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European Journal of Radiology 77 (2011) 495501

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European Journal of Radiology
j our nal homepage: www. el sevi er . com/ l ocat e/ ej r ad
Immediate reactions following iodinated contrast media injection:
A study of 38 cases
Pascale Dewachter
a,
, Dominique Laroche
b,1
, Claudie Mouton-Faivre
c,2
,
Evelyne Bloch-Morot
d,3
, Jean-Pierre Cercueil
e,4
, Liliane Metge
f,5
,
Marie-France Carette
g,6
, Marie-Claude Vergnaud
h,7
, Olivier Clment
i,8
a
Service dAnesthsie-Ranimation Chirurgicale & SAMU de Paris, Hpital Necker-Enfants Malades, AP-HP, Universit Paris-Descartes,
149 Rue de Svres, 75015 Paris, France
b
Service de Biophysique, Centre Hospitalier Universitaire, Avenue de la Cte de Nacre, Caen, France
c
Ple dAnesthsie-Ranimation Chirurgicale, Centre Hospitalier Universitaire-Hpital Central, Avenue du Marchal de Lattre de Tassigny, Nancy, France
d
Service de Mdecine Interne, Hpital Europen Georges Pompidou, 20 Rue Leblanc, Paris, France
e
Dpartement dImagerie Medicale, Centre Hospitalier Universitaire, Hpital du Bocage, 2, Boulevard du Marchal de Lattre de Tassigny, Dijon, France
f
Dpartement dImagerie Mdicale, Centre Hospitalier Universitaire Caremeau, Place du Pr Robert Debr, Nmes, France
g
Service de Radiologie, Hpital Tenon, 4 Rue de la Chine, Paris, France
h
Service de Mdecine Polyvalente, Centre Hospitalier Universitaire, Avenue de la Cte de Nacre, Caen, France
i
Service de Radiologie, Hpital Europen Georges Pompidou, AP-HP, Universit Paris Descartes, 20 Rue Leblanc, Paris, France
a r t i c l e i n f o
Article history:
Received 2 August 2009
Accepted 17 September 2009
Keywords:
Anaphylaxis
Contrast media
Hypersensitivity
Immediate
Skin tests
Histamine
Tryptase
a b s t r a c t
Objectives: Toinvestigatethepathomechanisms involvedincases of immediatehypersensitivityreactions
occurring after the administration of iodinated contrast media.
Materials and methods: Patients having presented clinical signs of immediate hypersensitivity suggesting
allergy after iodinated contrast medium were investigated. Histamine and tryptase concentrations were
measured, and/or skin tests were performed. Patients with positive skin tests to the culprit contrast agent
were classied as IgE-mediated allergic hypersensitivity (Group I) and patients with negative skin tests
as non-allergic hypersensitivity (Group II).
Results: 38 patients were included. Most reactions appeared after non-ionic (n=32). Reactions were more
frequentlyseverefollowingionic thannon-ionic (p=0.014). Skintestingwas not performedin11patients.
Skin tests with the culprit contrast agent were negative in 26% of the patients (Group II, n=7) whereas
they were found positive with the contrast agent in 73% of the patients (Group I, n=19). Latex-induced
reaction was diagnosed in one patient, and was consequently excluded from the cohort. In Group I, the
frequency of cross-reactivity with the other commercialized iodinated contrast media was low (7%).
Cardiovascular signs were present in Group I (52.6%, n=10), and absent in Group II (p=0.023). Histamine
and tryptase concentrations were higher in patients who had cardiovascular signs (p<0.02).
Conclusion: Immediate reactions with clinical signs suggesting allergy along with positive skin tests with
the administered contrast agent conrmimmediate allergic hypersensitivity (anaphylaxis) to this agent.
Consequently, the culprit contrast agent should be denitely avoided as well as cross-reactive ICM in
order to prevent further recurrences.
2009 Elsevier Ireland Ltd. All rights reserved.

Corresponding author. Tel.: +33 1 44 49 54 07; fax: +33 1 44 49 54 10.


E-mail addresses: pascale.dewachter@yahoo.fr (P. Dewachter), laroche-do@chu-caen.fr (D. Laroche), claudie.mouton@wanadoo.fr (C. Mouton-Faivre),
ebloch-morot@club-internet.fr (E. Bloch-Morot), jean-pierre.cercueil@chu-dijon.fr (J.-P. Cercueil), liliane.metge@chu-nimes.fr (L. Metge),
marie-france.carette@tnn.ap-hop-paris.fr (M.-F. Carette), vergnaud-mc@chu-caen.fr (M.-C. Vergnaud),
olivier.clement@inserm.fr (O. Clment).
1
Tel.: +33 2 31 06 47 03; fax: +33 2 31 06 51 60.
2
Tel.: +33 3 83 85 14 03; fax: +33 3 83 85 85 59.
3
Tel.: +33 1 56 09 27 92; fax: +33 1 56 09 38 45.
4
Tel.: +33 3 80 29 36 86; fax: +33 3 80 29 32 43.
5
Tel.: +33 4 66 68 33 10; fax: +33 4 66 68 38 12.
6
Tel.: +33 1 56 01 62 91; fax: +33 1 56 01 69 32.
7
Tel.: +33 2 31 06 46 79; fax: +33 2 31 06 51 92.
8
Tel.: +33 1 56 09 38 51, Fax: +33 1 56 09 38 50.
0720-048X/$ see front matter 2009 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.ejrad.2009.09.019
496 P. Dewachter et al. / European Journal of Radiology 77 (2011) 495501
1. Introduction
Anaphylaxis remains one of the rare but signicant events
specically related to iodinated contrast media (ICM) that can lead
to morbidity and mortality, even in previously healthy patients.
However, patients experiencing immediate reactions in the radi-
ological area are usually not explored. Thus, in the absence of
systematic follow-upandinvestigationof these patients along with
underreporting of these reactions, the incidence of anaphylaxis
following ICM remains currently unknown. However, immediate
reactions to ICM are a major concern for radiologists, even if their
overall frequency has probably diminished with the increasing
use of non-ionic ICM [1]. Thus, a multidisciplinary network of
radiologists, allergologists, biochemists and anesthesiologists was
created in order to collect clinical cases of documented immedi-
ate reactions following ICM. The aim of the present study was to
identify the pathomechanisms involved during immediate reac-
tions following ICM on the basis of denite clinical signs and
allergological assessment. This evaluation included skin testing
and biochemical assessment in order to prove the diagnosis of
anaphylaxis, identify the culprit agent and therefore to prevent
recurrences.
2. Materials and methods
2.1. Patients
Patients who experienced an immediate reaction occurring
less than one hour following injection of ICM had biochemical
measurements and/or skin tests. Patients experiencing immedi-
ate reactions with clinical signs suggestive of allergy and positive
skin tests with the culprit ICM entered Group I (IgE-mediated
allergic hypersensitivity, i.e. immunological mechanism strongly
suspected) whereas those with negative skin tests entered Group
II (non-allergic hypersensitivity, i.e. immunological mechanism
excluded) [2].
2.2. Data collection
The following data were collected: age at the time of the reac-
tion, gender, history of asthma, atopy, drug, food or latex allergy,
premedication before the injection, name of the contrast agent
injected, onset delay between the ICMinjection and the occurrence
of the clinical reaction, previous exposures to ICM and previous
reaction(s) to ICM. Clinical signs were classied according to the
Ring and Messmer four-step grading severity scale [3], adapted as
follows: Grade I involves cutaneous-mucous signs, Grade II corre-
sponds to moderate clinical signs associating cutaneous-mucous,
cardiovascular or respiratory signs. The cardinal sign of Grade III
reaction is cardiovascular collapse which may be associated with
cutaneous-mucous symptoms or bronchospasm and Grade IV is
cardiac arrest. Dyscomfort and subjective signs, such as a sensation
of heat, pain or dizziness were not considered.
2.3. Biochemical assessment
Blood samples were collected in EDTA and plain tubes as soon
as the patient was clinically stable. Plasma or serum was obtained
by centrifugation at 1015

C, followed by gentle aspiration as far


as possible from the white cell layer, and was frozen at 20

C
until use. Biochemical tests included duplicate measurements
of plasma histamine (Immunotech Radioimmunoassay, Beckman
Coulter, Luminy, France) and serum total tryptase concentrations
(UniCAP Fluoroimmunoassay, Pharmacia & Upjohn, Uppsala, Swe-
den).
2.4. Allergological assessment
After informed consent was obtained, skin tests (prick-tests fol-
lowed by intradermal tests) were performed with ICM at least 4
weeks after the occurrence of the immediate reaction. Prior to skin
testing, cutaneous reactivity was assessed with a positive (codeine
phosphate 50gmL
1
) and a negative (saline solution) controls.
Prick-tests (PTs) were performed on the forearm and were con-
sidered positive if, within 15min of injecting the pure drug on
the forearm, a wheal equal to at least half the positive control
and larger than the negative control appeared. Intradermal tests
(IDTs) were performed after PTs, on the patients back, by inject-
ing 0.020.03mL of the ICM solution at a diluted concentration
ranging from 1:1000 to the pure solution, raising a wheal of about
3mm. The IDT was considered positive if anerythematous and pru-
riginous wheal, at least doubling the size of the injection wheal,
and surrounded by a are, appeared within 1520min after the
injection. IDTs were performed with the culprit ICM and with
the other commercially available ICM. PTs were also performed
with two standardized commercial natural rubber latex extracts
(Stallergnes, Antony, France and Allerbio, Varennes-en-Argonne,
France) as recommended elsewhere [4].
2.5. Statistical analysis
Results were expressed as meanSD. The Chi-square test and
Fishers exact test were used to compare qualitative data between
groups. The MannWhitney rank test was used to compare quan-
titative data between groups (Statview 5.0, SAS Cary NC, USA).
Signicance was assumed when p<0.05.
3. Results
3.1. Total cohort characteristics
Thirty-eight patients (23 female, 15 male) who had an immedi-
ate reaction following ICMinjection were studied between January
2001 and December 2003 (Tables 13). Mean age was 47.717.6
years (range: 1378 years); 44.014.7 years for women and
53.520.5 years for men(p>0.05). The clinical severity of the reac-
tion was Grade I in 15 patients, Grade II in 13 patients, Grade
III in 8 patients and Grade IV in 2 patients. Cutaneous-mucous
signs were present in 35 patients (urticaria =21; angioedema =17;
erythema =15), cardiovascular signs in 13 (hypotension=3; car-
diovascular collapse =8; cardiac arrest =2), respiratory signs in
12 (cough=7, dyspnea =8, bronchospasm=1) and gastrointestinal
signs in 4 (nausea =3; diarrhea =1). The precise interval between
ICM injection and onset of the reaction was recorded in 27 cases,
and was 5min or less in 19 cases (70.4%) and between 6 and
20min in 8 cases (29.6%). The reactions occurred after non-ionic
ICM injection in 32 cases (84.2%) and after ionic ICM injection in 6
cases (15.8%). The reactions were life-threatening in6 patients who
reacted after non-ionic ICM (18.7%) and in 4 patients who reacted
after ionic ICM (66.7%) (p=0.014). Eight patients were pretreated
and 19 were not (data missing for 11 patients). The frequency of
life-threatening reactions was 37.5% (n=3) in patients who had
received pretreatment and 26.3% (n=5) in patients who had not
(p>0.05). Nine patients had a positive previous allergological his-
tory and 25 had not (data missing for 4 patients), the respective
frequencies of life-threatening reactions were 22.2%(n=2) and 24%
(n=6) (p>0.05). The frequency of life-threatening reactions was
31.8% (7 cases out of 22) in patients who previously received an
ICM and 16.7% (2 cases out of 12) in patients who did not (p>0.05)
(data missing for 4 patients). Among the 22 patients who previ-
ously received ICM, 5 had a clinical history of previous reaction and
P
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Table 1
Clinical and biochemical characteristics of the patients of Group I (positive skin tests to the culprit ICM) suggesting allergic hypersensitivity (normal values of plasma histamine and serum tryptase are <6nmol l
1
and <13gl
1
,
respectively).
Patient Age Sex Severity
grade
Time to onset
(min)
Culprit ICM Previous ICM
injection
Previous reaction
(grade)
Premedication Cutaneous-
mucous
signs
Gastrointestinal
signs
Cardiovascular
signs
Respiratory
signs
Histamine
(nmol l
1
)
Tryptase
(gl
1
)
1 52 M IV MD Ioxaglate Yes Yes (IV) No Cardiac arrest ND ND
2 73 M III 2 Iohexol Yes No No U, A Nausea CVC 1305 76
3 54 F III 1 Iomeprol Yes No MD U, A CVC Bronchospasm ND ND
4 32 F III 1 Iopamidol Yes No MD A CVC ND ND
5 76 M III 1 Ioxaglate Yes Yes (I) Anti-H
1
GE CVC 4 34.2
6 56 F III MD Ioxaglate Yes No Anti-H
1
A CVC ND 12.9
7 49 F III 5 Ioxaglate Yes Yes (I) Anti-H
1
, corticoids U, A CVC Dyspnea ND ND
8 73 M II 20 Iodixanol No Anti-H
1
, corticoids GE Hypotension ND ND
9 32 M II 1 Iohexol Yes No No A Cough ND ND
10 51 F II MD Iohexol Yes Yes (II) MD GE Dyspnea ND ND
11 31 F II 5 Iomeprol MD MD A Dyspnea ND ND
12 43 F II 5 Iopentol Yes No MD GE Hypotension ND ND
13 32 F II 5 Iobitridol No Anti-H
1
U Hypotension Cough 14.2 5
14 25 F II 1 Iopamidol No Anti-H
1
U Cough, dyspnea ND 5
15 53 F I 15 Iobitridol Yes No No U, A 116 9.7
16 18 F I 10 Iobitridol No No GE, U, A ND ND
17 32 F I 5 Iobitridol No No GE, A 18.1 8.5
18 68 M I 20 Iobitridol Yes No No GE, U 3.9 3.4
19 66 F I 1 Iopentol Yes No Anti-H1
GE, A 6 5.2
GE: generalized erythema; U: urticaria; A: angioedema; CVC: cardiovascular collapse. MD: missing data, ND: not done.
Table 2
Clinical and biochemical characteristics of the patients of Group II (negative skin tests to the culprit ICM) suggesting non-allergic hypersensitivity mechanism(normal values of plasma histamine and serumtryptase are <6nmol l
1
and <13gl
1
, respectively).
Patient Age Sex Severity
grade
Time to onset
(min)
Culprit ICM Previous ICM
injection
Previous reaction
(grade)
Premedication Cutaneous-mucous
signs
Gastrointestinal
signs
Respiratory signs Histamine
(nmol l
1
)
Tryptase
(gl
1
)
20 37 F II MD Iobitridol Yes No MD U Cough, dyspnea ND ND
21 63 M II 2 Iohexol Yes No No A Cough 1.1 5.7
22 68 M II MD Iohexol Yes Yes (I) No U Nausea dyspnea 3.5 11.4
23 78 M I MD Iobitridol Yes No No U 2.3 5
24 73 F I MD Iobitridol Yes No MD U ND ND
25 29 F I 10 Iohexol No No GE, U, A 2.7 16.4
26 45 F I 2 Iobitridol No No GE, U, A 1 6.9
GE: generalized erythema; U: urticaria; A: angioedema; MD: missing data; ND: not done.
498 P. Dewachter et al. / European Journal of Radiology 77 (2011) 495501
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the current reaction was life-threatening in 3 of them. Among the
17 patients who had no previous history of reaction, 4 had a life-
threatening reaction. The frequencies of life-threatening reactions
between previous reactors and others were not different (p>0.05).
Skin tests were performed in 27 patients, together with bio-
chemical tests in 14 (Tables 1 and 2), whereas 11 patients only had
biochemical investigations (Table 3).
3.2. Biochemical tests
Blood samples were drawn after the reaction in 25 patients out
of 38. Plasmahistamineconcentrations wereincreasedin9patients
(range: 61305nmol l
1
, normal values <6nmol l
1
), and tryptase
concentrations in 4 patients (range: 16.476gl
1
, normal val-
ues <13gl
1
). Concentrations of histamine (358632 versus
10.625.9nmol l
1
; p=0.019) and tryptase (33.927.3 versus
6.53.6; p=0.004) were higher in patients with life-threatening
reactions (Grades III and IV) than in patients with moderate reac-
tions (Grades I and II). Similarly, histamine (290569nmol l
1
versus 1027nmol l
1
; p=0.009) and tryptase (29.127.1gl
1
versus 6.53.7gl
1
; p=0.016) concentrations were higher in
patients who had presented cardiovascular signs than in patients
whohadnot. Nosignicant differencewas seeninpatients withand
without respiratory signs for histamine or tryptase concentrations.
3.3. Allergological assessment
One patient (Grade III reaction: cardiovascular collapse; data not
shown) had negative IDTs with ICM but positive PTs with latex. He
was excludedfromthe cohort because the diagnosis was supported
by a latex-induced allergic reaction. Latex allergy was ruled out by
negative PTs with latex in the other 26 patients.
These 26 patients were classied into two groups, according to
the results of skin tests with the administered ICM. Group I com-
prised 19 patients (73.1%) with positive skin tests. Skin tests with
the injected ICMwere positive in 56% of patients with Grade I reac-
tions, in 70% with Grade II reactions and 100% with Grade III or IV
reactions. The culprit ICM were: iobitridol (n=5), ioxaglate (n=4),
iohexol (n=3), iomeprol (n=2), iopamidol (n=2), iopentol (n=2)
and iodixanol (n=1). The 19 patients had positive intradermal tests
to the culprit ICM, while only one patient (6%) had a positive PT.
The positive IDTs were obtainedwiththe ICMdilutedat 1:100 in
3 cases (15.8%), 1:10 in 9 cases (47.4%) and with the pure ICMsolu-
tion in 7 cases (36.8%) (Table 4). Skin cross-reactivity was assessed
in the 19 patients with one through 10 other ICM (Table 5). Nine
out of the 129 IDTs (7%) performed appeared positive. Skin cross-
reactivity to one or two ICM different from the culprit one was
present in 6 patients whereas the 13 other patients had positive
IDT with the culprit ICM alone.
Group II consisted of 7 patients (26.9%) with negative PTs and
IDTs to the culprit ICM (Table 2). IDTs were negative with the pure
solution in all of them. No cross-reactivity with the other ICM was
found (59 IDTs performed with non-culprit ICM).
3.4. Comparison of Group I and Group II (Tables 1 and 2)
3.4.1. Characteristics of the patients
Group I (IgE-mediated allergic hypersensitivity) comprised 13
female and 6 male patients, and Group II (non-allergic hyper-
sensitivity) comprised 4 female and 3 male patients. The gender
distribution and the patients age (48.217.8 years in Group I;
56.119.1 years in Group II) were not different between the two
groups. Non-ionic ICM were more frequently involved than ionic
in both groups (78.9% in Group I and 100% in Group II; p>0.05).
The reactions occurred less than 5min after the ICM injection in
75% and in 66.6% of cases in Group I and II, respectively (p>0.05).
P. Dewachter et al. / European Journal of Radiology 77 (2011) 495501 499
Table 4
Skin tests results in Group I (Allergic hypersensitivity): prick-tests (PT) and intradermal tests (IDT) expressed as the diameters (mm) of the injection papule (IP) and of the
nal papule (FP) (IP/FP) obtained with the culprit ICM at different dilutions, and cross-reactivity to other ICM (see Table 5).
Patient Culprit ICM PT IDT 10
3
IDT 10
2
IDT 10
1
IDT pure Cross-reactivity
1 Ioxaglate Positive Negative Negative 3/8 Negative
2 Iohexol Negative Negative Negative 4/11 Negative
3 Iomeprol Negative Negative Negative Negative 3/8 Negative
4 Iopamidol Negative Negative Negative Negative 3/8 Negative
5 Ioxaglate Negative Negative Negative 3/8 Ioxitalamate
6 Ioxaglate Negative Negative Negative 3/9 Ioxitalamate, iobitridol
7 Ioxaglate Negative Negative Negative 3/8 Negative
8 Iodixanol Not done Negative Negative 3/7 Negative
9 Iohexol Negative Negative Negative 3/9 Ioversol, iomeprol
10 Iohexol Negative Negative Negative Negative 3/8 Iopromide
11 Iomeprol Not done Negative Negative 3/8 Negative
12 Iopentol Negative Negative 3/13 Negative
13 Iobitridol Negative Negative Negative Negative 4/11 Negative
14 Iopamidol Negative Negative Negative Negative 3/12 Negative
15 Iobitridol Negative Negative 3/8 Ioxitalamate, iohexol
16 Iobitridol Negative Negative Negative Negative 2/9 Negative
17 Iobitridol Negative Negative Negative 4/12 Negative
18 Iobitridol Negative Negative Negative Negative 3/6 Iopromide
19 Iopentol Negative Negative 3/12 Negative
Life-threatening reactions were frequent in Group I (n=7, 36.8%)
but absent in Group II (p>0.05). Cutaneous or cutaneous-mucous
signs were present in 18 patients (94.7%) of Group I and in all the
patients of Group II (p=NS). Cardiovascular signs were present in
10 patients (52.6%) of Group I and were not observed in Group II
(p=0.023). Respiratory signs were observed in 36.8% of patients of
Group I and 42.8% of patients of Group II (p>0.05). Gastrointestinal
signs were seen in one patient of each group.
Fourteen of the skin-tested patients had biochemical measure-
ments. Plasma histamine concentrations were higher in Group I
(210485nmol l
1
; n=7) thaninGroupII (2.11.1nmol l
1
; n=5)
(p=0.0045). Serum tryptase concentrations did not differ between
Group I (17.823.7gl
1
; n=9) and Group II (9.14.8gl
1
;
n=5) (p>0.05).
3.4.2. Previous allergological and radiological histories
In Group I, 6 patients (33.3%) had a previous positive allergolog-
ical history (asthma, conjunctivitis, drug allergy in 2 cases each)
(data missing for 1 patient). In Group II, 3 patients (42.8%) had
a previous positive allergological history (rhinitis, asthma, drug
allergy in 1 case each). Thirteen patients in Group I (data miss-
ing for 1 patient) had previously received an ICM, 4 had a previous
immediate reaction(itching, urticaria, erythema withdyspnea, car-
diovascular collapse in one case each). In Group II, 5 patients had
previously received an ICM, in one case it was followed by a cuta-
neous reaction (urticaria).
3.4.3. Pretreatment
In Group I, 7 patients were pretreated (H
1
-receptor antagonists
in 7 cases associated to corticosteroids in 2 cases) (data missing
for 5 patients). Three life-threatening reactions and 4 moderate
reactions were observed (Table 1). None of the patients in Group II
had been pretreated (data missing for 2 patients), only moderate
reactions were seen (Table 2).
4. Discussion
Immediate reactions following ICM can occur through multi-
ple mechanisms. However, the most severe reactions are probably
directly related to allergic hypersensitivity, i.e. anaphylaxis [511].
In the present study, immediate reactions to ICM were classied
on the basis of clinical ndings and skin tests results. The clinical
Table 5
Cross-reactivity with the different ICM, diluted and pure, in the patients of Group I (Allergic hypersensitivity). Intradermal tests (IDT) are expressed as the diameters (mm)
of the injection papule (IP) and of the nal papule (FP) (IP/FP) (see Table 4 for culprit ICM).
Patient Amidotrizoate Ioxaglate Ioxitalamate Iobitridol Iodixanol Iohexol Iomeprol Iopamidol Iopentol Iopromide Ioversol
1 ND Culprit Negative ND Negative Negative ND ND ND ND ND
2 Negative Negative Negative Negative Negative Culprit Negative Negative Negative Negative Negative
3 Negative Negative Negative Negative Negative Negative Culprit Negative Negative Negative Negative
4 ND Negative ND Negative ND Negative Negative Culprit Negative ND ND
5 ND Culprit 10
1
3/6 ND ND ND ND Negative
a
Negative
a
ND Negative
a
6 ND Culprit Pure 2/5 Pure 2/5 Negative Negative ND Negative Negative ND Negative
7 Negative Culprit ND ND ND ND ND Negative ND Negative Negative
8 ND Negative Negative Negative Culprit Negative Negative Negative Negative Negative Negative
9 ND Negative Negative Negative Negative Culprit 10
1
3/15 Negative Negative Negative 10
1
3/15
10 ND Negative ND Negative Negative Culprit ND Negative Negative Pure 3/8 Negative
11 ND ND ND ND ND ND Culprit Negative ND ND ND
12 ND Negative Negative Negative Negative Negative ND Negative Culprit Negative Negative
13 Negative Negative Negative Culprit Negative Negative Negative Negative Negative Negative Negative
14 ND Negative Negative Negative Negative Negative Negative Culprit Negative Negative Negative
15 ND ND 10
2
5/12 Culprit ND 10
2
5/10 ND ND ND ND ND
16 Negative Negative Negative Culprit Negative Negative Negative Negative Negative Negative Negative
17 Negative
a
Negative
a
Negative
a
Culprit Negative
a
Negative
a
ND Negative
a
ND ND ND
18 Negative Negative Negative Culprit Negative Negative Negative Negative Negative Pure 3/6 Negative
19 ND Negative ND ND Negative Negative Negative ND Culprit ND ND
ND: not done.
a
Tests performed only up to 10
1
dilution.
500 P. Dewachter et al. / European Journal of Radiology 77 (2011) 495501
eligibility criteria for this study were: (i) the occurrence of clinical
signs belonging to the Ring and Messmer adapted scale [3,4], along
with (ii) an onset delay of less than one hour between the ICM
injection and the occurrence of the clinical reaction. In most cases,
the onset delay was less than 5min, a time-frame consistent with
immediate allergic hypersensitivity reactions. In the present study,
non-ionic ICM were more frequently involved than ionic ICM, this
trend probably reects the current market share. Skin testing with
immediate reading was used to classify the patients between aller-
gic and non-allergic hypersensitivity [12]. Intradermal tests were
performed with diluted ICM up to the pure solution. It is unusual
to use pure drug solutions for IDTs, and we anticipated that false-
positive results could occur due to the high osmolality or toxicity of
theICMcommercial solution. However veryfewtests (9/188=4.8%)
appearedpositivewhenusingpurenon-culprit ICM, demonstrating
that this hypothesis was not true. This nding conrms that skin
mast cells do not release histamine in vivo through non-specic
mechanisms, as it was previously shown in vitro [13]. The positive
IDTs with the pure ICM solution were thus considered as specic,
indicating an allergic mechanism. Thus, an ICM-induced allergic
hypersensitivity reaction was considered proven in 73% of the
patients. On the contrary, prick-tests with ICMshowed insufcient
diagnostic sensitivity. For these patients, 93% of IDTs performed
with the other commercialized ICMwere negative, indicating a low
rate of cross-reactivity among the different commercialized ICM
despite closely related molecular structures. Thus, we suggest that
cross-reactivity with other ICM should be assessed by using IDTs,
in order to propose a safe alternative (i.e. non-reactive ICM by skin
testing) for further procedures.
Two recent reports studied skin reactivity of ICM reactors by
using IDTs with 1:10 diluted solutions. The former found positive
IDTs in 28% of the 32 patients [14]. The latter, a European mul-
ticentric study, found positive IDTs in 24.6% of the 122 patients
[15]. The percentages of positivity were lower than in the present
study, even when considering the same dilutions, as we found pos-
itive IDTs with 1:100 or 1:10 dilution in at least 46% of the patients
(n=12/26). In the present study, the higher frequency of skin tests
positivity may be explained by the precise knowledge of the name
of the culprit ICM for each patient, whereas in the other studies, it
was unknownfor 60%and48%of patients, respectively [14,15]. This
emphasizes that a detailed description of all administered drugs
and the chronology of the clinical event are fundamental in order
to performthe appropriate skintests. Radiologists should therefore
conform to the recommendation of indicating the precise name of
the injected ICM on every radiological report.
Takenaltogether, these previous studies andour results indicate
that immediate allergic hypersensitivity to ICM must be con-
sidered. In our series, allergic hypersensitivity to ICM appeared
three times more frequent than non-allergic hypersensitivity. Res-
piratory and/or cutaneous signs did not discriminate between
allergic and non-allergic mechanisms. Conversely, cardiovascu-
lar signs and/or life-threatening reactions were only seen during
allergic hypersensitivity reactions, conrming previous reports
[5,6,811,16]. Surprisingly, about 30% of patients who had an aller-
gic reaction had not been exposed to ICM previously, suggesting
that they were sensitized by other means and therefore indicating
that anaphylaxis may follow a rst-time ICM administration.
Several anaphylactic reactions occurred despite pretreatment,
as reported for other cases [5,10,11] and their severity was inde-
pendent of pretreatment.
Histamine and tryptase concentrations were higher during
life-threatening reactions, i.e. anaphylaxis than during moderate
reactions therefore conrming a previous study [6] and case-
reports [10]. Histamineconcentrations werehigher inpatients with
positive skintests, suggestingthat histamine is more likelyreleased
duringallergic thanduringnon-allergic reactions. Tryptaseconcen-
trations were higher in patients with cardiovascular signs, but not
in patients with respiratory signs. A raised tryptase concentration
indicates mast cell activation and is consistent with anaphylaxis
[1719]. In the present series, only 3 patients out of 9 with posi-
tive skin tests had increased or borderline tryptase concentrations.
These 3 patients had Grade III reactions, while the 6 others expe-
rienced Grade I or II reactions. The mild severity of the reactions
might explain the lower levels of tryptase [6,20]. The comparison
with the baseline level has been suggested to interpret such data
[17], but was not available in this study. Alternatively, inappro-
priate delays between reaction and sampling could lead to false
negative values, as samples obtained during the rst 15min may
not contain tryptase yet, and as tryptase may have disappeared in
samples obtained hours after the reaction [17].
Finally, our results conrm other reports [6,10,14,15] demon-
strating that allergic hypersensitivity is a frequently involved
pathomechanism elicitating immediate reactions to ICM. Allergic
hypersensitivity reactions usually recur with possibly increased
severity on re-challenge, and despite pretreatment. Thus, in case of
anICMdocumentedanaphylaxis, theculprit ICMandtheskincross-
reactive ICM should be avoided. Negative skin-tested ICM may be
proposed for subsequent radiological procedures [21].
Inconclusion, following animmediate reactionto ICM, the com-
bination of clinical, biochemical and skin test evidence will identify
the culprit agent and will allow the practitioner to avoid recur-
rences.
Conict of interest
The authors disclose any actual or potential conict of inter-
est including any nancial, personal or other relationships with
other people or organizations within 3 years of beginning the work
submitted that could inappropriately inuence their work.
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