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Original Research |
1 Department of Dermatology and Venerology, University of Rostock, Rostock,
Germany.
2 Department of Dermatology, Venerology, and Allergology, University of
Würzburg, Josef Schneider Strasse 2, 97080 Würzburg, Germany.
Received July 14, 2007;
accepted after revision September 25, 2007.
Address correspondence to A. Trautmann
(trautmann_a{at}klinik.uni-wuerzburg.de).
Abstract
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SUBJECTS AND METHODS. We evaluated 96 patients with anaphylaxis symptoms after contrast material application using standardized intradermal skin testing. In patients with positive skin tests, the IgE-mediated allergy was further evaluated with in vitro and challenge tests.
RESULTS. In four patients (suffering from anaphylaxis grades 2 and 3) out of the 96 (4.2%), skin tests and basophil activation tests strongly suggested IgE-mediated allergy to the contrast materials iopromide (two patients), iomeprol, and iopentol. In two patients with allergies to iopromide and iomeprol, alternative nonionic monomer contrast materials were tolerated, as identified in controlled challenge tests with iopamidol and iopromide, respectively.
CONCLUSION. The evaluation of patients with contrast
material–induced anaphylaxis (at least those with anaphylaxis 
grade
2) should always include appropriate skin tests ensuring that patients with an
IgE-mediated allergy are not missed. Moreover, allergologic testing may
identify a contrast material of the group of nonionic monomers that will be
tolerated in future radiologic interventions.
Keywords: adverse reaction • allergy • anaphylaxis • basophil activation test • contrast media • IgE-mediated allergic hypersensitivity • radiocontrast media
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The symptoms of nonallergic anaphylaxis to contrast material are caused by histamine release from mast cells and basophils either directly by the osmolality effect of the contrast material solution and nonspecific binding of contrast material on membrane receptors or indirectly by complement–kinin activation [7, 8]. On the other hand, evidence for an immunoglobulin E (IgE)-mediated allergic anaphylaxis to contrast material was reported in the literature [9–12]. During the past 6 years, we evaluated all patients who presented with a history of anaphylaxis to contrast material using our standardized allergologic workup. The purpose of our study was to identify and differentiate IgE-mediated allergy and nonallergic contrast material–induced hypersensitivity. Furthermore, the objective of our diagnostic procedures was not only to identify the culprit contrast material but also to find an alternative contrast material for future radiologic interventions.
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Patients
From 2000 to 2006, all patients referred to our allergy clinic with a
history of anaphylaxis to iodinated contrast material were subjected to a
standardized skin test. Written informed consent for allergologic workup was
obtained. Because determination of potential allergy is part of routine
diagnostic practice, further ethical approval was not required. The reported
anaphylaxis symptoms were classified according to severity
[14]
(Table 1). Grade 1 consists of
cutaneous symptoms such as urticaria and angioedema; grades 2 and 3 include
symptoms of the following organ systems: cardiovascular (hypotension,
tachycardia), respiratory (dyspnea, bronchoconstriction), and digestive
(vomiting, abdominal pain, incontinence). Only patients with clearly
documented symptoms of at least grade 1 anaphylaxis were evaluated. Pain at
the injection site, heat sensation, flushing or erythema, headache, and nausea
were considered pharmacologic side effects.
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Skin Test
We performed intradermal tests on the volar forearm with iopamidol
(Solutrast, Altana), iopromide (Ultravist, Bayer HealthCare), iomeprol
(Imeron, Altana), iopentol (Imagopaque, Amer-sham) and, where necessary, the
culprit contrast material. After 20 minutes, the intradermal test was defined
as 1 +, positive reaction with a wheal diameter of 3–5 mm; 2 +, positive
reaction with a wheal diameter of 6–10 mm; and 3 +, positive reaction
with a wheal diameter of 11–15 mm. All tests were performed according to
the EAACI recommendations
[15]. In individual cases,
allergic or nonallergic hypersensitivity to other drugs admin i stered
concomitantly with the contrast material and latex allergy (e.g., natural
rubber latex from stoppers, tubes, or gloves) that may be responsible for the
symptoms as well were excluded using skin and challenge tests.
Tryptase Measurement
Commercially available ImmunoCAP Tryptase (Phadia) was used as an in vitro
test for the quantitative measurement of tryptase concentration in human serum
[16].
Basophil Activation Test
In cases of positive intradermal skin tests, blood (5 mL) from patients and
nonallergic controls was used within 6 hours of blood sampling for the
basophil activation test. The basophil activation test, synonymously called
"flow-cytometric cellular allergen stimulation test (Flow-CAST),"
is based on the in vitro allergen-induced specific activation of basophils
[17]. The assay was performed
using a kit according to the instructions of the manufacturer. Briefly,
leukocytes were stimulated in vitro with contrast material, control antigen
(bee and wasp venom), and positive control (activating anti
Fc
RI antibody). Because there is little experience with the basophil activation
capacity of contrast material, a broad spectrum of dilutions ranging from
10–12 to 1 µg/mL was covered. The cells were double
stained with anti-CD63-PE- and anti-IgE-FITC–labeled antibodies. A
minimum of 500 basophils (IgE-positive cells) per sample were collected, and
activated basophils (CD63 + and IgE ++ double positive cells) were assessed by
flow cytometry at 488 nm on a FACS Calibur system using the CellQuest software
(Becton, Dickinson Immunocytometry Systems). Drugs usually give lower basophil
activation percentages than inhalants, food, or hymenoptera allergens
[18,
19]. Therefore, to obtain
optimal sensitivity and specificity, a cutoff value of 5% was applied so far
as negative control was maximally 2.5%. Therefore, activation of the patients'
basophils after stimulation with contrast material was considered positive if
data analysis yielded more than 5% activated basophils, provided that the
stimulation index (SI), which is the con trast material stimulation divided by
the negative control, was equal to or greater than 2 (SI 2).
IV Contrast Material Challenge
Two patients with IgE-mediated contrast material allergy were challenged
with skin- and basophil activation test–negative contrast material
according to our established protocol using standardized doses of contrast
material: 0.05, 0.5, 1, 5, 7.5, 10, and 25 mL for a total of 49.05 mL. The
general principles of our challenge protocol were as follows: the time
interval since the anaphylactic reaction was at least 6 weeks; during the
entire challenge procedure, the patient was observed and equip ment for
emergency treatment was available; the dosage of contrast material increased
stepwise to a normal dose with intervals of 30 minutes between the individual
doses; there was strict adherence to absolute and relative contraindications
for drug challenge tests; and before challenge testing, written informed
consent was obtained from each patient.
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Skin Tests
In 92 patients, the intradermal skin tests with iopamidol, iopromide,
iomeprol, iopentol, and the culprit contrast material were completely
negative. In four patients, diagnosis of IgE-mediated allergic anaphylaxis was
suspected on the basis of positive intradermal skin tests. In
Table 3, the contrast material,
the application of contrast material, latency, and symptoms are shown for
these four patients. Results of intradermal tests are summarized in
Table 4.
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Tryptase Measurement
Raised baseline serum tryptase level (obtained either before the
anaphylaxis event or at least 1 day after resolution of the clinical signs) as
a symptom of systemic mastocytosis reflects an elevated mast cell burden and
constitutes a substantial risk factor for severe or hypotensive anaphylaxis
[6,
16]. In the four patients with
IgE-mediated allergy to contrast material, tryptase levels (measured at least
6 weeks after the anaphylactic reaction) were within the normal range.
Basophil Activation Test
In three patients with IgE-mediated contrast material allergy, significant
activation of basophils with different contrast material was seen
(Table 4). The basophil
activation test yielded maximally 15% activated basophils at 1 µg/mL,
whereas activation of basophils was not induced at very low concentrations of
contrast material (10–10 to 10–12 µg/mL). In
contrast, in contrast material–stimulated samples of the controls,
basophil activation was negative with all contrast material
concentrations—that is, 1% to 2% activated basophils at 1 µg/mL.
Stimulation with control antigen (bee and wasp venom) was also negative in two
patients, and positive controls with activating anti-FcRI
antibody yielded basophil activation between 40% and 60% in patients and
controls. As a further internal control, in patient number 2, positive skin
test results with wasp venom correlated with the basophil activation test
findings (bee venom, negative; wasp venom, positive). Because of the wasp
venom allergy, this patient is being treated with immunotherapy.
IV Contrast Material Challenge
Despite knowledge of the IgE-mediated iomeprol-allergy of patient number 1,
the radiologist administered 50 mL of iomeprol (Imeron 300) IV in the course
of a CT examination. Despite premedication with 16 mg dimethindene 1 hour
prior and 750 mg prednisolone 12 hours before contrast material
administration, the patient again developed within 5 minutes grade 2
anaphylaxis symptoms. In contrast, no systemic or cutaneous reactions occurred
during controlled IV challenge with negatively tested iopamidol (Solutrast
300) and iopromide (Ultravist 300) in the two patients (numbers 4 and 1) with
IgE-mediated allergy against iopromide and iomeprol, respectively
(Table 4). After the controlled
challenge test, CT with contrast material was again indicated in patient
number 1, and the patient tolerated iopromide (Ultravist 300) without
application of premedication at a dosage of 75 mL.
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The occurrence of IgE-mediated contrast material allergy has been repeatedly questioned in the literature [21, 22]. In a review for the American Academy of Family Physicians, it is stated that anaphylactic contrast material reactions are not true allergic reactions because they occur in patients who have not been exposed to contrast material previously and IgE antibodies have not been shown [23]. An article investigating breakthrough adverse reactions to low-osmolar contrast material despite steroid premedication questioned the possibility of an IgE-mediated pathogenesis as well [24]. Further investigations by an allergologist to identify IgE-mediated allergy are not mentioned in these publications. As a consequence, patients at particularly high risk for severe contrast material–induced anaphylaxis despite premedication remain undiscovered.
The IgE mechanism could explain the high risk of recurrence of the reaction and the ineffectiveness of premedication in some patients [12, 24, 25]. Our study and investigations including the basophil activation test confirmed that IgE-mediated anaphylaxis is rare but may be one of the possible mechanisms. If clear-cut symptoms of anaphylaxis evolve during or minutes after injection of contrast material, an allergologic examination should be performed. Especially after anaphylaxis of at least grade 2, skin tests are indicated to identify patients suffering from IgE-mediated contrast material allergy. For use as skin tests, intradermal tests with a 10% dilution of the contrast material are particularly suitable. After several improvements, the basophil activation test has become a robust and reliable test for in vitro investigations of IgE-mediated allergy [17]. However, each allergen has to be assessed to determine its optimal concentration and the threshold for positivity [26].
After diagnosis of an IgE-mediated allergy to one or more contrast material, the question of possible cross-reactivity among other contrast material arises. Only a very small number of patients with anaphylaxis have a positive skin test for the administered contrast material [11, 12]. Because the contrast material concentrations used for skin tests and basophil activation tests have been constantly negative in most patients and in control subjects, the positive predictive value is likely to be high, whereas the negative predictive value is uncertain. Consequently, careful controlled challenge testing may be attempted to verify negative in vivo and in vitro test results. The majority of patients refuse challenge tests. The reasons are fear of anaphylaxis and no current need for contrast media.
Future administration of contrast material in a patient is certainly facilitated by prior allergologic testing and issued allergologic documents mentioning the causal contrast material and alternative tolerated contrast material. Comparison of the chemical structures of contrast material does not give a clue of potential cross-reactivity in individual patients: one of our patients (patient number 4) has an iopromide–iomeprol allergy and tolerates iopamidol, whereas patient number 1 has an iomeprol allergy and tolerates iopromide. For patients with undiagnosed previous anaphylaxis to contrast material (i.e., allergologic testing not performed yet), imaging procedures that do not require the administration of iodinated contrast material should be considered or a contrast material of another class should preferentially be used [27].
The use of steroids and antihistamines to prevent contrast material–induced anaphylaxis has been recommended by several authors but has not gained wide acceptance [28–30]. Data supporting the usefulness of premedication in patients with a history of allergic anaphylaxis are lacking and physicians who are dealing with these patients should therefore not rely on the efficacy of premedication [31]. Accordingly, one of our patients (patient number 1) with known iomeprol allergy developed grade 2 anaphylaxis after reexposure to iomeprol despite premedication. It is therefore important that physicians using contrast material routinely should be trained to recognize and treat anaphylaxis early and appropriately [32, 33].
Naturally, after anaphylaxis in temporal relationship to the application of contrast material, other causes for the symptoms always have to be considered [6]. During radio graphic investigations, the patient may have contact with natural rubber latex. Nonsteroidal antiinflammatory drugs, β-blockers, or angiotensin-converting enzyme inhibitors can trigger symptoms of anaphylaxis, IgE-mediated allergy against β-lactam antibiotics is overestimated but nevertheless relatively frequent. Finally, contrast material injections are capable of precipitating symptoms of occult mastocytosis. Besides exact and careful clinical history, certain laboratory tests (i.e., tryptase measurement, IgE specific for natural latex or penicillins), skin tests, and drug challenge tests help to clarify the diagnosis. Contrast material reactions are frequently falsely considered as an allergy to iodine because contrast materials are iodine based. However, neither contrast material–induced anaphylaxis correlated to IgE-mediated iodine allergy [34] nor allergic contact dermatitis due to iodine-containing antibacterial preparations should be considered evidence of IgE-mediated contrast material allergy [35].
In conclusion, IgE-mediated anaphylaxis is rare but may be one of the possible mechanisms of severe adverse reactions to contrast material. To identify these patients, at least all patients with a history of anaphylaxis symptoms of grade 2 or 3 should be subjected to an allergologic workup. Skin testing (and basophil activation testing, if available) with a panel of different contrast materials appears to be useful for confirming the presence of an IgE-mediated allergy and for identifying alternative contrast material that can be used safely.
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