CT Slice: Allergic Reaction
By Nicole R. Wulf, PharmD, and Joan Kapusnik-Uner, PharmD, FASHP, FCSHP
Radiology Today
Vol. 23 No. 3 P. 26

Researchers say iodine is wrongly implicated in contrast media reactions.

Due to persistent myths about potential cross-reactions to iodinated contrast media (ICM) and despite evidence-based guidance to the contrary, many health care professionals continue to ask patients whether they have an “iodine” or seafood allergy prior to performing an imaging study. However, as early as 1997, if not before, medical literature indicated that true allergies to iodine are impossible because iodine occurs naturally in the thyroid gland.1

We recently led an extensive review of literature dating from 1947, which reinforced these earlier assertions. Our literature review, published in the American Journal of Health-System Pharmacy, a peer-reviewed journal of the American Society of Health-System Pharmacists, failed to uncover a single finding of a patient reaction being caused by iodine.

Our study, conducted with John Schmitz, MD, a radiologist at Mayo Clinic in Rochester, Minnesota, and Amy Choi, PharmD, BCPS, who was at Memorial Care in Fountain Valley, California, when the study was conducted, focused on the iodine contained in various contrast media, as well as amiodarone, povidone-iodine, and other iodine-containing compounds.

Dispelling the iodine and seafood myth as a cause of a hypersensitivity-mediated cross-reaction to ICM is an ongoing effort. The latest guidelines from the ACR state that restricting contrast medium use or premedicating solely on the basis of unrelated allergies is not recommended.2 Yet more work needs to be done to educate clinicians and patients regarding the cause of ICM-related reactions so decisions do not deviate from current guidance.

By better understanding the mechanism and true cause of a patient‘s past history of documented reaction to ICM or seafood, clinicians can be comfortable proceeding with the highest-quality imaging studies using ICM, ensuring radiological results that are important for the patient’s health and outcomes.

Inconsistencies With ICM Reactions
Our literature review focused on 81 articles that met our inclusion criteria, out of an original group of 435 papers concerning true allergy or hypersensitivity reactions to iodine. In regard to ICM, we found studies where patients suffered acute reactions such as nausea, vomiting, rash, and numerous others, as well as delayed reactions with similar symptoms. However, reactions from contrast media are often a result of their hyperosmolar components and electron charge and not hypersensitivity due to a component of the molecule.

However, we also found significant inconsistencies with many of the papers regarding ICM. Limited information was sometimes provided in case reports, irritant reactions to povidone-iodine were reported as hypersensitivity, testing often was unable to demonstrate immunoglobulin E (IgE) antibodies to ICM in patients’ serum, and patients often exhibited no reaction after repeat exposure. Most case reports did not show any cross-reactivity between ICM and other iodine-containing compounds. Often, skin testing, eg, skin prick tests, intradermal tests, and/or patch tests, was positive for only ICM.

Studies of patients with delayed ICM reactions have shown that they are driven by T cells, which recognize the drug as an antigen and release cytokines. However, it is unlikely the iodine itself is recognized by T cells or produces IgE antibodies, due to the fact that it is an essential element in the body. While researchers have proposed that iodine-protein complexes can form in patients given ICM, no evidence to support this hypothesis has been found, nor did the data indicate that iodine caused delayed reactions.

Across studies included in our review, numerous skin and other allergy tests were performed to elicit a reaction from ICM, but no obvious correlation between responses induced by ICM or iodine was found. In the 50 allergy/hypersensitivity articles we analyzed that mentioned ICM, 40 articles provided no supporting evidence that ICM was the cause, and none of the research substantiated the notion that iodine is an allergen.

Identify the Source
Other than further dispelling the iodine allergy myth, another goal of our review was to ensure that more radiologists and other physicians are made aware of current guidance.

Researchers in a study we reviewed found that changing the ICM product formulation can reduce subsequent adverse reactions, regardless of the initial product administered. This study compared the use of premedication (such as a steroid or antihistamine) with switching the contrast agent in patients who had a previous reaction to ICM. Only three mild reactions were observed in the ICM-switch group, compared with 47 in a group that received premedication and used an agent that caused the initial reaction.3

We share the ICM-switching study to demonstrate that there are options other than avoiding ICM altogether or premedicating. Clinicians, when possible, should determine and document specifically the brand or product name for the causative ICM to ensure patients receive the most appropriate imaging and care. If the patient has no history with contrast media but claims or has documented a seafood allergy (as nearly 4% of adults, or approximately 9.5 million Americans, do), then education is warranted if the patient expresses concern.4 The “allergies” may be based only on a dislike or intolerance to seafood, the latter of which, as other investigators determined, is likely due to tropomyosin or parvalbumin.5

Highly targeted medication alerts at the point of ordering could also support physicians and patients in understanding the patient’s true risks and care options. These alerts could prompt subsequent allergy testing or an investigation into potential other causes of the reactions, such as an interaction with another medication or dehydration.

Hopefully, our study and the continued research into this decades-old public misunderstanding of iodine, which has continued to be enabled by legacy patient-screening protocols, will lead to change. Health care industry leaders will have to drive that long-overdue evolution through consumer and clinician outreach and education.

With so much clinical benefit to be had from following the current guidance, we all should do everything possible to remove the obstacles that stand in the way and embrace the prevailing evidence that leads to the best possible patient care.

— Nicole R. Wulf, PharmD, is a clinical pharmacist at First Databank.

— Joan Kapusnik-Uner, PharmD, FASHP, FCSHP, is vice president of clinical content at First Databank.

Editor’s Note: In April 2022, the FDA issued a drug safety communication recommending thyroid monitoring for infants and children who receive iodinated contrast materials. The authors of this article agree with that approach and recommend using decision support to send monitoring reminders.

1. Coakley FV, Panicek DM. Iodine allergy: an oyster without a pearl? AJR Am J Roentgenol. 1997;169(4):951-952.

2. ACR Committee on Drugs and Contrast Media. ACR Manual on Contrast Media. https://www.acr.org/-/media/ACR/files/clinical-resources/contrast_media.pdf. Published 2021.

3. Abe S, Fukuda H, Tobe K, Ibukuro K. Protective effect against adverse reactions to iodinated contrast medium: premedication vs. changing the contrast medium. Eur Radiol. 2016;26(7):2148-2154.

4. Gupta RS, Warren CM, Smith BM, et al. Prevalence and severity of food allergies among US adults. JAMA Netw Open. 2019;2(1):e185630.

5. Lopata AL, Kleine-Tebbe J, Kamath SD. Allergens and molecular diagnostics of shellfish allergy: part 22 of the Series Molecular Allergology. Allergo J Int. 2016;25(7):210-218.