
ratio: 0.329; P = 0.001).
• Steroid premedication did not show protective effects
against recurrent HSR.

Immediate HSR

Delayed HSR

Desensitization
12-step intravenous protocol starting with a
1/10,000 th of the full dose, with a doubling
of the doses every 15 minutes
Allergy. 2021;76:1302–1303

Gadolinium-based contrast
agents Hypersensitivity
F1 Pongsawat Rodsaward

Gadolinium-based contrast agents (GBCAs)
•Gadolinium-based contrast agents (GBCAs) are used in radiology to
increase the sensibility and specificity of magnetic resonance imaging
(MRI) examinations.
•After approval of gadopentetate dimeglumine by the US Food and Drug
Administration (FDA) in 1988, the use of GBCAs has multiplied, aiding
lesion depiction and therapeutic guidance in over 500 million patients
worldwide.
Front Allergy. 2022 Mar 17;3:813927.

Can Assoc Radiol J. 2018 May;69(2):136-150.
Gadolinium-based contrast
agents (GBCAs)

Possible cross reactivity ?
Dotarem
Prohance
Gadovist
Magnevist
MultiHance
Primovist
Omniscan
Allergy Asthma Immunol Res. 2021 Nov;13(6):933-938

Characteristic of GBCAs
Radiology. 2018 Feb;286(2):471-482.

Epidemiology
•Hypersensitivity reactions (HRs) are uncommon and vary in frequency from
0.004 to −0.7%.
•The most frequent reactions are immediate reactions where skin
manifestations are presented in 75–100% of cases
•Anaphylaxis occurs in 0.01% of cases
• The death rate due to gadolinium contrast-induced anaphylaxis is 0.0019%
Invest Radiol. 2019 Oct;54(10):633-637.

Epidemiology
•Delayed hypersensitivity reactions
• incidence of 0.05%. (15 in 30,373 injection)
•The reported symptoms were urticaria (67%), rash (33%), and pruritus
(7%).
•Delayed reactions appeared
• on the same day in 46% of cases
• on the following day in 20% of cases
• the moment of manifestation was uncertain in 33% of cases.
Radiology. 2016 Oct;281(1):72-7.

Radiology 2022; 303:329–336
Reviewed using the electronic medical
record–based Contrast Safety Monitoring and
Management (CoSM2 oS) database in Seoul
National University Hospital between July 1,
2012, and June 30, 2020

Characteristics of Hypersensitivity Reactions by Onset Type
Radiology 2022; 303:329–336

Acute HSRs
Radiology 2022; 303:329–336

Delayed HSRS
Radiology 2022; 303:329–336

Delayed HSRS

• a 62-year-old woman with early stage lung
cancer presented with extensive
erythematous skin eruptions
• Two days previously, she had received 7.5
mL of 1.0 M gadobutrol
• The eruptions appeared on her abdomen 4
to 5 hours after the administration of
gadobutrol, and then gradually spread to
almost her entire body
• The patient had received GBCA three times
before the last administration of
gadobutrol: 5 mL of gadobutrol, 7.5 mL of
gadobutrol, and 15 mL of meglumine
gadoterate were administered 24 days, 8
days, and 7 days before the last
administration
LTT performed 21 days after the development of the skin
reaction, was negative.
29 days after onset
J Allergy Clin Immunol Pract. May-Jun 2017;5(3):850-851.

Incidence of Hypersensitivity Reactions for Each GBCAs
Radiology 2022; 303:329–336
(Gadovist)
(Dotarem)
(Primovist)
(Prohance)
(Multihance)
(Magnevit)
No reported hypersensitivity reaction in gadodiamide (Omniscan)

Radiology. 2018 Feb;286(2):471-482.
Incidence of Hypersensitivity Reactions
for Each GBCAs
the lowest rate of immediate allergic adverse
events with use of the nonionic linear GBCA
gadodiamide in comparison with those of ionic
linear or nonionic macrocyclic GBCAs.

Radiology. 2018 Feb;286(2):471-482.
A higher rate of immediate
allergic adverse events was
associated with ionicity, protein
binding, and macrocyclic
structure.

Radiology. 2018 Feb;286(2):471-482.

GBCAs associated with anaphylaxis
•The GBCAs associated with anaphylaxis were
• gadoteridol at 0.02% (three of 19862)
• gadobutrol at 0.01% (eight of 156657)
• gadoxetate disodium at 0.003% (one of 33918)
Radiology 2022; 303:329–336

Skin test
•Undiluted GBCAs used for SPTs
•Dilutions of 1:100 to 1:10 for IDTs
J Investig Allergol Clin Immunol. 2021 Dec;31(6):504-506.

Cross-Reactivity
Number of patients Culprit Crossreactivity
11 Gadobenate dimeglumine -
1 Gadobenate dimeglumine Gadoteric acid
1 Gadobenate dimeglumine Gadobutrol
2 Gadoteric acid Gadobenate dimeglumine
1 Gadoteric acid Gadobenate dimeglumine
Gadobutrol
3 Gadobutrol -
Cross reactivities seem to affect most
frequently gadoteric acid and gadobutrol
33 patients with immediate
hypersensitivity reactions to GBCA
• 13 patients – negative skin test
• 20 patients – positive skin test
J Allergy Clin Immunol Pract. May-Jun 2017;5(3):846-849.
Gadoteric acid = Gadoterate meglumine

Can Assoc Radiol J. 2018 May;69(2):136-150.

J Allergy Clin Immunol Pract . 2021 Apr;9(4):1746-1749.

J Allergy Clin Immunol Pract . 2021 Apr;9(4):1746-1749.
Cross-reactivity concerned 38% of ST-positive
patients and involved especially macrocyclic GCs
Cross-Reactivity
Among the 132 tested patients, eighteen patients (13.6%) were
considered allergic based on positive skin tests

Cross-Reactivity
Journal of Asthma and Allergy 2021:14

Cross-Reactivity
•61-year-old woman developed a anaphylactic shock (pruritus, generalized
erythema, and hypotension) within minutes after the first injection of
gadoterate meglumine
•Negative skin test
• gadodiamide, gadopentetate dimeglumine, gadobenate dimeglumine, and
gadoteridol
•Can use gadobenate dimeglumine
AJR Am J Roentgenol. 2011 Dec;197(6):W1163.

Int J Immunopathol Pharmacol. Jan-Dec 2021;35:20587384211015061.
In gadolinium-based contrast media, one case
report and three case series reported a positive
skin test in 19.2%–57.6% of patients that had an
IHR
• In the case of IHR with positive skin tests, a
provocation was performed with an alternative
gadolinium-based contrast medium a negative skin test
• all provocations mostly were negative (28/30)

Premedication and switched to a different GBCA
Radiology 2022; 303:329–336
Regimen
• Mild
• 4 mg of IV chlorpheniramine
(30 minutes before CM administration)
• Moderate
• 40 mg of IV methylprednisolone with
4 mg of IV chlorpheniramine
(1 hour before CM administration)
• Severe
• 40-mg dose of IV methylprednisolone
(4 hours and 1 hours before CM)
• 4 mg of IV chlorpheniramine
(1 hours before CM administration)
Premed Not premed
Switch 5% (21/441) 6% (6/100)
Not switch 19% (149/786) 31% (37/118)

The prevalence of HSRs to GBCAs was significantly higher in
patients with a history of ICM hypersensitivity
Premedication and switched to a different GBCA
Radiology 2022; 303:329–336

Management

Unmet needs and future research
•To improve knowledge of mechanisms involved in IHRs and NIHRs
•To identify the epitopes involved in immune reactions to GBCAs
•To determine sensitivity and specificity of skin tests in IHRs and NIHRs
•Development of in vitro studies for diagnosis
•To further clarify cross-reactivity among the different GBCAs
•To assess the usefulness of premedication in the prevention of reactions

Iodinated contrast media hypersensitivity.pdf

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