Comparison of Immediate Hypersensitivity Reaction Rate According to the Type of Radiocontrast Media

ORIGINAL ARTICLE Asian Pacific Journal of Allergy and Immunology

Comparison of immediate hypersensitivity reaction rate according to the type of radiocontrast media

Hye Jung Park,1* Hye Sun Lee,2 Sinae Kim,2 Chul Hwan Park3

Abstract

Background: Various types of radiocontrast media (RCM), which can be substituted for each other, are used in clinical settings. However, data on comparisons of hypersensitivity reactions (HSR) based on types of RCM are lacking.

Objectives: We aimed to compare HSR rates to facilitate the choice of appropriate RCM types.

Methods: From January 2011 to December 2015, we retrospectively reviewed 209,027 clinical events involving seven different RCM in Gangnam Severance Hospital. We analyzed immediate HSR events using an internally developed adverse drug reaction reporting system. Furthermore, we defined risk factors for HSR, including RCM type.

Results: During the 5-year study period, 209,027 RCM usage occurred in 97,374 patients. During that period, 108 HSR happened in 88 patients (0.05% events). The HSR rate for iodixanol (0.16%) was the highest, followed by that for iopamidol (0.08%), iopromide (0.04%), iobitridol (0.04%), ioversol (0.02%), ioxitalamic acid (0.01%), and iohexol (0.01%). Multivariate generalized estimating equation analysis showed age (odds ratio [OR], 0.980; 95% confidence interval [CI], 0.969-0.990; P < 0.001), urticaria (OR, 1.936; 95% CI, 1.003-3.737; P = 0.049), drug allergy (OR, 9.212; 95% CI, 5.353- 15.853; P < 0.001), iopamidol use (OR, 8.327; 95% CI, 1.129-61.401; P = 0.038, compared to iohexol), iodixanol use (OR, 18.780; 95% CI, 2.564-137.560; P = 0.004, compared to iohexol), and use in 2014-2015 (OR, 2.704; 95% CI, 1.780-4.108; P < 0.001) were significant HSR-associated risk factors.

Conclusion: Among the RCMs, iodixanol (iso-osmolar RCM) and iopamidol (low-osmolar RCM) showed a significantly higher risk for immediate HSR than did other agents.

Key words: contrast media, hypersensitivity, iodixanol, iopamidol, iopramide

From: * Corresponding author: 1 Department of Internal Medicine, Gangnam Severance Hospital, Hye Jung Park Yonsei University College of Medicine, Seoul, Korea Department of Internal Medicine, Gangnam Severance Hospital, 2 Biostatistics Collaboration Unit, Yonsei University College of Medicine Yonsei University College of Medicine, 211 Eonju-ro Gangnam-gu, 3 Department of Radiology, Gangnam Severance Hospital, Seoul 06273 Yonsei University College of Medicine, Seoul, Korea E-mail: [email protected]

Introduction The use of radiocontrast media (RCM) has increased along iso- and low-osmolar RCM, which can be easily substituted with the increase in the use of imaging modalities, especially each other, have been used. computed tomography (CT).1 The hypersensitivity reaction However, recent large-scale studies have revealed that ad- (HSR) rate associated with RCM is known to be fairly high;2,3 verse drug reaction (ADR) rates differ significantly according therefore efforts to reduce the HSR rate has been the focus of to the type of RCM. Gomi et al.14 compared the incidence of numerous studies. Non-ionic RCM were introduced to replace acute ADRs among five low-osmolar RCM including iomeprol, ionic RCM, which reduced the HSR rate.4,5 Moreover, the HSR iopamidol, iohexol, iopromide, and ioversol. They discovered rate reduced consderably after high-osmolar RCM were re- that the use of iopamidol, iohexol, and ioversol significantly placed by iso- and low-osmolar types.6-8 Further, there have reduced the incidence of ADRs. Kim et al.15 reviewed 286,087 been reports that HSR rates among iso- and low-osmolar RCM cases of low-osmolar RCM use and found that compared to were not significantly different.9-13 To date, various types of iohexol, iopamidol, and iopromide, iobitridol significantly Asian Pac J Allergy Immunol DOI 10.12932/AP-191017-0182

reduced immediate HSR. Morales-Cabeza et al.16 showed im- skin-mucosal tissue, respiratory compromise, reduced BP or mediate reaction was significantly lower in iopamidol and io- associated symptoms, or persistent gastrointestinal symptoms) versol rather than iomeprol. To date, data on the comparison that occur rapidly after exposure to a likely allergen; reduced BP of HSR rates based on the type of RCM are lacking. Therefore, after exposure to known allergen.20 we aimed to compare the HSR rate to facilitate the selection of appropriate and safe RCM in clinical practice. Statistical analysis We used the Student’s t-test with an analysis of variance Methods (ANOVA) and chi-square tests to identify any differences in Data collection continuous and categorized variables between groups, respec- We retrospectively reviewed 215,135 incidences of tively. Univariate and multivariate analyses were used to deter- RCM use that occurred at Gangnam Severance Hospital from mine significant factors associated with HSR using a logistic January 2011 to December 2015. Gangnam Severance Hospi- regression analysis and generalized estimating equation (GEE) tal, which is a branch of Severance Hospital, implemented a analysis. The Statistical Package for the Social Sciences (SPSS) previously described spontaneous reporting program at Sever- v18.0 (IBM Corp, Armonk, NY, USA) was used, and a P < 0.05 ance Hospital to report ADRs from 2005.15,17 Doctors, nurses, was considered statistically significant. and paramedics have spontaneously reported ADRs using this program. We analyzed HSR events among ADRs in patients in Ethics whom RCM were used, by using this internally developed ADR This study was exempted from requiring an approval by the reporting system. Institutional Review Board of the Gangnam Severance Hospi- tal, Yonsei University Health System (approval number: 3-2016 RCM analyzed in this study -0207) The RCM investigated in this study were iohexol (Bonorex® 300, GE Healthcare, Amersham, UK), ioxitalamic acid (Tele- Results brix® 30, Guerbet, Sulzbach, Germany), ioversol (Optiray® 320, Clinical characteristics Guerbet, Sulzbach, Germany), iobitridol (Xenetix® 300, Guerbet, During the 5-year study period, 209,027 incidences of RCM Sulzbach, Germany), iopromide (Ultravist® 300, Bayer, Leverku- use occurred in 97,374 patients. During that period, 108 HSR sen, Germany), iopamidol (Pamiray® 300, Bracco, Milan, Italy), events occurred in 88 patients (0.05% events). We divided the and iodixanol (Visipaque®, GE Healthcare, Amersham, UK). patients into subjects without and with HSR (n = 97,286 and 88, Among them, ioxitalamic acid is an ionic RCM and iodixanol is respectively). Age, sex, and the prevalence of asthma, allergic a non-ionic iso-osmolar RCM. Except for these two, the others rhinitis, atopic dermatitis, hypertension, diabetes mellitus, liver are non-ionic low-osmolar RCM. disease, and chronic renal disease were not significantly different between the two groups. However, prevalence of urticaria Definition of HSR and severity of HSR (10.2%) was significantly higher in subjects with HSR than that HSR was defined as a particular condition causes the im- in subjects without HSR (3.3%, P = 0.003). The prevalence of mune system to overreact and included all allergic reactions food allergy (3.4%) and drug allergy (19.3%) was also signifi- (which is defined as one type of HSR when immune system cantly higher in subjects with HSR than that in subjects without overreacts to harmless substances) and various non-allergic re- HSR (0.6 and 1.2%), respectively (Table 1). actions according to American Academy of Allergy Asthma & Immunology definition.18 Immediate HSR was defined as a HSR Clinical manifestations of HSR occurring within 1 hour after administration of a RCM. Among the 108 HSR events, cutaneous symptoms including The HSR severity was classified as follows: mild (itching, rash, pruritus, and urticaria were the most frequent manifes- urticaria, flushing, nausea, mild vomiting, and/or chills, i.e. tations (88.9%). Nausea/vomiting (13.0%), angioedema (5.6%), symptoms that are self-limited, without evidence of progres- and dyspnea (3.7%) were also frequently observed. Chest pain, sion), moderate (severe vomiting, systemic urticaria, mild unconsciousness, and shock were rarely observed (0.9%, Table bronchospasm, face and/or larynx angioedema, throat tight- 2). ness, tachycardia, bradycardia, mild dyspnea, hypoxia, and/or temporary hypotension, i.e. symptoms that are more pro- HSR rates according to time nounced and commonly require medical management), and The HSR rates in 2014 and 2015 (0.09% and 0.07%) were severe (shock, pulmonary edema, prolonged hypoxia, cardio- significantly higher than those in 2011-2013 (0.03%,P < 0.001). pulmonary arrest, and/or convulsions, i.e. symptoms that are Further, upon categorizing them into 2011-2013 and 2014- often life-threatening and can result in permanent morbidity or 2015, the differences were still significantTable ( 3). death if not managed appropriately).19 In addition, we defined anaphylaxis as a serious allergic reaction that is rapid in onset HSR rates according to the type of RCM and may cause death , when any one of the following 3 criteria The HSR rate for iodixanol (0.16%) was the highest, followed are fulfilled: acute onset of an illness with involvement of the by that for iopamidol (0.08%), iopromide (0.04%), and iobitri- skin, mucosal tissues, or both and other sympotms (respisratory dol (0.04%). Ioversol (0.02%), ioxitalamic acid (0.01%), and compromise or reduced BP or associated symptoms of end-or- iohexol (0.01%) were associated with relatively low incidences gan dysfunction); two or more symptoms (involvement of the of HSR. The difference in HSR rate was significant among the HSR rate according to radiocontrast media

Table 1. Clinical characteristics according to HSR occurence Table 2. Clinical manifestations of HSR

Parameters Number Number Total P-value Clinical manifestations Number of HSR of subjects of subjects number of (%) without HSR with HSR subjects Cutaneous symptoms (rash, pruritus, and/or urticaria) 96 (88.9) (%) (%) Nausea/vomiting 14 (13.0) Age, years 50.7 ± 17.5 50.6 ± 14.6 50.7 ± 17.5 0.932 Angioedema 6 (5.6) (mean ± SD) Anaphylaxis 6 (5.6) Dyspnea 4 (3.7) Gender 0.396 Fever 2 (1.9) Men 45,031 (46.4) 37 (42.0) 45,338 Headache 2 (1.9) Women 51,985 (53.6) 51 (58.0) 52,036 Dizziness 2 (1.9) Asthma > 0.999 Chest pain 1 (0.9) With 1,913 (2.0) 1 (1.1) 1,914 Unconsciousness 1 (0.9) Without 95,373 (98.0) 87 (0.1) 95,460 Shock 1 (0.9) Allergic 0.930 Severity of HSR rhinitis Mild-moderate 103 (95.4%) With 5,743 (5.9) 5 (5.7) 5,748 Severe 5 (4.6%) Without 91,543 (94.1) 83 (94.3) 91,626 Number of HSR Atopic > 0.999 Only one 87 (80.6%) dermatitis More than two 21 (19.4%) With 457 (0.5) 0 (0.0) 457 Total 108 (100.0) Without 96,829 (99.5) 88 (100.0) 96,917 Urticaria 0.003 * HSR, hypersensitivity reaction With 3,195 (3.3) 9 (10.2) 3,204 Table 3. HSR rates according to time and RCM type Without 94,091 (96.7) 79 (89.8) 94,170 Food allergy 0.003 Number of cases Number of HSR P-value With 586 (0.6) 3 (3.4) 589 (%) (rate, %) Without 96,700 (99.4) 85 (96.6) 96,785 Time (year) Drug allergy < 0.001 Every 1 year < 0.001 With 1,211 (1.2) 17 (1.4) 1,228 2011 30,554 (14.6) 10 (0.03) Without 96,075 (98.8) 71 (19.3) 96,146 2012 43,471 (20.8) 12 (0.03) 2013 46,149 (22.1) 16 (0.03) Hypertension 0.711 2014 43,871 (21.0) 38 (0.09) With 19,469 (20.0) 19 (21.6) 19,488 2015 44,982 (21.5) 32 (0.07) Without 77,817 (80.0) 69 (78.4) 77,886 2 categories < 0.001 Diabetes 0.853 2011-2013 120,174 (57.5) 38 (0.03) mellitus 2014-2015 88,853 (42.5) 70 (0.08) With 9,383 (9.6) 9 (0.1) 9,392 RCM type < 0.001 Without 87,903 (90.4) 79 (1.1) 87,982 Iohexol 10,097 (4.8) 1 (0.01) Liver disease 0.337 Ioxitalamic acid 7,200 (3.4) 1 (0.01) With 2,894 (3.0) 4 (4.5) 2,898 Ioversol 38,644 (18.5) 6 (0.02) Without 94,392 (97.0) 84 (95.5) 94,476 Iobitridol 39,503 (18.9) 15 (0.04) Iopromide 49,099 (23.5) 19 (0.04) Chronic renal 0.773 Iopamidol 48,476 (23.2) 40 (0.08) disease Iodixanol 16,008 (7.7) 26 (0.16) With 3,505 (3.6) 2 (2.3) 3,507 Without 93,781 (96.4) 86 (97.7) 93,867 Total 209,027 (100.0) 108 (0.05) Total 97,286 88 97,374 * HSR, hypersensitivity reaction; RCM, radiocontrast media (100.0) * HSR, hypersensitivity reaction

RCM types (P < 0.001, Table 3 and Figure 1).

Logistic regression analysis of the risk factors for HSR Univariate logistic regression analysis showed age (odds ratio [OR], 0.988; 95% confidence interval [CI], 0.977-0.999;P = 0.037), urticaria (OR, 2.812; 95% CI, 1.542-5.125; P = 0.001), drug allergy (OR, 9.664; 95% CI, 5.996-15.577; P < 0.001), and use in 2014-2015 (OR, 2.493; 95% CI, 1.679-3.700; P < 0.001) were the significant risk factors for HSR. The use of iopamidol (OR, 8.338; 95% CI, 1.146-60.655; P = 0.03) and iodixanol (OR, 16.420; 95% CI, 2.228-121.050; P = 0.006) were more significant Figure 1. HSR rates according to the type of RCM risk factors for HSR than that of iohexol was. Asian Pac J Allergy Immunol DOI 10.12932/AP-191017-0182

Table 4. Univariate and multivariate analysis for HSR using logistic analysis

Parameters Univariate analysis Multivariate analysis OR (95% CI) P-value OR (95% CI) P-value Age 0.988 (0.977-0.999) 0.037 0.980 (0.968-0.991) 0.001 Gender (women) 0.738 (0.503-1.082) 0.119 Asthma 0.421 (0.059-3.013) 0.389 Allergic rhinitis 1.244 (0.629-2.462) 0.531 Atopic dermatitis 0.894 (0.055-14.424) 0.937 Urticaria 2.812 (1.542-5.125) 0.001 1.936 (1.043-3.593) 0.036 Hypertension 0.893 (0.578-1.381) 0.612 Food allergy 3.000 (0.952-9.461) 0.061 Drug allergy 9.664 (5.996-15.577) < 0.001 9.212 (5.612-15.121) < 0.001 Diabetes mellitus 0.899 (0.513-1.577) 0.711 Liver disease 1.843 (0.931-3.648) 0.078 Chronic renal disease 0.495 (0.157-1.560) 0.230 Type of contrast Iohexol Reference Reference Ioxitalamic acid 1.402 (0.088-22.425) 0.811 1.497 (0.093-24.050) 0.776 Ioversol 1.568 (0.189-13.024) 0.677 1.535 (0.184-12.804) 0.692 Iobitridol 3.835 (0.507-29.036) 0.193 3.933 (0.519-29.819) 0.185 Iopromide 3.908 (0.523-29.199) 0.184 4.591 (0.612-34.410) 0.138 Iopamidol 8.338 (1.146-60.655) 0.036 8.327 (1.142-60.712) 0.037 Iodixanol 16.420 (2.228-121.050) 0.006 18.780 (2.543-138.710) 0.004 Year 2011-2013 Reference Reference 2014-2015 2.493 (1.679-3.700) < 0.001 2.704 (1.814-4.030) < 0.001 * HSR, hypersensitivity reaction; OR, odds ratio; CI, confidence interval

Table 5. Univariate and multivariate analysis for HSR using GEE analysis

Parameters Univariate analysis Multivariate analysis OR (95% CI) P-value OR (95% CI) P-value Age 0.988 (0.978-0.998) 0.016 0.980 (0.969-0.990) < 0.001 Gender (women) 0.738 (0.494-1.102) 0.138 Asthma 0.420 (0.059-3.014) 0.389 Allergic rhinitis 1.244 (0.588-2.631) 0.568 Atopic dermatitis - - Urticaria 2.811 (1.539-5.134) 0.001 1.936 (1.003-3.737) 0.049 Hypertension 0.893 (0.557-1.433) 0.640 Food allergy 3.000 (0.945-9.528) 0.062 Drug allergy 9.664 (5.877-15.893) < 0.001 9.212 (5.353-15.853) < 0.001 Diabetes mellitus 0.899 (0.480-1.684) 0.740 Liver disease 1.843 (0.824-4.120) 0.136 Chronic renal disease 0.495 (0.157-1.561) 0.230 Type of contrast Iohexol Reference Reference Ioxitalamic acid 1.402 (0.088-22.379) 0.811 1.497 (0.094-23.770) 0.775 Ioversol 1.568 (0.179-13.693) 0.684 1.535 (0.170-13.882) 0.703 Iobitridol 3.835 (0.506-29.047) 0.193 3.933 (0.514-30.124) 0.187 Iopromide 3.908 (0.523-29.208) 0.184 4.591 (0.605-34.864) 0.141 Iopamidol 8.338 (1.146-60.677) 0.036 8.327 (1.129-61.401) 0.038 Iodixanol 16.420 (2.228-121.090) 0.006 18.780 (2.564-137.560) 0.004 Year 2011-2013 Reference Reference 2014-2015 2.493 (1.664-3.733) < 0.001 2.704 (1.780-4.108) < 0.001 * HSR, hypersensitivity reaction; GEE, generalized estimating equation HSR rate according to radiocontrast media

Multivariate analysis with adjustment showed that drug for arteriography. However, iodixanol is approximately twice allergy (OR, 9.212; 95% CI, 5.612-15.121; P < 0.001), use of as viscous as nonionic monomer (low-osmolar) RCM are.23 iopamidol (OR, 8.327; 95% CI, 1.142-60.712; P = 0.037), use of The high viscosity is associated with a high laminar flow, which iodixanol (OR, 18.780; 95% CI, 2.543-138.710; P = 0.004), and may lead to renal toxicity.24 However, some researchers have use in 2014-2015 (OR, 2.704; 95% CI, 1.814-4.030; P < 0.001) reported opposite findings.25,26 Although we assumed that the were significant risk factors for HSR Table( 4). results obtained in this study are due to the high viscosity of iodixanol, further studies are needed to verify this finding. GEE analysis of the risk factors for HSR This study showed that the use of ioxitalmic acid, which is In the univariate GEE analysis with reflecting repeated an ionic monomer, is not a high risk factor for HSR. Although events in one patient, age (OR, 0.988; 95% CI, 0.978-0.998; P various RCM with lower osmolarity and low toxicity have = 0.01), urticaria (OR, 2.811; 95% CI, 1.539-5.134; P = 0.001), been developed, ioxitalmic acid is still used clinically. The low drug allergy (OR, 9.664; 95% CI, 5.877-15.893; P < 0.001), use of viscosity of ioxitalmic acid makes it suitable for use in thinner iopamidol (OR, 8.338; 95% CI, 1.146-60.677; P = 0.036), use of -walled catheters. Furthermore, the relatively low biological iodixanol (OR, 16.420; 95% CI, 2.228-121.090; P = 0.006), and tolerability of ionic RCM also contributed to its widespread use in 2014-2015 (OR, 2.493; 95% CI, 1.664-3.733; P < 0.001) use.23 In addition, the highly water-soluble characteristics of were significant risk factors for HSR. ionic RCM are also important factors for its continued used.27 The multivariate GEE analysis showed that age (OR, 0.980; We suggest that ioxitalmic acid can be used relatively safely for 95% CI, 0.969-0.990; P < 0.001), urticaria (OR, 1.936; 95% CI, some specific purposes. 1.003-3.737; P = 0.049), drug allergy (OR, 9.212; 95% CI, 5.353- We found that age, urticaria, and drug allergy were sig- 15.853; P < 0.001), use of iopamidol (OR, 8.327; 95% CI, 1.129- nificant risk factors for HSR. These factors are already well 61.401; P = 0.038), use of iodixanol (OR, 18.780; 95% CI, 2.564- -established risk factors for HSR as previously reported in 137.560; P = 0.004), and use in 2014-2015 (OR, 2.704; 95% CI, the literature.22,28 However, two previous large-scale studies 1.780-4.108; P < 0.001) were significant risk factors for HSR conducted to compare the incidence of HSR among RCM by (Table 5). Gomi et al.14 and Kim et al.15 did not consider these factors. In addition, these studies did not adjust for these factors in their Discussion comparisons. Our consideration of these factors with adjust- We defined the significant risk factors for HSR, based on a ment has contributed to strengthening this present study. For retrospective review of 209,027 RCM use events that occurred the first time, we have defined the significant difference in the in one institute. Seven types of RCM were used, and five were HSR rate among RCM while adjusting for age, urticaria, and classified as low-osmolar RCM, which have been widely used drug allergy. recently. Among the five types of low-osmolar RCM, iopa- The timing of use was also a significant risk factor for midol use was a significant risk factor for HSR. Identifying HSR in this study. However, we thought that this factor is not RCM with high and low risks for HSR is very important in a clinically significant, but likely just a confounding factor. The clinic setting because the prevalence of HSR with RCM use is HSR event data were collected using an internally developed increasing. Furthermore, numerous guidelines and researchers ADR reporting system. Following the launch of this reporting recommend that RCM that have induced HSR in a subject system in this institute, allergy specialists, pharmacists, and should be replaced with another agent and that premedication other drug-related professionals encouraged doctors, nurses, will be helpful to reduce risk for recurrence of HSR, but some and paramedics to use this system for several years. This others showed skeptical results.19,21,22 Until now, no consen- increased the ADR reporting rate significantly according to sus has been reached on the types of RCM that are safer and the time. This factor might also be a confounding factor. We suitable substitutes for avoiding ADRs. We also cannot firmly adjusted this factor in the multivariate analysis, and the results recommend which RCM is safer and suitable. But the results were not affected by this confounding factor. of this study which showed that iopamidol has a relatively This study had some limitations, which are worth men- higher risk associated with its use than that associated with tioning. First, the spontaneous reporting rate was supposed to be low. Compared to previous studies, which reported the iohexol or ioversol use will be informative when clinicians 14,29-31 chose type of RCM. Gomi et al.14 also showed that the inci- incidence of ADR as 0.1-2.5% . the reported ADR rate dence of ADRs with iopamidol use (2.2%) was relatively higher in this study (0.03-0.17%) is slightly low. The reported ADR than that with iohexol (2.0%) and ioversol use (1.8%). Kim et rate in this study might not reflect all the ADRs that occurred al.15 also showed that incidence of anaphylaxis with iopamidol because the data were not collected automatically, but were use (0.023%) was relatively higher than it was with iohexol use collected by using a spontaneous reporting system. Second, (0.018%). These results will be helpful to choose type of ADR in this study was performed in only one institute with selected clinical setting. RCM, which are concordant with only one product. The char- We discovered that the iso-osmolar RCM, iodixanol, ex- acteristics of RCM used in this study may be limited to the hibited the highest risk for HSR. The transition from the use specific products, and may not apply to all products contain- of ionic monomers to nonionic monomers (low-osmolar) and ing these ingredients. Third, we did not include GEE analysis then to nonionic dimers (iso-osmolar RCM) was initiated to of severe HSR, separately, as it can cause distorted results. Last, reduce toxicity. Iodixanol is one of the first-generation non premedication could not be assessed in this study. -ionic dimers that are manufactured as isotonic agents useful Asian Pac J Allergy Immunol DOI 10.12932/AP-191017-0182

Conclusion 11. Ohlsen H, Albrechtsson U, Billstrom A, Calissendorff B, Gustavsson S, Jensen R, et al. Comparison of iopromide versus iohexol in aortobifemoral This study showed that use of iodixanol (iso-osmolar RCM) arteriography. A Swedish multi-center study of 446 patients. Acta Radiol. is a high risk factor for immediate HSR. Among the low-osmo- 1991;32:130-3. lar RCM, iopamidol use is associated with a significantly higher 12. Kennedy C, Rickards D, Lee S, Sharp MB, Dawson P. A double-blind study risk for immediate HSR than iohexol or ioversol use is. Com- comparing the efficiency, tolerance and renal effects of iopromide and iopamidol. Br J Radiol. 1988;61:288-93. pared to other RCM, ioxitalamic acid (ionic RCM) use is not 13. Hoogewoud HM, Woessmer B. Iobitridol 300 compared to iopromide 300 a high risk factor for immediate HSR. This information may - a double-blind randomized phase-III study of clinical tolerance in total be helpful to clinicians in choosing the most appropriate RCM body CT. Acta Radiol Suppl. 1996;400:62-4. type. 14. Gomi T, Nagamoto M, Hasegawa M, Katoh A, Sugiyama M, Murata N, et al. Are there any differences in acute adverse reactions among five low -osmolar non-ionic iodinated contrast media? Eur Radiol. 2010;20:1631-5. Acknowledgments 15. Kim SR, Lee JH, Park KH, Park HJ, Park JW. Varied incidence of immediate adverse reactions to low-osmolar non-ionic iodide None declared radiocontrast media used in computed tomography. Clin Exp Allergy. 2017; 47:106-12. 16. Morales-Cabeza C, Roa-Medellin D, Torrado I, De Barrio M, Fernandez Conflict of interest -Alvarez C, Montes-Acenero JF, et al. Immediate reactions to iodinated None declared contrast media. Ann Allergy Asthma Immunol. 2017;119:553-7. 17. Lee JH, Park KH, Moon HJ, Lee YW, Park JW, Hong CS. Spontaneous reporting of adverse drug reactions through electronic submission from Funding information regional society healthcare professionals in Korea. Yonsei Med J. 2012;53: None declared 1022-7. 18. AAAAI: American Academy of Allergy Asthma & Immunology [Internet]. Milwaukee: American Academy of Allergy, Asthma & Immunology; c2018 Author contribution [cited 2018 Apr 11]. Hypersensitivity Reactions; [about 1 screen]. Available HJP designed the study, conducted data generation, an- from: https://www.aaaai.org/conditions-and-treatments/conditions-dictio nary/hypersensitivity-reactions. alyzed and interpreted data, prepared the manuscript draft. 19. Park HJ, Park JW, Yang MS, Kim MY, Kim SH, Jang GC, et al. Re-exposure CHP recruited and analyzed data, and contribute to prepare to low osmolar iodinated contrast media in patients with prior moderate manuscript draft. 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