Radiocontrast media hypersensitivity Presented by Athit Wutthisanwatthana, MD. October25, 2019

1. Radiographic Contrast Media
Hypersensitivity
A Wutthisanwatthana

2. Outline
• Overview of radiographic contrast media
• Epidemiology
• Risk factors
• Symptoms
• Pathophysiology
• Diagnosis
• Prophylaxis

3. Radiographic Contrast Media

4. Radiographic Contrast Media
• Positive contrast agent
• Water-soluble iodine-based agents
• Non-water-soluble barium agents
• Negative contrast agent
• Other contrast agents
• MR contrast agents
• Gadolinium-based contrast agents
• Ultrasound contrast agents
Thomsen HS, Bellini MF, Jakobsen JA ̊, Webb JAW. Contrast media classification and terminology. In: Thomsen HS, Webb JAW. Contrast media safety issues and ESUR
guidelines. Berlin; Springer; 2014. 3-11

5. Water-Soluble Iodine-Based Agents
• Iodine (53I) produces the radiopacity
• Other portions of the molecule
• Carriers for the iodine
• Improving solubility
• Reducing the toxicity
Thomsen HS, Reimer P. Intravascular contrast media for radiography, CT, MRI and ultrasound. In: Adam A, Adrian K, Gillard J, Schaefer-Prokop C. Grainger & Allison’s
Diagnostic Radiology, sixth edition. Elsevier. 2015

6. Triiodobenzene
• C6H3I3
• Very hydrophilic
• Low lipid solubility
• Low toxicity
• Low binding affinities for
protein, receptors or
membranes
• Molecular weights <2000
National Center for Biotechnology Information. PubChem Database. 1,3,5-Triiodobenzene, CID=12282, https://pubchem.ncbi.nlm.nih.gov/compound/1_3_5-
Triiodobenzene
Thomsen HS, Reimer P. Intravascular contrast media for radiography, CT, MRI and ultrasound. In: Adam A, Adrian K, Gillard J, Schaefer-Prokop C. Grainger & Allison’s
Diagnostic Radiology, sixth edition. Elsevier. 2015

7. Yeh BM, FitzGerald PF, Edic PM, Lambert JW, Colborn RE, Marino ME, et a. Opportunities for new CT contrast agents to maximize the diagnostic potential of emerging
spectral CT technologies. Adv Drug Deliv Rev. 2017 Apr;113:201-222

8. Thomsen HS, Bellini MF, Jakobsen JA ̊, Webb JAW. Contrast media classification and terminology. In: Thomsen HS, Webb JAW. Contrast media safety issues and ESUR
guidelines. Berlin; Springer; 2014. 3-11
Rosado IA, Doña DI, Cabañas MR, Moya QMC, García-Avilés C, García NI, et al. Clinical Practice Guidelines for Diagnosis and Management of Hypersensitivity Reactions
to Contrast Media. J Investig Allergol Clin Immunol. 2016;26(3):144-55
≥1400 mOsm/kg H2O 500-900 mOsm/kg H2O 290 mOsm/kg H2O

9. Thomsen HS, Bellini MF, Jakobsen JA ̊, Webb JAW. Contrast media classification and terminology. In: Thomsen HS, Webb JAW. Contrast media safety issues and ESUR
guidelines. Berlin; Springer; 2014. 3-11

10. Thomsen HS, Bellini MF, Jakobsen JA ̊, Webb JAW. Contrast media classification and terminology. In: Thomsen HS, Webb JAW. Contrast media safety issues and ESUR
guidelines. Berlin; Springer; 2014. 3-11

11. Contrast agent ratio =
number of iodine atoms
number of particles in solution
Thomsen HS, Bellini MF, Jakobsen JA ̊, Webb JAW. Contrast media classification and terminology. In: Thomsen HS, Webb JAW. Contrast media safety issues and ESUR
guidelines. Berlin; Springer; 2014. 3-11

12. Viscosity
• A function of solution concentration, molecular shape, and weak
interactions among the contrast agents and water molecules,
including contrast media self-association
• ↑delayed adverse effects
Thomsen HS, Bellini MF, Jakobsen JA ̊, Webb JAW. Contrast media classification and terminology. In: Thomsen HS, Webb JAW. Contrast media safety issues and ESUR
guidelines. Berlin; Springer; 2014. 3-11
Rosado IA, Doña DI, Cabañas MR, Moya QMC, García-Avilés C, García NI, et al. Clinical practice guidelines for diagnosis and management of hypersensitivity reactions
to contrast media. J Investig Allergol Clin Immunol. 2016;26(3):144-55

13. Thomsen HS, Bellini MF, Jakobsen JA ̊, Webb JAW. Contrast media classification and terminology. In: Thomsen HS, Webb JAW. Contrast media safety issues and ESUR
guidelines. Berlin; Springer; 2014. 3-11

14. Pharmacology
• Redistributed rapidly via capillary permeability to the extravascular
space
• Do not enter the interior of blood or tissue cells
• Excretion
• Renal 80% after 4 h, 98% after 24 h
• <1% via bile
Thomsen HS, Reimer P. Intravascular contrast media for radiography, CT, MRI and ultrasound. In: Adam A, Adrian K, Gillard J, Schaefer-Prokop C. Grainger & Allison’s
Diagnostic Radiology, sixth edition. Elsevier. 2015
Rathmell JP. Radiation safety and use of radiographic contrast agents in pain medicine. In: Benzon H, Rathmell J. Christopher L, Turk D, Argoff C, Hurley R. Practical
management of pain. Elsevier; 2014

15. Epidemiology

16. Brockow K, Christiansen C, Kanny G, Clément O, Barbaud A, Bircher A. Management of hypersensitivity reactions to iodinated contrast media. Allergy. 2005
Feb;60(2):150-8
Nephrotoxicity, neurotoxicity

17. Epidemiology
• 75 million procedures per year worldwide
• Immediate hypersensitivity reactions
• 0.7%-3% of nonionic RCM
• 0.02%-0.04% severe reaction
• 0.00001%-0.003% fatal
• Nonimmediate hypersensitivity reaction 0.5%-3%
• Higher incidence in dimeric nonionic RCM
Brockow K, Sánchez-Borges M. Hypersensitivity to contrast media and dyes. Immunol Allergy Clin North Am. 2014 Aug;34(3):547-64

18. Cochran ST, Bomyea K, Sayre JW. Trends in adverse events after IV administration of contrast media. AJR Am J Roentgenol. 2001 Jun;176(6):1385-8

19. • >90% allergic like reaction (sneezing and nasal congestion; hives,
itching, rash, and swelling)
• 0.02-0.05% severe reaction
• 2 deaths
• Intraventricular hemorrhage
• Ventricular fibrillation
Cochran ST, Bomyea K, Sayre JW. Trends in adverse events after IV administration of contrast media. AJR Am J Roentgenol. 2001 Jun;176(6):1385-8

20. Risk Factors

21. Risk Factors for Hypersensitivity Reaction to RCM
Sánchez-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 Jan;7(1):61-65
Brockow K, Sánchez-Borges M. Hypersensitivity to contrast media and dyes. Immunol Allergy Clin North Am. 2014 Aug;34(3):547-64
Renal insufficiency, food allergy, contact allergy (for NIHRs), and interleukin-2 treatment (for NIHRs)

22. Symptoms

23. Katayama H, Yamaguchi K, Kozuka T, Takashima T, Seez P, Matsuura K. Adverse reactions to ionic and nonionic contrast media. A report from the Japanese Committee
on the Safety of Contrast Media. Radiology. 1990 Jun;175(3):621-8
Adverse Drug Reactions

24. Time of Onset of ADR
Katayama H, Yamaguchi K, Kozuka T, Takashima T, Seez P, Matsuura K. Adverse reactions to ionic and nonionic contrast media. A report from the Japanese Committee
on the Safety of Contrast Media. Radiology. 1990 Jun;175(3):621-8

25. Nonimmediate Hypersensitivity Reaction
• Maculopapular exanthems
• Fixed drug eruption
• Erythema multiforme
• Pompholyx (dyshidrotic eczema)
• Symmetric drug-related intertriginous and flexural examthema
• DRESS
• Vasculitis
• SJS, TEN
• Anaphylactoid manifestations such as hypotension, fever, abdominal pain,
dyspnea
Brockow K, Sánchez-Borges M. Hypersensitivity to contrast media and dyes. Immunol Allergy Clin North Am. 2014 Aug;34(3):547-64

26. Time of Onset of ADR
Brockow K, Romano A, Aberer W, Bircher AJ, Barbaud A, Bonadonna P. Skin testing in patients with hypersensitivity reactions to iodinated contrast media - a European
multicenter study. Allergy. 2009 Feb;64(2):234-41

27. Pathophysiology

28. Sánchez-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 Jan;7(1):61-65
• Activation of the complement system
• Direct bradykinin formation

29. Immediate Reactions – IgE-Mediated
• Specific IgE to ionic RCM
• Higher level than control (moderate-to-severe immediate reaction)
• 43% in history of past reactions, 16.2% within 24 h
• Positive skin test results for patients with severe immediate reactions
• Positive basophil activation test
• Severe cardiovascular reactions to low amount (0.5-1 mL) of contrast
media
Brockow K. Immediate and delayed reactions to radiocontrast media: is there an allergic mechanism? Immunol Allergy Clin North Am. 2009 Aug;29(3):453-68

30. Skin Test
• Positive skin tests were observed in 32 of 122 patients (26%)
• Positive SPT 4/122
• Positive ID
• 30/121 patients (25%) after 20 min
• 3/121 patients (2.5%) when read after 10–24 h
Brockow K, Romano A, Aberer W, Bircher AJ, Barbaud A, Bonadonna P. Skin testing in patients with hypersensitivity reactions to iodinated contrast media - a European
multicenter study. Allergy. 2009 Feb;64(2):234-41

31. Brockow K. Immediate and delayed reactions to radiocontrast media: is there an allergic mechanism? Immunol Allergy Clin North Am. 2009 Aug;29(3):453-68

32. Immediate Reactions
• Higher histamine release after incubation with mast cells, basophil
• HOCM > LOCM
• Complement system
• ↓CH50 in the presence of RCM (in vitro)
• ↑C3a and C4a in a fraction of patients with immediate life-threatening
reactions to RCM
• Bradykinin
• Ionic and nonionic contrast media inhibit kininase II (in vitro)
Brockow K. Immediate and delayed reactions to radiocontrast media: is there an allergic mechanism? Immunol Allergy Clin North Am. 2009 Aug;29(3):453-68

33. Sánchez-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 Jan;7(1):61-65
• Histopathology identical to other drugs
• Dermal lymphocyte-rich infiltrate
• Intraepidermal spongiosis
• Hydropic degeneration of the basal cell layer

34. Torres MJ, Mayorga C, Cornejo-Garcia JA, Lopez S, Chaves P, Rondon C. Monitoring non-immediate allergic reactions to iodine contrast media. Clin Exp Immunol. 2008
May; 152(2): 233–8
• Mainly CD4+, CD8+ (CD45RO+) T cells
• Moderate CD25 expression
• High HLA-DR, CLA, CD69 expression

35. Nonimmediate Reactions
• Contrast medium-specific T cells
• Enhanced in vitro proliferation of PBMCs
• Flow cytometric analysis
• CD4+: CD69, CD25, HLA-D
• CD8+: Perforin
Brockow K. Immediate and delayed reactions to radiocontrast media: is there an allergic mechanism? Immunol Allergy Clin North Am. 2009 Aug;29(3):453-68

36. Diagnosis

37. Skin Testing
Readings
SPT 20 min, day 2 or 3
ID 20 min, day 1, day 2, day 3
Patch test after 2 day  15 min and 24 h after removal
Brockow K, Romano A, Aberer W, Bircher AJ, Barbaud A, Bonadonna P. Skin testing in patients with hypersensitivity reactions to iodinated contrast media - a European
multicenter study. Allergy. 2009 Feb;64(2):234-41
• 12 centers
• 220 patients with immediate or nonimmediate reactions
• Jan 2003 – Dec 2006

38. Sánchez-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 Jan;7(1):61-65
Skin Test Concentrations

39. Brockow K, Romano A, Aberer W, Bircher AJ, Barbaud A, Bonadonna P. Skin testing in patients with hypersensitivity reactions to iodinated contrast media - a European
multicenter study. Allergy. 2009 Feb;64(2):234-41
Overall Positivity 26% (SPT 3.3%, ID 25%)
Positivity 50% (2-6 months)
Specificity 96.3%
Overall Positivity 38% (delay SPT 3%, ID 32%, PT 22%)
Positivity 47% (within 6 months)
Specificity 100%

40. Brockow K, Romano A, Aberer W, Bircher AJ, Barbaud A, Bonadonna P. Skin testing in patients with hypersensitivity reactions to iodinated contrast media - a European
multicenter study. Allergy. 2009 Feb;64(2):234-41

41. Brockow K, Romano A, Aberer W, Bircher AJ, Barbaud A, Bonadonna P. Skin testing in patients with hypersensitivity reactions to iodinated contrast media - a European
multicenter study. Allergy. 2009 Feb;64(2):234-41

42. Skin test cross-reactivity in patients with IHR
N-(2,3-dihydroxypropyl) carbamoyl side chain
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 Jul - Aug;6(4):1246-54

43. Skin test cross-reactivity in patients with IHR
N-(2,3-dihydroxypropyl) carbamoyl side chain
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 Jul - Aug;6(4):1246-54

44. Basophil Activation Test
• Detect basophil activation markers
(CD45, CD18, and CD63)
• Not widely available and needs to be
validated
Salas M, Gomez F, Fernandez TD, Doña I, Aranda A, Ariza A. Diagnosis of immediate hypersensitivity reactions to radiocontrast media. Allergy. 2013 Sep;68(9):1203-6
Rosado IA, Doña DI, Cabañas MR, Moya QMC, García-Avilés C, García NI, et al. Clinical practice guidelines for diagnosis and management of hypersensitivity reactions
to contrast media. J Investig Allergol Clin Immunol. 2016;26(3):144-55
62.5% positive BAT

45. Lymphocyte Transformation Test
• Ability of T cells to proliferate upon contact with ICM
• Stimulation index (SI) = ratio between the mean values of counts per
minute obtained in cultures with drug and those obtained in cultures
without drug.
• SI ≥2.0  positive
• Sensitivity 13-75%
Torres MJ, Mayorga C, Cornejo-Garcia JA, Lopez S, Chaves P, Rondon C. Monitoring non-immediate allergic reactions to iodine contrast media. Clin Exp Immunol. 2008
May; 152(2): 233–8
Rosado IA, Doña DI, Cabañas MR, Moya QMC, García-Avilés C, García NI, et al. Clinical practice guidelines for diagnosis and management of hypersensitivity reactions
to contrast media. J Investig Allergol Clin Immunol. 2016;26(3):144-55

46. Drug Provocation Test
Yocum MW, Heller AM, Abels RI. Efficacy of intravenous pretesting and antihistamine prophylaxis in radiocontrast media--sensitive patients. J Allergy Clin Immunol.
1978 Nov;62(5):309-13
Ex. 5, 15, 30, and 50 mL
Immediate reations
• At 30- to 45-minute intervals
Nonimmediate reactions
• At 1-hour intervals, with observation times at 3, 6, and 24
hours
No data to support that the procedure is safer than giving 1/10
and 9/10 of a target dose

47. Drug Provocation Test
Ex. 5, 15, 30, and 50 mL
Immediate reations
• At 30- to 45-minute intervals
Nonimmediate reactions
• At 1-hour intervals, with observation times at 3, 6, and 24 hours
No data to support that the procedure is safer than giving 1/10 and 9/10 of a target dose
Severe systemic reactions
1. 5, 10 and 15 cc of CM
2. 20, 30 and 50 cc one week later
Sánchez-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 Jan;7(1):61-65
Torres MJ, Gomez F, Doña I, Rosado A, Mayorga C, Garcia I, Blanca-Lopez N, Canto G, Blanca M. Diagnostic evaluation of patients with nonimmediate cutaneous
hypersensitivity reactions to iodinated contrast media. Allergy. 2012 Jul;67(7):929-35

48. Sánchez-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 Jan;7(1):61-65
SPT

49. Sánchez-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 Jan;7(1):61-65

50. Rosado IA, Doña DI, Cabañas MR, Moya QMC, García-Avilés C, García NI, et al. Clinical practice guidelines for diagnosis and management of hypersensitivity reactions
to contrast media. J Investig Allergol Clin Immunol. 2016;26(3):144-55

51. Premedication

52. Premedication
Greenberger PA, Patterson R. Adverse reactions to radiocontrast media. Prog Cardiovasc Dis. 1988 Nov-Dec;31(3):239-48
Greenberger PA, Patterson R. The prevention of immediate generalized reactions to radiocontrast media in high-risk patients. J Allergy Clin Immunol. 1991
Apr;87(4):867-72

53. Greenberger PA, Patterson R. The prevention of immediate generalized reactions to radiocontrast media in high-risk patients. J Allergy Clin Immunol. 1991
Apr;87(4):867-72

54. Greenberger PA, Patterson R. The prevention of immediate generalized reactions to radiocontrast media in high-risk patients. J Allergy Clin Immunol. 1991
Apr;87(4):867-72

55. Benefits
• ↓immediate adverse events in HOCM
• ↓mild immediate adverse events LOCM
• Underpowered to evaluate the effect on moderate and severe reactions
• NNT = 69 for any severity
• NNT = 569 for severe reaction
ACR committee on drugs and contrast media. ACR manual on contrast media version 10.3. 2018

56. Regimen - Elective
• Corticosteroid
• Prednisolone 50 mg PO at 13 h, 7 h, 1 h before
• Hydrocortisone 200 mg IV
• Methylprednisolone 32 mg PO at 12 h, 2 h before
• Diphenhydramine 50 mg IV/IM/PO at 1 h before
ACR committee on drugs and contrast media. ACR manual on contrast media version 10.3. 2018

57. Regimen - Accelerated
1. Methylprednisolone 40 mg IV OR stat then q 4 h
Hydrocortisone 200 IV
Diphenhydramine 50 mg IV 1 h before
2. Dexamethasone 7.5 mg IV stat then q 4 h
Diphenhydramine 50 mg IV 1 h before
3. Methylprednisolone 40 mg IV OR 1 h before
Hydrocortisone 200 IV
Diphenhydramine 50 mg IV 1 h before
ACR committee on drugs and contrast media. ACR manual on contrast media version 10.3. 2018

58. Morzycki A, Bhatia A, Murphy KJ. Adverse Reactions to Contrast Material: A Canadian Update. Can Assoc Radiol J. 2017 May;68(2):187-93

59. แนวทางเวชปฏิบัติสาหรับการดูแลผู้ป่วยที่มีการแพ้ชนิดรุนแรง พ. ศ. 2560

60. Breakthrough Reactions
• Exposure to ICM more than 4 times HR 1.834 (1.204-2.792)
• Age younger than 50 years HR 1.662 (1.183-2.335)
• Severe index reaction HR 1.509 (1.384-4.921)
• Injection of the same ICM agent that caused the prior reaction
HR 1.405 (1.258-1.637)
Bellin MF, Stacul F, Webb JA, Thomsen HS, Morcos SK, Almén T, et al; Contrast Media Safety Committee of European Society of Urogenital Radiology (ESUR). Late
adverse reactions to intravascular iodine based contrast media: an update. Eur Radiol. 2011 Nov;21(11):2305-10

61. Nonimmediate Reaction Prophylaxis
• Unclear value
• Not necessarily protect against a repeat reaction
• Case report use of 6-α-methylprednisolone and cyclosporine 1 week
before and 2 weeks after four angiograms in a patent with MP rash1
Bellin MF, Stacul F, Webb JA, Thomsen HS, Morcos SK, Almén T, et al; Contrast Media Safety Committee of European Society of Urogenital Radiology (ESUR). Late
adverse reactions to intravascular iodine based contrast media: an update. Eur Radiol. 2011 Nov;21(11):2305-10
1Romano A, Artesani MC, Andriolo M, Viola M, Pettinato R, Vecchioli-Scaldazza A. Effective prophylactic protocol in delayed hypersensitivity to contrast media: report
of a case involving lymphocyte transformation studies with different compounds. Radiology. 2002 Nov;225(2):466-70

62. Iodine and Radiocontrast Media
Scherer K, Harr T, Bach S, Bircher AJ. The role of iodine in hypersensitivity reactions to radio contrast media.
Clin Exp Allergy. 2010 Mar;40(3):468-75