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Iodinated Contrast Media Hypersensitivity

Iodinated Contrast Media Hypersensitivity

Presented by Puttatida Chetwong, MD.

November13, 2020

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Iodinated Contrast Media Hypersensitivity

  1. 1. Iodinated Contrast Media Hypersensitivity Puttatida Chetwong
  2. 2. Iodinated contrast media
  3. 3. Iodinated contrast media • ICM are iodine salts whose basic chemical structure comprises a benzene ring with at least 3 iodine atoms (triiodobenzene) • The iodine atoms being responsible for producing radiopacity • An ICM is ionic if it transforms into ions or charged particles in aqueous solution • The ionization capacity of a given medium is directly related to the frequency and severity of the adverse reaction. A Rosado Ingelmo, 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
  4. 4. Osmolality ICM can also be classified according to osmolality (the number of particles generated in solution) into • high-osmolality ICM (≥1400 mOsm/kg H2O) • low-osmolality ICM (500-900 mOsm/kg H2O) • isosmolar ICM(290 mOsm/kg H2O) A Rosado Ingelmo, 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
  5. 5. Viscosity • The viscosity of ICM is directly associated with the size of the molecule, the iodine concentration, and an increase in the frequency of delayed adverse effects. • However, since viscosity decreases with increasing temperature, it can be reduced by heating the ICM to body temperature (37°C) before administration A Rosado Ingelmo, 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
  6. 6. ICM can be classified into 4 categories based on their capacity for ionization and number of triiodobenzene rings • 1) Ionic monomers: salts comprising 1 negatively charged triiodinated benzene ring, together with a sodium and/or meglumine as a cation. Ionic monomers have the highest osmolality (>1400 mOsm/kg H2O) • 2) Ionic dimers, which consist of 2 triiodobenzene rings, contain a carboxyl radical, and have low osmolality (600 mOsm/kg H2O) • 3) Nonionic monomers, which are triiodinated compounds with hydrophilic hydroxyl groups. Nonionic monomers are second-generation agents and have low osmolality (500-850 mOsm/kg H20) • 4) Nonionic dimers, which contain 2 nonionic triiodinated benzene rings. Nonionic dimers have the lowest osmolality of all ICM (290 mOsm/kg H20) A Rosado Ingelmo, 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
  7. 7. Amipaque Hypaque Biliscopin Bilivist Conray Hexabrix Omnipaque Isovue Ultravist Optiray Imeron Xenetix Oxilan Imagopaque Visipaque Isovist Schönmann C. Ann Allergy Asthma Immunol. 2020 Feb;124(2):156-164.
  8. 8. American College of Radiology Manual on Contrast Media 2020.
  9. 9. American College of Radiology Manual on Contrast Media 2020.
  10. 10. IopamidolIobitridol Iohexol
  11. 11. Epidemiology
  12. 12. Epidemiology • The prevalence of allergic reactions to ICM is estimated to be 1:170 000, that is, 0.05%-0.1% of patients undergoing radiologic studies with ICM. • These percentages are generally higher for ionic ICM (0.16%-12.66%) than for nonionic ICM (0.03%-3%) • High-osmolality ICM were associated with a high incidence of immediate reactions • Reactions to ICM are usually mild to moderate A Rosado Ingelmo, 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. 13. • Anaphylactoid reactions occur inapproximately 1% to 3% of patients who receive ionic RCM and less than 0.5% of patients who receive nonionic RCM. Drug Allergy: An Updated Practice Parameter 2020
  14. 14. The overall prevalence of hypersensitivity reactions (HSRs) to iodinated contrast media (ICM) was 0.73% (1433 of 196 081), and severe reactions occurred in 0.01% (17 of 196 081) of patients. Radiology. 2019 Oct;293(1):117-124.
  15. 15. Reactions – immediate, non- immediate
  16. 16. Knut Brockow, Johannes Ring. Classification and pathophysiology of radiocontrast media hypersensitivity. Chem Immunol Allergy. 2010;95:157-169. Nonimmediate RCM hypersensitivity reactions usually have a mild to moderate severity and are self-limiting
  17. 17. • 104 cases of RCM induced anaphylaxis • Anaphylactic patients presenting with shock were older (57.4 vs. 50.1 years, p=0.026) and had a history of more frequently exposure to RCM (5.1-7.8 vs. 1.9-3.3, p=0.004) compared to those without hypotension. • Skin test positivity to RCM was 64.7% (patients with anaphylaxis) and 81.8% (patients with anaphylactic shock) PLoS One. 2014 Jun 16;9(6)
  18. 18. • Delayed reactions to RCM, defined as reactions occurring 1 hour to 1 week after administration, occur in approximately 2% patients. • Most are mild, self-limited cutaneous eruptions that appear to be T-cell mediated, although more serious reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS syndrome have been described. Drug Allergy: An Updated Practice Parameter 2020
  19. 19. Risk factors
  20. 20. Mario Sánchez-Borges, et al. Controversies in Drug Allergy: Radiographic Contrast Media. J Allergy Clin Immunol Pract. 2019 Jan;7(1):61-65. Risk factors for anaphylactoid reactions to RCM include • female sex • Atopy • concomitant use of beta-blocking drug • a history of previous reactions to RCM. Drug Allergy: An Updated Practice Parameter 2020
  21. 21. • Of a total of 205 726 exposures to LOCM in 86 328 patients, we detected 2004 immediate HSRs during the study period (incidence of 0.97%). • The incidence of mild, moderate, and severe reactions was 0.85%, 0.10%, and 0.02%, respectively. Lee SY. J Investig Allergol Clin Immunol. 2019;29(6):444-450.
  22. 22. 32,964 outpatients at the Mayo Clinic who were referred to the Department of Diagnostic Roentgenology for excretory urography during a 27 month period D M Witten. Am J Roentgenol Radium Ther Nucl Med, 119 (1973), pp. 832-840 MYTH
  23. 23. • Specific sensitivity to seafood (which is mediated by IgE directed to proteins) does not further increase this risk. • There is no evidence that sensitivity to iodine predisposes patients to RCM reactions. Drug Allergy: An Updated Practice Parameter 2020
  24. 24. Pathophysiology
  25. 25. Immediate hypersensitivity • The pathophysiology of IHR to contrast agents and dyes is not fully understood yet. • Histamine or tryptase release has been demonstrated in many cases, but this just indicates a mechanism of mast cell (or basophil) activation and not necessarily an immunoglobulin E (IgE)-mediated allergic reaction. • The pathophysiology of possible nonallergic mechanisms (eg, direct mast cell or basophil activation, complement activation, bradykinin formation) is not fully understood yet. Schönmann C, Brockow K. Adverse reactions during procedures Hypersensitivity to contrast agents and dyes. Ann Allergy Asthma Immunol. 2020 Feb;124(2):156-164.
  26. 26. Non-immediate hypersensitivity • Strong evidence exists for a T cell-mediated mechanism of NIHRs to ICM • Time of onset and type of skin eruptions • Presence of positive patch tests • Activated T cells in positive skin test sites • Positive lymphocyte transformation tests • In addition, the generation of ICM-specific T cell clones has been reported for NIHR to ICM. Schönmann C, Brockow K. Adverse reactions during procedures Hypersensitivity to contrast agents and dyes. Ann Allergy Asthma Immunol. 2020 Feb;124(2):156-164.
  27. 27. Cross-reactivity
  28. 28. S.H. Yoon, et al. Skin tests in patients with hypersensitivity reaction to iodinated contrast media: a meta-analysis. Allergy. 2015 Jun;70(6):625-37.
  29. 29. S.H. Yoon, et al. Skin tests in patients with hypersensitivity reaction to iodinated contrast media: a meta-analysis. Allergy. 2015 Jun;70(6):625-37.
  30. 30. Diagnosis
  31. 31. Schönmann C. Ann Allergy Asthma Immunol. 2020 Feb;124(2):156-164. Patients who only experienced 1 symptom, such as feeling of warmth or erythema on injection side, nausea, myalgia/arthralgia, paresthesia, headache, or dizziness most likely suffered from a toxicity- related adverse event
  32. 32. Brockow K, et al. Allergy. 2013 Jun;68(6):702-12. • Skin testing is recommended in the work-up of iodinated contrast media hypersensitivity (high/strong). • It is advisable to use a panel of ICM so as to identify cross-reactivity and safe alternatives • Skin prick tests and patch tests should be performed using undiluted solutions (high/strong). • For IDT, a 1/10 dilution of ICM is recommended, as undiluted contrast media may be irritating (weak/high) • In delayed reactions, both delayed reading IDT and patch test should be carried out to enhance sensitivity (moderate/high). False-negative skin tests in NIHRs do occur. Schönmann C. Ann Allergy Asthma Immunol. 2020 Feb;124(2):156-164.
  33. 33. • Retrospective evaluation clinical and diagnostic data from 45 consecutive patients with RCM hypersensitivity • Intradermal testing • At least 3 RCM (which are most commonly used by the radiologists in the geographical region of our allergy center) including the culprit RCM were tested in a 1:10 dilution of the original RCM preparation in physiological saline solution. • Readings at 15 minutes and on days 2, 3, and 4 Trautmann A, et al. J Allergy Clin Immunol Pract 2019; 7: pp. 2218-2224. • Iodine skin testing • In cases with a history of RCM- induced delayed-type MPE, prick and patch tests with iodine tincture and 2%Lugol’s solution were performed in addition to RCM intradermal testing • Intravenous RCM provocation • Provocation with a skin test-negative RCM was performed to exclude RCM allergy and to determine the reliability of a negative skin test result
  34. 34. Trautmann A, et al. J Allergy Clin Immunol Pract 2019; 7: pp. 2218-2224.
  35. 35. Trautmann A, et al. J Allergy Clin Immunol Pract 2019; 7: pp. 2218-2224. all 18 tested patients tolerated intravenous provocation with a skin test-negative RCM
  36. 36. • Anaphylaxis-like reactions occurring within minutes after injection of iodinated RCM may result from either nonallergic hypersensitivity or presumed genuine IgE- mediated allergy. • Nonallergic hypersensitivity reactions are generally mild, with symptoms remaining confined to the skin, and premedication is recommended to prevent future reactions. • Intradermal testing of RCM at dilutions of 1:10 may be an appropriate method for the diagnosis of RCM allergy. • Intravenous provocation with a skin test-negative RCM as final proof of tolerance appears safe in both delayed- and immediate-type RCM allergy and may someday become the gold standard of testing. Trautmann A, et al. J Allergy Clin Immunol Pract 2019; 7: pp. 2218-2224.
  37. 37. A case of a 28-year old female, who experienced an anaphylactic shock (generalized urticaria, angio-edema, dizziness, severe hypotension with immeasurable blood pressure during the first 30 minutes, and loss of consciousness) immediately after administration of iomeprol (Iomeron®) for cardiac computed tomography. Protocol 100 μL aliquots of endotoxin-free heparinised whole blood were stimulated with dilution buffer as a negative control, anti-IgE (10μg/mL) as a positive control and serial dilutions (stimulation concentration 10, 100 and 1000 μg/mL) of the iodinated contrast media. E Philipse. Acta Clin Belg. Mar-Apr 2013;68(2):140-2.
  38. 38. 1000 μg/mL stimulation concentration Advantages of BAT It allows multiple simultaneous evaluations without the risk of endangering the health of the patient. It can be performed almost immediately after the acute reaction, although it is currently recommended to postpone it up to 4 weeks after the acute event.
  39. 39. Drug Provocation Test • Intravenous drug provocation test (DPT) with a skin test-negative contrast agent has been increasingly described, but it is neither part of routine allergological workup yet nor standardized and validated. • Performing DPT may be considered especially in patients after severe anaphylaxis with a skin test-negative alternative contrast medium, because DPT has a higher sensitivity than skin testing alone. Schönmann C. Adverse reactions during procedures Hypersensitivity to contrast agents and dyes. Ann Allergy Asthma Immunol. 2020 Feb;124(2):156-164.
  40. 40. DPT - Protocol • Timing: the time interval since immediate-type reactions was at least 4 weeks, and recovery from MPE was at least 8 weeks ago • Incremental doses were given intravenously every 30 minutes. • Patients with a history of anaphylaxis received 0.05, 0.5, 1.0, 5.0, 7.5, 10.0, and 25.0 mL (total 49.05 mL). • Patients who reported a delayed-type reaction received 1.0, 5.0, 7.5, 10.0, and 25.0 mL (total 48.5 mL). • All patients were observed for at least 1 hour after the last injection and were advised to present for objective examination if any symptoms developed within the next days. Trautmann A, et al. Radiocontrast Media Hypersensitivity: Skin Testing Differentiates Allergy From Nonallergic Reactions and Identifies a Safe Alternative as Proven by Intravenous Provocation. J Allergy Clin Immunol Pract 2019; 7: pp. 2218-2224.
  41. 41. • Doses of 5, 15, 30, and 50 mL • at 30- to 45-minute intervals for immediate reactions • at 1-hour intervals for non-immediate reactions, with observation times at 3, 6, and 24 hours • There are no data to support that the procedure is safer than giving 1/10 and 9/10 of a target dose. • Furthermore, more than 3 doses may induce desensitization and provide a false sense of security. DPT - Protocol Mario Sánchez-Borges, et al. Controversies in Drug Allergy: Radiographic Contrast Media. J Allergy Clin Immunol Pract. 2019 Jan;7(1):61-65.
  42. 42. Premedication
  43. 43. Premedication • Premedication with corticosteroids, antihistamines, and sympathomimetics to prevent severe reactions to RCM was proposed by Greenberger and Patterson • In Europe the value of premedication is considered controversial, because it provides patients and physicians a false sense of security • Although it may be useful to reduce mild immediate nonallergic reactions, its efficacy for immediate moderate-to-severe and nonimmediate reactions has not been confirmed Mario Sánchez-Borges, et al. Controversies in Drug Allergy: Radiographic Contrast Media. J Allergy Clin Immunol Pract. 2019 Jan;7(1):61-65.
  44. 44. P A Greenberger, R Patterson. The prevention of immediate generalized reactions to radiocontrast media in high-risk patients. J Allergy Clin Immunol 1991; 87: pp. 867-872.
  45. 45. • Patients who experienced previous anaphylactoid reactions to RCM should receive nonionic, iso-osmolar agents and be treated with a premedication regimen, including systemic corticosteroids and histamine1re-ceptor antihistamines; this will significantly reduce, but not eliminate, the risk of anaphylactoid reaction with re-exposure to contrast material. Drug Allergy: An Updated Practice Parameter 2020
  46. 46. แนวทางเวชปฏิบัติสาหรับผู้ป่วยที่มีการแพ้ชนิดรุนแรง 2560
  47. 47. American College of Radiology Manual on Contrast Media 2020.
  48. 48. Indications for Premedication American College of Radiology Manual on Contrast Media 2020.
  49. 49. American College of Radiology Manual on Contrast Media 2020.
  50. 50. • No premedication strategy is a substitute for pre-administration preparedness. • Contrast reactions occur despite premedication [34], and radiology teams must be prepared to treat breakthrough reactions when they occur. • Patients should receive information concerning their risk of a reaction according to local policy and practice. American College of Radiology Manual on Contrast Media 2020.
  51. 51. Schönmann C. Ann Allergy Asthma Immunol. 2020 Feb;124(2):156-164.
  52. 52. Special Condition Myasthenia gravis
  53. 53. Intravenous administration of low-osmolality iodinated contrast material is associated with a significant increase (P = .01) in the frequency of acute (less than 1 day) disease-related symptoms in patients with myasthenia gravis (6.3% with contrast-enhanced CT [seven of 112 patients; 95% CI: 0.03, 0.12] vs 0.6% with unenhanced CT [one of 155 patients; 95% CI: 0.0002, 0.04]) Radiology. 2013 Jun;267(3):727-34.
  54. 54. Khandelwal A, Shamim R, Supriya. Low – osmolality contrast agents - A risk for myasthenics. Neurol India 2016;64:558-9 A case of acute exacerbation of myasthenic symptoms immediately after the administration of low- osmolality iodinated contrast agent in a 41-year female patient scheduled for a contrast-enhanced computed tomography (CECT) scan of the thorax for detection of a thymoma. Presented to our hospital with chief complaints of drooping of eyelids (right > left), diplopia, dysphagia, nasal intonation of voice, and easy fatigability since 5 months Her clinical signs and symptoms along with the significant elevation of acetylcholine receptor antibodies and repetitive nerve stimulation were consistent with the diagnosis of myasthenia gravis.
  55. 55. She was subsequently scheduled for contrast enhanced computed tomogram (CECT) of the thorax for screening of the thymoma. She was stable prior to the computed tomographic scan. However, immediately following administration of approximately 50 ml of iodinated contrast agent (Ultravist 370), she developed new onset acute respiratory distress, stridor, restlessness, tachycardia and desaturation. The blood pressure did not fluctuate, and there were no skin rashes. Management Supplemental oxygen administered through the face mask did not improve her oxygen saturation. She was intubated after administering 50 mg of intravenous propofol alone and admitted to the Intensive Care Unit where mechanical ventilation was initiated. She was treated with steroids and intravenous immunoglobulin and was comfortably weaned off and extubated on the 3rd day. Khandelwal A, Shamim R, Supriya. Low – osmolality contrast agents - A risk for myasthenics. Neurol India 2016;64:558-9
  56. 56. A 48-year-old Sinhalese man diagnosed as having myasthenia gravis, was evaluated for progressive dysphagia with an upper gastrointestinal contrast study. Iodinated contrast material (iohexol) was used as the contrast medium and there was direct evidence of contrast aspiration during the study. Several minutes after the procedure, severe respiratory distress with evidence of myasthenic crisis requiring intubation and intensive care admission was noted. Treatment with intravenous immunoglobulin, high-dose steroids, and broad-spectrum intravenously administered antibiotics led to an uneventful recovery, although the latter part of the clinical course was complicated with total left lung collapse. Respiratory support was graduallyreduced over 72-hour period. J Med Case Rep. 2019 May 31;13(1):166.
  57. 57. A patient with poorly-controlled symptoms of myasthenia gravis was administered intravenous contrast during computed tomography (CT) pulmonary angiogram. 70 ml of Ultravist® 370 (iopromide) contrast solution was administered and the CTPA was completed. Approximately, seven minutes following contrast administration, the patient became nauseated and acutely hypoxic, with saturations of 90% on six litres of oxygen by mask. About four minutes later, she became drowsy, and a minute later developed respiratory arrest and was intubated on the CT table. Hemodynamic stability was maintained throughout with pulse rate of 115 beats per minute and blood pressure of 160/70 mmHg. A further CT head did not find acute intracranial abnormality. No rashes or other skin changes were noted. Ngan DKY. Moon HH. Contrast-provoked myasthenic crisis: A case report and review of literature. Case Rep Int 2018;7:100049Z06DN2018.
  58. 58. Myasthenic exacerbation was suspected, and subsequent assessment by the neurology team in the intensive care unit found mild bilateral fatigable ptosis with full preservation of extraocular movements, as well as mild to moderate neck flexion weakness. No limb weakness was present. Nerve conduction studies were performed and induced an approximate 20% early decrement in compound muscle action potential, consistent with myasthenia crisis. Her serum azathioprine level was found to be subtherapeutic and she was instead prescribed mycophenolate mofetil with improvement. She remained intubated for six days. Her ptosis resolved completely during admission, and she was discharged with outpatient follow-up. Ngan DKY. Moon HH. Contrast-provoked myasthenic crisis: A case report and review of literature. Case Rep Int 2018;7:100049Z06DN2018.

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