key: cord-0890941-oss7ksf6
authors: Wulf, Nicole R; Schmitz, John; Choi, Amy
title: Iodine allergy: Common misperceptions
date: 2021-02-06
journal: Am J Health Syst Pharm
DOI: 10.1093/ajhp/zxab033
sha: 5a9315fdfd85a51bef09bc9a607e6ef91b4cb658
doc_id: 890941
cord_uid: oss7ksf6

DISCLAIMER: In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: The current evidence regarding iodine-containing compounds and iodine allergy cross-reactivity is reviewed. SUMMARY: Iodine is an essential human nutrient found in the thyroid gland. It is used in the synthesis of the thyroid hormones thyroxine and triiodothyroxine. Patients who report having adverse reactions to iodine-containing substances are often labelled as having an “iodine allergy,” which can result in delays in care or patients being denied essential ICM or other iodine-containing drugs. A literature review was conducted to evaluate the evidence regarding iodine allergy and iodine-containing drugs. Of 435 articles considered potentially appropriate for full review (plus 12 additional articles included on the basis of references from the eligible articles), 113 could not be obtained. After exclusion of 353 articles that did not meet all inclusion criteria, the remaining 81 articles were included in the review. The results of the literature review indicated that iodine has not been shown to be the allergen responsible for allergic reactions to iodinated contrast media, amiodarone, povidone-iodine, and other iodine-containing compounds. CONCLUSION: There is a lack of evidence to support cross-reactivity between iodine-containing compounds in so called iodine-allergic individuals.

A c c e p t e d M a n u s c r i p t Am J Health-Syst Pharm. 2021;78:xxx-xxx Sixty-six percent to 89% of physicians routinely ask patients prior to a radiographic procedure if they have a shellfish or other seafood allergy or iodine allergy. 1,2 Many healthcare providers and patients believe that because shellfish and some other types of seafood ("shellfish/seafood" hereafter) contain iodine, there will be cross reactions with iodinated contrast media (ICM) and/or other iodine-containing substances. 3 Patients who report having adverse reactions to iodine-containing substances are often labelled as having an "iodine allergy," which can result in delays in care or patients being denied essential ICM or other iodine-containing drugs. For patients with seafood/shellfish or iodine allergy, surveys indicate physicians withhold the radiographic study or recommend premedication in 20% to 75% of cases. [2] [3] [4] [5] [6] Research indicates premedication increases costs, increases hospital stay duration, may itself result in adverse effects, and delays imaging studies. 7, 8 Further, studies have shown that the usefulness of premedication is doubtful. 7 With over 75 million imaging studies conducted annually worldwide, approximately 5.9% of people having seafood allergies, and physicians routinely basing treatment decisions on these food allergies, this perception of an iodine cross-sensitivity likely influences millions of treatment decisions each year. 9, 10 Iodine is an essential human nutrient that is obtained naturally from foods. 11, 12 Iodine is converted to iodide in the digestive process and then concentrates in the thyroid gland (75% of total body stores) for ongoing synthesis of thyroxine and triiodothyroxine. In the United States, dietary iodine intake is approximately 240 to 300 µg per day for men and 190 to 210 µg per day for women, with recommended intake being 150 µg per day for most adults. 11 A c c e p t e d M a n u s c r i p t "Iodine allergy" confusion is compounded by inaccuracies and inconsistencies in the labeling of iodine-containing drugs (Table 1) . Some labeling omits mention of iodine as a potential allergen 31 ; other labelling states that "iodine allergy" is not an absolute contraindication [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] or that the iodine-containing drugs are contraindicated in patients with a known hypersensitivity to iodine. [28] [29] [30] [31] [32] [33] [34] An allergy or hypersensitivity reaction is an immunologically mediated response of the body to a foreign substance (eg, an antigen). Drug allergies are commonly classified by the Gell-Coombs classification of hypersensitivity, which includes immunoglobulin E (IgE)mediated (type I), cytotoxic (type II), immune complex (type III), and cellular mediated (type IV) hypersensitivity. A more recent classification divides type IV reactions into 4 categories according to the cells recruited. 35 Hypersensitivity reactions include anaphylactoid reactions that manifest like anaphylactic reactions, with similar signs and symptoms, but have a different mechanism and may occur without prior exposure to the antigen. 3 Our objective in the study described here was to evaluate the evidence regarding "iodine allergy" and iodine-containing drugs. Our hypothesis was that the literature would not support iodine as the agent responsible for hypersensitivity reactions reported in association with use of iodine-containing drugs and, moreover, that cross-sensitivity between drug agents does not occur (that is, an adverse reaction to one iodine-containing drug is not a contraindication to administration of another iodine-containing drug). A c c e p t e d M a n u s c r i p t iodopyridones, contrast media, iodine, povidone-iodine, potassium iodide (KI), amiodarone, iobenguane, indocyanine green (ICG), shellfish, and seafood. All journal articles or article abstracts referring to hypersensitivity to iodine-containing drugs that mentioned patient allergy history, testing to determine allergenic component, or administration of multiple iodine-containing drugs were included if they mentioned different classes of iodinecontaining drugs. The references within articles that met inclusion criteria were hand searched for additional articles.

Articles included in this review were evaluated for evidence to confirm or refute iodine as an allergen. Iodine-containing compounds evaluated in the review included ICM, povidone-iodine, potassium iodide, radioiodine, indocyanine green, and shellfish/seafood. Pertinent information in the articles was included in a table for review. Key findings from the review of articles were used to categorize articles according to whether or not they supported the misperception of iodine as an allergen. Articles were categorized as possibly supportive of the concept of iodine allergy if evidence presented supported iodine acting as an allergen (eg, case reports demonstrated that patients had positive skin or allergy tests to multiple iodine-containing compounds, evidence of a reaction to multiple iodine-containing compounds, or evidence of IgE antibody recognizing multiple iodine-containing compounds). Evidence presented in reviewed articles was categorized as inconclusive if conflicting evidence was presented (eg, a report documented positive patch tests to one iodine-containing compound but not to others). Articles were categorized as no supportive if no clear, concrete evidence was presented. Food and Drug Administration (FDA)approved labeling for various drugs was reviewed for supporting data.

One investigator (NW) independently reviewed the titles and abstracts from the search and obtained the required data from studies and case reports that met the inclusion A c c e p t e d M a n u s c r i p t criteria. Data were reviewed by the other investigators, and any concerns were addressed by the first investigator.

As illustrated in Figure 1 , the search provided 3,346 citations. After discarding duplicates and non-English-language articles, 2,387 items remained, of which 1,953 did not meet the inclusion criteria. Of the remaining 435 articles considered potentially appropriate for full review, 113 could not be obtained. Twelve additional articles were included on the basis of references from the eligible articles. Three hundred fifty-three reviewed articles were then excluded because they did not meet inclusion criteria, and the remaining 81 articles were included in this review.

The types of reactions documented included a variety of symptoms (eg, rash, anaphylaxis, contact dermatitis, itching, nausea/vomiting) found in multiple categories of the Gell-Coombs classification schema, as well as symptoms not normally recognized as an allergic reaction (eg, nausea/vomiting). The reaction frequency in reviewed studies ranged from 0% to 26.7%, but in most studies the reported reaction frequency was 0%. Most articles did not mention pretreatment.

Iodinated contrast media. ICM are the most widely used contrast agents and are standard for many diagnostic radiographic procedures. 1 All ICM share a common core structure called a tri-iodinated benzene ring. The tri-iodinated structure enables ICM to block x-rays, creating regions of higher density, or contrast, on x-rays and computed tomography scans and thereby allowing visualization of blood vessels, organs, and other body tissues. 9 A c c e p t e d M a n u s c r i p t ICM can be classified as monomers or dimers according to whether they have 1 or 2 tri-iodinated rings ( Figure 2 ) and whether they are ionic or nonionic. Ionic molecules have a carboxylate substituent, while nonionic molecules do not. Ionic agents usually have higher osmolarity (1,500-2,000 mOsm/L) than nonionic agents (290-860 mOsm/L) ( Table 2 ). The hyperosmolarity and the presence of a charge, which disrupts the electric potential of cell membranes, are thought to contribute to the increased toxicity seen with ionic agents. 9 Severe acute reactions to ICM are reported, but several observations are inconsistent with true IgE-mediated anaphylaxis: (1) prior exposure to ICM is not necessary;

(2) IgE antibodies cannot be consistently demonstrated; and (3) reactions do not consistently recur in a patient. 9 One study found increased levels of total IgE but not anti-IgE, to the specific ICM. 39 Another study found IgE antibodies specific to ioxaglate; however, the ICM was found to have a very low affinity for IgE. 40 Most of the patients who reacted were found to have no detectable IgE in their serum.

Acute hypersensitivity reactions occur within 1 hour of administration and at a higher frequency with use of high-osmolarity agents (5%-15%) vs low-osmolarity agents (0.2%-0.7%). 41, [42] [43] [44] Reported rates often include allergic-like acute reactions and physiologic reactions. The use of high-osmolarity agents has declined because of the greater likelihood of acute reactions. 9, 37 ICM may have a direct stimulant effect on mast cells and basophils due to the hyperosmolarity of a contrast agent compared to blood, or they may act on mast cells through activation of the complement system. 37, 45 Chemotoxic effects may occur because of the presence of basic groups, the large size of ICM, and the complexity of the molecule, which may favor histamine release. 37 A c c e p t e d M a n u s c r i p t Delayed hypersensitivity reactions occur 1 hour to 1 week after patients receive ICM and may have an incidence as high as 14%. 41, 46 The highest risk is seen with use of nonionic, iso-osmolar agents (nonionic dimers). Studies of patients with delayed reactions have shown that reactions are T cell mediated. [47] [48] [49] T cells recognize a drug as an antigen and release cytokines. 38 Delayed reactions to ICM can present similarly to acute reactions, but mild symptoms like rash and pruritus are the most common symptoms (Box 1). 9,37,47 It is not likely that unbound iodine can be recognized by T cells or IgE because it is a very small molecule. It has been hypothesized that iodine may act as a hapten, a molecule that is too small to elicit an immune response but becomes immunogenic by associating with a carrier molecule such as a protein. 37, 47 Researchers have shown that iodine-protein complexes can form in patients given ICM. While these were hypothesized to play a role in delayed reactions, no evidence to support this hypothesis has been found. [49] [50] [51] Although one study found that broad cross-sensitivity between ICM was a result of the presence of ICM-specific T cells, no data indicating that iodine was the causative moiety in ICM delayed reactions was found. 47 A similar study used lymphocyte activation tests to analyze T-cell reactivity. 48 Skin prick tests (SPTs), intradermal tests (IDTs), and patch tests in 9 patients showed positive skin tests to multiple ICM. Skin biopsy specimens showed T-cell infiltrate (CD4+ and/or CD8+ T cells) in the dermis. Many of the patients had other drug allergies. Lymphocyte transformation tests have been used to study whether ICM reactions have an immunologic etiology. 49 Tests were done on several patient groups: patients with or without a history of ICM allergy and patients with or without exposure to ICM.

Administration of Iodo-proteins created for the experiment did not result antigenicity in patients who had amidotrizoate reactions. KI was used for lymphocyte proliferation tests to Lugol's solution and ICM, but no information about the type of reaction was given and the patient was not tested with other compounds besides ICM. One report did not include information on the vehicle or concentration used for the patch test substances. 52 Another report used a concentration of povidone-iodine known to cause irritant reactions. 53 Ridley et al. presented a case of rash to diatrizoate and topical iodine, which is known to cause irritant reactions. 54 Another study provided limited information on patients who had positive skin tests to iodine, povidone-iodine, povidone, and ICM including if these were separate incidents or if individuals reacted to multiple substances. 55 Other case reports did not show cross-reactivity between ICM and other iodinecontaining compounds. [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] In most reports, patients had an SPT, IDT, and/or patch tests to iodine, povidone-iodine, KI, and ICM to evaluate cross-sensitivity, but only ICM tests were positive and irritant reactions to povidone-iodine were common. None of the reports supported the notion that iodine is an allergen.

Four studies evaluated the administration of ICM to patients with previous intolerance to an iodine-containing compound in 231 patients. [66] [67] [68] [69] Some patients received premedication. No reactions occurred. One study surveyed patients before receiving ICM about previous reactions to ICM and if they had a drug and/or food allergy. No risk factors for allergic reactions to ICM were found to be more prevalent in the subjects reporting an A c c e p t e d M a n u s c r i p t allergic reaction, including patients with allergy to iodine, povidone-iodine, or seafood. 70 In one study, only 1 of 13 patients with a history of hypersensitivity to ICM developed a reaction after an oral provocation test with iodine. 71 Studies have also shown that changing the ICM can reduce subsequent adverse reactions to ICM. One study compared use of premedication vs contrast agent switching on the rate of adverse reactions to ICM. Three mild reactions were observed in the ICM switch group (reaction rate, 5.2%; P < 0.001 for comparison with a control group of patients who received a previously offending contrast agent without premedication); among patients in the premedication-only group there were 47 reactions (reaction rate, 17.3%; P < 0.01 for comparison with control group). 72 Another study showed similar results in patients with moderate to severe hypersensitivity reactions to low-osmolar ICM. Switching to an alternative contrast agent was associated with a significantly lower rate of a reaction compared to administering the same ICM responsible for the initial reaction (27.6% vs 13.4%, P = 0.002). 73

Amiodarone. Another drug with iodine in its structure is amiodarone, an antiarrhythmic. Amiodarone-induced hypersensitivity reactions are rare, with only a couple published cases of anaphylaxis. The FDA-approved labeling for amiodarone list anaphylactic and anaphylactoid reactions, angioedema, and urticaria as having occurred in postmarketing reports. 31 Five articles mention amiodarone, including 4 case reports and 1 retrospective study. [74] [75] [76] [77] [78] [79] The retrospective study was classified as possibly supportive, while the case reports were classified as providing no supporting evidence. The retrospective review studied patients with an "allergy" to iodine and/or ICM who received amiodarone. 74, 75 In the study group, 167 patients (71%) reported a reaction to ICM, 55 patients (24%) to iodine, and M a n u s c r i p t 12 patients (5%) to both. After amiodarone administration, only 1 patient (0.4%) from the iodine group had a hypersensitivity reaction, but no additional information was provided about the prior reaction.

Two case series including 6 patients reported uneventful amiodarone administration to amiodarone-naïve patients with documented reactions to ICM. 76, 77 In another report, a patient developed itching and urticaria during iohexol injection. 78 After the surgery, the patient developed atrial fibrillation and was given intravenous amiodarone. Three days later the patient was started on oral amiodarone and developed lip swelling and tingling. It is unlikely that this reaction was the result of iodine cross-sensitivity because the patient tolerated the intravenous amiodarone. The patient either reacted to an excipient in the tablet or was sensitized to amiodarone the first time he received it. In another report, a patient with a shellfish allergy tolerated amiodarone. 79 Some amiodarone reactions could be the result of iodine toxicity resulting from more than 1 mg/day of iodine being absorbed (Table 3) . A 300-mg maintenance dose of amiodarone has been reported to yield 9 mg/day of iodine at steady state, 80 well in excess of the highest normal dietary intake of iodine (190-300 µg/day). 11 Iodine toxicity case reports include sensitivity reactions, iodide mumps, thyroiditis, hypothyroidism, and hyperthyroidism. 81, 82 Povidone-iodine. Povidone-iodine is a broad-spectrum topical antiseptic used to treat and prevent infection. 28, 83 It is a complex of povidone (synthetic polymer of 1-vinyl-2pyrrolidone) and iodine. Allergic contact dermatitis and irritant contact dermatitis (ICD) are adverse reactions seen with topical antibacterial preparations containing iodide. One study found the incidence of contact dermatitis with povidone-iodine use to be 0.4%. 83 A c c e p t e d M a n u s c r i p t Importantly, there are cases of individuals reacting to povidone-iodine but having negative skin tests for other iodine-containing substances. 54,71,86-101 Patients often had reactions described as erythematous, vesicular, or maculopapular. Some of these case reports were able to show that povidone was the allergen recognized by the immune system. 99, 100 Other reports analyzed cases that involved positive tests for more than 1 iodine-containing substance. [102] [103] [104] [105] [106] However, often there was a lack of information in the reports to sufficiently analyze the case, the reports were not reliable (ie, a low Naranjo probability score 107 was calculated), allergy testing was not conducted properly, or test results were interpreted as irritant reactions. The Naranjo adverse drug reaction probability scale estimates the probability of a drug being the cause of an adverse event (eg, allergy), A c c e p t e d M a n u s c r i p t and a low Naranjo probability score indicates that it is doubtful that a suspected offending drug was the cause of an adverse event.

In the other study categorized as possibly supportive of the concept of iodine allergy, patients with delayed reactions to ICM had SPTs, IDTs, and patch tests with ICM, povidoneiodine (1% and 10% aqueous), iodized alcohol, iodoform 5%, and KI. 105 Only 3 patients had positive patch tests to povidone-iodine and iodized alcohol and 1 to povidone-iodine and KI.

The high concentration used likely caused an irritant reaction.

Six articles discussed the irritant potential of povidone-iodine. A study with 24 volunteers tested iodine in petrolatum or 70% isopropyl alcohol and povidone-iodine to determine the irritant potential and threshold of iodine. 84 Iodine was found to have an irritant threshold of 1%, and vehicles used were found to increase the irritant potential of iodine. Another study in patients with povidone-iodine contact dermatitis found a high frequency of irritant reactions to patch tests with various povidone-iodine preparations in controls. 96 Only 2 of the cases were interpreted as positive for povidone-iodine rather than irritant. Another study had similar results, as all seven patients had irritant reactions to povidone-iodine and patch tests with iodine 0.5% (petrolatum) were negative. 97 Potassium iodide. Potassium iodide is sometimes used as an expectorant, to decrease viscosity of mucus in chronic pulmonary conditions and to block radioactive iodine from entering the thyroid. [29] [30] Skin rashes are the most common reaction seen with KI, but reactions may include angioedema and symptoms of serum sickness (fever, arthralgia, lymph node enlargement, and eosinophilia). Some of the adverse reactions seen with KI may be the result of iodine toxicity rather than an immunologically mediated reaction.

Eighteen articles mention KI, including 10 case reports, 5 prospective studies, 1 retrospective study, and 2 in vitro studies. Three articles were classified as possibly supportive, 2 as inconclusive, and 13 articles as providing no supporting evidence. Articles classified as possibly supportive included 1 case report, 1 retrospective study, and 1 prospective study. All of these were discussed in previous sections.

One reported case involving KI described dermatitis associated with use of a topical formulation of bismuth-iodoform impregnated gauze; the patient had positive patch tests to the gauze, to iodoform, and to high-concentration KI 25% (petrolatum). 109 Radioiodine treatment. Iobenguane I 131 and iobenguane I 123 (MIBG; 3iodobenzylguanidine) are substituted benzylguanidines with 131 I or 123 I in the meta position of the benzene ring. They are used for the treatment of hyperthyroidism and cancer. The labeling for iobenguane I 123 lists hypersensitivity as a possible rare adverse reaction. 25, 26 Four case reports included in this review mention radioiodine, and all were classified as not providing supporting evidence. [110] [111] [112] [113] In 2 reports, patients with ICM hypersensitivity (eg, anaphylaxis) tolerated radioiodine. [110] [111] In another report, a patient who previously tolerated KI developed a maculopapular eruption after an injection of I 131 MIBG. 112 Patch, A c c e p t e d M a n u s c r i p t scratch, and drug-induced lymphocyte stimulation tests with KI were negative. Another report of urticaria after I 131 and I 123 administration was attributed to an inactive ingredient in the capsule. 113 The patient later tolerated a test dose of I 131.

Indocyanine green. Indocyanine green (ICG) is a tricarbocyanine dye used for determining cardiac output, hepatic function, liver blood flow, and ophthalmic angiography. 32 It contains approximately 5% sodium iodide. Anaphylactoid and urticarial reactions have been reported with ICG use. Michie et al 114 demonstrated that reactions to ICG likely involve nonimmunologic histamine release rather than an antigen-antibody reaction. Interestingly there is also a report of an adverse reaction with an iodine-free formula of ICG. 115 Three articles mention ICG; all are case reports and were classified as not providing supporting evidence. 114, 116, 117 Bjerregaard et al 116 reported a case of hypotension after ICG injection in a patient with ICM allergy who tolerated ICG later. In another case, a woman developed urticaria after intravenous ICG, and SPTs with sodium iodide were negative. 117

Seafood. IgE-mediated seafood allergy has never been attributed to iodine. In shellfish, the major allergens are proteins called tropomyosin, and in fish the allergen is parvalbumin. 45 Unlike reactions reported in association with ICM administration, allergic reactions to seafood are usually immediate reactions and include urticaria, angioedema, asthma, rhinitis, vomiting, and diarrhea. 118 Eleven articles mention seafood, including 1 case report, 5 prospective studies, 4 retrospective studies, and 1 systematic review. One article (a retrospective study) was classified as possibly supportive and 9 articles as providing no supporting evidence. In this case-control study of 55,286 subjects, seafood allergy was found to occur in 41 or 579 patients (7.1%) with ICM allergy compared to 21 patients (1.8%) in a control group. 119 M a n u s c r i p t Approximately 13.1% of patients had a history of other drug allergies. However, no comparison to other food allergies was made.

Witten et al 120 asked patients about their allergy history before diatrizoate administration. Twenty-five percent of the patients had a history of allergy, many with multiple allergies. 166 patients with a positive allergy history developed minor adverse effects (eg, nausea, vomiting, arm pain), and 74 patients developed acute reactions (eg, urticaria, edema, bronchospasm, hypotension, shock). Of these patients, 6% had allergy to seafood, 6% to other foods, and 13% to iodides. Later studies did not show the same increased risk. In a large review of ICM administration, 5% of patients had a hypersensitivity reaction. 121 The incidence of a reaction in patients with seafood allergy was 14.98% compared to an incidence of 14.63% for patients with egg, milk, or chocolate allergy. In an observational retrospective study of 70 patients with reactions to ICM, researchers conducted SPT, IDT, and patch tests to shrimp. 122 Only 1 patient had a positive reaction to shrimp. This patient had developed a shrimp allergy several years after the reaction to ICM.

Recent guidance by the American College of Radiology (ACR) and the American Academy of Allergy, Asthma, and Immunology (AAAAI) advises that there is no cross reaction of ICM and iodine or seafood allergies. 35, 41 In addition to the more detailed information provided above, summary data on the literature reviewed are provided in the appendix.

A c c e p t e d M a n u s c r i p t

There is a misconception that ICM hypersensitivity reactions are related to their iodine content. Iodine, however, as an atom that is an essential nutrient, cannot be an allergen. People who react to medications or foods containing iodine are reacting to other allergens.

Studies have found that ICM reactions are more frequent in patients with prior reactions to ICM, other drug allergy, food allergy, or atopic conditions. 45, 120 The type of food or drug allergy was not found to be significant. Patients with hypersensitivity to multiple iodine-containing compounds may have a "multiple drug allergy syndrome," in which a person who is allergic to one drug is more likely to be allergic to other drugs. [123] [124] [125] FDA-approved prescribing information is sometimes updated, but there is a lack of incentive to update the labeling and change warnings regarding iodine. It is unlikely that manufacturers would conduct allergy studies with iodine derivatives to determine if warnings regarding iodine could be removed from labeling. A reluctance to update the labeling has serious consequences for healthcare, as some providers exclusively follow the recommendations in the labeling instead of the actual evidence.

Overall, only 3 articles were classified as inconclusive and 11 articles were classified as possibly supporting "iodine allergy." However, looking closer at the evidence in the studies and case reports, it is clear that the evidence is weak. Different methods, types of tests, concentrations, vehicles, and iodine-containing compounds are discussed in the articles. Some studies only included a small number of patients and did not include a control group. Most articles evaluated clearly show that iodine is not the allergen responsible for the adverse reactions seen with iodine-containing compounds.

A c c e p t e d M a n u s c r i p t

The likely mechanisms of adverse reactions to iodine-containing compounds do not appear to involve IgE-mediated responses to iodine. ICM adverse reactions are likely the result of activation of nonspecific immune mediators by the ICM. Hypersensitivity reactions to seafood are IgE-mediated reactions to tropomyosin or parvalbumin. Adverse reactions to iodine-containing antiseptics are likely ICD or povidone allergy. Little or no evidence exists that iodine or iodide can behave as an antigen that is recognized by the immune system.

We identified a number of limitations of this review. First, most of the included articles are case reports that were produced retrospectively on the basis of patient and provider recall. Data from medical records may be limited and not contain all relevant data. Case reports are also subjective, and the quality and interpretation of the observation can be affected by the observer's subjectivity. Non-English-language papers were excluded, which could have constituted selection bias. Lastly, the authors were not able to obtain all the articles that were chosen to be analyzed.

Iodine is an essential trace element, and iodine deficiency results in serious health consequences. The idea that iodine cross-sensitivity can exist between various iodinated substances is not supported by evidence. The use of the term "iodine allergy" can result in individuals not receiving radiologic procedures that could be lifesaving and essential to improving their health. Guidelines published by ACR and AAAAI state that there is no reason to avoid ICM use in patients with "allergies" to seafood or iodine; instead, the specific agents that are causing the adverse reactions (eg, iohexol, seafood, povidone-iodine) should be documented in the allergy record. Clinical decision support systems should be updated to stop broad alert triggering upon ordering of iodine derivatives.

A c c e p t e d M a n u s c r i p t M a n u s c r i p t iodine. The asterisk on povidone-iodine represents that the structure is repeated. Iodinated contrast media have 1 or 2 tri-iodinated benzene rings. Ionic tendency is governed by the presence or absence of a carboxylate functional group present on an organic side chain.

Ionic contrast media have a salt cation, such as sodium, calcium, or methylglucamine.

Sources: references 36 and 37.

 There is little or no published evidence that iodine or iodide can behave as an antigen that is recognized by the immune system.  The term "iodine allergy" should no longer be used because its use substantiates a crosssensitivity that is not supported by evidence.

 There is a lack of evidence to support cross-reactivity between iodine-containing compounds in so called iodine-allergic individuals. M a n u s c r i p t Indocyanine green IC-Green Contraindications IC-Green contains sodium iodide and should be used with caution in patients who have a history of allergy to iodides because of the risk of anaphylaxis.

Iobenguane I 123 MIBG)

Prior to administration, question the patient for a history of prior reactions to iodine, an iodine-containing contrast agent or other products containing iodine. If the patient is known or strongly suspected to have hypersensitivity to iodine, an iodine-containing contrast agent or other products containing iodine, the decision to administer AdreView should be based upon an assessment of the expected benefits compared to the potential hypersensitivity M a n u s c r i p t risks.

Iobenguane I 131 MIBG Azedra None None

There is an increased risk in patients with a history of a previous reaction to contrast agent, and known allergies (ie, bronchial asthma, drug or food allergies) or other hypersensitivities.

There is an increased risk in patients with a history of a previous reaction to contrast agent, and known allergies (ie, bronchial asthma, drug or food allergies) or other hypersensitivities.

Oraltag Contraindications Oraltag is contraindicated in patients with a known hypersensitivity to iodinated contrast agents.

Isovue, Isovue-M, Scanlux

Precautions Patients at increased risk include those with a history of a previous reaction to a contrast medium, patients with a known sensitivity to iodine per se, and patients with a known clinical hypersensitivity (bronchial asthma, hay fever, and food allergies).

Increased risk is associated with a history of previous reaction to a contrast agent (3-fold risk increase), a known sensitivity to iodine and known allergic disorders (that is, bronchial asthma, hay fever and food allergies) or other hypersensitivities (2-fold risk increase).

A positive history of bronchial asthma or allergy, including food allergy, a family history of allergy, or a previous

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Shellfish allergy and relation to iodinated contrast media: United Kingdom survey

Debunking myths about "allergy" to radiocontrast media in an academic institution

Shellfish allergy & risk for iodinated radiocontrast reactions: a perpetuated myth

Misconceptions about shellfish allergies and iodine radiocontrast media administration

Iodinated contrast media and the alleged "iodine allergy": an inexact diagnosis leading to inferior radiologic management and adverse drug reactions

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Formation of potential antigens from radiographic contrast media

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Analysis of cross-reactivity among radiocontrast media in 97 hypersensitivity reactions

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Is "iodine allergy" a contraindication to iodinated contrast media? The spread of a myth

Delayed hypersensitivity reaction to the non-ionic X-ray contrast medium Visipaque (iodixanol)

Anaphylaxis due to iodinated contrast media

Recurrent flexural exanthema (SDRIFE or baboon syndrome) after administration of two different iodinated radio contrast media

Recall-like phenomenon" appearing on an area previously affected by herpes zoster

Late-type allergy to the x-ray contrast medium Solutrast (iopamidol)

Hypersensitivity reaction to ioversol

Iododerma due to radiographic contrast medium

Occupational allergic contact dermatitis to a non-ionic iodinated contrast medium containing iomeprol

Iodide mumps after contrast media imaging: a rare adverse effect to iodine

Iodide mumps

Iopamidol myelography: morbidity in patients with previous intolerance to iodine derivatives

Metrizamide myelography in patients with iodine allergy or previous adverse reactions to iodinated contrast media

Prospective evaluation of adverse reactions to iodinecontaining contrast media after ERCP

Risk evaluation of endoscopic retrograde cholangiopancreatography-related contrast media allergic-like reaction: a single centre experience

Prevalence of adverse reactions to radiopaque contrast reported by patients presenting for interventional pain procedure

The role of iodine in hypersensitivity reactions to radiocontrast media

Protective effect against adverse reactions to iodinated contrast medium: premedication vs. changing the contrast medium

Re-exposure to low osmolar iodinated contrast media in patients with prior moderate-to-severe hypersensitivity reactions: a multicenter retrospective cohort study

Incidence of amiodarone hypersensitivity in patients with previous allergy to iodine or iodinated contrast agents

Incidence of amiodarone hypersensitivity reactions in hospitalized patients with prior allergic reaction to iodine or iodinated contrast

Amiodarone use in patients with documented allergy to iodine-containing compounds

Amiodarone use in patients with documented hypersensitivity to intravenous contrast dye

Hypersensitivity reaction to amiodarone in a patient with a previous reaction to an iodinated radiocontrast agent

Use of amiodarone in a patient with a shellfish allergy

New Zealand prescribing information

Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic

Iodine: deficiency and therapeutic considerations

Allergic contact dermatitis from povidone-iodine: a re-evaluation study

Allergic contact dermatitis from iodine preparations: a conundrum

An evaluation of the irritancy potential of povidone iodine solutions: comparison of subjective and objective assessment techniques

Acute IgE-mediated generalized urticaria-angioedema after topical application of povidone-iodine

Anaphylactic reaction to povidone secondary to drug ingestion in a young child

Anaphylaxis to polyvinylpyrrolidone after vaginal application of povidone-iodine

IgE-mediated povidone allergy presenting with anaphylaxis: a cause of multiple drug allergy

The results of ingredient patch testing in contact dermatitis elicited by povidone-iodine preparations

Allergic contact dermatitis from povidoneiodine

Delayed-type hypersensitivity to a nonionic, radiopaque contrast medium

Hypersensitivity reactions to iodinated contrast media-our experience

Immediate reactions to iodinated contrast mediaeight case reports

Iododerma after computed tomographic scan with intravenous radiopaque contrast media

Occupational allergic contact dermatitis to povidone-iodine

What do you think… allergic or irritant contact dermatitis?

Anaphylactic shock due to povidone

First case of anaphylaxis to iodinated povidone

Anaphylaxis to polyvinylpyrrolidone in eye drops administered to an adolescent

Allergic contact dermatitis from povidone-iodine

Contact dermatitis from a compound mixture of sugar and povidone-iodine

Iodine allergy induced by consumption of iodinecontaining food

Low negative predictive value of skin tests in investigating delayed reactions to radio-contrast media

Allergic contact dermatitis to povidone-iodine

A method for estimating the probability of adverse drug reactions

Investigation of irritant skin reaction by 10% povidone-iodine solution after surgery

Contact allergy to iodoform and bismuth subnitrate

Radioiodine treatment of differentiated thyroid cancer despite history of 'iodine allergy'. Endocrinol Diabet Metab Case Rep

Radioiodine treatment of Grave's disease despite history of iodine allergy

Adverse allergic reaction to 131 I MIBG

Skin rash after radioactive iodine caught on a cell phone camera

Adverse reactions associated with the administration of a tricarbocyanine dye (Cardio-Green) to uremic patients

Hypotensive shock as a complication of infracyanine green injection

Occurrence of severe hypotension after indocyanine green injection during the intraoperative period. A A Case Rep

Adverse reactions after administration of indocyanine green

Hypersensitivity reactions to crustacea and mollusks

Adverse reactions to iodinated contrast media: prevalence, risk factors and outcome-the results of a 3-year period

Acute reactions to urographic contrast medium. Incidence, clinical characteristics and relationship to history of hypersensitivity states

Adverse reactions to intravascularly administered contrast media. A comprehensive study based on a prospective survey

Shrimp and iodinated contrast media allergy: myth or reality?

Evaluation and management of a patient with multiple drug allergies

Multiple drug intolerance syndrome: prevalence, clinical characteristics, and management

Multiple drug intolerance syndrome: a large-scale retrospective study

Joan Kapusnik-Uner, PharmD, and Christine Sommer, PharmD, are acknowledged for their contributions to this work.

The authors have declared no potential conflicts of interest.

A c c e p t e d M a n u s c r i p t M a n u s c r i p t reaction or hypersensitivity to a contrast agent, may imply a greater than usual risk.

The susceptible population includes patients with a history of a previous reaction to a contrast medium, patients with a known sensitivity to iodine per se and patients with a known clinical hypersensitivity: bronchial asthma, hay fever, and food allergies. A positive history of allergies or hypersensitivity does not arbitrarily contraindicate the use of a contrast agent where a diagnostic procedure is thought essential, but caution should be exercised.

There is an increased risk in patients with a history of a previous reaction to contrast agent, and known allergies (ie, bronchial asthma, drug or food allergies), and other hypersensitivities.Ioxaglate meglumine, Ioxaglate sodium

A positive history of bronchial asthma or allergy (including food allergy), a family history of allergy, or a previous reaction or hypersensitivity to a contrast agent may imply a greater than usual risk.

Increased risk is associated with a history of previous reaction to a contrast agent, a known sensitivity to iodine and known allergies (ie, bronchial asthma, hay fever, and food allergies) other hypersensitivities, and underlying immune disorders, autoimmunity or immunodeficiencies that A c c e p t e d M a n u s c r i p t predispose to specific or nonspecific mediator release.

Contraindications Use is contraindicated in patients with a known sensitivity to iodides.Povidone-iodine Betadine Contraindications Do not use on individuals known to be sensitive to iodine, or other components of this product.Abbreviation: MIBG, meta iodobenzylguanidine.A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t Table 3 . Iodine Content of Select Iodine-Containing Compounds

Iodine Content Amiodarone 31 75 mg in 200-mg tablet 18.7 mg/mL of iodine in 50-mg/mL solution Cod, baked, 3 oz 11 99 µg Iobenguane I 123 or I 131 110 20 µg of sodium iodide in 100 mCi Iodized salt, approximately ¼ tsp 11 71 µg 5% Lugol's solution 34 50 mg/mL of iodine; 100 mg/mL of potassium iodide Potassium iodide 28-30, 64 1 g/mL of solution 65 mg per tablet Povidone-iodine 64 10 mg/mL Seaweed, 1 g 11 16-2,984 µg Shrimp, 3 oz 11 35 µg Tuna, 3 oz 11 17 µg A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t