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Pharmacological prevention of delayed hypersensitivity reactions caused by iodinated contrast media

  • Jung-Hyun Kim
    Affiliations
    Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea

    Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, South Korea

    Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea

    Department of Internal Medicine, Korean Armed Forces Capital Hospital, Seongnam, South Korea
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  • Sang Il Choi
    Affiliations
    Department of Radiology, Seoul National University Bundang Hospital, Seongnam-si, South Korea
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  • Yoon Jin Lee
    Affiliations
    Department of Radiology, Seoul National University Bundang Hospital, Seongnam-si, South Korea
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  • Byung-Keun Kim
    Affiliations
    Department of Internal Medicine, Korea University Medical Center Anam Hospital
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  • Heung-Woo Park
    Affiliations
    Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea

    Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, South Korea
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  • Sang-Heon Cho
    Affiliations
    Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea

    Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, South Korea
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  • Yoon-Seok Chang
    Affiliations
    Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea

    Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, South Korea

    Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
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  • Sae-Hoon Kim
    Correspondence
    Corresponding author. Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 82 Gumi-ro 173 beon-gil, Bundang-gu, Seongnam, 13620, Republic of Korea
    Affiliations
    Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea

    Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, South Korea

    Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
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Open AccessPublished:July 01, 2021DOI:https://doi.org/10.1016/j.waojou.2021.100561

      Abstract

      Background

      Delayed hypersensitivity reactions (DHRs) to radiocontrast media (RCM) occur in approximately 0.5–23.0% of patients and are thought to be caused by T cell-mediated mechanisms. However, an optimal pharmacological preventive strategy is not yet established in patients with histories of delayed reactions to RCM.

      Objective

      We aimed to evaluate the efficacy of pharmacological prevention in patients with histories of delayed reactions to non-ionic low-osmolar RCM when re-exposed to RCM.

      Methods

      A retrospective review of electronic medical records of 117 patients with previous histories of DHRs to RCM who visited an allergy clinic for the prevention of reactions after the re-exposure to RCM was conducted. The effects of pharmacological prevention were compared according to the symptom scores of previous reactions based on their intensities and durations with electronic medical records (EMRs).

      Results

      Of the 117 patients who experienced DHRs after RCM injection, we confirmed the outcomes of RCM re-exposure in 101 patients. For pharmacological prevention, 92 patients (91.1%) received steroids before RCM injection and among them, 50 patients (49.5%) received additional steroids after RCM injection. With this pharmacological prevention, patients of symptoms improved or no recurrence, recurrence of similar previous symptoms, and recurrence of worse symptoms were 98 (97.0%), 2 (2.0%), and 1 (1.0%), respectively. The proportions of no recurrence after pharmacological prevention were lower in patients with severe reactions and higher symptom scores.

      Conclusion

      Pharmacological prevention showed a beneficial effect in most patients with delayed hypersensitivity to RCM. Further investigations are needed to establish an effective protocol for the prevention of delayed reactions to RCM.

      Keywords

      Introduction

      Radiocontrast media (RCM) are used more than 75 million times per year for enhancing radiographic images, and frequent adverse reactions after RCM administration are well known.
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      Although the frequency of immediate adverse reactions to RCM was 3.8–12.7% in patients receiving high-osmolar ionic RCM and 0.7–3.1% in patients receiving low-osmolar non-ionic RCM, delayed adverse reactions occurred in approximately 0.5–23.0% of patients with a large variation because it is not clear whether the occurrence of apparent symptoms is due to RCM.
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      a large proportion of delayed-type reactions comprise mild reactions in which symptoms are seen only in the skin, and they are generally self-limited or easily controlled with medication.
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      Our allergy clinic frequently encountered clinical situations requiring preventive management in patients who had experienced DHRs to RCM and needed radiological tests or procedures using RCM. Although the standard prophylactic protocol has not yet been validated, we had administered pharmacological preventive management in these patients.
      In non-immediate reactions, the likelihood of recurrence during re-exposure is high due to frequent cross-reactivity of RCM, and changing to an alternative RCM by skin test result is now recommended for patients who had experienced DHR to RCM.
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      To evaluate the efficacy of pharmacological prevention in patients with previous delayed reactions to non-ionic low osmolar RCM when they were re-exposed to RCM, we retrospectively analyzed the outcomes of pharmacological preventions and the clinical factors related to failure of the pharmacological prevention.

      Methods

      Study design and participants

      A retrospective review of electronic medical records was conducted in 117 patients with a history of DHRs to iodinated RCM who visited the allergy clinic for the prevention of reaction after the re-exposure to non-ionic, low-osmolar RCMs at referral hospital from January 1, 2015, to December 31, 2018. Patients were aged ≥18, and those who had previously experienced severe adverse reactions such as SJS or TEN were excluded from the rechallenge. After re-exposure to RCM, the patient visited an allergy clinic or the clinic that had prescribed the imaging test. The outcomes of pharmacological prevention after re-exposure to RCM were evaluated by a clinician to determine whether the delayed reaction had recurred and to assess the severity of symptoms if they recurred. The protocol was approved by the institutional review board of Seoul National University Bundang Hospital (IRB no. B-1804-465-105) with waiver of informed consent.

      Pharmacological prevention

      Pharmacological prevention options were determined by an allergist prior to the next RCM administration for the patients, depending on the previous extent and duration of the adverse reactions to RCM. Systemic corticosteroids and antihistamines were used for the prevention before and/or after RCM exposure without changing the previously administered RCM. After the pharmacological prevention, the patient was referred to the allergy clinic to check whether the prevention was effective.

      Symptom severity score for prior delayed-type reaction

      We scored the symptom severity of prior reactions according to the duration of the symptom and the extent of the involvement and classified the severity into 3 grades (mild, moderate, and severe) according to the scores. According to symptom duration, the scores were defined as follows: 1) symptoms that disappear within 24 h without treatment, 2) symptoms that persist for 24–72 h or require medication to improve them, and 3) any symptoms that last for >72 h. According to involvement, the symptom scores were defined as follows: 1) skin reaction in one part of the body (each body part was divided into head and neck, upper extremities, lower extremities, and trunk) or nausea only; 2) skin reactions in 2 or more parts or angioedema only; and 3) whole body skin lesion or any skin lesion with angioedema or any other systemic reaction. By multiplying the score of symptom duration with that of involvement, the final values ranging from 1 to 9 were divided into 3 groups, and the symptom severity was classified into mild, moderate, and severe grades.

      Outcome assessment

      The primary objective of this study was to determine whether patients had recurrent symptoms during re-exposure to contrast media after pharmacological prevention. For the outcome assessment, the patients were classified into responders and non-responders according to the degree of recurrence after pharmacological prevention. Depending on the symptoms following pharmacological prevention, and compared to the previous reaction to contrast media, the patients were classified into: 1) a recurrence of worse symptoms group with an increased range or a longer duration of symptoms, 2) a recurrence of similar previous symptoms group with a similar range or duration of symptoms, 3) a partial-improvement group with a reduced range or a shorter duration of symptoms, and 4) a no recurrence group without any symptoms. Of these, the no recurrence and partial-improvement groups were regarded as responders whereas the other groups were considered as non-responders. As a secondary objective, the clinical factors affecting the outcomes of pharmacological prevention were also evaluated. The clinical characteristics of the patient groups who had recurrent hypersensitivity reactions despite pharmacological prevention were compared with those of the no recurrence group.

      Statistical analyses

      Comparisons of continuous variables between groups were performed using Student's t-test. The categorical variables were analyzed using Fisher's exact test and the chi-square test. P values < 0.05 were considered statistically significant. All the analyses were performed using SPSS version 18.0 (SPSS Inc., Chicago, IL, USA). To analyze the odds ratio of clinical variables for complete remission, a binary logistic regression test adjusted for age, sex, and severity grade of the previous reaction was performed.

      Results

      Clinical characteristics of study participants and previous reactions

      Among the 117 patients who had experienced previous DHRs after RCM injection and were planned to be re-exposed to RCM, the outcomes of RCM rechallenge could be confirmed in 101 patients. The mean age of the study population was 56.5 ± 12.5 years of which 68.4% (n = 80) were women. The time of onset of reactions was between 1 and 12 h after exposure in 41% of the patients, and there were 6 patients whose symptoms occurred more than 3 days after exposure to RCM. Hypersensitivity reactions occurred during the first RCM administration in 34 patients (29.1%). Skin manifestations were present in most patients (96.6%, n = 113), and urticaria (41.6%) and maculopapular exanthema (38.9%) were the most common (Table 1).
      Table 1Demographic and clinical characteristics of the study subjects
      Variables
      Age (mean ± SD, years)56.5 ± 12.5 (n = 117)
      Sex (female %, n)68.4 (n = 80)
      Onset of previous symptoms after contrast exposure (hours)
       1–1241.0 (n = 48)
       12–2431.6 (n = 37)
       24–4811.1 (n = 13)
       48–7211.1 (n = 13)
       72~5.1 (n = 6)
      Occurred when RCM was administered for the first time (yes, %)29.2 (n = 28)
      Number of RCM administration before hypersensitivity occurred (mean ± SD)3.9 ± 3.2 (n = 63)
      Types of previous delayed reactions to RCM
      Cutaneous system96.6 (n = 113)
       Urticaria only36.3 (n = 41)
       Urticaria with angioedema5.3 (n = 6)
       Angioedema only8.8 (n = 10)
       Maculopapular exanthema38.9 (n = 44)
       Itching only10.6 (n = 12)
      Gastrointestinal4.3 (n = 5)
      Cardiovascular0.9 (n = 1)
      Respiratory6.8 (n = 8)
      Nervous system1.8 (n = 2)
      Others3.5 (n = 4)
      Underlying disease (%)
       Neoplasm (solid malignancy)59.0 (n = 69)
       Diabetes mellitus9.4 (n = 11)
       Hypertension14.5 (n = 17)
       Thyroid disease6.8 (n = 8)
       Kidney disease1.7 (n = 2)
       Cardiovascular disease18.8 (n = 22)
      Past history of allergic disease26.5 (n = 31)
       Asthma16.1 (n = 5)
       Allergic rhinitis29.0 (n = 9)
       Atopic dermatitis3.2 (n = 1)
       Chronic urticaria29.0 (n = 9)
       Food hypersensitivity12.9 (n = 4)
       Drug hypersensitivity
      Histories of hypersensitivities to radiocontrast media were excluded
      16.1 (n = 5)
      Abbreviations: RCM: radiocontrast media.
      a Histories of hypersensitivities to radiocontrast media were excluded

      The outcomes of pharmacological prevention

      Of the 101 patients in whom the results of pharmacological prevention were confirmed, through chart review, 98 (97.0%) were categorized as responders, ie, symptoms improved in these patients, whereas similar symptoms occurred in 2 patients, and symptoms worsened in 1 patient after RCM re-exposure with pharmacological prevention (Fig. 1 (A), Supplemental Table 1). All the 3 non-responders were administered systemic corticosteroids before RCM administration, and 2 patients were administered systemic steroid after RCM administration; however, the symptoms were not mitigated after RCM exposure (Supplemental Table 2). These non-responders repeatedly performed the tests using iodine contrast media 1–3 times afterwards, but non-immediate reaction recurred continuously. Eventually, 1 patient no longer used iodine contrast and replaced the examination method to MRI (Magnetic Resonance Imaging). The number of non-responders was too small to evaluate the statistical difference in clinical factors determining the response of pharmacological prevention. A total of 89 patients (90.8%) were administered systemic steroids before RCM exposure (methylprednisolone 40 mg intravenous (IV) or methylprednisolone 20 mg IV 1 h before RCM exposure), and 48 patients (49.0%) were administered systemic steroids after RCM exposure in responders (Supplemental Table 1).
      Fig. 1
      Fig. 1Outcomes of pharmacological prevention for delayed radiocontrast media hypersensitivity. (A) Proportions by outcomes in the total number of patients. (B) Outcomes by symptom severity. (C) Outcomes of radiocontrast media re-exposure by systemic steroid administration. - Data were analyzed by Fisher's exact test.
      When the patients were divided into mild, moderate, and severe groups according to the symptom score system, significant differences in outcomes were observed among the 3 groups. The proportion of complete remission was significantly smaller in the severe groups than in the other groups (Fig. 1 (B)). There were no significant differences in the clinical outcomes according to the administration of systemic steroids before or after RCM exposure. This seems to be related to more frequent premedication with steroids in severe cases (Fig. 1(C)).

      Clinical factors affecting outcomes

      On comparing the patients with symptom recurrence with those with no recurrence, the mean age was greater and the female sex was prevalent in patients with symptom recurrence despite pharmacological prevention. The patients with recurrence had previous RCM reactions of more severe symptoms with longer durations and wider involvements of the body (Table 2). Next, we performed a logistic regression analysis with age, sex, and symptom score by multiplying symptom duration with symptom involvement. The severity of previous reactions was a significant clinical risk factor for determining the failure of pharmacological prevention in DHRs to RCM (Table 3).
      Table 2Clinical features of patients with symptom recurrence and complete remission after pharmacological prevention
      Symptom recurrence (n = 31)No recurrence (n = 70)P-value
      Age (mean ± SD, years)61.0 ± 11.054.5 ± 12.40.011
      Sex (female %, n)51.6 (n = 16)72.9 (n = 51)0.037
      Onset of previous symptoms after contrast exposure (hours)
      1–1245.2 (n = 14)42.9 (n = 30)0.282
      12–2429.0 (n = 9)27.1 (n = 19)
      24–483.2 (n = 1)15.7 (n = 11)
      48–7212.9 (n = 4)11.4 (n = 8)
      72~9.7 (n = 3)2.9 (n = 2)
      Occurred when RCM was administered the first time (yes, %)41.9 (n = 13)23.1 (n = 15)0.057
      Number of RCM administration before hypersensitivity occurred (mean ± SD)5.3 ± 4.0 (n = 16)3.7 ± 3.0 (n = 39)0.110
      Underlying disease (%)
       Neoplasm (solid malignancy)64.5 (n = 20)62.9 (n = 44)0.873
       Diabetes mellitus6.5 (n = 2)12.9 (n = 9)0.496
       Hypertension16.1 (n = 5)14.3 (n = 10)0.771
       Thyroid disease9.7 (n = 3)5.7 (n = 4)0.673
       Kidney disease6.5 (n = 2)0.092
       Cardiovascular disease22,6 (n = 7)15.7 (n = 11)0.406
       Allergy history
      P values were calculated using Student's t-test for continuous variables and the chi-square test for categorical variables. P values < 0.05 are in bold
      32.3 (n = 10)24.3 (n = 17)0.404
      Steroid prescription before RCM administration90.3 (n = 28)91.4 (n = 64)1.000
      Steroid administration after RCM administration64.5 (n = 20)42.9 (n = 30)0.054
      Symptom duration
       Gr 1) <24 h17.1 (n = 12)0.001
       Gr 2) 24–72 h, needed administration of medication22.6 (n = 7)55.7 (n = 39)
       Gr 3) >72 h or needed hospital admission77.4 (n = 24)27.1 (n = 19)
      Symptom involvement
       Gr 1) Skin reaction in 1 part
      P values were calculated using Student's t-test for continuous variables and the chi-square test for categorical variables. P values < 0.05 are in bold
      or nausea only
      22.9 (n = 16)0.001
       Gr 3) skin reactions in two or more parts or angioedema only12.9 (n = 4)31.4 (n = 22)
       Gr 3) whole body skin lesion or any skin lesion with angioedema or any systemic reaction87.1 (n = 27)45.7 (n = 32)
      Severity
       Mild (1,2)20.0 (n = 14)0.001
       Moderate (3,4)3.2 (n = 1)32.9 (n = 23)
       Severe (6,9)96.8 (n = 30)47.1 (n = 33)
      Abbreviations: RCM: radiocontrast media.
      a P values were calculated using Student's t-test for continuous variables and the chi-square test for categorical variables. P values < 0.05 are in bold
      Table 3Factors affecting outcomes of pharmacological prevention in delayed hypersensitivity to radiocontrast media
      VariableCategoryOdds ratio95% CIP value
      LowerUpper
      AgeYears0.9620.9221.0040.077
      SeverityWhen symptom duration score and involvement scores were multiplied;

      Mild to moderate; score 1–4

      Severe: score 6–9
      0.0290.0040.2270.001
      SexFemale to male2.6850.0590.9657.469
      Binary logistic regression adjusted for age, sex, and severity by multiplied symptom score.
      Abbreviations: CI: confidence interval.

      Discussion

      In this study, we confirmed that even in DHRs to RCM, the recurrence of the reaction can be inhibited or the severity of the symptoms could be mitigated by pharmacological intervention before or after RCM injection without changing the contrast media. The group with persistent symptoms despite pharmacological prevention showed male dominance and a higher mean age. In addition, it was found that if the previous reactions were more severe and had long durations and a wider involvement, the symptoms could persist despite pharmacological prevention. To the best of our knowledge, this is the first report to evaluate the outcome of pharmacological prevention of DHRs to RCM.
      As the use of radiological tests and interventions has increased in healthcare and clinical practice, the use of contrast media has increased enormously and has become inevitable in many clinical situations, for example, in diagnostic and therapeutic radiological interventions for vascular diseases and for the evaluation of malignancy. Hypersensitivity to RCM is the most important clinical condition in which the use of RCM is avoided, if possible. However, if the degree of hypersensitivity is mild or tolerable with preventive management and symptomatic treatment and the use of RCM is required for more precise diagnostic evaluation and more effective treatment, the risks and benefits of RCM use should be considered.
      The use of systemic steroids was based on previous case reports of preventive management or on proposed mechanisms of delayed hypersensitivity reactions.
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      Late adverse reactions to intravascular iodine based contrast media: an update.
      Our study revealed that pharmacological prevention using steroids and/or antihistamines was effective in most patients, except in a few with severe previous reactions. The severity of the prior reaction was the most critical factor in determining the outcome of preventive measures, although the majority of patients with severe previous reactions showed favorable responses to the prevention. Our study suggests that pharmacological prevention may be applied to delayed hypersensitivity reactions to RCM with special caution for patients with severe prior reactions.
      In our study, we evaluated the outcomes of pharmacological prevention in patients who were re-exposed to the RCM without opting for an alternative. Recent studies of hypersensitivity reaction to RCM demonstrated that changing RCM is helpful in reducing the recurrence of reactions on re-exposure.
      • Cha M.J.
      • Kang D.Y.
      • Lee W.
      • et al.
      Hypersensitivity reactions to iodinated contrast media: a multicenter study of 196 081 patients.
      ,
      • Iordache A.M.
      • Docea A.O.
      • Buga A.M.
      • et al.
      The incidence of skin lesions in contrast media-induced chemical hypersensitivity.
      The cross-reactivity between RCM is frequent as reported about 67% in both immediate and delayed hypersensitivity to RCM.
      • Lerondeau B.
      • Trechot P.
      • Waton J.
      • et al.
      Analysis of cross-reactivity among radiocontrast media in 97 hypersensitivity reactions.
      The cross reaction in non-immediate reaction could be related to the chemical structures and a group of RCM with carbamoyl side chain showed high cross-reactivity.
      • Lerondeau B.
      • Trechot P.
      • Waton J.
      • et al.
      Analysis of cross-reactivity among radiocontrast media in 97 hypersensitivity reactions.
      ,
      • Bellin M.F.
      • Stacul F.
      • Webb J.A.
      • et al.
      Late adverse reactions to intravascular iodine based contrast media: an update.
      ,
      • Torres M.J.
      • Gomez F.
      • Dõna I.
      • et al.
      Diagnostic evaluation of patients with nonimmediate cutaneous hypersensitivity reactions to iodinated contrast media.
      ,
      • Torres M.J.
      • Trautmann A.
      • Bohm I.
      • et al.
      Practice Parameters for Diagnosing and Managing Iodinated Contrast Media Hypersensitivity.
      Changing to RCM in other groups of chemical structures or RCM showing negative skin test could be an option to prevent non-immediate hypersensitivity reaction to RCM.
      • Broyles A.D.
      • Banerji A.
      • Barmettler S.
      • et al.
      Practical guidance for the evaluation and management of drug hypersensitivity: specific drugs.
      ,
      • Lerondeau B.
      • Trechot P.
      • Waton J.
      • et al.
      Analysis of cross-reactivity among radiocontrast media in 97 hypersensitivity reactions.
      ,
      • Torres M.J.
      • Trautmann A.
      • Bohm I.
      • et al.
      Practice Parameters for Diagnosing and Managing Iodinated Contrast Media Hypersensitivity.
      However, in order to evaluate the effect of pharmacological prevention, the patients who underwent the test or procedure with RCMs different than the previous one were excluded from our study.
      Our study has several limitations. First, since the unified intervention protocol was not planned before the study and the analysis was performed through retrospective EMR review, there were differences in the cumulative total dose and timing of systemic steroids and antihistamine administrations. Larger amounts of steroids were administered to patients with more severe prior reactions according to the judgment of the clinician. To overcome this limitation, we adjusted the severity of the prior reaction in the analysis of risk factors for unfavorable outcomes of prevention. In delayed RCM hypersensitivity, systemic steroids are administered at least 24 h prior to RCM exposure and for several days after exposure if the clinician determines that steroid administration is helpful
      • Brockow K.
      Immediate and delayed reactions to radiocontrast media: is there an allergic mechanism?.
      ,
      • Macy E.M.
      Current epidemiology and management of radiocontrast-associated acute- and delayed-onset hypersensitivity: a review of the literature.
      ,
      • Romano A.
      • Artesani M.C.
      • Andriolo M.
      • Viola M.
      • Pettinato R.
      • Vecchioli-Scaldazza A.
      Effective prophylactic protocol in delayed hypersensitivity to contrast media: report of a case involving lymphocyte transformation studies with different compounds.
      However, to date, there is no standardized premedication regimen for DHR with proven efficacy and evidence for a premedication.
      • Torres M.J.
      • Trautmann A.
      • Bohm I.
      • et al.
      Practice Parameters for Diagnosing and Managing Iodinated Contrast Media Hypersensitivity.
      Second, there was no separate control group with re-exposure to RCM without any pharmacological intervention. In practice, it is difficult to re-administer RCM without any preventive measures in patients who had previously experienced hypersensitivity to RCM. A prospective study with control group will be needed to clarify the effectiveness of pharmacological prevention in the future. Third, delayed hypersensitivity to RCM was diagnosed by the assessment of clinical history without other diagnostic tests such as patch tests, in vitro tests, or intravenous provocation. Therefore, the effectivity of pharmacologic intervention could be overestimated in our study, related to the fact that some patients were not hypersensitive to RCM, thus they would have tolerated RCM even without premedication. A recent guideline recommended to perform skin prick test or intradermal test with delayed reading followed by patch test with RCM before additional exposure to RCM.
      • Broyles A.D.
      • Banerji A.
      • Barmettler S.
      • et al.
      Practical guidance for the evaluation and management of drug hypersensitivity: specific drugs.
      ,
      • Torres M.J.
      • Gomez F.
      • Dõna I.
      • et al.
      Diagnostic evaluation of patients with nonimmediate cutaneous hypersensitivity reactions to iodinated contrast media.
      Skin testing for RCM is also performed to provide guidance on tolerability of alternatives in patients with a history of RCM-induced immediate reaction and DHR,
      • Torres M.J.
      • Trautmann A.
      • Bohm I.
      • et al.
      Practice Parameters for Diagnosing and Managing Iodinated Contrast Media Hypersensitivity. Allergy.
      ,
      • Broyles A.D.
      • Banerji A.
      • Barmettler S.
      • et al.
      Practical guidance for the evaluation and management of drug hypersensitivity: specific drugs.
      ,
      • Torres M.J.
      • Gomez F.
      • Dõna I.
      • et al.
      Diagnostic evaluation of patients with nonimmediate cutaneous hypersensitivity reactions to iodinated contrast media.
      and there have been several reports supporting the need for skin test in delayed RCM hypersensitivity
      • Webb J.A.
      • Stacul F.
      • Thomsen H.S.
      • Morcos S.K.
      Members of the contrast media safety committee of the European society of urogenital R. Late adverse reactions to intravascular iodinated contrast media.
      ,
      • Bellin M.F.
      • Stacul F.
      • Webb J.A.
      • et al.
      Late adverse reactions to intravascular iodine based contrast media: an update.
      ,
      • Kim S.H.
      • Jo E.J.
      • Kim M.Y.
      • et al.
      Clinical value of radiocontrast media skin tests as a prescreening and diagnostic tool in hypersensitivity reactions.
      ,
      • Seitz C.S.
      • Pfeuffer P.
      • Raith P.
      • Brocker E.B.
      • Trautmann A.
      Radiocontrast media-associated exanthema: identification of cross-reactivity and tolerability by allergologic testing.
      However, it takes at least 48–72 h to perform the skin test for DHR, which could be applied according to each medical situation in real clinical practice. The drug provocation test might be a confirmatory test and could be necessary to identify a safe alternative RCM, but it is also hardly performed for the diagnosis of delayed hypersensitivity to RCM in clinical practice.
      • Tasker F.
      • Fleming H.
      • McNeill G.
      • Creamer D.
      • Walsh S.
      Contrast media and cutaneous reactions. Part 2: delayed hypersensitivity reactions to iodinated contrast media.
      ,
      • Torres M.J.
      • Trautmann A.
      • Bohm I.
      • et al.
      Practice Parameters for Diagnosing and Managing Iodinated Contrast Media Hypersensitivity. Allergy.
      ,
      • Rosado Ingelmo A.
      • Dona Diaz I.
      • Cabanas Moreno R.
      • et al.
      Clinical practice guidelines for diagnosis and management of hypersensitivity reactions to contrast media.
      Lastly, there may be concerns about adverse effects induced by systemic steroid use. However, the total amount of steroids prescribed to patients was similar to the amount generally recommended for premedication for immediate RCM hypersensitivity reactions.
      • Bumbacea R.S.
      • Petrutescu B.
      • Bumbacea D.
      • Strambu I.
      Immediate and delayed hypersensitivity reactions to intravascular iodine based radiocontrast media -- an update.
      ,
      • Schrijvers R.
      • Demoly P.
      • Chiriac A.M.
      Premedication for iodinated contrast media induced immediate hypersensitivity reactions.
      In line with the opinions of expert groups, we support that the benefits of pharmacological prevention could outweigh the potential harm.
      • Sanchez-Borges M.
      • Aberer W.
      • Brockow K.
      • et al.
      Controversies in drug allergy: radiographic contrast media.
      Despite these limitations, our study provides novel information regarding delayed hypersensitivity to RCM that pharmacological prevention using steroids and/or antihistamines may be helpful for inhibiting or mitigating the recurrence of reactions when patients are re-exposed to RCM. Furthermore, the severity of the previous reaction was revealed to be an important risk factor for unfavorable responses to pharmacological prevention. A prospective study to validate the efficacy of pharmacological prevention is warranted for better management of delayed hypersensitivity to RCM in the future.

      Abbreviations

      RCM, radiocontrast media; DHR, delayed hypersensitivity reaction.

      Funding source

      There is no funding source.

      Submission declaration

      This manuscript has not been published or presented elsewhere in part or in entirety and is not under consideration by another journal.

      Author contributions

      Study design: JH Kim, SH Kim, YS Chang; data collection: JH Kim, SH Kim, SI Choi, YJ Lee, BK Kim, YS Chang; data analysis: JH Kim, SH Kim, YS Chang, HW Park, SH Cho; data interpretation: all authors; writing of the manuscript: JH Kim and SH Kim; reviewing of the manuscript: all authors; final approval of the manuscript: all authors.

      Consent for publication

      We hereby declare that we all participated in the study and in the development of the manuscript titled “Pharmacological prevention of delayed hypersensitivity reactions caused by iodinated contrast media”. We have read the final version and give our consent for the article to be published in the World Allergy Organization Journal.

      Availability of data and materials

      The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.

      Ethics approval

      The protocol of this study was reviewed and approved by the institutional review board from Seoul National University Bundang Hospital. (IRB approval number: B-1804-465-105).

      Declaration of competing interest

      The authors declare that there are no conflicts of interest.

      Acknowledgement

      None.

      Appendix ASupplementary data

      The following is the Supplementary data to this article:

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