Iodinated Contrast Media Hypersensitivity

Iodinated Contrast Media
Hypersensitivity
Puttatida Chetwong

Iodinated contrast media
• ICM are iodine salts whose basic chemical
structure comprises a benzene ring with
at least 3 iodine atoms (triiodobenzene)
• The iodine atoms being responsible for producing radiopacity
• An ICM is ionic if it transforms into ions or charged particles in
aqueous solution
• The ionization capacity of a given medium is directly related to the
frequency and severity of the adverse reaction.
A Rosado Ingelmo, 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

Osmolality
ICM can also be classified according to osmolality (the
number of particles generated in solution) into
• high-osmolality ICM (≥1400 mOsm/kg H2O)
• low-osmolality ICM (500-900 mOsm/kg H2O)
• isosmolar ICM(290 mOsm/kg H2O)

Viscosity
• The viscosity of ICM is directly associated with the size of the
molecule, the iodine concentration, and an increase in the frequency
of delayed adverse effects.
• However, since viscosity decreases with increasing temperature, it can
be reduced by heating the ICM to body temperature (37°C) before
administration

ICM can be classified into 4 categories based on their
capacity for ionization and number of triiodobenzene rings
• 1) Ionic monomers: salts comprising 1 negatively charged triiodinated
benzene ring, together with a sodium and/or meglumine as a cation. Ionic
monomers have the highest osmolality (>1400 mOsm/kg H2O)
• 2) Ionic dimers, which consist of 2 triiodobenzene rings, contain a carboxyl
radical, and have low osmolality (600 mOsm/kg H2O)
• 3) Nonionic monomers, which are triiodinated compounds with
hydrophilic hydroxyl groups. Nonionic monomers are second-generation
agents and have low osmolality (500-850 mOsm/kg H20)
• 4) Nonionic dimers, which contain 2 nonionic triiodinated benzene rings.
Nonionic dimers have the lowest osmolality of all ICM (290 mOsm/kg H20)

Amipaque
Hypaque
Biliscopin
Bilivist
Conray
Hexabrix
Omnipaque
Isovue
Ultravist
Optiray
Imeron
Xenetix
Oxilan
Imagopaque
Visipaque
Isovist
Schönmann C. Ann Allergy Asthma Immunol. 2020 Feb;124(2):156-164.

American College of Radiology Manual on Contrast Media 2020.

Epidemiology
• The prevalence of allergic reactions to ICM is estimated to be 1:170
000, that is, 0.05%-0.1% of patients undergoing radiologic studies
with ICM.
• These percentages are generally higher for ionic ICM (0.16%-12.66%)
than for nonionic ICM (0.03%-3%)
• High-osmolality ICM were associated with a high incidence of
immediate reactions
• Reactions to ICM are usually mild to moderate

• Anaphylactoid reactions occur inapproximately 1% to 3% of
patients who receive ionic RCM and less than 0.5% of
patients who receive nonionic RCM.
Drug Allergy: An Updated Practice Parameter 2020

The overall prevalence of
hypersensitivity reactions (HSRs) to
iodinated contrast media (ICM) was
0.73% (1433 of 196 081), and severe
reactions occurred in 0.01% (17 of 196
081) of patients.
Radiology. 2019 Oct;293(1):117-124.

Reactions – immediate, non-
immediate

Knut Brockow, Johannes Ring. Classification and pathophysiology of radiocontrast media hypersensitivity. Chem Immunol Allergy. 2010;95:157-169.
Nonimmediate RCM
hypersensitivity reactions usually
have a mild to moderate severity
and are self-limiting

• 104 cases of RCM induced anaphylaxis
• Anaphylactic patients presenting with shock were older (57.4 vs. 50.1 years, p=0.026) and had a history of more
frequently exposure to RCM (5.1-7.8 vs. 1.9-3.3, p=0.004) compared to those without hypotension.
• Skin test positivity to RCM was 64.7% (patients with anaphylaxis) and 81.8% (patients with anaphylactic shock)
PLoS One. 2014 Jun 16;9(6)

• Delayed reactions to RCM, defined as reactions occurring 1
hour to 1 week after administration, occur in approximately
2% patients.
• Most are mild, self-limited cutaneous eruptions that appear
to be T-cell mediated, although more serious reactions, such
as Stevens-Johnson syndrome, toxic epidermal necrolysis,
and DRESS syndrome have been described.

Mario Sánchez-Borges, et al. Controversies in Drug Allergy: Radiographic
Contrast Media. J Allergy Clin Immunol Pract. 2019 Jan;7(1):61-65.
Risk factors for anaphylactoid reactions to
RCM include
• female sex
• Atopy
• concomitant use of beta-blocking drug
• a history of previous reactions to RCM.

• Of a total of 205 726 exposures to LOCM in 86 328
patients, we detected 2004 immediate HSRs during the
study period (incidence of 0.97%).
• The incidence of mild, moderate, and severe reactions
was 0.85%, 0.10%, and 0.02%, respectively.
Lee SY. J Investig Allergol Clin Immunol. 2019;29(6):444-450.

32,964 outpatients at the Mayo Clinic
who were referred to the Department of
Diagnostic Roentgenology for excretory urography
during a 27 month period
D M Witten. Am J Roentgenol Radium Ther Nucl Med, 119 (1973), pp. 832-840
MYTH

• Specific sensitivity to seafood (which is mediated by IgE
directed to proteins) does not further increase this risk.
• There is no evidence that sensitivity to iodine predisposes
patients to RCM reactions.

Immediate hypersensitivity
• The pathophysiology of IHR to contrast agents and dyes is
not fully understood yet.
• Histamine or tryptase release has been demonstrated in
many cases, but this just indicates a mechanism of mast cell
(or basophil) activation and not necessarily an
immunoglobulin E (IgE)-mediated allergic reaction.
• The pathophysiology of possible nonallergic mechanisms
(eg, direct mast cell or basophil activation, complement
activation, bradykinin formation) is not fully understood yet.
Schönmann C, Brockow K. Adverse reactions during procedures Hypersensitivity to contrast agents and dyes. Ann Allergy Asthma Immunol. 2020 Feb;124(2):156-164.

Non-immediate hypersensitivity
• Strong evidence exists for a T cell-mediated mechanism of
NIHRs to ICM
• Time of onset and type of skin eruptions
• Presence of positive patch tests
• Activated T cells in positive skin test sites
• Positive lymphocyte transformation tests
• In addition, the generation of ICM-specific T cell clones has been
reported for NIHR to ICM.
Schönmann C, Brockow K. Adverse reactions during procedures Hypersensitivity to contrast agents and dyes. Ann Allergy Asthma Immunol. 2020 Feb;124(2):156-164.

S.H. Yoon, et al. Skin tests in patients with hypersensitivity reaction to iodinated contrast media: a meta-analysis. Allergy. 2015 Jun;70(6):625-37.

Patients who only experienced
1 symptom, such as feeling of
warmth or erythema on injection
side, nausea, myalgia/arthralgia,
paresthesia, headache, or dizziness
most likely suffered from a toxicity-
related adverse event

Brockow K, et al. Allergy. 2013 Jun;68(6):702-12.
• Skin testing is recommended in the work-up of
iodinated contrast media hypersensitivity
(high/strong).
• It is advisable to use a panel of ICM so as to
identify cross-reactivity and safe alternatives
• Skin prick tests and patch tests should be
performed using undiluted solutions (high/strong).
• For IDT, a 1/10 dilution of ICM is recommended, as
undiluted contrast media may be irritating
(weak/high)
• In delayed reactions, both delayed reading IDT and
patch test should be carried out to enhance
sensitivity (moderate/high). False-negative skin
tests in NIHRs do occur.

• Retrospective evaluation clinical and
diagnostic data from 45 consecutive patients
with RCM hypersensitivity
• Intradermal testing
• At least 3 RCM (which are most commonly
used by the radiologists in the geographical
region of our allergy center) including the
culprit RCM were tested in a 1:10 dilution of
the original RCM preparation in physiological
saline solution.
• Readings at 15 minutes and on days 2, 3, and 4
Trautmann A, et al. J Allergy Clin Immunol Pract 2019; 7: pp. 2218-2224.
• Iodine skin testing
• In cases with a history of RCM-
induced delayed-type MPE, prick and
patch tests with iodine tincture and
2%Lugol’s solution were performed
in addition to RCM intradermal
testing
• Intravenous RCM provocation
• Provocation with a skin test-negative
RCM was performed to exclude RCM
allergy and to determine the
reliability of a negative skin test
result

all 18 tested patients tolerated
intravenous provocation with
a skin test-negative RCM

• Anaphylaxis-like reactions occurring within minutes after injection of iodinated RCM
may result from either nonallergic hypersensitivity or presumed genuine IgE-
mediated allergy.
• Nonallergic hypersensitivity reactions are generally mild, with symptoms remaining
confined to the skin, and premedication is recommended to prevent future reactions.
• Intradermal testing of RCM at dilutions of 1:10 may be an appropriate method for the
diagnosis of RCM allergy.
• Intravenous provocation with a skin test-negative RCM as final proof of tolerance
appears safe in both delayed- and immediate-type RCM allergy and may someday
become the gold standard of testing.

A case of a 28-year old female, who
experienced an anaphylactic shock
(generalized urticaria, angio-edema, dizziness,
severe hypotension with immeasurable blood
pressure during the first 30 minutes, and loss of
consciousness) immediately after
administration of iomeprol (Iomeron®) for
cardiac computed tomography.
Protocol
100 μL aliquots of endotoxin-free
heparinised whole blood were
stimulated with dilution buffer as a
negative control, anti-IgE (10μg/mL)
as a positive control and serial
dilutions (stimulation concentration
10, 100 and 1000 μg/mL) of the
iodinated contrast media.
E Philipse. Acta Clin Belg. Mar-Apr 2013;68(2):140-2.

1000 μg/mL stimulation concentration
Advantages of BAT
It allows multiple simultaneous evaluations
without the risk of endangering the health of
the patient.
It can be performed almost immediately after
the acute reaction, although it is currently
recommended to postpone it up to 4 weeks
after the acute event.

Drug Provocation Test
• Intravenous drug provocation test (DPT) with a skin test-negative
contrast agent has been increasingly described, but it is neither part
of routine allergological workup yet nor standardized and validated.
• Performing DPT may be considered especially in patients after severe
anaphylaxis with a skin test-negative alternative contrast medium,
because DPT has a higher sensitivity than skin testing alone.
Schönmann C. Adverse reactions during procedures Hypersensitivity to contrast agents and dyes. Ann Allergy Asthma Immunol. 2020 Feb;124(2):156-164.

DPT - Protocol
• Timing: the time interval since immediate-type reactions was at least 4
weeks, and recovery from MPE was at least 8 weeks ago
• Incremental doses were given intravenously every 30 minutes.
• Patients with a history of anaphylaxis received 0.05, 0.5, 1.0, 5.0, 7.5, 10.0,
and 25.0 mL (total 49.05 mL).
• Patients who reported a delayed-type reaction received 1.0, 5.0, 7.5, 10.0,
and 25.0 mL (total 48.5 mL).
• All patients were observed for at least 1 hour after the last injection and
were advised to present for objective examination if any symptoms
developed within the next days.
Trautmann A, 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: pp. 2218-2224.

• Doses of 5, 15, 30, and 50 mL
• at 30- to 45-minute intervals for immediate reactions
• at 1-hour intervals for non-immediate reactions, with observation
times at 3, 6, and 24 hours
• There are no data to support that the procedure is safer than
giving 1/10 and 9/10 of a target dose.
• Furthermore, more than 3 doses may induce desensitization
and provide a false sense of security.
DPT - Protocol
Mario Sánchez-Borges, et al. Controversies in Drug Allergy: Radiographic Contrast Media. J Allergy Clin Immunol Pract. 2019 Jan;7(1):61-65.

Premedication
• Premedication with corticosteroids, antihistamines, and
sympathomimetics to prevent severe reactions to RCM was proposed
by Greenberger and Patterson
• In Europe the value of premedication is considered controversial,
because it provides patients and physicians a false sense of security
• Although it may be useful to reduce mild immediate nonallergic
reactions, its efficacy for immediate moderate-to-severe and
nonimmediate reactions has not been confirmed
Mario Sánchez-Borges, et al. Controversies in Drug Allergy: Radiographic Contrast Media. J Allergy Clin Immunol Pract. 2019 Jan;7(1):61-65.

P A Greenberger, R Patterson. The prevention of immediate generalized reactions to radiocontrast media in high-risk patients. J Allergy Clin Immunol 1991; 87: pp. 867-872.

• Patients who experienced previous anaphylactoid reactions to RCM
should receive nonionic, iso-osmolar agents and be treated with a
premedication regimen, including systemic corticosteroids and
histamine1re-ceptor antihistamines; this will significantly reduce, but
not eliminate, the risk of anaphylactoid reaction with re-exposure to
contrast material.

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Indications for Premedication

• No premedication strategy is a substitute for pre-administration
preparedness.
• Contrast reactions occur despite premedication [34], and radiology
teams must be prepared to treat breakthrough reactions when they
occur.
• Patients should receive information concerning their risk of a reaction
according to local policy and practice.

Special Condition
Myasthenia gravis

Intravenous administration of low-osmolality iodinated
contrast material is associated with a significant
increase (P = .01) in the frequency of acute (less than 1
day) disease-related symptoms in patients with
myasthenia gravis (6.3% with contrast-enhanced CT
[seven of 112 patients; 95% CI: 0.03, 0.12] vs 0.6% with
unenhanced CT [one of 155 patients; 95% CI: 0.0002,
0.04])
Radiology. 2013 Jun;267(3):727-34.

Khandelwal A, Shamim R, Supriya. Low – osmolality contrast agents - A risk for myasthenics. Neurol India 2016;64:558-9
A case of acute exacerbation of
myasthenic symptoms immediately
after the administration of low-
osmolality iodinated contrast agent in
a 41-year female patient scheduled for
a contrast-enhanced computed
tomography (CECT) scan of the thorax
for detection of a thymoma.
Presented to our hospital with chief
complaints of drooping of eyelids
(right > left), diplopia, dysphagia,
nasal intonation of voice, and easy
fatigability since 5 months
Her clinical signs and symptoms
along with the significant elevation
of acetylcholine receptor antibodies
and repetitive nerve stimulation
were consistent with the diagnosis
of myasthenia gravis.

She was subsequently scheduled for contrast enhanced computed tomogram (CECT)
of the thorax for screening of the thymoma.
She was stable prior to the computed tomographic scan.
However, immediately following administration of approximately 50 ml of
iodinated contrast agent (Ultravist 370), she developed new onset acute
respiratory distress, stridor, restlessness, tachycardia and desaturation.
The blood pressure did not fluctuate, and there were no skin rashes.
Management
Supplemental oxygen administered through the face mask did not improve her
oxygen saturation. She was intubated after administering 50 mg of intravenous
propofol alone and admitted to the Intensive Care Unit where mechanical ventilation
was initiated. She was treated with steroids and intravenous immunoglobulin and
was comfortably weaned off and extubated on the 3rd day.
Khandelwal A, Shamim R, Supriya. Low – osmolality contrast agents - A risk for myasthenics. Neurol India 2016;64:558-9

A 48-year-old Sinhalese man diagnosed as having myasthenia gravis, was evaluated for
progressive dysphagia with an upper gastrointestinal contrast study.
Iodinated contrast material (iohexol) was used as the contrast medium and there was direct
evidence of contrast aspiration during the study.
Several minutes after the procedure, severe respiratory distress with evidence of
myasthenic crisis requiring intubation and intensive care admission was noted.
Treatment with intravenous immunoglobulin, high-dose steroids, and broad-spectrum
intravenously administered antibiotics led to an uneventful recovery, although the latter part of
the clinical course was complicated with total left lung collapse. Respiratory support was
graduallyreduced over 72-hour period.
J Med Case Rep. 2019 May 31;13(1):166.

A patient with poorly-controlled symptoms of myasthenia gravis was administered intravenous contrast
during computed tomography (CT) pulmonary angiogram.
70 ml of Ultravist® 370 (iopromide) contrast solution was administered and the CTPA was completed.
Approximately, seven minutes following contrast administration, the patient became nauseated and
acutely hypoxic, with saturations of 90% on six litres of oxygen by mask.
About four minutes later, she became drowsy, and a minute later developed respiratory arrest and was
intubated on the CT table. Hemodynamic stability was maintained throughout with pulse rate of 115 beats
per minute and blood pressure of 160/70 mmHg. A further CT head did not find acute intracranial
abnormality. No rashes or other skin changes were noted.
Ngan DKY. Moon HH. Contrast-provoked myasthenic crisis: A case report and review of literature. Case Rep Int 2018;7:100049Z06DN2018.

Myasthenic exacerbation was suspected, and subsequent assessment by the neurology
team in the intensive care unit found mild bilateral fatigable ptosis with full
preservation of extraocular movements, as well as mild to moderate neck flexion
weakness. No limb weakness was present.
Nerve conduction studies were performed and induced an approximate 20% early
decrement in compound muscle action potential, consistent with myasthenia crisis.
Her serum azathioprine level was found to be subtherapeutic and she was instead
prescribed mycophenolate mofetil with improvement.
She remained intubated for six days. Her ptosis resolved completely during admission,
and she was discharged with outpatient follow-up.
Ngan DKY. Moon HH. Contrast-provoked myasthenic crisis: A case report and review of literature. Case Rep Int 2018;7:100049Z06DN2018.

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