Anaphylaxis to Iodinated Contrast Media: Clinical

Characteristics Related with Development of

Anaphylactic Shock
Min-Hye Kim1,2,3,4, Suh-Young Lee1,2, Seung-Eun Lee1,2, Min-Suk Yang1,2,5, Jae-Woo Jung2,6, Chang
Min Park7, Whal Lee7, Sang-Heon Cho1,2,3, Hye-Ryun Kang1,2,3*
1 Department of Internal Medicine, Division of Allergy and Clinical Immunology, Seoul National University Hospital, Seoul, Republic of Korea, 2 Institute of Allergy and
Clinical Immunology, Seoul National University Medical Research Center, Seoul, Republic of Korea, 3 Seoul National University Hospital Regional Pharmacovigilance
Center, Seoul, Republic of Korea, 4 Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul, Republic of Korea, 5 Department of Internal
Medicine, SMG-SNU Boramae Medical Center, Seoul, Republic of Korea, 6 Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Republic of
Korea, 7 Department of Radiology and Institute of Radiation Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea

Abstract
Objective: Anaphylaxis is the most severe form of radiocontrast media (RCM) induced hypersensitivity and can be life-
threatening if profound hypotension is combined. With increased use of iodine based RCM, related hypersensitivity is
rapidly growing. However, the clinical characteristics and risk factors of RCM induced anaphylaxis accompanied by
hypotension (anaphylactic shock) are not clearly defined. This study was performed to investigate the risk factors of RCM
induced anaphylactic shock and the clinical value of RCM skin testing to identify causative agents in affected patients.

Methods: We analyzed the data of RCM induced anaphylaxis monitored by an inhospital pharmacovigilance center at a
tertiary teaching hospital from January 2005 to December 2012 and compared the clinical features and skin test results
according to the accompanying hypotension.

Results: Among total of 104 cases of RCM induced anaphylaxis, 34.6% of patients, developed anaphylaxis on their first
exposure to RCM. 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 (5.167.8 vs. 1.963.3, p = 0.004) compared to those without hypotension. Among RCMs,
hypotension was more frequent in anaphylaxis related to iopromide compared to other agents (85.0% vs. 61.4%, p = 0.011).
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.

Conclusion: RCM induced anaphylactic shock is related to multiple exposures to RCM and most patients showed skin test
positivity to RCM.

Citation: Kim M-H, Lee S-Y, Lee S-E, Yang M-S, Jung J-W, et al. (2014) Anaphylaxis to Iodinated Contrast Media: Clinical Characteristics Related with Development
of Anaphylactic Shock. PLoS ONE 9(6): e100154. doi:10.1371/journal.pone.0100154
Editor: Jacques Zimmer, Centre de Recherche Public de la Santé (CRP-Santé), Luxembourg
Received January 24, 2014; Accepted May 22, 2014; Published June 16, 2014
Copyright: ß 2014 Kim et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This research was supported by a grant from Ministry of Food and Drug Safety to operation of the regional pharmacovigilance center in 2014. The
funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: helenmed@snu.ac.kr

Introduction in 1–3 per 100,000–1,000,000 administrations regardless of

ionicity [5,6]. Presently, the clinical characteristics and risk factors
Anaphylaxis is a rapid-onset severe hypersensitivity reaction for the development of anaphylactic shock are not clearly defined.
that can be fatal. Although death from anaphylaxis is not common The principle of post-anaphylaxis management is to avoid the
and most episodes of anaphylaxis can be reversed by a single dose causative agents. Although other imaging can be used as an
of epinephrine, severe anaphylaxis accompanied with cardiovas- alternative test in RCM hypersensitivity patients, CT imaging has
cular collapse can be resistant to treatment and result in death. its own advantage and unavoidable in some clinical situations.
As the use of computed tomography (CT) is rapidly growing, Although antihistamines and systemic steroids can be used as
iodine based radiocontrast media (RCM) is administered about preventive measures, they cannot ensure complete prevention of
75,000,000 times per year worldwide [1]. As low osmolality non- RCM induced anaphylaxis [7,8]. Currently, there are no
ionic contrast agents replaced high-osmolality ionic ones, the established guidelines on premedication for RCM induced
incidence of immediate RCM hypersensitivity diminished remark- anaphylaxis [9]. Therefore, information on a causal agent and
ably from 3.8–12.7% to 0.7–3.1% [2–4]. Similarly, the incidence safer substitutes will be very useful for patients who need contrast
of severe immediate RCM hypersensitivity also decreased from
enhanced CT scan despite previous history of RCM induced
0.1–0.4% to 0.01–0.04%. However, anaphylactic deaths still occur

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 Contrast Media Induced Anaphylactic Shock

anaphylaxis. Until recently, diagnostic value of RCM skin test has only with CT procedures, not with other procedures such as
been underestimated and there are only a limited number of cardiac catheterization or coronary angiography.
studies which evaluated the sensitivity of RCM skin testing to All the medical records were thoroughly re-evaluated by two
various RCM [10–12]. allergy specialists to assess clinical features of anaphylaxis and the
This study was performed to investigate the risk factors for the presence of previous contrast hypersensitivity reactions. Anaphy-
development of hypotension and the clinical value of RCM skin laxis was diagnosed if cases satisfied the criteria of anaphylaxis
testing to identify causative agents in RCM induced anaphylaxis. suggested by the National Institute of Allergy and Infectious
Disease and Food Allergy and the Anaphylaxis Network [13].
Methods Hypotension was considered as a systolic blood pressure less than
90 mmHg or greater than 30% decrease from an individual’s
1. Study Subjects baseline. [13] Hypotension unrelated with underlying diseases or
This study protocol was approved by the institutional review other drugs was considered a manifestation of anaphylaxis.
board (IRB) of Seoul National University Hospital. Informed After completing review, patients with anaphylaxis were
consents of patients were exempted from IRB because this study classified into two groups depending on combined hypotension.
only used retrospective chart review data and all personal data was We analyzed the data to identify risk factors for the development
eliminated and coded as arbitrary number which were not of anaphylactic shock by comparing anaphylactic patients
personally-identifiable. Research data was accessed only by combined with and without hypotension.
researchers using password.
We extracted all the cases of RCM induced hypersensitivity 2. Skin Tests with Iodinated Contrast Agents
based on ATC code of causative agents (V08A: X-ray contrast Skin tests were carried out after experiencing RCM induced
media, iodinated, V08B: X-ray contrast media, non-iodinated)’ anaphylaxis for those patients who agreed to undergo skin testing.
and WHOART (ARRN: 0712 allergic reaction, 0713 anaphylac- Skin prick and intradermal tests were performed on the volar part
tic shock, 0714 anaphylactoid reaction, 2237 anaphylactic of the forearm with 6 different RCM used in our hospital -
reaction, 2268 documented hypersensitivity to administered drug) iopromide (UltravistH, Bayer Healthcare, Brussels, Belgium),
from our inhospital pharmacovigilance database collected from iopamidol (PamirayH, Dongkook Pharm. Co., Ltd, Korea),
January 2005 to December 2012 at Seoul National University iomeprol (IomeronH, Bracco, Milan, Italy), iohexol (OmnipaqueH,
Hospital, in Seoul, Korea. Demographic and clinical data of Armersham Health, Princeton, NJ), iodixanol (VisipaqueH,
affected patients such as age, sex, number of contrast exposures, Armersham Health, Princeton, NJ), and iobitridol (XeneticsH,
laboratory test results, and underlying diseases based on ICD-10 Guerbet, Gorinchem, Netherlands). Undiluted solution and 1:10
were collected from electronic medical records. This study dealt diluted solution were used for the skin prick test and intradermal

Figure 1. Anaphylactic reactions and total number of RCM use in every year of the study period.
doi:10.1371/journal.pone.0100154.g001

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 Contrast Media Induced Anaphylactic Shock

Table 1. Clinical characteristics according to the development of hypotension.

Total (N, %) Anaphylactic shock (N, %) Normotensive anaphylaxis (N, %) P-value

Number 104 78 26
Age (years)* 55.6613.4 57.4613.2 50.1613.0 0.024
Male gender, % 43 (41.3) 35 (44.9) 8 (30.8) 0.254
Number of previous exposure to RCM* 4.367.1 5.167.8 1.963.3 0.004
None 36 (34.6) 24 (30.8) 12 (46.2) 0.369
1 17 (16.3) 13 (16.7) 4 (15.4)
$2 51 (49.0) 41 (52.6) 10 (38.5)
Previous RCM reactions 21/68 (30.9) 18/54 (33.3) 3/14 (21.4) 0.362
WBC count (/mL) 5,844.761,883.8 5,88661,921 5,61761,720 0.668
Eosinophil count (/mL) 62.0684.4 64.2686.9 50.0671.4 0.574
Hypersensitivity Symptoms
Skin symptoms 69 (66.3) 49 (62.8) 20 (76.9) 0.235
Urticaria/erythema 53 (51.0) 36 (46.2) 17 (65.4) 0.114
Angioedema 34 (32.7) 21 (26.9) 13 (50.0) 0.052
Respiratory symptoms* 50 (48.1) 32 (41.0) 18 (69.2) 0.022
Dyspnea{ 42 (40.4) 24 (30.8) 18 (69.2) 0.001
Cardiovascular symptoms{ 88 (84.6) 78 (100.0) 10 (38.5) ,0.001
Gastrointestinal symptoms 20 (19.2) 16 (20.5) 4 (15.4) 0.775
Underlying allergic diseases 12 (11.5) 8 (10.3) 4 (15.4) 0.464
Radiocontrast media`
Iopromide* 60 (57.7) 51 (65.4) 9 (34.6) 0.011
Iopamidol 12 (11.6) 8 (10.3) 4 (15.4) 0.726
Iomeprol 11 (10.6) 8 (10.3) 3 (11.5) 1.000
Iohexol 7 (6.7) 3 (3.8) 4 (15.4) 0.064
Iobitridol 3 (2.9) 3 (3.8) 0 (0.0) 0.571
Iodixanol 4 (3.8) 3 (3.8) 1 (3.8) 1.000
Unidentified agents* 7 (6.7) 2 (2.6) 5 (19.2) 0.010
Positive skin test{ 33/51 (64.7) 27/33 (81.8) 6/18 (33.3) 0.001
Skin prick test 1/51 (2.0) 1/33 (3.0) 0/18 (0.0) 1.000
Intradermal test{ 33/51 (64.7) 27/33 (81.8) 6/18 (33.3) 0.001

Continuous variables are expressed as mean 6 standard deviation.

*P,0.05, {P,0.01. `Among the total 104 subjects, radiocontrast media involved in anaphylaxis could not be identified in seven patients who had experienced
anaphylaxis prior to the introduction of electronic medical recording system.
doi:10.1371/journal.pone.0100154.t001

test, respectively, as used in previous studies [10,12,14,15]. the univariate analysis, and other clinically important factors such
Histamine and normal saline were used as positive and negative as age and sex. A P-value less than 0.05 was considered statistically
control, respectively. The results were interpreted 15 minutes after significant.
the prick or the intradermal injection. Skin prick test was
determined to be positive when wheal diameter was greater than Results
3 mm, and intradermal test was determined to be positive when
wheal diameter increased 3 mm or more than the initial bleb [12]. 1. Clinical Characteristics of the Study Subjects and
The rate and factors contributing to the positivity of RCM skin test Accompanied Anaphylaxis
were analyzed. A total number of contrast-enhanced CT scans during the study
period was 632,513. A total of 104 cases of RCM related
3. Statistical Analysis anaphylaxis were monitored during the study period. The
SPSS (version 19.0) was used to analyze the data. To compare incidence of contrast-induced anaphylaxis was 0.016%. As the
the clinical features of two groups, Student t-test or Mann- total number of RCM use increased over the study period, the
Whitney test was used for continuous variables, and Chi-square RCM related anaphylaxis also showed increasing tendency in
test or Fisher’s exact test was used for categorical variables. To number (Figure 1). The mean age was 55.6613.1 years and 41.3%
identify the risk factors related with anaphylactic shock and a (43/104) of them were male (Table 1).
positive skin test, multiple logistic regression was used. We The median number of previous RCM exposures was 1.0
included adjustment factors that had a P-value less than 0.1 in (interquartile range (IQR), 0.0–5.0) before the development of the

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 Contrast Media Induced Anaphylactic Shock

Figure 2. Comparison of the number of contrast exposures according to the presence of hypotension. *p,0.05.
doi:10.1371/journal.pone.0100154.g002

first anaphylaxis. While anaphylaxis developed at the first The mean interval between the time of anaphylaxis and skin test
exposure to RCM in 34.6% (36/104) of patients, 65.4% (68/ was 14.8 months (IQR 3.4–38.9). Skin test was performed in 41%
104) of patients experienced anaphylaxis on repeated exposure to of patients within one year since they experienced anaphylaxis.
RCM and 21 of 68 (30.9%) had a milder form of hypersensitivity The remaining patients underwent skin test at the time when more
reactions in previous exposure to RCM. than one year passed since anaphylaxis occurred (IQR 21.8–64.1).
Among hypersensitivity symptoms present in patients with Among those 51 patients with RCM skin test results, 33 (64.7%)
anaphylaxis, cardiovascular symptoms were the most common had a positive response to at least one RCM while 18 patients
(88/104, 84.6%), followed by skin symptoms (69/104, 66.3%) and (35.3%) did not show positivity to any RCM tested. In
respiratory symptoms (50/104, 48.1%) (Table 1). Most symptoms anaphylactic patients accompanied by hypotension, skin test
occurred within several minutes after the RCM injection. Seventy- showed 81.8% positivity. Among 33 patients with positive RCM
eight patients experienced anaphylaxis with hypotension (anaphy- skin test results, mean 1.1 contrast media (1.161.1) were positive
lactic shock) and 26 patients had anaphylaxis without hypotension. per person.
Precise information on the culprit RCM was available in 29
2. Comparison of Clinical Characteristics According to the patients. Twenty-two (75.9%) patients showed positivity to RCM
Development of Hypotension including their culprit RCM; 14 patients showed single positivity
Compared to anaphylactic patients without hypotension, to the culprit RCM; 8 patients showed positivity to other RCMs in
patients who presented with anaphylactic shock were older (57.4 addition to the culprit one. Another 7 patients responded to RCM
vs. 50.1 years, p = 0.026) and had significantly higher number of agents other than the culprit one.
previous RCM exposures (5.167.8 vs. 1.963.3, p = 0.004). Of The positivity rate of skin test for each contrast agent is varied
note, the number of patients who underwent previous CT more from 0.0% to 100.0% (Table 2). Iobitridol showed the highest
than two times was 52.6% and 38.5%, respectively in anaphylactic sensitivity (100%) followed by iopromide (59.3%) and iodixanol
patients with and without hypotension. Especially, the proportion (50.0%). However, all 5 patients who experienced iohexol induced
of previous exposure to RCM more than 5 times showed anaphylaxis were negative in skin test with iohexol.
significant difference between anaphylactic patients with and In patients with a positive RCM skin test, hypotension (79.4%
without hypotension (35.4% vs. 9.1%, p = 0.018, Figure 2). vs. 35.3%, p = 0.004) and gastrointestinal symptoms (28.1% vs.
In terms of the causative contrast agent, hypotension was more 0.0%, p = 0.047) were more frequent compared to patients who
frequent among anaphylaxis related to iopromide compared to had a negative RCM skin test. With multiple logistic regression
other agents (85.0% vs. 61.4%, p = 0.011). Iopromide use was analysis after adjustment by age, sex and diabetes, the presence of
more frequently observed in patients with hypotension than in hypotension was a characteristic associated with a RCM skin test
patients without it among patients with anaphylaxis (65.4% vs positivity (OR 10.0, 95% CI 2.105–47.098, p = 0.004). However,
34.6%, p = 0.011). With multiple logistic regression analysis after skin test positive rate was not different according to the history of
adjustment of age, sex, diabetes, and number of previous contrast previous RCM hypersensitivity reactions, accumulated number of
exposure, iopromide use was still a risk factor for an anaphylactic exposures to the RCM, and underlying allergic disease.
shock (OR 3.088, 95% confidential interval (CI) = 1.078–8.843,
p = 0.036). Discussion
Incidence of anaphylaxis is increasing rapidly and known to be
3. Comparison of Clinical Characteristics According to 4–50/100,000 person-years [16]. In adults, drugs are the most
Skin Test Positivity common cause of anaphylaxis [16,17] and radiocontrast media
Fifty-one patients with anaphylaxis followed the recommenda- was the most commonly involved drug in a study of Korean
tion of allergists and underwent RCM skin test and the other 53 tertiary care hospital [18]. Although the incidence of RCM
patients refused to perform skin test because they did not have a hypersensitivity decreased as high-osmolality ionic contrasts were
scheduled follow-up CT in the near future.

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 Contrast Media Induced Anaphylactic Shock

Table 2. Sensitivity and false negative rate on skin test.

Causative RCM Sensitivity False negative rate

To any RCM N (%) To culprit RCM N (%) To any RCM N (%) To culprit RCM N (%)

Iopromide 20/27 (74.1) 16/27 (59.3) 7/27 (25.9) 11/27 (40.7)

Iopamidol 2/5 (40.0) 1/5 (20.0) 3/5 (60.0) 4/5 (80.0)
Iomeprol 4/5 (80.0) 2/5 (40.0) 1/5 (20.0) 3/5 (60.0)
Iohexol 1/5 (20.0) 0/5 (0.0) 4/5 (80.0) 5/5 (100.0)
Iobitridol 2/2 (100.0) 2/2 (100.0) 0/2 (0.0) 0/2 (0.0)
Iodixanol 1/2 (50.0) 1/2 (50.0) 1/2 (50.0) 1/2 (50.0)
Total 30/46 (65.2)* 22/46 (47.8) 16/46 (32.6) 24/46 (52.1)

*Five patients in whom causal contrast media could not be identified were excluded from this analysis among 51 patients with skin test results.
Iopromide, iopamidol, iomeprol, iohexol, and iobitridol are low-osmolar contrast media. Iodixanol is an iso-osmolar contrast media.
doi:10.1371/journal.pone.0100154.t002

replaced by low-osmolality non-ionic ones, anaphylactic death still RCM, it is more likely that IgE mediated hypersensitivity may
occurred regardless of ionicity [5,6]. have a role in the development of RCM induced anaphylaxis
Traditionally, immediate hypersensitivity reactions to RCM when presented with hypotension.
were considered representative of non-IgE mediated ‘anaphylac- Skin test is widely used to identify the causative agents in IgE
toid reaction’ since it can occur on the first exposure and does not mediated hypersensitivity [12,15,16]. Previously, sensitivity of the
always recur on the repeated exposure [1,10,11,19]. However, a intradermal test was reported as high as 73% when performed
previous report showed that only 30% of immediate RCM with undiluted solutions [20]. However, this result may have been
hypersensitivity developed at the first exposure to RCM [20] and overestimated by irritation with undiluted RCM and a 1:10
our study also revealed that only 35% of RCM induced solution has been preferred for intradermal test with RCM in
anaphylaxis occurred at the first exposures to RCM. We found general. The positive rate of the intradermal skin test was variable
that milder hypersensitivity symptoms heralded anaphylaxis in 1/3 and reported as low as 4.2% among patients with RCM
of the patients on preceding exposure to RCM. Multiple exposures hypersensitivity [10]. On the other hand, data from the European
and a previous hypersensitivity reaction prior to RCM induced Network of Drug Allergy multicentre study demonstrated a 50%
anaphylaxis suggest that an immunologic mechanism may have positive rate of RCM skin test in immediate reactors [14].
some role in the development of some RCM induced anaphylaxis. Recently, Kim et al. reported that a significantly higher sensitivity
Anaphylaxis is a severe, life-threatening systemic hypersensitiv- positive rate of RCM skin test in severe immediate reactions
ity reaction involving at least two or more organs at the same time. (57.1%) compared with mild (12.9%) and moderate reactions
However, diagnosis of anaphylaxis can be made if sudden (25.0%) and suggested their modest utility in evaluating severe
hypotension develops after exposure to a known allergen. Based adverse reactions retrospectively [24]. In this study, we observed
upon symptoms, anaphylaxis can be classified into mild, moderate, much higher positive rate of RCM skin test in patient with RCM
and severe grade. [21] When hypotension occurs as a manifesta- induced anaphylaxis (64.7%). Positive rate went up as high as
tion of anaphylaxis either as a sole feature or with other symptoms, 81.8% among patients with anaphylactic shock and it is the
physicians should pay attention to the development of potential highest value ever reported in RCM hypersensitivity. Three
cardiovascular collapse which is the main cause of mortality in quarter of patients who showed skin test positivity responded to the
anaphylaxis [22]. There are several known risk factors for a severe very same RCM used at the time of anaphylaxis and cross
RCM hypersensitivity such as previous history of RCM hyper- reactivity rate to other RCMs was low. These findings suggest that
sensitivity, asthma, allergies requiring medical treatment, use of a substantial proportion of patients with RCM induced anaphy-
beta-adrenergic blockers, female gender, Indian and Mediterra- laxis, especially anaphylactic shock, may have specificity to
nean ethnicity, and malignant tumor [23]. However, there was no causative agents and skin tests can provide information on the
data on the risk factors for the development of hypotension in safe substitutes. However, considering negativity in one third of
anaphylaxis. In this study, we reported risk factors for anaphylactic patients, skin test is not helpful to choose safe alternative RCMs in
shock such as older age, previous multiple exposures to RCM, some populations and clinical reasoning is needed on interpreting
iopromide use. However, we do not have a clear picture of what the results.
the overall anaphylaxis rate is using iopromide or the other study Although we could not perform skin test in negative controls,
contrast agents, since patients without anaphylaxis are not skin test positivity in the negative control is known to be negligible.
included in the study. Secondly, the number of administrations There are several studies which elucidated very low positivity of
of other contrast agents was too small to provide statistically skin test in the negative controls. Brockow et al. reported that
significant results. In other words, we cannot conclude from this positivity of skin test was 0.0% (0/11)–4.2% (3/71) in the negative
study that iopromide is more likely to cause anaphylaxis than any controls [14]. Kim et al. performed RCM skin testing on 1,048
of the other contrast agents, but among the anaphylactic patients, Korean subjects before contrast-enhanced CT and found only 1
iopromide was associated with more severe forms of anaphylaxis case of positive immediate skin test (0.09%) [24].
(anaphylaxis with hypotension). In addition, anaphylaxis with There are several limitations in this study. The main limitation
hypotension showed stronger association with RCM skin test is its retrospective design and underreporting of adverse reaction
positivity than anaphylaxis without hypotension. Although skin to spontaneous reporting systems. Another limitation is the lack of
test positivity might be the result of direct mast cell activation by information on the number of individual RCM used in contrast-

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 Contrast Media Induced Anaphylactic Shock

enhanced CT during the study period. Thus, large scale Author Contributions
prospective studies including sufficient number of patients reacting
Conceived and designed the experiments: H-RK S-HC. Performed the
to each RCM are needed in order to define the exact incidence experiments: M-HK S-YL S-EL M-SY J-WJ. Analyzed the data: C-MP
and risk factors of RCM induced anaphylaxis. WL. Contributed reagents/materials/analysis tools: M-HK S-YL S-EL M-
SY J-WJ C-MP WL S-HC H-RK. Wrote the paper: M-HK H-RK.
Conclusion
RCM induced anaphylactic shock is related with multiple
exposure to RCM and skin test positivity to RCM.

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