Hypersensitivity Reactions to Iodinated Contrast Media

    Authors

    Abstract

    Iodinated contrast agents are used to enhance X-ray procedures and can cause both immediate and non-immediate hypersensitivity reactions. Due to their increased use, related hypersensitivity reactions are also on the rise. Following the introduction of nonionic, low-osmolar contrast media the number of hypersensitivity reactions has decreased, but possible severe reactions, such as anaphylaxis, still represent a major concern. Radiologists and cardiologists should keep in mind that previously non-exposed patients could already be sensitized, and could present with a hypersensitivity reaction following the first administration. In previous reactors, especially in cases of severe reactions, an allergy work-up could provide useful information regarding contrast media selection. In patients with a confirmed allergy to contrast media, a contrast medium that has a negative skin test should be chosen, with additional premedication. However, we must keep in mind that none of these measures offer a complete protection from repeated reaction.

    Keywords

    adverse reaction, iodinated contrast media, premedication

    DOI

    https://doi.org/10.15836/ccar.2015.269

    Full Text

    ## Introduction Iodinated contrast agents are concentrated solutions of iodinated benzene derivatives used to enhance X-ray procedures ( 1 ). These agents are generally considered safe but can cause both immediate (<1 hour after treatment) and non-immediate (>1 hour after treatment) hypersensitivity reactions. Adverse reactions following the administration of contrast media are usually divided into allergic and non-allergic hypersensitivity reactions, toxic reaction and reactions that are not related to contrast media exposure ( 2 ). More than 75 million iodine-based radiocontrast media are used worldwide every year ( 3 ), and due to their increased use, related hypersensitivity reactions are also on the rise. Iodinated contrast media are divided into four classes: ionic and non-ionic monomers, and ionic and non-ionic dimers. Ionic contrast agents with higher osmolality more commonly cause adverse reactions than low osmolality non-ionic contrast agents, and the latter have thus been recommended by The American College of Radiology for patients with increased risk of adverse reactions. However, even newer generations of contrast media can cause immediate and non-immediate reactions in an average of 1% to 3% of applications ( 4 ). Following the introduction of nonionic, low-osmolar contrast media, the number of hypersensitivity reactions to contrast media has decreased. Possible occurrence of life-threatening, severe reactions, such as anaphylaxis, still represents a major concern for physicians and patients. ## Clinical findings and risk factors The majority of hypersensitivity reactions occur following intravenous administration of contrast media and are immediate reactions occurring within the first hour ( 5 , 6 ). The most common manifestation of immediate reaction is pruritus and urticaria, occurring in around 70% of patients ( 4 , 5 ). In more severe cases, the respiratory and cardiovascular system could be involved, with dyspnea, bronchospasm, laryngeal edema, hypotension, tachycardia and arrhythmia, and shock. Finally, a possibly fatal anaphylactic reaction could occur following contrast media administration ( 4 , 7 , 8 ). Anaphylactic reactions are a life-threatening, severe, systemic hypersensitivity reaction that can occur at the first exposure to contrast media in 30-35% of cases. The most important risk factor for developing both immediate and non-immediate adverse reactions is previous hypersensitivity reaction to contrast media. Previous reactors have a 21-60% risk of a repeated reaction following re-exposure to the same or similar ionic contrast media ( 4 , 9 , 10 ). Other known risk factors for developing severe hypersensitivity reactions include asthma or other serious allergies requiring systemic treatment, treatment with beta-blockers, cardiac disease, female sex, malignant tumors, Mediterranean and Indian ethnicity, and even history of seafood allergy ( 7 , 9 , 11 ). Switching from an ionic contrast to non-ionic contrast media in previous reactors resulted in a 10-fold reduction of the incidence of severe repeat reactions ( 10 ). The non-immediate reactions generally appear within 48 hours and are usually manifested as exanthematous skin eruptions, most commonly maculopapular rash ( 5 , 12 , 13 ). Other frequent non-immediate reactions include erythema, macular exanthema, urticaria, and angioedema ( 14 , 15 ). Generally, non-immediate reactions are mild, transient, and self-limiting, but occasionally severe skin reactions can occur, such as cutaneous vasculitis, drug reactions with eosinophilia, Stevens-Johnson syndrome, or toxic epidermal necrolysis ( 15 ). Some risk factors for non-immediate reactions include a previous contrast media adverse reaction, interleukin-2 therapy, increased serum creatinine level >2.0 mg/dL, and history of contact and drug allergy ( 12 , 16 ). It has been suggested that mastocitosis, autoimmune diseases, and viral infection at time of administration of contrast media could influence the severity of a hypersensitivity reaction ( 17 , 18 ). ## Diagnosis Contrast media hypersensitivity reactions have usually been classified as non-allergic reactions ( 2 ). A recent prospective multicenter study suggested that at least 50% of hypersensitivity reactions following the administration of contrast media are due to immunological mechanisms ( 5 ). Previous studies reported variable sensitivity of the intradermal skin test, from 4.2% among patients with contrast media hypersensitivity ( 19 ) to about 50% in a French study ( 15 ), and up to 57.1% in severe immediate reactions ( 20 ). The frequency of positive tests significantly decreases with time due to loss of sensitization over time, especially in cases of immediate reactions ( 5 ). In the majority of immediate reactors, immunoglobulin E -mediated allergy had not been detected so the underlying mechanism remained unknown. Skin tests, both prick and intradermal, are performed in the diagnosis of immediate allergy to contrast media and have been shown to be useful in identifying the causative agent in cases of immediate reaction, as well as in some cases of non-immediate reaction. They also play an important role in the selection of a safe contrast media in previous reactors ( 5 , 21 , 22 ). A provocation or challenge test is important and effective in identifying high-risk patients, but time consuming and potentially threatening for the patient. During in vivo testing, certain contrast media specific IgE antibodies were detected by some investigators, but the presence varied greatly from 2-3% ( 23 ) to 47% ( 24 ) in immediate reactors. The potential role of in vitro direct histamine release tests and other in vitro basophil activation tests in the diagnosis of contrast media allergy remains to be determined, although previous studies have shown increased histamine release in previous reactors as compared with healthy volunteers ( 25 ). In non-immediate reactions, T cell mediated hypersensitivity is considered to be the mechanism causing the reaction, as confirmed by frequently positive patch skin tests and delayed intradermal tests in previous reactors ( 26 - 28 ) as well as the reappearance of the eruption after challenge testing ( 29 ). In some cases of non-immediate hypersensitivity, a lymphocyte transformation test was used ( 27 ) but it is not recommended for routine usage. Other in vitro tests include flow cytometry, lymphocyte cultures, cell lines, and hybridomas ( 30 ). ## Premedication and contrast media selection In patients with risk factors or a previous adverse reaction, low-osmolar non-ionic contrast media are generally used due to lower incidence of hypersensitivity reactions ( 31 , 32 ). In patients with a previous adverse reaction to a certain type of contrast media, a contrast medium that is skin test negative should be chosen if re-exposure is required. Due to cross-reactivity between different contrast media, hypersensitivity reactions can occur even if the contrast medium is changed. It is advisable to avoid contrast media re-exposure in patients with previous severe immediate reaction induced by contrast media, such as anaphylaxis. In such cases, alternative contrast agents such as carbon dioxide and gadolinium could be used ( 33 ). Use of premedication in previous reactors and patients at risk is a common practice, but one must keep in mind that breakthrough reactions could develop ( 34 ). Previous reactors have been associated with increased risk of new reaction following re-exposure to contrast media, and premedication appears to reduce symptoms in previous reactors. In patients with a previous moderate to severe immediate reaction, premedication with corticosteroids alone or in combination with antihistamines and other drugs is commonly used ( 30 , 34 ). A systematic review suggested that the majority of unselected patients required an oral double dose of methylprednisolone to prevent a potentially life threatening adverse reaction to contrast media ( 34 ). Unfortunately, data supporting the efficacy of premedication administration in at-risk patients are still lacking ( 34 ). ## Discussion Radiologists and cardiologists should keep in mind that at least 50% of hypersensitivity reactions to contrast media are due to an immunological mechanism. It has been shown that 30% of patients with positive skin tests had been administered contrast media for the first time, indicating that previously non-exposed patients could already be sensitized and could present with hypersensitivity reactions following the first administration ( 5 , 21 ). In previous reactors, especially in cases of severe reactions, an allergy work-up could provide useful information regarding contrast media selection ( 5 ). Skin testing has been shown to be a good tool for diagnosing contrast media allergy and in selecting a safe product in previously sensitized patients. In patients with a confirmed allergy to contrast media, a contrast medium that is skin test negative should be chosen in association with premedication. However, as mentioned earlier, only a fraction of patients with severe adverse reactions to contrast media have a positive skin test, so one must keep in mind that none of these measures offer complete protection from a repeat reaction. Physicians working with contrast media should not rely only on the efficacy of premedication but should be trained to recognize and treat severe adverse reactions if these appear.

    Cardiologia Croatica
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    Hypersensitivity Reactions to Iodinated Contrast Media

    Review Article
    Issue11-12
    Published
    Pages269-273
    PDF via DOIhttps://doi.org/10.15836/ccar.2015.269
    adverse reaction
    iodinated contrast media
    premedication

    Authors

    Željko Plazonić*ORCIDCroatia
    Tanja BatinacORCIDCroatia
    Marija BukvićORCIDCroatia

    Abstract

    Iodinated contrast agents are used to enhance X-ray procedures and can cause both immediate and non-immediate hypersensitivity reactions. Due to their increased use, related hypersensitivity reactions are also on the rise. Following the introduction of nonionic, low-osmolar contrast media the number of hypersensitivity reactions has decreased, but possible severe reactions, such as anaphylaxis, still represent a major concern. Radiologists and cardiologists should keep in mind that previously non-exposed patients could already be sensitized, and could present with a hypersensitivity reaction following the first administration. In previous reactors, especially in cases of severe reactions, an allergy work-up could provide useful information regarding contrast media selection. In patients with a confirmed allergy to contrast media, a contrast medium that has a negative skin test should be chosen, with additional premedication. However, we must keep in mind that none of these measures offer a complete protection from repeated reaction.

    Full Text

    ## Introduction Iodinated contrast agents are concentrated solutions of iodinated benzene derivatives used to enhance X-ray procedures ( 1 ). These agents are generally considered safe but can cause both immediate (<1 hour after treatment) and non-immediate (>1 hour after treatment) hypersensitivity reactions. Adverse reactions following the administration of contrast media are usually divided into allergic and non-allergic hypersensitivity reactions, toxic reaction and reactions that are not related to contrast media exposure ( 2 ). More than 75 million iodine-based radiocontrast media are used worldwide every year ( 3 ), and due to their increased use, related hypersensitivity reactions are also on the rise. Iodinated contrast media are divided into four classes: ionic and non-ionic monomers, and ionic and non-ionic dimers. Ionic contrast agents with higher osmolality more commonly cause adverse reactions than low osmolality non-ionic contrast agents, and the latter have thus been recommended by The American College of Radiology for patients with increased risk of adverse reactions. However, even newer generations of contrast media can cause immediate and non-immediate reactions in an average of 1% to 3% of applications ( 4 ). Following the introduction of nonionic, low-osmolar contrast media, the number of hypersensitivity reactions to contrast media has decreased. Possible occurrence of life-threatening, severe reactions, such as anaphylaxis, still represents a major concern for physicians and patients. ## Clinical findings and risk factors The majority of hypersensitivity reactions occur following intravenous administration of contrast media and are immediate reactions occurring within the first hour ( 5 , 6 ). The most common manifestation of immediate reaction is pruritus and urticaria, occurring in around 70% of patients ( 4 , 5 ). In more severe cases, the respiratory and cardiovascular system could be involved, with dyspnea, bronchospasm, laryngeal edema, hypotension, tachycardia and arrhythmia, and shock. Finally, a possibly fatal anaphylactic reaction could occur following contrast media administration ( 4 , 7 , 8 ). Anaphylactic reactions are a life-threatening, severe, systemic hypersensitivity reaction that can occur at the first exposure to contrast media in 30-35% of cases. The most important risk factor for developing both immediate and non-immediate adverse reactions is previous hypersensitivity reaction to contrast media. Previous reactors have a 21-60% risk of a repeated reaction following re-exposure to the same or similar ionic contrast media ( 4 , 9 , 10 ). Other known risk factors for developing severe hypersensitivity reactions include asthma or other serious allergies requiring systemic treatment, treatment with beta-blockers, cardiac disease, female sex, malignant tumors, Mediterranean and Indian ethnicity, and even history of seafood allergy ( 7 , 9 , 11 ). Switching from an ionic contrast to non-ionic contrast media in previous reactors resulted in a 10-fold reduction of the incidence of severe repeat reactions ( 10 ). The non-immediate reactions generally appear within 48 hours and are usually manifested as exanthematous skin eruptions, most commonly maculopapular rash ( 5 , 12 , 13 ). Other frequent non-immediate reactions include erythema, macular exanthema, urticaria, and angioedema ( 14 , 15 ). Generally, non-immediate reactions are mild, transient, and self-limiting, but occasionally severe skin reactions can occur, such as cutaneous vasculitis, drug reactions with eosinophilia, Stevens-Johnson syndrome, or toxic epidermal necrolysis ( 15 ). Some risk factors for non-immediate reactions include a previous contrast media adverse reaction, interleukin-2 therapy, increased serum creatinine level >2.0 mg/dL, and history of contact and drug allergy ( 12 , 16 ). It has been suggested that mastocitosis, autoimmune diseases, and viral infection at time of administration of contrast media could influence the severity of a hypersensitivity reaction ( 17 , 18 ). ## Diagnosis Contrast media hypersensitivity reactions have usually been classified as non-allergic reactions ( 2 ). A recent prospective multicenter study suggested that at least 50% of hypersensitivity reactions following the administration of contrast media are due to immunological mechanisms ( 5 ). Previous studies reported variable sensitivity of the intradermal skin test, from 4.2% among patients with contrast media hypersensitivity ( 19 ) to about 50% in a French study ( 15 ), and up to 57.1% in severe immediate reactions ( 20 ). The frequency of positive tests significantly decreases with time due to loss of sensitization over time, especially in cases of immediate reactions ( 5 ). In the majority of immediate reactors, immunoglobulin E -mediated allergy had not been detected so the underlying mechanism remained unknown. Skin tests, both prick and intradermal, are performed in the diagnosis of immediate allergy to contrast media and have been shown to be useful in identifying the causative agent in cases of immediate reaction, as well as in some cases of non-immediate reaction. They also play an important role in the selection of a safe contrast media in previous reactors ( 5 , 21 , 22 ). A provocation or challenge test is important and effective in identifying high-risk patients, but time consuming and potentially threatening for the patient. During in vivo testing, certain contrast media specific IgE antibodies were detected by some investigators, but the presence varied greatly from 2-3% ( 23 ) to 47% ( 24 ) in immediate reactors. The potential role of in vitro direct histamine release tests and other in vitro basophil activation tests in the diagnosis of contrast media allergy remains to be determined, although previous studies have shown increased histamine release in previous reactors as compared with healthy volunteers ( 25 ). In non-immediate reactions, T cell mediated hypersensitivity is considered to be the mechanism causing the reaction, as confirmed by frequently positive patch skin tests and delayed intradermal tests in previous reactors ( 26 - 28 ) as well as the reappearance of the eruption after challenge testing ( 29 ). In some cases of non-immediate hypersensitivity, a lymphocyte transformation test was used ( 27 ) but it is not recommended for routine usage. Other in vitro tests include flow cytometry, lymphocyte cultures, cell lines, and hybridomas ( 30 ). ## Premedication and contrast media selection In patients with risk factors or a previous adverse reaction, low-osmolar non-ionic contrast media are generally used due to lower incidence of hypersensitivity reactions ( 31 , 32 ). In patients with a previous adverse reaction to a certain type of contrast media, a contrast medium that is skin test negative should be chosen if re-exposure is required. Due to cross-reactivity between different contrast media, hypersensitivity reactions can occur even if the contrast medium is changed. It is advisable to avoid contrast media re-exposure in patients with previous severe immediate reaction induced by contrast media, such as anaphylaxis. In such cases, alternative contrast agents such as carbon dioxide and gadolinium could be used ( 33 ). Use of premedication in previous reactors and patients at risk is a common practice, but one must keep in mind that breakthrough reactions could develop ( 34 ). Previous reactors have been associated with increased risk of new reaction following re-exposure to contrast media, and premedication appears to reduce symptoms in previous reactors. In patients with a previous moderate to severe immediate reaction, premedication with corticosteroids alone or in combination with antihistamines and other drugs is commonly used ( 30 , 34 ). A systematic review suggested that the majority of unselected patients required an oral double dose of methylprednisolone to prevent a potentially life threatening adverse reaction to contrast media ( 34 ). Unfortunately, data supporting the efficacy of premedication administration in at-risk patients are still lacking ( 34 ). ## Discussion Radiologists and cardiologists should keep in mind that at least 50% of hypersensitivity reactions to contrast media are due to an immunological mechanism. It has been shown that 30% of patients with positive skin tests had been administered contrast media for the first time, indicating that previously non-exposed patients could already be sensitized and could present with hypersensitivity reactions following the first administration ( 5 , 21 ). In previous reactors, especially in cases of severe reactions, an allergy work-up could provide useful information regarding contrast media selection ( 5 ). Skin testing has been shown to be a good tool for diagnosing contrast media allergy and in selecting a safe product in previously sensitized patients. In patients with a confirmed allergy to contrast media, a contrast medium that is skin test negative should be chosen in association with premedication. However, as mentioned earlier, only a fraction of patients with severe adverse reactions to contrast media have a positive skin test, so one must keep in mind that none of these measures offer complete protection from a repeat reaction. Physicians working with contrast media should not rely only on the efficacy of premedication but should be trained to recognize and treat severe adverse reactions if these appear.