This study prospectively observed 10,540 exposures to low-osmolar contrast media to determine the incidence and risk factors of late adverse reactions. They found that the incidence of late reactions ranged from 1.2-8.3% depending on the specific contrast media, with most (90.9%) occurring within the first week. Female sex and a history of allergic disease or drug allergy increased the risk. Among those with late reactions, 4% had a recurrence upon re-exposure within 3 years, which was reduced by using premedication or waiting longer between exposures. This study provides useful information about late adverse reactions that are difficult to capture.

1. Journal Article Presentation
Avinesh Shrestha
M.Sc.MIT
Bir, NAMS

2. Incidence and risk factors of late adverse reactions to
low-osmolar contrast media: A prospective observational
study of 10,540 exposures

3. Web Page
 European Journal of Radiology: https://www.ejradiology.com/article/S0720-048X(21)00582-9/fulltext
 PubMed: https://pubmed.ncbi.nlm.nih.gov/34952368/
 Science Direct: https://www.sciencedirect.com/science/article/pii/S0720048X21005829
 Google Scholar
 PMID: 34952368
 DOI: 10.1016/j.ejrad.2021.110101

4. Journal Rating
CiteScore
 Calculating the CiteScore is based on the number
of citations to documents (articles, reviews,
conference papers, book chapters, and data
papers) by a journal over four years, divided by
the number of the same document types indexed
in Scopus and published in those same four
years.
 For example, the 2019 CiteScore counts the
citations received in 2016-2019 to articles,
reviews, conference papers, book chapters, and
data papers published in 2017-2020, and divides
this by the number of these documents published
in 2016-2019.

5. Journal Rating
Impact Factor
 The Journal Impact Factor is published each year by Clarivate Analytics.
 It is a measure of the number of times an average paper in a particular journal is cited during the
preceding two years.
For example: 2016 impact factor = A/B.
 A = the number of times articles published in a specific journal in 2014 and 2015 were cited by
journals during 2016.
 B = the total number of 'citable items' published by that journal in 2014 and 2015. ('Citable
items' are usually articles, reviews, proceedings, etc.; not editorials or letters-to-the-editor.)

6. Journal Rating
 European Journal of Radiology
https://www.scopus.com/sourceid/16677#tabs=0

7. Journal Rating
https://www.scopus.com/sourceid/16677#tabs=0
 European Journal of Radiology

8. Search Strategy and Selection
 Used different search engines and websites like Google scholar, PUBMED, Science direct
(Elsevier journals), RSNA (Radiographics) , AJR , BJR and KJR
 Reviewed many articles related with
 Photon Counting detector (PCD) Computed Tomography,
 Artificial Intelligence (AI)
 Deep learning based Computer Aided Diagnosis (CAD),
 Deep learning based Image Reconstruction (DLR), and
 Iodinated contrast media .

9. Artificial Intelligence

10. Artificial Intelligence

11. Deep learning based Computer Aided Diagnosis (CAD)

12. Deep learning based Reconstruction (DLR)

13. Deep learning based Reconstruction (DLR)

14. Photon Counting detector (PCD) Computed Tomography

15. Search Strategy and Selection
 Although PCD, AI, CAD and DLR is an emerging technological advancement in radiology, these
technologies are yet to be practiced in routine clinical scenario. Also, these technologies are still
out of reach in developing countries like Nepal
 Therefore, as LOCM is routinely and increasingly used in radiology department, I selected this
topic for todays presentation

17. Selection, Relevance
 Latest article –December 2021
 Relevant to us as imaging technologist
 Helpful in understanding the Late adverse reaction of non-ionic low-osmolar iodinated contrast media as
it is frequently used in all contrast enhanced CT scans
 Late AR can is more challenging to identify than Acute AR as patient are not in the radiology department
for long hours. Therefore, information about late AR is important to radiology technologist so that RT can
address the queries related to LOCM for the patient and make them aware about the possibilities.
 Useful while counselling patients and patient’s visitor before any LOCM related radiological examination

18. Article Info
Publication History
 Published online: December 10, 2021
 Accepted: December 7, 2021
 Received in revised form: November 22, 2021
 Received: August 19, 2021
Identification
 DOI: https://doi.org/10.1016/j.ejrad.2021.110101
Copyright
 © 2021 Elsevier B.V. All rights reserved.

19. Article Citation
Authors: Dong Yoon Kang, Suh-Young Lee, Yoon Hae Ahn, Soon Ho Yoon, Young Hoon Choi, Whal Lee,
Hye-Ryun Kang,
Title: Incidence and risk factors of late adverse reactions to low-osmolar contrast media: A
prospective observational study of 10,540 exposures,
European Journal of Radiology,
Volume 146,
Year 2022,
Article No. 110101,
ISSN 0720-048X,
https://doi.org/10.1016/j.ejrad.2021.110101.
(https://www.sciencedirect.com/science/article/pii/S0720048X21005829)

20. Authors
1. Dong Yoon Kang a,1
2. Suh-Young Lee b, c, 1
3. Yoon Hae Ahn b
4. Soon Ho Yoon d
5. Young Hoon Choi d
6. Whal Lee d
7. Hye-Ryun Kang a, b, c, *
a Drug Safety Monitoring Center, Seoul National
University Hospital, Seoul, Republic of Korea
b Department of Internal Medicine, Seoul National
University Hospital, Seoul, Republic of Korea
c Institute of Allergy and Clinical Immunology, Seoul National
University Medical Research Center, Seoul, Republic of
Korea
d Department of Radiology, Seoul National
University Hospital, Seoul, Republic of Korea
1 Both authors contributed equally to this work.
*Corresponding author at: Department
of Internal Medicine, Seoul National
University College of Medicine, 101
Daehak-ro, Jongno-gu, Seoul 03080,
Republic of Korea.
helenmed@snu.ac.kr

21. Background
 LOCM is the most commonly used type of contrast agent in radiologic imaging. As the use of LOCM is
increasing worldwide, reports of adverse reactions (ARs) related to LOCM use are also increasing.
 A late AR is defined as an AR that occurs after one hour and up to one week following exposure to a
contrast medium and has a peak incidence from 3 h to two days after exposure
 Common symptoms of late ARs include allergic-like ARs (maculopapular rashes, erythema, swelling,
pruritus) and non-allergic-like ARs (nausea, vomiting, headache, musculoskeletal pain, and fever)
 Compared to acute ARs, information regarding the incidence, severity, and risk factors of late ARs to
LOCM is limited because monitoring is difficult in the outpatient setting

22. Aim/Objective
General Objective
 The aim of this study was to determine the incidence, risk factors, and clinical characteristics of late
ARs to LOCM.
Specific objective
 To determine the incidence rate of Late AR to LOCM
 To find out the clinical features of late AR to LOCM
 To determine the risk factors for Late AR to LOCM

23. Methodology
This study was approved by the institutional review board of Seoul National University Hospital (SNUH-1906-
052-1038).
Study subjects and design
 Study Design- Prospective, Cohort
 Study Subject: All patients who received contrast enhanced computed tomography scans
 Study period- July 17 to August 20, 2017. Patients who experienced late AR were followed up for three
years
 Study place- Seoul National University Hospital
 Sample size- 10,540 (based on the number of LOCM exposures as individual cases rather than the
number of patients included in the study)
 Sampling Method- Non Probability, Purposive

24. Methodology
 A total of 6 different types of LOCM were used:
 iobitridol (Xenetix™ 350, Guerbet Korea, Seoul, Korea),
 iohexol (Iobrix™ 240, Taejoon Pharm, Seoul, Korea; Bonorex™ 350, Daihan Pharm, Seoul,
Korea; Omnihexol™ 350, Korea United Pharm, Seoul, Korea; Omnipaque™ 350, GE
Healthcare, Seoul, Korea),
 iomeprol (Iomeron™ 400, Bracco Imaging Korea, Seoul, Korea),
 iopamidol (Pamiray™ 300, Dongkook Pharm, Seoul, Korea; Pamiray™ 370, Dongkook Pharm,
Seoul, Korea),
 iopromide (Ultravist™ 370, Bayer Korea, Seoul, Korea), and
 ioversol (Optiray™ 320, Imaging Solution Korea, Seoul, Korea; Iversense™ 350, Taejoon
Pharm, Seoul, Korea).

25. Methodology
The following information was recorded for each case:
1. baseline characteristics including age, sex, and past medical history,
2. past history of LOCM use and LOCM-related ARs,
3. past history of drug allergy, asthma, or other allergic diseases including allergic rhinitis, atopic
dermatitis, and food allergy,
4. family (limited to first-degree relatives) history of LOCM-related ARs and allergic diseases
5. name and dose of the administered LOCM,
6. premedication regimen (if applicable),
7. symptom, severity, time of onset, duration, and causality of ARs, and
8. management of ARs.

26. Methodology
 All patients were kept under nurse surveillance for any ARs for one hour after LOCM injection.
 Once discharged, patients were monitored through text message surveys sent one week after LOCM
exposure.
 Responders who answered the text message survey as ‘no’ were recorded as ‘no occurrence of ARs’;
non-responders as well as responders who answered ‘yes’ to the survey were contacted via telephone.
 All patients were instructed to contact a pharmacovigilance nurse if any symptoms developed after day
7 up to day 28, instead of regular contact.

27. Methodology
 Premedication was defined as the use of antihistamine (equivalent to 4 mg of chlorpheniramine)
and/or steroids (equivalent to 40 mg of methylprednisolone) on the day of the CT scan prior to LOCM
exposure.
 The premedication regimen was determined by the severity of the previous AR. While a combination of
steroids and antihistamines was given to patients with a history of moderate to severe AR, patients
with a history of mild AR received antihistamine only.

28. Methodology
Classification of Ars
Patients’ self-reported symptoms after LOCM exposure were recorded. Of these symptoms, only cases with
possible causality according to the World Health Organization-Uppsala Monitoring Center (WHO-UMC)
causality assessment criteria [13] were defined as ARs
 ARs to LOCM were classified according to the onset time as
 ‘acute’ (within an hour) and
 late (after 1 h): Late ARs were subdivided into
 ‘late onset’ (after 1 h to day 7) and
 ‘very late onset’ (after day 7)

29. Methodology
 Severity classification: The European Society of Urogenital Radiology (ESUR) criteria were used to define
and classify the severity of an AR [3]. Symptoms that were not included in the ESUR criteria were assessed
according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [14]
 Mild (Grade 1)
 Moderate (Grade 2)
 Severe (Grade 3)
 For patients with late ARs in this study, re-exposure to LOCM were monitored for three years after their
index reactions to assess the recurrence rate of late ARs.

30. Methodology
Tolerant controls
 In order to analyze risk factors for late ARs to LOCM use, tolerant controls were set as patients without
any AR after LOCM use during the study period.
 Patients with a history of AR to LOCM or those who had received premedication were excluded from
tolerant controls.
 The past medical history and family history of tolerant controls were also collected.

31. Methodology
Statistical methods
 Data was expressed as the mean and standard deviation for continuous variables and as a numeral with
a percentage for categorical variables.
 Chi-square analysis was performed to compare the incidence of ARs according to the LOCM product.
 student t-test for continuous variables and the Chi-square test for categorical variables were used to
compare risk factors of the AR cases and tolerant controls.
 All statistical tests were performed at a significance level of p < 0.05.
 All analyses were performed using IBM® SPSS Statistics (version 25.0; SPSS Inc., Chicago, IL, USA).

32. Flow Of Study

33. Results

34.  Incidence and clinical features of late AR to LOCM
Differences in incidence of late ARs ranging from 1.2% to 8.3% and 0.8% to 2.6% were observed among the
different LOCM and concentrations, respectively .These differences, however, were not statistically significant

35. The severity of the reactions
did not differ between late
onset and very late onset
ARs;
Nineteen cases reported AR
between days 8 and 20, were
classified as ’very late onset
ARs’.

36.  Trend of late AR occurrence over time
90.9% occurred at the end of the first week (late onset AR).The last reported AR occurred 20
days after LOCM exposure, and manifested as skin rash with pruritus. Late ARs persisted for 4 ± 2
days.

37. Risk factors of late AR to LOCM
 No significant difference in age between the late
AR cases and tolerant controls
 Risk of late AR was not statistically different in
patients younger than 5 years and over 60 years of
age
 Female sex and past history of allergic disease and
drug allergy showed a higher risk of developing late
Ars

38. Risk factors of late AR to LOCM
 History of previous LOCM use, asthma, chronic
diseases, family history of AR to LOCM or allergic
disease did not affect the risk of late ARs
 Compared to cases without previous LOCM use, the
overall risk of AR was lower in cases who had been
exposed to LOCM at least once in the past 10
years. These findings were seen mainly in late ARs

39.  Results of re-exposure to LOCM in subjects with late AR
Among the 207 cases with late ARs in this study, 57 patients were
re-exposed to LOCM after their index reactions
• For 3 years after the index reaction, 57 patients
with late ARs were re-exposed to LOCM on 272
occasions
• 94 cases were re-exposed to the culprit LOCM
without premedication: 12 cases used the same
LOCM and 82 cases used different LOCMs
• 178 cases received premedication prior to LOCM re-
exposure; of these cases, 26 cases used the same
LOCM and 152 cases used different LOCMs
• total of 11 cases of AR (4.0%) developed upon re-
exposure

40.  Results of re-exposure to LOCM in subjects with late AR
• Time to re-exposure and the use of antihistamine
premedication significantly reduced the risk of
recurrence in patients with a history of late ARs.
• Similarly, the time to re-exposure and the severity
of the previous AR (mild compared to moderate)
reduced the risk of recurrent reactions in patients
with a history of acute ARs to LOCM.

41. Although the recurrence rate was not reduced by changing the LOCM (same LOCM 5.3% vs. different LOCM
3.8%; p = 0.655), the rate was significantly lower in cases that received premedication compared to those
that did not (1.7% vs. 8.5%; p = 0.016)

42. Discussion
 The incidence of late ARs has been reported to range from 0.36% to 23%, and this incidence rate
varies significantly according to the study population and investigation methods
 Owing to the difficulty in gathering reliable data, the incidence and risk factors of late ARs remain
relatively obscure in comparison to acute ARs.
 In this prospective cohort study, they identified the actual incidence rate and risk factors of late
ARs associated with intravenous LOCM use.
 late ARs can occur beyond one week: 9.1% of late ARs occurred after one week and up to day 20
after LOCM exposure. These results emphasize the importance of educating patients of the
possibility of late onset of LOCM-related ARs beyond the traditional one-week timeframe.

43. Discussion
 They found that the incidence of late ARs was 2.0%, which was two times higher than that of acute
Ars which is in accordance with findings of previous study [20].
 The proportion of moderate ARs was higher than that of acute ARs. In light of these findings, we
must remain vigilant for the development of late ARs.
 Although most acute ARs usually manifested in the form of urticaria or angioedema, late ARs
frequently presented as cutaneous reactions.
 Switching to a different LOCM was also ineffective in reducing the recurrence of late ARs.

44. Discussion
 Although rare, thyroid disorders have also been reported to increase the risk of ARs to LOCM [32];
among the 10,540 patients in this study, 23 patients had a history of thyroid disease and one patient
had an acute, physiologic reaction (tachycardia) to LOCM. The presence of underlying diseases such
as heart failure, diabetes mellitus, and chronic kidney disease showed no correlation with the
incidence of late ARs.
 In this study, the use of antihistamine premedication had a significant preventative effect on AR
recurrence in patients with a history of late Ars.

45. Discussion
 existing literature showed that patients below 5 years or older than 60 years have an increased risk of
acute ARs [31], while young adults have a higher risk of developing late reactions [17]. Contrary to
these findings, the incidence rate did not show a significant difference by age.
 Meanwhile, females and patients with a history of allergies had a higher risk of developing late ARs, and
these results were consistent with that of aforementioned studies
 Family history was previously reported to be a risk factor for acute ARs to LOCM [28], however, they
found no cases of late ARs occurring in patients with a positive family history.
 The preventative effects of antihistamine premedication may have been overestimated as the study
population included patients who were taking antihistamines for other indications on a daily basis.

46. Limitation
 Study population only included patients from a single hospital with a predilection for patients with
complex medical histories including cancer.
 Most of the patients had been previously exposed to LOCM, and patients with a previous history of
ARs may tend to avoid further LOCM use leading to selection bias.
 Most patients were exposed to LOCM more than once, analyses based on the number of times each
patient was re-exposed to LOCM during follow up could not be standardized.
 The assessment of late ARs was relatively subjective, as monitoring was conducted based on
patients’ self-reporting of symptoms rather than through direct inspection by medical staff.

47. Limitation
 Interpretation bias may have occurred due to the difficulty of causality assessment for LOCM use,
especially in very late ARs.
 This survey itself may have triggered patients to use other therapeutic drugs or interventions
which could influence results.

48. Conclusion
 In conclusion, the incidence of late ARs following LOCM exposure was twice that of acute Ars
 Symptoms in most cases developed within one week.
 A history of drug allergy and other allergic diseases was a significant risk factor in the occurrence of
late ARs.
 In patients with a history of AR to LOCM, the risk of recurrent reactions decreases with longer time
intervals between exposures.
 Premedication with antihistamines may also be effective in reducing the recurrence of patients with
late AR.

49. Credit authorship contribution statement
 Dong Yoon Kang: Methodology, Software, Formal analysis, Writing – review &
editing.
 Suh-Young Lee: Writing – original draft, Validation.
 Yoon Hae Ahn: Writing – review & editing.
 Soon Ho Yoon: Resources, Investigation.
 Young Hoon Choi: Resources, Investigation.
 Whal Lee: Funding acquisition, Project administration.
 Hye-Ryun Kang: Conceptualization, Visualization, Supervision.

50. Declaration of Competing Interest
 The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.

51. Acknowledgement
 This research was supported by the National Institute of Food and Drug Safety Evaluation

52. Appendix A. Supplementary material
 Supplementary data to this article can be found online at https://doi. org/10.1016/j.ejrad.2021.110101.

53. Analysis - Strength
 Was the study relevant?
 Yes, the study is highly relevant to radiology technologist in the current scenario of
increasing number of contrast enhanced CT examination. CECT is a routinely happening
examination with rapid trend of increment in these examination
 Is the information helpful to the current practice?
 Yes, as CECT with the use of LOCM is one of the most frequent radiological examination
in todays scenario.

54. Analysis - Strength
 What is the significance of the study?
 It is difficult to monitor for late ARs as they usually occur once the patient leaves the
hospital.
 The results emphasize the importance of educating patients of the possibility of late
onset of LOCM-related ARs beyond the traditional one-week timeframe.
 As radiology technologist, we repeatedly perform CECT in our day to practice. This study
has given the insight about the higher possibility of late AR than Acute AR to the patient.
As a health professional, it is our responsibility to make sure the patient and visitors are
aware of these possibilities.

55. Analysis- Limitations
 Was the research objective fulfilled by this study?
 Yes, the study objectives were fulfilled.
 Is the sample size adequate?
 Sample size can not be said to be inadequate. However, sample size is based on the exposure to
LOCM rather than individual patient. In this context, the sample size should be increased on the
basis of individual patient.
 Hypersensitivity reactions to iodinated contrast media: A multicenter study of 196 081 patients
(28) vs 10540 exposure (not patient)

56. Analysis- Strength
 Does it present ideas for future research?
 Yes, similar kind of study with large study population and longitudinal study is necessary to further
validate the result of this study as some of the results presented in this study contradict the
results of previous study
 Comparison of the preventive effects of each premedication (antihistamines vs. steroid vs. both)
method was not possible which is a potential future research area
 We can conduct similar research for iso-osmolar iodinated contrast media

57. Analysis- Limitations
 Was the Radiation dose considered?
 As the sample size is based on re-exposure to the same patient, there is some concern regarding
radiation dose to patient involved in this research. However, the information about radiation
dose is lacking in this article.
 There is no information about how many times an individual patient was subjected to radiation
and LOCM

58. Analysis- Limitations
 Conflicting Information
 While a combination of steroids and antihistamines was given to patients with a history of
moderate to severe AR, patients with a history of mild AR received antihistamine only.
(methodology)
 In addition, past studies have also shown that patients who take oral steroids on a daily basis are
at higher risk of developing breakthrough reactions [36]. As such patients were included in our
analysis, this may in part explain the relatively lesser preventative potential of steroid
premedication observed in our study. (discussion)
 Although results of previous studies have stated that steroid premedication may be effective in
preventing ARs in patients with a history of severe reactions, we were unable to validate these
results due to the small sample size. (discussion)

59. References