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Validation of the Prescreening Intradermal Skin Test for Predicting Hypersensitivity to Iodinated Contrast Media: A Prospective Study with ICM Challenge
Original Article
Validation of the Prescreening Intradermal Skin Test for Predicting Hypersensitivity to Iodinated Contrast Media: A Prospective Study with ICM Challenge Ji-Hyang Lee, MDa,*, Oh Young Kwon, MDa,*, So-Young Park, MD, PhDa,b, Bomi Seo, MDa, Ha-Kyeong Won, MDa, Yewon Kang, MDa, Jin An, MDa, Hyouk-Soo Kwon, MD, PhDa, Woo-Jung Song, MD, PhDa, You Sook Cho, MD, PhDa, Hee-Bom Moon, MD, PhDa, Hwan Seok Yong, MD, PhDc, Gyu-Young Hur, MD, PhDd, and Tae-Bum Kim, MD, PhDa Seoul, Korea
What is already known about this topic? The role of intradermal skin test for predicting hypersensitivity reaction to iodinated contrast media has not been fully evaluated due to limited data of positive predictive value. What does this article add to our knowledge? Skin testing before a computed tomography scan does not predict the occurrence of hypersensitivity reactions to iodinated contrast media because of its extremely low sensitivity and positive predictive value. How does this study impact current management guidelines? Intradermal skin test before performing computed tomography has no clinical value for prediction of a hypersensitivity reaction and should not be performed routinely. BACKGROUND: The number of hypersensitivity reactions associated with iodinated contrast media (ICM) is increasing with widespread use of radiographic contrast agents. These hypersensitivity reactions are unpredictable and sometimes lead to severe reactions such as anaphylaxis. OBJECTIVE: To investigate the value of intradermal skin test (IDT) as a clinical screening tool for prediction of a hypersensitivity reaction to ICM. METHODS: We performed IDT in the patients scheduled to receive an iodinated contrast agent between September 2015 and April 2017. After IDT, the contrast agent tested was administered intravenously, regardless of the results of skin testing, and the patients were carefully monitored. RESULTS: We recruited 2,918 patients in 2 hospitals, and 2,843 were included in the final analysis. Fifteen (0.5%) of the 2843 patients had a positive IDT result before scheduled computed tomography scan; however, none of these patients experienced a hypersensitivity reaction after the administration of a full dose of ICM. Meanwhile, 19 patients who experienced hypersensitivity
a
Department of Allergy and Clinical Immunology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea b Department of Internal Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Konkuk University Medical Center, Seoul, Korea c Department of Radiology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea d Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea This work was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health and Welfare, Republic of Korea (grant nos. HI15C1074 and HI18C1392).
reactions after ICM challenge had showed a negative IDT result. The sensitivity and the positive predictive value of IDT for ICM were both 0%. CONCLUSIONS: Routine IDT before the administration of an iodinated contrast agent does not predict hypersensitivity considering its extremely low sensitivity and a low positive predictive value. Ó 2019 American Academy of Allergy, Asthma & Immunology (J Allergy Clin Immunol Pract 2019;-:---) Key words: Hypersensitivity reaction; Intradermal skin test; Iodinated contrast media; Screening test; Sensitivity; Positive predictive value
INTRODUCTION Various types of iodinated contrast media (ICM) are presently administered about 75,000,000 times per year worldwide as a result of the rapidly growing use of computed tomography (CT)
Conflicts of interest: The authors declare that they have no relevant conflicts of interest. Received for publication April 10, 2019; revised July 29, 2019; accepted for publication August 1, 2019. Available online -Corresponding author: Tae-Bum Kim, MD, PhD, Department of Allergy and Clinical Immunology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea. E-mail: tbkim@amc. seoul.kr. * These authors contributed equally to this work. 2213-2198 Ó 2019 American Academy of Allergy, Asthma & Immunology https://doi.org/10.1016/j.jaip.2019.08.001
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Abbreviations used CT- Computed tomography ICM- Iodinated contrast media IDT- Intradermal skin test PPV- Positive predictive value
examinations.1 This widespread use of ICM has raised concerns regarding hypersensitivity reactions. However, there is still no validated method for predicting and reducing these reactions.2,3 In 1991, Yamaguchi et al4 investigated whether pretesting with an intravenous injection of ICM could predict an adverse reaction and found that it could not.4 After emergence of evidence that IgE participates in hypersensitivity reactions to ICM,5-7 several studies were attempted to identify a skin test that can predict an adverse reaction to a contrast agent.8-11 However, low positivity of the skin test and hesitance of challenging positively skin tested ICM for CT scan resulted in obtaining only negative predictive values of skin test. Therefore, there is no convincing clinical evidence regarding whether a skin test is a useful screening tool for predicting a hypersensitivity reaction to an iodinated contrast agent. Some physicians perform intradermal skin test (IDT) for prediction of a hypersensitivity reaction before the administration of an iodinated contrast agent despite scarce evidence for the value of IDT as a screening tool. Because hypersensitivity reactions to ICM are unpredictable and potentially fatal, it is an important issue whether they can be avoided if possible. Given the increasing use of CT examinations, there is an urgent need for clear guidelines about performing skin tests before injection of ICM. Therefore, we planned a large prospective study to determine the clinical value of IDT for prediction of hypersensitivity reactions to iodinated contrast agents by evaluating its sensitivity, specificity, and positive and negative predictive values.
METHODS Study design and participants From September 2015 to April 2017, we prospectively recruited patients who were scheduled to undergo contrastenhanced CT at either of 2 participating university hospitals (Asan Medical Center and Korea University Guro Hospital). Patients were excluded if they were younger than 18 years, were pregnant, had dermographism, had previously experienced a severe hypersensitivity reaction to ICM, or had been treated with medications that may affect the results of skin tests, such as corticosteroids or antihistamines. The study protocol was approved by the institutional review board and ethics committees of the participating hospitals. All study participants were fully informed about the study protocol and they provided written informed consent.
Skin test Once enrolled, all subjects underwent IDT with the iodinated contrast agent that was planned for use at the time of the scheduled CT examination. The skin test was performed about 30 minutes before CT scanning. The contrast agents used in the tests were as follows: iopromide (Ultravist; Bayer Healthcare, Brussels, Belgium); iohexol (Omnipaque; GE Healthcare, Chicago, Ill); iopamidol (Pamiray; Dongkook Pharm Co, Ltd, Seoul, Korea); ioversol (Optiray; Mallinckrodt PLC, St Louis, Mo); iobitridol (Xenetics; Guerbet, Gorinchem, The Netherlands);
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iomeprol (Iomeron; Bracco, Milano, Italy); and iodixanol (Visipaque; GE Healthcare, Chicago, Ill). All solutions had a strength of 270 to 370 mg/mL (iopromide, 370 mg/mL; iohexol, 300 mg/mL; iopamidol, 300 mg/mL; ioversol, 320 mg/mL; iobitridol, 300 mg/mL; iomeprol, 300 mg/mL; and iodixanol, 270 mg/mL). We used a 1:10 solution of contrast agent diluted with 0.9% NaCl, which is known to be a nonirritant concentration. Histamine and saline were used as positive and negative controls, respectively. The test solution (0.03-0.05 mL) was injected intradermally to produce a bleb measuring 2 to 4 mm in diameter. A skin test result was considered positive if the diameter of the initial wheal had increased by at least 3 mm and was surrounded by erythema after 15 to 20 minutes. All skin tests in each center were performed by the same trained nurse to minimize the interoperator variability.
Assessment of hypersensitivity reaction after ICM challenge After skin testing, the same contrast agent as that used for IDT was administered intravenously for the originally planned CT examination regardless of the skin test results. Even if the result of IDT was positive, the CT examination was performed as scheduled without premedication. Cardiopulmonary resuscitation equipment was readily available. For evaluation and management of immediate hypersensitivity reactions, all patients were monitored during and for 1 hour after ICM injection. To assess delayed reactions, we instructed the patients to contact us if they experienced any adverse reaction after discharge. Otherwise, telephone surveys were carried out 1 week later.
Statistical analysis The statistical analyses were performed using SPSS version 18.0 software (IBM Corp, Armonk, NY). Qualitative data were expressed as the frequency and percentage and the quantitative data as the mean and range. The c2 test was used to analyze categorical variables. A P value of less than .05 was considered statistically significant.
RESULTS Study population In total, 2,918 patients were enrolled in the study (Asan Medical Center, n ¼ 1,606; Korea University Guro Hospital, n ¼ 1,312). Seventy-five of these patients were excluded from the final analysis because they had received medication that could have affected the result of IDT as well as the likelihood of a hypersensitivity reaction. These 75 exclusions included 3 patients who required premedication with antihistamines and corticosteroids because of a history of severe hypersensitivity to ICM, 2 who wanted premedication before their CT examination because of a positive IDT result, and 70 who were taking antihistamines, steroids, or immunosuppressants for other medical conditions (Figure 1). Patient characteristics at baseline Table I presents the characteristics of the total study population at baseline. The mean age of the patients was 55.78 (18-89) years. A total of 2644 patients (90.6%) had previously been exposed to ICM. Six patients did not know whether they had been exposed to an iodinated contrast agent before. Eighteen patients experienced an ICM-related adverse reaction. Ninetytwo (3.2%) of the 2918 patients had allergic conditions, including history of drug hypersensitivity, allergic rhinitis, and
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FIGURE 1. Outcomes of IDT for hypersensitivity to iodinated contrast agents.
TABLE I. Patients’ demographic and clinical characteristics at baseline Characteristic
Female:male Age (y), mean (range) History of ICM exposure Previous ICM-related adverse reaction Comorbidities Drug hypersensitivity Asthma Allergic rhinitis Concomitant medication Beta-blocker ACE inhibitor Type of ICM Iohexol Ioversol Iopamidol Iopromide Iobitridol Iomeprol Iodixanol
Cases (%)
1123:1795 55.78 2644 18
(38.5:61.5) (18-89) (90.6) (0.6)
46 (1.6) 12 (0.4) 34 (1.2) 70 (2.3) 127 (4.4) 789 623 613 365 323 203 2
(27.0) (21.4) (21.0) (12.5) (11.1) (7.0) (0.1)
TABLE II. Characteristics of patients with a positive screening IDT who did not have a hypersensitivity reaction to the same iodinated contrast agent when used during CT examination
Patient no.
A527 A679 A687 A792 A822 A831 A1138 A1148 G9 G12 G43 G49 G51 G59 G78
Sex/age (y)
History of ICM exposure
Previous ICM-related adverse reaction
ICM used
M/64 M/66 M/76 M/68 F/78 M/75 M/20 F/35 F/69 F/64 M/55 F/44 F/75 F/19 M/51
None Yes Yes Yes Yes Yes Yes Yes Unknown Unknown Unknown Yes Yes None Unknown
None None None None None None None None Unknown Unknown Unknown None None None Unknown
Iohexol Iopamidol Iohexol Iohexol Iohexol Iohexol Iohexol Iohexol Iohexol Iohexol Iopamidol Iopromide Iohexol Iobitridol Iopromide
F, Female; M, male.
ACE, Angiotensin-converting enzyme.
asthma. One hundred twenty-seven patients (4.4%) were receiving an angiotensin-converting enzyme inhibitor and 70 (2.3%) were on a beta-blocker. Iohexol was the most frequently used contrast agent (n ¼ 789 [27.0%]) followed by ioversol (n ¼ 623 [21.3%]) and iopamidol (n ¼ 613 [21.0%]).
Positive skin test results Fifteen of the 2843 patients included in the study had a positive IDT result with the scheduled ICM (Table II). None of these 15 patients experienced an immediate hypersensitivity reaction when the contrast agent that had produced a positive IDT result was injected for CT scanning without premedication. Two of these patients had never been exposed to an iodinated contrast agent before and 9 had been exposed; none of the 9 latter patients had ever experienced a hypersensitivity reaction. Iohexol was used in 10 (66.7%) of the 15 cases, followed by iopamidol (n ¼ 2 [13.3%]) and iopromide (n ¼ 2 [13.3%]). Eight of the
15 patients were from Asan Medical Center and 7 were from Korea University Guro Hospital.
Hypersensitivity reactions Nineteen patients experienced hypersensitivity reactions even though they had reported a negative IDT result for the contrast agent used in the CT examination (Table III). Sixteen patients had a history of exposure to ICM, 1 of whom experienced a hypersensitivity reaction, that is, urticaria. Iopamidol was the most common culprit agent (7 cases) followed by ioversol (6 cases) and iohexol (4 cases). All patients experienced a skin reaction, mostly urticaria. Eleven of the 19 hypersensitivity reactions occurred within 1 hour and 8 cases occurred after 1 hour. Although these 8 reactions occurred between 1 and 48 hours after injection of ICM and were classified as nonimmediate reactions, their clinical expressions were similar to those of the immediate reactions. The treatment of hypersensitivity was based mainly on the American College of Radiology guidelines.12 However, there may have been some slight variation in
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TABLE III. Characteristics of patients with a negative screening IDT who had a hypersensitivity reaction to the same iodinated contrast agent when used during CT examination
Patient no.
Sex/age (y)
History of ICM exposure
Previous ICM-related adverse reaction
M/57 M/24 M/76 M/41 F/66 M/78 F/50 F/36 M/29 F/45 F/68 M/47 F/66 F/62 F/40 F/61 M/54 F/58 M/68
Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Unknown None None Yes Yes Yes Yes
None None None None None None None None Yes None None None Unknown None None None None None None
A113 A394 A427 A1059 A1461 G146 G202 G576 G695 G1179 G1284 G19 G38 G101 G282 G406 G609 G733 G879
ICM used
Hypersensitivity reaction
Time to hypersensitivity reaction
Treatment
Ioversol Ioversol Iohexol Ioversol Iohexol Iopamidol Iopamidol Iopamidol Iopamidol Iopamidol Iobitridol Iopamidol Iohexol Iopamidol Ioversol Iopromide Ioversol Iohexol Ioversol
Urticaria Urticaria Angioedema Urticaria Urticaria Urticaria Urticaria Urticaria Urticaria Urticaria Urticaria, Urticaria Urticaria Urticaria Urticaria Urticaria Urticaria Urticaria Urticaria
15 min 30 min 30 min 1h 30 min 30 min 0 min 0 min 30 min 0 min 30 min 48 h 2h 10 h 24 h 5h 5h 5h 6h
Antihistamine Antihistamine Antihistamine Antihistamine Antihistamine None Dexamethasone None None None Antihistamine Antihistamine Antihistamine Antihistamine Antihistamine None None Antihistamine None
F, Female; M, male.
treatment from patient to patient. According to the American College of Radiology manual, treatment is often unnecessary for scattered and/or transient urticaria. However, if symptomatic, clinicians can consider prescribing an antihistamine. Eleven patients were treated with antihistamine and 1 with dexamethasone. The remaining 7 patients recovered without medication. There were no severe reactions, such as anaphylaxis. Five of the 19 patients were from Asan Medical Center and 14 were from Korea University Guro Hospital.
Screening skin test for ICM hypersensitivity IDT for hypersensitivity to ICM was found to have a sensitivity of 0%, a specificity of 99.47%, a negative predictive value of 99.33%, and a positive predictive value (PPV) of 0% (Figure 1). DISCUSSION In this prospective study, data for 2843 patients were used to assess the validity of IDT for prediction of hypersensitivity to ICM. Fifteen (0.5%) of these patients had a positive IDT result but did not experience an immediate or nonimmediate hypersensitivity reaction when they subsequently underwent a CT examination using the same contrast agent. Eleven of the remaining 2828 patients who had a negative IDT result experienced an immediate hypersensitivity reaction and 8 experienced a nonimmediate hypersensitivity reaction when the CT examination was performed. Regardless of the time of onset of the hypersensitivity reaction, the most common reactions were urticaria. Therefore, IDT was calculated to have a sensitivity of 0%, a specificity of 99.47%, a negative predictive value of 99.33%, and a PPV of 0% for prediction of hypersensitivity to an iodinated contrast agent.
The clinical usefulness of skin testing for hypersensitivity to ICM can be assessed in 2 contexts (ie, for prediction of a hypersensitivity reaction before the administration of a contrast agent, or for diagnosis of hypersensitivity reaction after exposure to a contrast agent). Contrary to the traditional theory that hypersensitivity reactions to iodinated contrast agents are nonimmunologic and mediated by direct stimulation of mast cells, emerging evidence suggests that a substantial proportion of hypersensitivity reactions to ICM are caused by immune mechanisms that involve IgE.13,14 Consequently, a number of studies have sought to determine the role of IDT to overcome this unsolved safety issue.7,10,13,15 However, the clinical value of skin testing in prediction of hypersensitivity reactions has not been fully validated as yet. Several studies have been conducted to assess the potential of IDT as a screening tool for predicting hypersensitivity reactions to ICM and reported negative predictive values ranging from 93.1% to 97%.8-11 However, the PPV could not be obtained in those studies because subjects showing positive skin test result were not generally rechallenged. To our knowledge, this is the first prospective study of the likelihood of a hypersensitivity reaction after injection of a full dose of iodinated contrast agent that has included patients with a positive IDT result. Therefore, we were able to calculate the PPV of IDT, which is needed to determine its usefulness as a screening test. Overall, 15 (0.5%) of our 2843 patients had a positive IDT result. This figure is higher than the rate of 0.2% in a similarly designed study by Kim et al.8 Although the factors impacting the result of IDTs using iodinated contrast agents have not yet been fully elucidated and there is always the possibility of a falsepositive skin test result, several factors could affect the results of IDTs, including history of exposure to a contrast agent and the type of contrast medium used. In our study, about 90% of
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the subjects had a history of exposure to a contrast agent, whereas only about 36% of those in the study by Kim et al8 had been exposed. Furthermore, in the study by Kim et al,8 iopromide and iomeprol were used for IDT in all but 4 patients, whereas the patients in the present study received a broader range of iodinated contrast agents. In our study, 10 of the 15 patients with a positive IDT result had received iohexol. When we compared the prevalence of a positive IDT result between the different types of the ICM, a significant difference was detected between the ICM (P ¼ .03) (data not shown). The highest IDT positivity rate was found for iohexol (1.3%), followed by iopromide (0.5%), iopamidol (0.3%), and iobitridol (0.3%). No positive IDT results were reported when using ioversol, iomeprol, or iodixanol. All the contrast agents tested were nonionic monomers (except for iodixanol, which is a nonionic dimer), so it remains uncertain whether a particular moiety is responsible for a positive IDT result. The positivity of skin tests was similar between 2 hospitals (Asan Medical Center, 8 of 1596 [0.50%]; Korea University Guro Hospital, 7 of 1247 [0.56%]; P ¼ .83). Because tests were performed by a trained nurse in each center, it could be assumed that the operator did not affect the positivity of IDT. Nineteen (0.7%) of the 2,843 patients experienced hypersensitivity reactions; this prevalence rate is consistent with that in a previous study of 120,000 cases.16 Sixteen (84%) of these 19 patients had a history of exposure to ICM, and 1 experienced a mild hypersensitivity reaction. Iopamidol was the most common culprit agent, followed by ioversol, iohexol, iobitridol, and iopromide. All patients experienced a skin reaction, which was treated with an antihistamine in 11 cases. Like in previous studies, no severe hypersensitivity reactions occurred in patients with a negative IDT result.9,11 However, it is difficult to conclude that a severe hypersensitivity reaction to ICM would not occur after a negative IDT result. Severe hypersensitivity reactions, such as anaphylaxis, are rare, reportedly occurring in 0.01% to 0.04% of cases,17-19 so a study that includes a larger number of subjects is required to assess the relationship between IDT results and severe hypersensitivity reactions. There was a significant difference in the prevalence of hypersensitivity reactions between the 2 participating hospitals (Asan Medical Center, 5 of 1596 [0.31%]; Korea University Guro Hospital, 14 of 1247 [1.1%]; P ¼ .009). However, the prevalence of immediate hypersensitivity reactions was similar (Asan Medical Center, 5 of 1596 [0.31%]; Korea University Guro Hospital, 6 of 1247 [0.48%]; P ¼ .47). The difference in the rate of nonimmediate reactions could be explained by a difference in the technique used or the attitude of the interviewer. There might also have been a degree of recall bias because the telephone survey was conducted 1 week after the CT examination. Generally, a skin test is performed to identify the culprit agent when a patient has experienced an adverse drug reaction, especially when an IgE-mediated reaction is highly suspected. Given its rapid and easy process, a skin test is an attractive screening method when all requirements are met. Although we did not find IDT to be helpful for predicting a hypersensitivity reaction to ICM, this test can have an important role in specific situations, especially in patients who have previously experienced a hypersensitivity reaction.20 In a meta-analysis by Yoon et al,21 the pooled per-patient positive skin test rate was 17%, and the rate increased to 52% when only severe immediate hypersensitivity reactions were included. We recently suggested a
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novel algorithm that uses IDT not only for diagnostic purposes but also for selection of a safer contrast agent for patients who have previously experienced a hypersensitivity reaction to ICM.22 However, this still needs large, prospective, multicenter studies to establish standardized guidelines. There are some limitations to this study. First, there was no information about the ICM that the patients had been exposed to previously. Therefore, we could not find a relationship between previous exposure to ICM and the results of IDT or intravenous challenge. Second, we cannot exclude the possibility of differences in the IDT procedures and the interpretation of results. However, to minimize interobserver difference, skin tests in a hospital were exclusively performed by 1 person. Third, the medical history of allergy was based on patient recall. Therefore, the exact prevalence of the comorbidity was hard to evaluate. Finally, patients who had previously experienced a severe hypersensitivity reaction were not eligible for participation in the study because most received premedication. Despite these limitations, our study evaluated the role of IDT as a screening tool in general population without history of severe adverse reaction to ICM.
CONCLUSIONS IDT before a CT examination has both a low positivity rate and an extremely low PPV, and so has no clinical value in terms of predicting a hypersensitivity reaction to ICM. Therefore, routine IDT before a CT examination is unnecessary. REFERENCES 1. Brockow K, Ring J. Anaphylaxis to radiographic contrast media. Curr Opin Allergy Clin Immunol 2011;11:326-31. 2. Sanchez-Borges M, Aberer W, Brockow K, Celik GE, Cernadas J, Greenberger PA, et al. Controversies in drug allergy: radiographic contrast media. J Allergy Clin Immunol Pract 2019;7:61-5. 3. Demoly P, Castells M. Important questions in drug allergy and hypersensitivity: consensus papers from the 2018 AAAAI/WAO international drug allergy symposium. World Allergy Organ J 2018;11:42. 4. Yamaguchi K, Katayama H, Takashima T, Kozuka T, Seez P, Matsuura K. Prediction of severe adverse reactions to ionic and nonionic contrast media in Japan: evaluation of pretesting. A report from the Japanese Committee on the Safety of Contrast Media. Radiology 1991;178:363-7. 5. Laroche D, Aimone-Gastin I, Dubois F, Huet H, Gerard P, Vergnaud MC, et al. Mechanisms of severe, immediate reactions to iodinated contrast material. Radiology 1998;209:183-90. 6. Mita H, Tadokoro K, Akiyama K. Detection of IgE antibody to a radiocontrast medium. Allergy 1998;53:1133-40. 7. Della-Torre E, Berti A, Yacoub MR, Guglielmi B, Tombetti E, Sabbadini MG, et al. Proposal of a skin tests based approach for the prevention of recurrent hypersensitivity reactions to iodinated contrast media. Eur Ann Allergy Clin Immunol 2015;47:77-85. 8. Kim SH, Jo EJ, Kim MY, Lee SE, Kim MH, Yang MS, et al. Clinical value of radiocontrast media skin tests as a prescreening and diagnostic tool in hypersensitivity reactions. Ann Allergy Asthma Immunol 2013;110:258-62. 9. Soyyigit S, Goksel O, Aydin O, Gencturk Z, Bavbek S. What is the clinical value of negative predictive values of skin tests to iodinated contrast media? Allergy Asthma Proc 2016;37:482-8. 10. Schrijvers R, Breynaert C, Ahmedali Y, Bourrain JL, Demoly P, Chiriac AM. Skin testing for suspected iodinated contrast media hypersensitivity. J Allergy Clin Immunol Pract 2018;6:1246-54. 11. Caimmi S, Benyahia B, Suau D, Bousquet-Rouanet L, Caimmi D, Bousquet PJ, et al. Clinical value of negative skin tests to iodinated contrast media. Clin Exp Allergy 2010;40:805-10. 12. American College of Radiology. ACR manual on contrast media. Version 10. Reston, VA: American College of Radiology; 2015. 13. Brockow K, Romano A, Aberer W, Bircher AJ, Barbaud A, Bonadonna P, et al. Skin testing in patients with hypersensitivity reactions to iodinated contrast media—a European multicenter study. Allergy 2009;64:234-41.
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14. Brockow K, Ring J. Classification and pathophysiology of radiocontrast media hypersensitivity. Chem Immunol Allergy 2010;95:157-69. 15. Prieto-Garcia A, Tomas M, Pineda R, Tornero P, Herrero T, Fuentes V, et al. Skin test-positive immediate hypersensitivity reaction to iodinated contrast media: the role of controlled challenge testing. J Investig Allergol Clin Immunol 2013;23:183-9. 16. Li X, Liu H, Zhao L, Liu J, Cai L, Liu L, et al. Clinical observation of adverse drug reactions to non-ionic iodinated contrast media in population with underlying diseases and risk factors. Br J Radiol 2017;90: 20160729. 17. Kim MH, Lee SY, Lee SE, Yang MS, Jung JW, Park CM, et al. Anaphylaxis to iodinated contrast media: clinical characteristics related with development of anaphylactic shock. PLoS One 2014;9:e100154.
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18. Cashman JD, McCredie J, Henry DA. Intravenous contrast media: use and associated mortality. Med J Aust 1991;155:618-23. 19. Wysowski DK, Nourjah P. Deaths attributed to X-ray contrast media on U.S. death certificates. AJR Am J Roentgenol 2006;186:613-5. 20. Greenberger PA. Hypersensitivity reactions to iodinated radiocontrast media: to skin test or not to skin test. J Allergy Clin Immunol Pract 2018;6:1255-6. 21. Yoon SH, Lee SY, Kang HR, Kim JY, Hahn S, Park CM, et al. Skin tests in patients with hypersensitivity reaction to iodinated contrast media: a metaanalysis. Allergy 2015;70:625-37. 22. Kwon OY, Lee JH, Park SY, Seo B, Won HK, Kang Y, et al. Novel strategy for the prevention of recurrent hypersensitivity reactions to radiocontrast media based on skin testing [published online ahead of print May 10, 2019]. J Allergy Clin Immunol Pract, https://doi.org/10.1016/j.jaip.2019.04.036.
Validation of the Prescreening Intradermal Skin Test for Predicting Hypersensitivity to Iodinated Contrast Media: A Prospective Study with ICM Challenge Ji-Hyang Lee, MDa,*, Oh Young Kwon, MDa,*, So-Young Park, MD, PhDa,b, Bomi Seo, MDa, Ha-Kyeong Won, MDa, Yewon Kang, MDa, Jin An, MDa, Hyouk-Soo Kwon, MD, PhDa, Woo-Jung Song, MD, PhDa, You Sook Cho, MD, PhDa, Hee-Bom Moon, MD, PhDa, Hwan Seok Yong, MD, PhDc, Gyu-Young Hur, MD, PhDd, and Tae-Bum Kim, MD, PhDa Seoul, Korea
What is already known about this topic? The role of intradermal skin test for predicting hypersensitivity reaction to iodinated contrast media has not been fully evaluated due to limited data of positive predictive value. What does this article add to our knowledge? Skin testing before a computed tomography scan does not predict the occurrence of hypersensitivity reactions to iodinated contrast media because of its extremely low sensitivity and positive predictive value. How does this study impact current management guidelines? Intradermal skin test before performing computed tomography has no clinical value for prediction of a hypersensitivity reaction and should not be performed routinely. BACKGROUND: The number of hypersensitivity reactions associated with iodinated contrast media (ICM) is increasing with widespread use of radiographic contrast agents. These hypersensitivity reactions are unpredictable and sometimes lead to severe reactions such as anaphylaxis. OBJECTIVE: To investigate the value of intradermal skin test (IDT) as a clinical screening tool for prediction of a hypersensitivity reaction to ICM. METHODS: We performed IDT in the patients scheduled to receive an iodinated contrast agent between September 2015 and April 2017. After IDT, the contrast agent tested was administered intravenously, regardless of the results of skin testing, and the patients were carefully monitored. RESULTS: We recruited 2,918 patients in 2 hospitals, and 2,843 were included in the final analysis. Fifteen (0.5%) of the 2843 patients had a positive IDT result before scheduled computed tomography scan; however, none of these patients experienced a hypersensitivity reaction after the administration of a full dose of ICM. Meanwhile, 19 patients who experienced hypersensitivity
a
Department of Allergy and Clinical Immunology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea b Department of Internal Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Konkuk University Medical Center, Seoul, Korea c Department of Radiology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea d Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea This work was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health and Welfare, Republic of Korea (grant nos. HI15C1074 and HI18C1392).
reactions after ICM challenge had showed a negative IDT result. The sensitivity and the positive predictive value of IDT for ICM were both 0%. CONCLUSIONS: Routine IDT before the administration of an iodinated contrast agent does not predict hypersensitivity considering its extremely low sensitivity and a low positive predictive value. Ó 2019 American Academy of Allergy, Asthma & Immunology (J Allergy Clin Immunol Pract 2019;-:---) Key words: Hypersensitivity reaction; Intradermal skin test; Iodinated contrast media; Screening test; Sensitivity; Positive predictive value
INTRODUCTION Various types of iodinated contrast media (ICM) are presently administered about 75,000,000 times per year worldwide as a result of the rapidly growing use of computed tomography (CT)
Conflicts of interest: The authors declare that they have no relevant conflicts of interest. Received for publication April 10, 2019; revised July 29, 2019; accepted for publication August 1, 2019. Available online -Corresponding author: Tae-Bum Kim, MD, PhD, Department of Allergy and Clinical Immunology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea. E-mail: tbkim@amc. seoul.kr. * These authors contributed equally to this work. 2213-2198 Ó 2019 American Academy of Allergy, Asthma & Immunology https://doi.org/10.1016/j.jaip.2019.08.001
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Abbreviations used CT- Computed tomography ICM- Iodinated contrast media IDT- Intradermal skin test PPV- Positive predictive value
examinations.1 This widespread use of ICM has raised concerns regarding hypersensitivity reactions. However, there is still no validated method for predicting and reducing these reactions.2,3 In 1991, Yamaguchi et al4 investigated whether pretesting with an intravenous injection of ICM could predict an adverse reaction and found that it could not.4 After emergence of evidence that IgE participates in hypersensitivity reactions to ICM,5-7 several studies were attempted to identify a skin test that can predict an adverse reaction to a contrast agent.8-11 However, low positivity of the skin test and hesitance of challenging positively skin tested ICM for CT scan resulted in obtaining only negative predictive values of skin test. Therefore, there is no convincing clinical evidence regarding whether a skin test is a useful screening tool for predicting a hypersensitivity reaction to an iodinated contrast agent. Some physicians perform intradermal skin test (IDT) for prediction of a hypersensitivity reaction before the administration of an iodinated contrast agent despite scarce evidence for the value of IDT as a screening tool. Because hypersensitivity reactions to ICM are unpredictable and potentially fatal, it is an important issue whether they can be avoided if possible. Given the increasing use of CT examinations, there is an urgent need for clear guidelines about performing skin tests before injection of ICM. Therefore, we planned a large prospective study to determine the clinical value of IDT for prediction of hypersensitivity reactions to iodinated contrast agents by evaluating its sensitivity, specificity, and positive and negative predictive values.
METHODS Study design and participants From September 2015 to April 2017, we prospectively recruited patients who were scheduled to undergo contrastenhanced CT at either of 2 participating university hospitals (Asan Medical Center and Korea University Guro Hospital). Patients were excluded if they were younger than 18 years, were pregnant, had dermographism, had previously experienced a severe hypersensitivity reaction to ICM, or had been treated with medications that may affect the results of skin tests, such as corticosteroids or antihistamines. The study protocol was approved by the institutional review board and ethics committees of the participating hospitals. All study participants were fully informed about the study protocol and they provided written informed consent.
Skin test Once enrolled, all subjects underwent IDT with the iodinated contrast agent that was planned for use at the time of the scheduled CT examination. The skin test was performed about 30 minutes before CT scanning. The contrast agents used in the tests were as follows: iopromide (Ultravist; Bayer Healthcare, Brussels, Belgium); iohexol (Omnipaque; GE Healthcare, Chicago, Ill); iopamidol (Pamiray; Dongkook Pharm Co, Ltd, Seoul, Korea); ioversol (Optiray; Mallinckrodt PLC, St Louis, Mo); iobitridol (Xenetics; Guerbet, Gorinchem, The Netherlands);
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iomeprol (Iomeron; Bracco, Milano, Italy); and iodixanol (Visipaque; GE Healthcare, Chicago, Ill). All solutions had a strength of 270 to 370 mg/mL (iopromide, 370 mg/mL; iohexol, 300 mg/mL; iopamidol, 300 mg/mL; ioversol, 320 mg/mL; iobitridol, 300 mg/mL; iomeprol, 300 mg/mL; and iodixanol, 270 mg/mL). We used a 1:10 solution of contrast agent diluted with 0.9% NaCl, which is known to be a nonirritant concentration. Histamine and saline were used as positive and negative controls, respectively. The test solution (0.03-0.05 mL) was injected intradermally to produce a bleb measuring 2 to 4 mm in diameter. A skin test result was considered positive if the diameter of the initial wheal had increased by at least 3 mm and was surrounded by erythema after 15 to 20 minutes. All skin tests in each center were performed by the same trained nurse to minimize the interoperator variability.
Assessment of hypersensitivity reaction after ICM challenge After skin testing, the same contrast agent as that used for IDT was administered intravenously for the originally planned CT examination regardless of the skin test results. Even if the result of IDT was positive, the CT examination was performed as scheduled without premedication. Cardiopulmonary resuscitation equipment was readily available. For evaluation and management of immediate hypersensitivity reactions, all patients were monitored during and for 1 hour after ICM injection. To assess delayed reactions, we instructed the patients to contact us if they experienced any adverse reaction after discharge. Otherwise, telephone surveys were carried out 1 week later.
Statistical analysis The statistical analyses were performed using SPSS version 18.0 software (IBM Corp, Armonk, NY). Qualitative data were expressed as the frequency and percentage and the quantitative data as the mean and range. The c2 test was used to analyze categorical variables. A P value of less than .05 was considered statistically significant.
RESULTS Study population In total, 2,918 patients were enrolled in the study (Asan Medical Center, n ¼ 1,606; Korea University Guro Hospital, n ¼ 1,312). Seventy-five of these patients were excluded from the final analysis because they had received medication that could have affected the result of IDT as well as the likelihood of a hypersensitivity reaction. These 75 exclusions included 3 patients who required premedication with antihistamines and corticosteroids because of a history of severe hypersensitivity to ICM, 2 who wanted premedication before their CT examination because of a positive IDT result, and 70 who were taking antihistamines, steroids, or immunosuppressants for other medical conditions (Figure 1). Patient characteristics at baseline Table I presents the characteristics of the total study population at baseline. The mean age of the patients was 55.78 (18-89) years. A total of 2644 patients (90.6%) had previously been exposed to ICM. Six patients did not know whether they had been exposed to an iodinated contrast agent before. Eighteen patients experienced an ICM-related adverse reaction. Ninetytwo (3.2%) of the 2918 patients had allergic conditions, including history of drug hypersensitivity, allergic rhinitis, and
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FIGURE 1. Outcomes of IDT for hypersensitivity to iodinated contrast agents.
TABLE I. Patients’ demographic and clinical characteristics at baseline Characteristic
Female:male Age (y), mean (range) History of ICM exposure Previous ICM-related adverse reaction Comorbidities Drug hypersensitivity Asthma Allergic rhinitis Concomitant medication Beta-blocker ACE inhibitor Type of ICM Iohexol Ioversol Iopamidol Iopromide Iobitridol Iomeprol Iodixanol
Cases (%)
1123:1795 55.78 2644 18
(38.5:61.5) (18-89) (90.6) (0.6)
46 (1.6) 12 (0.4) 34 (1.2) 70 (2.3) 127 (4.4) 789 623 613 365 323 203 2
(27.0) (21.4) (21.0) (12.5) (11.1) (7.0) (0.1)
TABLE II. Characteristics of patients with a positive screening IDT who did not have a hypersensitivity reaction to the same iodinated contrast agent when used during CT examination
Patient no.
A527 A679 A687 A792 A822 A831 A1138 A1148 G9 G12 G43 G49 G51 G59 G78
Sex/age (y)
History of ICM exposure
Previous ICM-related adverse reaction
ICM used
M/64 M/66 M/76 M/68 F/78 M/75 M/20 F/35 F/69 F/64 M/55 F/44 F/75 F/19 M/51
None Yes Yes Yes Yes Yes Yes Yes Unknown Unknown Unknown Yes Yes None Unknown
None None None None None None None None Unknown Unknown Unknown None None None Unknown
Iohexol Iopamidol Iohexol Iohexol Iohexol Iohexol Iohexol Iohexol Iohexol Iohexol Iopamidol Iopromide Iohexol Iobitridol Iopromide
F, Female; M, male.
ACE, Angiotensin-converting enzyme.
asthma. One hundred twenty-seven patients (4.4%) were receiving an angiotensin-converting enzyme inhibitor and 70 (2.3%) were on a beta-blocker. Iohexol was the most frequently used contrast agent (n ¼ 789 [27.0%]) followed by ioversol (n ¼ 623 [21.3%]) and iopamidol (n ¼ 613 [21.0%]).
Positive skin test results Fifteen of the 2843 patients included in the study had a positive IDT result with the scheduled ICM (Table II). None of these 15 patients experienced an immediate hypersensitivity reaction when the contrast agent that had produced a positive IDT result was injected for CT scanning without premedication. Two of these patients had never been exposed to an iodinated contrast agent before and 9 had been exposed; none of the 9 latter patients had ever experienced a hypersensitivity reaction. Iohexol was used in 10 (66.7%) of the 15 cases, followed by iopamidol (n ¼ 2 [13.3%]) and iopromide (n ¼ 2 [13.3%]). Eight of the
15 patients were from Asan Medical Center and 7 were from Korea University Guro Hospital.
Hypersensitivity reactions Nineteen patients experienced hypersensitivity reactions even though they had reported a negative IDT result for the contrast agent used in the CT examination (Table III). Sixteen patients had a history of exposure to ICM, 1 of whom experienced a hypersensitivity reaction, that is, urticaria. Iopamidol was the most common culprit agent (7 cases) followed by ioversol (6 cases) and iohexol (4 cases). All patients experienced a skin reaction, mostly urticaria. Eleven of the 19 hypersensitivity reactions occurred within 1 hour and 8 cases occurred after 1 hour. Although these 8 reactions occurred between 1 and 48 hours after injection of ICM and were classified as nonimmediate reactions, their clinical expressions were similar to those of the immediate reactions. The treatment of hypersensitivity was based mainly on the American College of Radiology guidelines.12 However, there may have been some slight variation in
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TABLE III. Characteristics of patients with a negative screening IDT who had a hypersensitivity reaction to the same iodinated contrast agent when used during CT examination
Patient no.
Sex/age (y)
History of ICM exposure
Previous ICM-related adverse reaction
M/57 M/24 M/76 M/41 F/66 M/78 F/50 F/36 M/29 F/45 F/68 M/47 F/66 F/62 F/40 F/61 M/54 F/58 M/68
Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Unknown None None Yes Yes Yes Yes
None None None None None None None None Yes None None None Unknown None None None None None None
A113 A394 A427 A1059 A1461 G146 G202 G576 G695 G1179 G1284 G19 G38 G101 G282 G406 G609 G733 G879
ICM used
Hypersensitivity reaction
Time to hypersensitivity reaction
Treatment
Ioversol Ioversol Iohexol Ioversol Iohexol Iopamidol Iopamidol Iopamidol Iopamidol Iopamidol Iobitridol Iopamidol Iohexol Iopamidol Ioversol Iopromide Ioversol Iohexol Ioversol
Urticaria Urticaria Angioedema Urticaria Urticaria Urticaria Urticaria Urticaria Urticaria Urticaria Urticaria, Urticaria Urticaria Urticaria Urticaria Urticaria Urticaria Urticaria Urticaria
15 min 30 min 30 min 1h 30 min 30 min 0 min 0 min 30 min 0 min 30 min 48 h 2h 10 h 24 h 5h 5h 5h 6h
Antihistamine Antihistamine Antihistamine Antihistamine Antihistamine None Dexamethasone None None None Antihistamine Antihistamine Antihistamine Antihistamine Antihistamine None None Antihistamine None
F, Female; M, male.
treatment from patient to patient. According to the American College of Radiology manual, treatment is often unnecessary for scattered and/or transient urticaria. However, if symptomatic, clinicians can consider prescribing an antihistamine. Eleven patients were treated with antihistamine and 1 with dexamethasone. The remaining 7 patients recovered without medication. There were no severe reactions, such as anaphylaxis. Five of the 19 patients were from Asan Medical Center and 14 were from Korea University Guro Hospital.
Screening skin test for ICM hypersensitivity IDT for hypersensitivity to ICM was found to have a sensitivity of 0%, a specificity of 99.47%, a negative predictive value of 99.33%, and a positive predictive value (PPV) of 0% (Figure 1). DISCUSSION In this prospective study, data for 2843 patients were used to assess the validity of IDT for prediction of hypersensitivity to ICM. Fifteen (0.5%) of these patients had a positive IDT result but did not experience an immediate or nonimmediate hypersensitivity reaction when they subsequently underwent a CT examination using the same contrast agent. Eleven of the remaining 2828 patients who had a negative IDT result experienced an immediate hypersensitivity reaction and 8 experienced a nonimmediate hypersensitivity reaction when the CT examination was performed. Regardless of the time of onset of the hypersensitivity reaction, the most common reactions were urticaria. Therefore, IDT was calculated to have a sensitivity of 0%, a specificity of 99.47%, a negative predictive value of 99.33%, and a PPV of 0% for prediction of hypersensitivity to an iodinated contrast agent.
The clinical usefulness of skin testing for hypersensitivity to ICM can be assessed in 2 contexts (ie, for prediction of a hypersensitivity reaction before the administration of a contrast agent, or for diagnosis of hypersensitivity reaction after exposure to a contrast agent). Contrary to the traditional theory that hypersensitivity reactions to iodinated contrast agents are nonimmunologic and mediated by direct stimulation of mast cells, emerging evidence suggests that a substantial proportion of hypersensitivity reactions to ICM are caused by immune mechanisms that involve IgE.13,14 Consequently, a number of studies have sought to determine the role of IDT to overcome this unsolved safety issue.7,10,13,15 However, the clinical value of skin testing in prediction of hypersensitivity reactions has not been fully validated as yet. Several studies have been conducted to assess the potential of IDT as a screening tool for predicting hypersensitivity reactions to ICM and reported negative predictive values ranging from 93.1% to 97%.8-11 However, the PPV could not be obtained in those studies because subjects showing positive skin test result were not generally rechallenged. To our knowledge, this is the first prospective study of the likelihood of a hypersensitivity reaction after injection of a full dose of iodinated contrast agent that has included patients with a positive IDT result. Therefore, we were able to calculate the PPV of IDT, which is needed to determine its usefulness as a screening test. Overall, 15 (0.5%) of our 2843 patients had a positive IDT result. This figure is higher than the rate of 0.2% in a similarly designed study by Kim et al.8 Although the factors impacting the result of IDTs using iodinated contrast agents have not yet been fully elucidated and there is always the possibility of a falsepositive skin test result, several factors could affect the results of IDTs, including history of exposure to a contrast agent and the type of contrast medium used. In our study, about 90% of
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the subjects had a history of exposure to a contrast agent, whereas only about 36% of those in the study by Kim et al8 had been exposed. Furthermore, in the study by Kim et al,8 iopromide and iomeprol were used for IDT in all but 4 patients, whereas the patients in the present study received a broader range of iodinated contrast agents. In our study, 10 of the 15 patients with a positive IDT result had received iohexol. When we compared the prevalence of a positive IDT result between the different types of the ICM, a significant difference was detected between the ICM (P ¼ .03) (data not shown). The highest IDT positivity rate was found for iohexol (1.3%), followed by iopromide (0.5%), iopamidol (0.3%), and iobitridol (0.3%). No positive IDT results were reported when using ioversol, iomeprol, or iodixanol. All the contrast agents tested were nonionic monomers (except for iodixanol, which is a nonionic dimer), so it remains uncertain whether a particular moiety is responsible for a positive IDT result. The positivity of skin tests was similar between 2 hospitals (Asan Medical Center, 8 of 1596 [0.50%]; Korea University Guro Hospital, 7 of 1247 [0.56%]; P ¼ .83). Because tests were performed by a trained nurse in each center, it could be assumed that the operator did not affect the positivity of IDT. Nineteen (0.7%) of the 2,843 patients experienced hypersensitivity reactions; this prevalence rate is consistent with that in a previous study of 120,000 cases.16 Sixteen (84%) of these 19 patients had a history of exposure to ICM, and 1 experienced a mild hypersensitivity reaction. Iopamidol was the most common culprit agent, followed by ioversol, iohexol, iobitridol, and iopromide. All patients experienced a skin reaction, which was treated with an antihistamine in 11 cases. Like in previous studies, no severe hypersensitivity reactions occurred in patients with a negative IDT result.9,11 However, it is difficult to conclude that a severe hypersensitivity reaction to ICM would not occur after a negative IDT result. Severe hypersensitivity reactions, such as anaphylaxis, are rare, reportedly occurring in 0.01% to 0.04% of cases,17-19 so a study that includes a larger number of subjects is required to assess the relationship between IDT results and severe hypersensitivity reactions. There was a significant difference in the prevalence of hypersensitivity reactions between the 2 participating hospitals (Asan Medical Center, 5 of 1596 [0.31%]; Korea University Guro Hospital, 14 of 1247 [1.1%]; P ¼ .009). However, the prevalence of immediate hypersensitivity reactions was similar (Asan Medical Center, 5 of 1596 [0.31%]; Korea University Guro Hospital, 6 of 1247 [0.48%]; P ¼ .47). The difference in the rate of nonimmediate reactions could be explained by a difference in the technique used or the attitude of the interviewer. There might also have been a degree of recall bias because the telephone survey was conducted 1 week after the CT examination. Generally, a skin test is performed to identify the culprit agent when a patient has experienced an adverse drug reaction, especially when an IgE-mediated reaction is highly suspected. Given its rapid and easy process, a skin test is an attractive screening method when all requirements are met. Although we did not find IDT to be helpful for predicting a hypersensitivity reaction to ICM, this test can have an important role in specific situations, especially in patients who have previously experienced a hypersensitivity reaction.20 In a meta-analysis by Yoon et al,21 the pooled per-patient positive skin test rate was 17%, and the rate increased to 52% when only severe immediate hypersensitivity reactions were included. We recently suggested a
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novel algorithm that uses IDT not only for diagnostic purposes but also for selection of a safer contrast agent for patients who have previously experienced a hypersensitivity reaction to ICM.22 However, this still needs large, prospective, multicenter studies to establish standardized guidelines. There are some limitations to this study. First, there was no information about the ICM that the patients had been exposed to previously. Therefore, we could not find a relationship between previous exposure to ICM and the results of IDT or intravenous challenge. Second, we cannot exclude the possibility of differences in the IDT procedures and the interpretation of results. However, to minimize interobserver difference, skin tests in a hospital were exclusively performed by 1 person. Third, the medical history of allergy was based on patient recall. Therefore, the exact prevalence of the comorbidity was hard to evaluate. Finally, patients who had previously experienced a severe hypersensitivity reaction were not eligible for participation in the study because most received premedication. Despite these limitations, our study evaluated the role of IDT as a screening tool in general population without history of severe adverse reaction to ICM.
CONCLUSIONS IDT before a CT examination has both a low positivity rate and an extremely low PPV, and so has no clinical value in terms of predicting a hypersensitivity reaction to ICM. Therefore, routine IDT before a CT examination is unnecessary. REFERENCES 1. Brockow K, Ring J. Anaphylaxis to radiographic contrast media. Curr Opin Allergy Clin Immunol 2011;11:326-31. 2. Sanchez-Borges M, Aberer W, Brockow K, Celik GE, Cernadas J, Greenberger PA, et al. Controversies in drug allergy: radiographic contrast media. J Allergy Clin Immunol Pract 2019;7:61-5. 3. Demoly P, Castells M. Important questions in drug allergy and hypersensitivity: consensus papers from the 2018 AAAAI/WAO international drug allergy symposium. World Allergy Organ J 2018;11:42. 4. Yamaguchi K, Katayama H, Takashima T, Kozuka T, Seez P, Matsuura K. Prediction of severe adverse reactions to ionic and nonionic contrast media in Japan: evaluation of pretesting. A report from the Japanese Committee on the Safety of Contrast Media. Radiology 1991;178:363-7. 5. Laroche D, Aimone-Gastin I, Dubois F, Huet H, Gerard P, Vergnaud MC, et al. Mechanisms of severe, immediate reactions to iodinated contrast material. Radiology 1998;209:183-90. 6. Mita H, Tadokoro K, Akiyama K. Detection of IgE antibody to a radiocontrast medium. Allergy 1998;53:1133-40. 7. Della-Torre E, Berti A, Yacoub MR, Guglielmi B, Tombetti E, Sabbadini MG, et al. Proposal of a skin tests based approach for the prevention of recurrent hypersensitivity reactions to iodinated contrast media. Eur Ann Allergy Clin Immunol 2015;47:77-85. 8. Kim SH, Jo EJ, Kim MY, Lee SE, Kim MH, Yang MS, et al. Clinical value of radiocontrast media skin tests as a prescreening and diagnostic tool in hypersensitivity reactions. Ann Allergy Asthma Immunol 2013;110:258-62. 9. Soyyigit S, Goksel O, Aydin O, Gencturk Z, Bavbek S. What is the clinical value of negative predictive values of skin tests to iodinated contrast media? Allergy Asthma Proc 2016;37:482-8. 10. Schrijvers R, Breynaert C, Ahmedali Y, Bourrain JL, Demoly P, Chiriac AM. Skin testing for suspected iodinated contrast media hypersensitivity. J Allergy Clin Immunol Pract 2018;6:1246-54. 11. Caimmi S, Benyahia B, Suau D, Bousquet-Rouanet L, Caimmi D, Bousquet PJ, et al. Clinical value of negative skin tests to iodinated contrast media. Clin Exp Allergy 2010;40:805-10. 12. American College of Radiology. ACR manual on contrast media. Version 10. Reston, VA: American College of Radiology; 2015. 13. Brockow K, Romano A, Aberer W, Bircher AJ, Barbaud A, Bonadonna P, et al. Skin testing in patients with hypersensitivity reactions to iodinated contrast media—a European multicenter study. Allergy 2009;64:234-41.
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14. Brockow K, Ring J. Classification and pathophysiology of radiocontrast media hypersensitivity. Chem Immunol Allergy 2010;95:157-69. 15. Prieto-Garcia A, Tomas M, Pineda R, Tornero P, Herrero T, Fuentes V, et al. Skin test-positive immediate hypersensitivity reaction to iodinated contrast media: the role of controlled challenge testing. J Investig Allergol Clin Immunol 2013;23:183-9. 16. Li X, Liu H, Zhao L, Liu J, Cai L, Liu L, et al. Clinical observation of adverse drug reactions to non-ionic iodinated contrast media in population with underlying diseases and risk factors. Br J Radiol 2017;90: 20160729. 17. Kim MH, Lee SY, Lee SE, Yang MS, Jung JW, Park CM, et al. Anaphylaxis to iodinated contrast media: clinical characteristics related with development of anaphylactic shock. PLoS One 2014;9:e100154.
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18. Cashman JD, McCredie J, Henry DA. Intravenous contrast media: use and associated mortality. Med J Aust 1991;155:618-23. 19. Wysowski DK, Nourjah P. Deaths attributed to X-ray contrast media on U.S. death certificates. AJR Am J Roentgenol 2006;186:613-5. 20. Greenberger PA. Hypersensitivity reactions to iodinated radiocontrast media: to skin test or not to skin test. J Allergy Clin Immunol Pract 2018;6:1255-6. 21. Yoon SH, Lee SY, Kang HR, Kim JY, Hahn S, Park CM, et al. Skin tests in patients with hypersensitivity reaction to iodinated contrast media: a metaanalysis. Allergy 2015;70:625-37. 22. Kwon OY, Lee JH, Park SY, Seo B, Won HK, Kang Y, et al. Novel strategy for the prevention of recurrent hypersensitivity reactions to radiocontrast media based on skin testing [published online ahead of print May 10, 2019]. J Allergy Clin Immunol Pract, https://doi.org/10.1016/j.jaip.2019.04.036.