1. 2018 분당서울대병원 내과 연수강좌
조영제 과민반응의 치료와 예방관리
분당서울대학교병원
알레르기내과
김세훈

2. 순서
조영제 과민반응의 분류, 역학, 기전
조영제 과민반응의 치료
조영제 과민반응의 예방과 관리

3. 조영제 과민반응의 분류, 역학, 기전

5. Contrast media Hypersensitivity
Increasing chance of exposure to CM in radiologic test and intervention
Wide use of contrast CT, MRI
Repeated test using contrast media
Still one of the common causative agents for drug adverse reaction in hospital

6. Contrast media : iodine vs. gadolinium
Iodinated contrast
Gadonium-based contrast
Mainly used for CT, angiography, etc.
Higher prevalence of adverse reactions such as hypersensitivity reactions, nephropathy, etc.
Mainly used for MRI
Less frequent hypersensitivity reactions
Rare, but severe adverse reaction noted: nephrogenic systemic fibrosis

7. Iodine contrast media: Structure and Classification
Tri-iodinated benzene derivatives
(4 classes based on osmolality and chemical structures)

8. Classification of adverse reactions to RCM

9. Clinical manifestations of RCM hypersensitivity
immediate reactions
Non-immediate reactions
Urticaria
Angioedema/facial edema
Exanthema (mostly macular or maculopapular drug eruption)
Abdominal pain, nausea, or diarrhea
Urticaria, angioedema
Rhinitis (sneezing, rhinorrhea)
Erythema multiforme minor
Hoarseness, cough
Fixed drug eruption
Dyspnea (bronchospasm, laryngeal edema)
Stevens-Johnson syndrome
Respiratory arrest
Toxic epidermal necrolysis
Hypotension, cardiovascular shock
Graft-versus-host reaction
Cardiac arrest
Drug related eosinophilia with systemic symptoms (DRESS)
Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE)
Vasculitis

10. Grading of immediate reactions according to severity of clinical symptoms
Grade
Symptoms
Skin
Abdomen
Respiratory tract
Cardiovascular system I
Pruritus, flush, urticaria, angioedema II
(not mandatory)
Nausea,
cramping
Rhinorrhea, hoarseness,
dyspnea
Tachycardia (>20 beats/min), BP change (>20 mmHg systolic), arrhythmia
III
Vomiting, defecation. diarrhea
Laryngeal edema, bronchospasm, cyanosis
Shock IV
Respiratory arrest
Cardiac arrest

11. Epidemiology Immediate hypersensitivity reaction
Ionic RCM
Mild reactions: 3.8% to 12.7% of procedures
Severe reactions: 0.1% to 0.4% of procedures
Non-ionic RCM
Mild reactions: 0.7% to 3.1% of procedures
Severe reactions: 0.02% to 0.04% of procedures
** Only well- established risk factor : Previous hypersensitivity reaction
Non-immediate hypersensitivity reactions
- 1% to 3% of RCM exposed patients
- Higher incidence exanthemas associated with dimeric non- ionic RCM (Visipaque®)
Other risk factors

12. Pathogenesis in immediate hypersensitivity
IgE
Direct activation
of contrast media
FceRI
Mast cell, Basophil
Non-immunologic reaction vs. IgE-mediated reaction

13. Changes in Pathogenesis
Increasing evidence of immunological mechanism (IgE-mediated) in some immediate RCM reactions
Positive basophil activation test
Positive skin tests in patients but not in controls
Rare cross-reactivity between different RCM
Non-immediate reactions mediated by cell-mediated hypersensitivity
- Skin test-positive on patch or delayed intradermal tests
- RCM reactive T cells in vitro and in vivo

14. 조영제 과민반응의 치료
즉시형 과민반응 및 급성 부작용의 치료
지연형 과민반응의 치료

16. Acute adverse reaction
Hypersensitivity reaction
Physiologic reaction to toxicity
Mild
Local pruritus, urticarial, angioedema
Throat itching
Nasal itching, sneezing, rhinorrheat, conjunctivitis
Mild, transient nausea, vomiting
Transient flushing, febrile, chilling sense
Headahce, dizziness, anxiety
Mild hypertension
Self-limiting vasovagal reaction
Moderate
Generalized urticarial, pruritus, angioedema, erythema
Facial edema, throat swelling, hoarseness
Bronchoconstriction without desaturation
Severe, persistent nausea, vomiting
Chest pain
Hypertensive urgency
Vasovagal reaction requiring treatment
Severe
Angioedema with dyspnea
Hypotension
Laryngeal edema with dyspnea
Bronchospasm with desaturation
Arrhythmia
Seizure
Hypertensive emergency
Vasovagal reaction unresponsive to treatment

17. Treatment of acute reaction
Physiologic reaction
Mostly mild in non-ionic RCM: self-limiting, rest & observation
Vomiting: metoclopramide in moderate-severe case
Hypersensitivity reaction
Mild pruritus, urticaria : self-limiting, rest & observation
Troublesome pruritus, urticarial : chlorpheniramine
Moderate-severe urticaria : chlorpheniramine, steroid
Angioedema: chlorpheniramine, steroid
Laryngeal edema with respiratory distress : airway patency, oxygen, chlorpheniramine, steroid, consider epinephrine
Bronchospasm: airway patency, oxygen, salbutamol nebulize, consider epinephrine
Anaphylaxis: epinephrine IM or SC, chlorpheniramine, steroid

18. Treatment of delayed reaction
Mostly cutaneous reaction
Drug eruption
- topical steroid for eruption
- antihistamines for pruritus
- systemic steroid for severe cases
Severe cutaneous reactions are also reported : SJS/TEN, DRESS, fixed drug eruption, etc.

19. 조영제 과민반응의 예방과 관리 피부반응시험은 예방에 도움이 되는가? 조영제 과민반응을 줄일 수 있는 전략
- 약물 전처치 및 조영제 선택

20. Skin test for prediction or diagnosis of RCM hypersensitivity

21. Outcomes of RCM prescreening skin tests before enhanced computed tomography
Kim SH et al. Ann Allergy Asthma Immunol, 2013

22. Results of post-adverse reaction skin tests according to the severity in patients with a history of RCM hypersensitivity reactions

23. Lesson from a case (F/63) #1. S-colon cancer
s/p laparoscopic AR (' )
s/p FOLFOX #12 (' ' )
#2. DM, Hypertension, VCA
# Previous history of exposure to RCM
Before Feb 2010: no reaction to RCM
CT in SNUBH: no reaction
CT in SNUBH: generalized urticaria, pruritis (immediate hypersensitivity reaction, culprit RCM - iopromide)
Skin test response was converted to positive
# Received contrast CT with the same RCM with premedication
(chlorpheniramine)
Cardiac arrest d/t anaphylaxis, recovered after 6 days of ICU admission

24. High skin test positivity in patients with previous RCM-induced anaphylactic shock
Kim MH et al. Plos One, 2014

25. Yoon SH et al. Allergy, 2015

26. Skin tests in RCM hypersensitivity
Conclusion
No clinical utility in predicting future hypersensitivity reactions
no previous exposure to RCM
previous exposure without RCM-associated reaction
history of mild RCM-associated reactions
Clinical value in diagnosing with RCM hypersensitivity
severe anaphylatic reaction > mild to moderate reaction
Positive skin test in patients with previous hypersensitivity reaction
- should not be ignored and use of alternative RCM with negative skin test response can lower the risk of severe adverse reaction

27. Risk factors of immediate hypersensitivity reactions to RCM
Patient-related
Previous moderate or severe acute reaction to an iodine-based contrast agent
Asthma
Allergy requiring medical treatment
Contrast-medium-related
High osmolality ionic contrast media

28. To reduce the risk of an immediate hypersensitivity reactions
For all patients
Use a non-ionic contrast medium.
Keep the patient in the Radiology Department for 30 min after contrast medium injection.
Have the drugs and equipment for resuscitation readily available
For patients at increased risk
- Consider an alternative test not requiring an iodine-based contrast agent.
- Use a different iodine-based agent for previous reactors to contrast medium.
Consider the use of premedication.

29. General principle of premedication
All patients with a history of moderate or severe immediate reaction to RCM
Selective patients with a history of mild reaction, other allergic disease, other drug hypersensitivity, asthma
But not all patients with previous hypersensitivity reaction to RCM
Most effective: corticosteroid + antihistamine
Corticosteroid
orally or intravenously, prednisolone 0.5 ~ 1.0 mg/kg
at least 4 ~ 6 hours prior to the injection of RCM
Antihistamine
orally or intravenously. IV chlorpheniramine
children mg/kg, adults - 4∼8 mg
at least 1 ~ 2 hours prior to the injection of RCM

30. Specific recommended premedication regimens from ACR guideline
Elective Premedication
Two frequently used regimens are:
Prednisone – 50 mg by mouth at 13 hours, 7 hours, and 1 hour before RCM injection, plus chlorpheniramine 4 mg IV, IM or PO hour before RCM injection
Methylprednisolone – 32 mg by mouth 12 hours and 2 hours before RCM injection. An anti-histamine (as in option 1) can also be added to this regimen injection
# If the patient is unable to take oral medication, 200 mg of hydrocortisone intravenously may be substituted for oral prednisone in the Greenberger protocol in 1980

31. Specific recommended premedication regimens from ACR guideline
Emergency Premedication (In Decreasing Order of Desirability)
Methylprednisolone 40 mg or hydrocortisone 200 mg IV q 4h until contrast study required plus chlorpheniramine 4 mg IV 1 hour prior to RCM injection
Dexamethasone 7.5 mg or betamethasone 6.0 mg IV q4h until contrast study must be done in patent with known allergy to methylprednisolone, aspirin, or non-steroidal anti-inflammatory drugs, especially if asthmatic. Also chlorpheniramine 4 mg IV 1 hour prior to contrast injection
3. Omit steroids entirely and give diphenhydramine 50 mg IV.
Note: IV steroids have not been shown to be effective when administered less than 4 to 6 hours prior to contrast injection.

32. Risk factors of non-immediate hypersensitivity reactions to RCM
Patient-related
- Previous late contrast medium reaction.
Interleukin-2 treatment
Contrast-medium-related
Use of nonionic dimers

33. Premedication for non-immediate hypersensitivity reaction to RCM
: generally not recommended
Patients with previous severe late reactions
: premedication with corticosteroid may be useful
e.g. oral medication with 50mg prednisone the day before and 25mg prednisone daily for 3 days after RCM exposure

34. Jung JW et al. Ann Allergy Asthma Immunol, 2016

35. Park HJ et al. Eur Radiol, 2017

36. Composite outcome of desirable behavior
Occurrence rate of hypersensitivity reactions
Yang MS et al. Allergy Asthma Immunol Res, 2017

37. RCM hypersensitivity prevention strategy in SNUBH allergy clinic
For high risk patients (previous reaction)
Acute mild reaction: chlorpheniramine 4 mg iv (1 hour before the study)
Acute moderate to severe reaction:
avoid RCM if possible.
use another RCM, if possible.
evaluate skin test if possible → use of RCM with negative skin test
premedication:
prednisolone 50 mg po. or equivalent dose of steroid iv
(13, 7 and 1 hours before the study)
+ chlorpheniramine 4 mg iv (1 hour before the study)
Delayed reaction: variable
Patient education

38. Summary Clinical features of RCM hypersensitivity have been changing.
Routine prescreening RCM skin test for all patients is not effective.
Identification of high risk patients by detailed history taking is important.
RCM skin test can be useful in patients with previous severe immediate hypersensitivity reaction.
Systematic approach using preventive measures can be beneficial in lowering the incidence of RCM adverse reaction.