Skin Testing for Radio Contrast Allergens

September 2, 2021
Skin Testing for Radio Contrast Allergens

Question
When would you recommend that the office-based practicing allergist should do skin testing for a patient requiring another study who had a moderately severe reaction?

Answer
From the Editors: Allergists may be changing their method of evaluating patients with radio contrast reactions. New research suggests that while perhaps the majority is anaphylactoid, for which skin testing is not of value, some may actually be IgE mediated. If it is true anaphylaxis, skin testing may be of value. Read what our world experts recommend.

By Dr. Marie Angelique Lazo-Betetta

Drug hypersensitivity reactions are among the most frequent reasons for consultation in allergy departments (1). Hypersensitivity reactions to radiocontrast media (RCM) are classically classified as immunologic (allergic), including IgE-mediated, or nonimmunologic. Nonimmunologic reactions are most common, especially when ionic radiocontrast agents are used. However, with the growing use of modern nonionic iso-osmolar RCM, the proportion of allergic reactions has increased.

The general risk of hypersensitivity reactions to RCM is reported to be 0.31% but may increase up to 35% in patients with a prior RCM allergy (2). Most hypersensitivity reactions to RCM, either immediate or delayed, are mild and self-limited; however, a small proportion of reactions require treatment and, if left untreated, could be life-threatening (3).

I agree with the recommendation to perform skin testing in a patient with a previous hypersensitivity reaction who requires a new exposure to RCM for diagnostic or therapeutic purposes, independently of the severity of the prior reaction (4). I suggest testing for the suspected culprit radiocontrast agent and a panel of alternative products, with the goal of finding the agent with the lowest risk of causing a reaction. We must consider that false negativity of skin tests to RCM is common; therefore, caution and monitoring is necessarily required in each use of RCM. In difficult cases, graded intravenous challenge with a radiocontrast agent could be performed as the gold standard allergy procedure to test tolerance (4). The risk of serious hypersensitivity reactions during RCM skin testing is minimal.

Intradermal RCM testing must meet certain parameters to achieve greater sensitivity and specificity. Generally, a non-irritating 1:10 dilution in saline is recommended for the last step. The dilution should be prepared no more than one hour before use and checked for signs of precipitation or inhomogeneity. 30 to 50 μL of the solution should be injected to form a 3 to 5 mm papule, as the sensitivity of the test may be affected if the papule is too small (4).

Regardless of patient skin testing results, history of a prior severe contrast reaction is considered a relative contraindication to receiving the same class of contrast agent in the future. If the same agent is obligatory and there are no alternatives, the agent could be tried with strict monitoring, availability of resuscitation and informed consent of the patient.

I would like to add two paragraphs regarding premedication. The major purpose of antiallergic premedication (corticosteroids and antihistamines) before RCM is to mitigate the occurrence and severity of an allergic-like reaction in high-risk patients. The most common regimen consists of 50 mg of oral prednisone administered at 13 hours, 7 hours, and 1 hour before the use of RCM, and 50 mg of oral diphenhydramine 1 hour before RCM. However, in some patients waiting 13 hours is not possible or desirable. In such cases, an accelerated premedication regimen has been recommended, although the efficacy of such regimens is not well studied (5).

It is mandatory to consider that premedication is not a panacea. Premedication does not fully prevent anaphylactic reactions and can even mask initial manifestations of anaphylaxis. No premedication strategy is a substitute for pre-administration preparedness. Contrast reactions occur despite premedication, 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 (5).

References:

1. Al-Ahmad M, Edin J, Musa F, Rodriguez-Bouza T. Drug Allergy Profile From a National Drug Allergy Registry. Front Pharmacol. 2020;11:555666.
2. Aykan AÇ, Altıntaş Aykan D, Katırcıbaşı MT, Özgül S. Management of radio-contrast allergy in radio-contrast allergic patients undergoing coronary angiography and intervention. Kardiologiia. 12 de noviembre de 2020;60(10):62-5.
3. UpToDate https://www.uptodate.com/contents/diagnosis-and-treatment-of-an-acute-reaction-to-a-radiologic-contrast-agent?topicRef=118730&source=see_link
4. Trautmann A, Brockow K, Behle V, Stoevesandt J. 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. octubre de 2019;7(7):2218-24.
5. American College of Radiology. ACR Manual on Contrast Media 2021. Available in: https://www.acr.org/Clinical-Resources/Contrast-Manual

By Prof. Sae-Hoon Kim

Based on my experience and studies of our group, positive rate of RCM skin test is quite high (over 50%) in patients with previous severe RCM hypersensitivity reaction, especially patients who experienced anaphylactic shock. Patients with previous mild reaction rarely show a positive response to the culprit RCM. I think the underlying mechanism of RCM hypersensitivity might differ between anaphylaxis (accompanied with systemic reaction) and mild-to-moderate urticaria (only cutaneous reaction). IgE-mediated immunologic mechanism seems to be involved in the pathogenesis of substantial portion of RCM-induced anaphylaxis. Non-ionic, low to iso osmolar RCM became popular these days, and the classical pseudoallergic reactions to RCM have decreased. Instead, IgE-mediated or T cell mediated immunologic reactions are increasing as the opportunity of sensitization to RCM increase due to the repeated and frequent exposure to RCM. Although more clinical and laboratory researches are needed to verify the clinical value of RCM skin testing, I think it would be appropriate to perform skin test to the patients with previous severe hypersensitivity reaction to identify the sensitization to specific RCM agent.

Not to mention, it would be the best to avoid the reuse of RCM for the patients with previous severe RCM hypersensitivity reaction. However, if another RCM-using imaging test or intervention is inevitable for them, I would recommend performing skin test for all the patients with previous severe RCM hypersensitivity reaction. Skin testing is needed more for the patients who are suspected to have IgE-mediated response to RCM, for example, patients who experienced allergic reaction after repeated exposure to RCM. But, skin test can be also positive in patients who experienced allergic reaction at the first exposure.

When the skin test is performed, the agents should include the one to which the patients reacted and the alternative ones. The positive predictive value of RCM skin test is uncertain at this stage, but the specificity of RCM skin test was quite high based on the previous studies. Thus, I would recommend avoiding RCM agents with positive response as much as possible and selecting the alternative one with negative skin test response.

Sae-Hoon Kim, MD
Department of Internal Medicine and the Institute of Allergy and Clinical Immunology
Seoul National University College of Medicine – Seoul, Korea

By Prof. Pascal Demoly

I would recommend that skin testing be done immediately because 6 months have already passed since the initial reaction and it has been shown that frequency of positive test results in immediate reactors to RCM is up to 50% in patients tested within 2–6 months, whereas at later time points, the frequency of positive tests decreases significantly.

Cross-reactivity is known to occur in immediate reactions (even though less frequently than in delayed reactions), and I would therefore recommend testing with the culprit RCM as well as alternative agents.

Systemic reactions have never been described during such tests and therefore can be performed in the office.

References:

Brockow K, Romano A, Aberer W, Bircher AJ, Barbaud A, Bonadonna P, Faria E, Kanny G, Lerch M, Pichler WJ, Ring J, Rodrigues Cernadas J, Tomaz E, Demoly P, Christiansen C; European Network of Drug Allergy and the EAACI interest group on drug hypersensitivity. Skin testing in patients with hypersensitivity reactions to iodinated contrast media – a European multicenter study. Allergy. 2009;64:234-41.

Dewachter P, Laroche D, Mouton-Faivre C, Bloch-Morot E, Cercueil JP, Metge L, Carette MF, Vergnaud MC, Clément O. Immediate reactions following iodinated contrast media injection: a study of 38 cases. European Journal of Radiology 2011;77:495-501.

Pascal Demoly, MD, PhD
Allergy Unit
Hôpital Arnaud de Villeneuve - Montpellier, France

By Dr. Roland Solensky

Immediate-type reactions to RCM have traditionally been considered to be anaphylactoid, or non-IgE-mediated (also referred to as non-immunologic) mechanism. Pre-treatment regimens consisting of corticosteroids and antihistamines have been shown to be very effective in preventing the vast majority of reactions, and this is consistent with the reactions being non-IgE-mediated (such pretreatment should not prevent truly IgE-mediated reactions). Recent studies from Europe and Asia indicate that at least some immediate reactions to RCM may be IgE-mediated. This might be because nonionic media has replaced use of ionic media, and the former is less likely to result in direct non-IgE-mediated mast cell degranulation. I believe at this point, based on limited studies (some of which I summarize below), it is still unclear what proportion of reactions are IgE-mediated. Also, I am not aware of any studies in the US that have demonstrated positive skin tests with RCM.

Brockow et al (Brockow et al, Allergy 2009; 64:234-41) studied 122 patients with a history of immediate reactions to RCM. 32/126 (26%) were skin test-positive. Of those evaluated 2-6 months after the index reaction (which was felt to the ideal time to limit false negative tests performed too soon after reactions and not too late before IgE wanted), 14/28 (50%) were skin test-positive.

Priesto-Garcia et al (Priesto-Garcia et al, J Investig Allergol Clin Immunol 2013; 23:183-9) is another large study of RCM from Europe. They studied 106 patients with immediate reactions to RCM and 11/106, or 10% were skin test-positive. Median time between reaction and skin testing was 4 months.

In Asia, Kim et al (Kim et al, Ann Allergy Asthma Immunol 2013; 110:258-62) evaluated skin testing prior to administration of RMC and found it had no clinical utility. Only one patient out of 1,048 had a positive immediate skin test, but there were 52 other skin test-negative patients who developed immediate reactions.

I believe available data indicate some reactions to RMC are IgE-mediated, but it is unclear what proportion of the total they comprise. We need more studies in which skin testing is utilized prior to administration of RCM, like the study by Kim et al, rather than just after a reaction has occurred. Also, importantly, we need studies on potential IgE-mediated reactions to RCM from the US.

I have not tried skin testing with RCM myself, and I'm not aware of anyone else in the United States who has tried. The unknown is whether someone who is skin test positive can be successfully pretreated to prevent reactions. If I encountered such a patient, I think an alternate agent shouldn't be difficult to find, so I would go with a different agent to which the patient is ST negative (so that would require skin testing with a 10-fold dilution of other agents. If a patient is ST negative, it is clear reactions still may occur based on those articles, so I would definitely still use pretreatment.

Roland Solensky, MD
Corvallis Clinic – Corvallis, Oregon, USA

References:

1. Brockow et al (Brockow et al, Allergy 2009; 64:234-41) studied 122 patients with a history of immediate reactions to RCM. 32/126 (26%) were skin test-positive. Of those evaluated 2-6 months after the index reaction (which was felt to the ideal time to limit false negative tests performed too soon after reactions and not too late before IgE wanted), 14/28 (50%) were skin test-positive. Read the entire answer.

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