Hypersensitivity Reaction To Iodinated Contrast Media

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Hypersensitivity Reaction To Iodinated Contrast Media

  1. 1. Hypersensitivity reaction to iodinated contrast media Thatchai Kampitak 20 May 2009
  2. 2. Scope <ul><ul><li>Contrast media </li></ul></ul><ul><ul><li>hypersensitivity reaction (immediate & delayed) </li></ul></ul><ul><ul><ul><li>Prevalence </li></ul></ul></ul><ul><ul><ul><li>Clinical manifestation </li></ul></ul></ul><ul><ul><ul><li>Pathophysiology </li></ul></ul></ul><ul><ul><ul><li>Diagnosis </li></ul></ul></ul><ul><ul><ul><li>Treatment </li></ul></ul></ul><ul><ul><ul><li>Prevention </li></ul></ul></ul>
  3. 3. Introduction <ul><ul><li>Iodinated contrast media (ICM) are one of the most common prescribed drugs in the world </li></ul></ul><ul><ul><li>More than 75 million CM-enhanced X-ray procedures are conducted yearly worldwide </li></ul></ul><ul><ul><li>Hypersensitivity reactions, although uncommon, may occur and can be fatal </li></ul></ul>
  4. 4. <ul><ul><li>Pathophysiology still remains unclear </li></ul></ul><ul><ul><li>Diagnosis is mainly based on clinical history due to lack of reliable diagnostic methods </li></ul></ul><ul><ul><li>Premedication remains controversial </li></ul></ul>
  5. 5. Iodinated contrast media <ul><ul><li>ICM were introduced for radiographic image enhancement since 1920 in bi-iodinated form </li></ul></ul><ul><ul><li>ICM containing tri-iodinated compound were introduced in 1950 </li></ul></ul><ul><ul><li>Low osmolar ICM were developed in 1960 </li></ul></ul><ul><ul><li>Non-ionic low osmolar ICM were developed in 1980 </li></ul></ul>Idee JM et al. Fundam Clin Pharmacol 2005;19:263-81
  6. 6. Gueant-Rodriguez RM et al. Curr Pharm Des 2006;12:3359-72
  7. 7. Idee JM et al. Fundam Clin Pharmacol 2005;19:263-81
  8. 8. Christensen C In Pichler WJ Drug hypersensitivity 2007
  9. 9. Pharmacokinetic <ul><ul><li>MW of ICM range between 750-850 for monomers and twice higher for dimers </li></ul></ul><ul><ul><li>ICM usually contain 270-400 mg iodine/mL </li></ul></ul><ul><ul><li>70% of ICM is cleared from plasma within 2-5 minutes after injection </li></ul></ul><ul><ul><li>Half life is about 1-2 hours and 75% is excreted in urine within 4 hours </li></ul></ul>Idee JM et al. Fundam Clin Pharmacol 2005;19:263-81 Gueant-Rodriguez RM et al. Curr Pharm Des 2006;12:3359-72
  10. 10. Brockow K et al. Allergy 2005;60:150-8
  11. 11. Immediate hypersensitivity reaction
  12. 12. Prevalence <ul><ul><li>Death rates are not different between ionic and non-ionic ICM </li></ul></ul><ul><ul><li>Estimated mortality rate is 1-3/100,000 examinations </li></ul></ul>Gueant-Rodriguez RM et al. Curr Pharm Des 2006;12:3359-72
  13. 13. Clinical manifestations <ul><ul><li>Most symptoms are apparent within 5-15 minutes after ICM administration and disappear within 30-60 minutes </li></ul></ul><ul><ul><li>Severe and fatal reactions are reported to occur immediately to 30 minutes </li></ul></ul>Brockow K et al. Allergy 2005;60:150-8 Idee JM et al. Fundam Clin Pharmacol 2005;19:263-81 Christensen C In Pichler WJ Drug hypersensitivity 2007
  14. 14. Brockow K et al. Allergy 2005;60:150-8
  15. 15. Risk factors <ul><ul><li>History of previous reaction to ICM </li></ul></ul><ul><ul><ul><li>OR 2.04 </li></ul></ul></ul><ul><ul><ul><li>21-60% risk of a repeat reaction when re-exposed to the same or a similar ionic CM </li></ul></ul></ul><ul><ul><li>History of allergy </li></ul></ul><ul><ul><ul><li>Asthma is the most important predisposing factor for severe reaction (OR 5.1) </li></ul></ul></ul><ul><ul><ul><li>No evidence that seafood allergy predispose to the reactions </li></ul></ul></ul>Idee JM et al. Fundam Clin Pharmacol 2005;19:263-81 Gueant-Rodriguez RM et al. Curr Pharm Des 2006;12:3359-72
  16. 16. <ul><ul><li>Age </li></ul></ul><ul><ul><ul><li>Higher prevalence in younger age groups but predominant of severe reactions in the older age groups </li></ul></ul></ul><ul><ul><li>Concomitant treatment with IL-2 or  -blocker </li></ul></ul><ul><ul><li>History of cardiac diseases </li></ul></ul><ul><ul><li>Female gender </li></ul></ul><ul><ul><li>Dose and rate </li></ul></ul><ul><ul><li>Route </li></ul></ul><ul><ul><ul><li>Intravenous > intraarterial </li></ul></ul></ul><ul><ul><li>Anxiety </li></ul></ul>Idee JM et al. Fundam Clin Pharmacol 2005;19:263-81 Gueant-Rodriguez RM et al. Curr Pharm Des 2006;12:3359-72
  17. 17. Pathophysiology <ul><ul><li>Unclear </li></ul></ul><ul><ul><li>Multifactorial </li></ul></ul><ul><ul><li>Associated with histamine release from mast cells and basophils </li></ul></ul><ul><ul><ul><li>Direct membrane effect related to the osmolarity or chemical structure of ICM </li></ul></ul></ul><ul><ul><ul><li>Activation of the complement system </li></ul></ul></ul><ul><ul><ul><li>IgE-mediated mechanism </li></ul></ul></ul>Brockow K et al. Allergy 2005;60:150-8
  18. 18. Szebeni J. Curr Allergy Asthma Rep 2004;4:25-30
  19. 19. Chemotoxic effect <ul><ul><li>Histamine release may be resulted from NHCO group, size, complexity and iodine concentration of ICM </li></ul></ul><ul><ul><li>ICM might inhibit acetylcholinesterase enzyme which leads to side effects such as flushing, bronchospasm, urticaria and abdominal pain </li></ul></ul>Gueant-Rodriguez RM et al. Curr Pharm Des 2006;12:3359-72
  20. 20. Osmolality <ul><ul><li>Discrepant results have been shown in histamine release </li></ul></ul><ul><ul><li>ICM with comparable osmolalities can induce different levels of histamine release </li></ul></ul>Gueant-Rodriguez RM et al. Curr Pharm Des 2006;12:3359-72
  21. 21. Complement activation <ul><ul><li>Decrease in CH 50 have been shown after ICM exposure </li></ul></ul><ul><ul><li>Increase of blood histamine and complement activation have been shown in both reactors and non-reactors to ICM without any difference </li></ul></ul><ul><ul><li>ICM may induce activation of coagulation and kinin-kallikrein system </li></ul></ul>Gueant-Rodriguez RM et al. Curr Pharm Des 2006;12:3359-72
  22. 22. IgE-mediated mechanism Idee JM et al. Fundam Clin Pharmacol 2005;19:263-81
  23. 23. Diagnosis <ul><ul><li>During of immediate after the reaction </li></ul></ul><ul><ul><ul><li>Serum histamine and tryptase </li></ul></ul></ul><ul><ul><ul><ul><li>Elevate in some patients with severe or fatal reactions </li></ul></ul></ul></ul>Brockow K et al. Allergy 2005;60:150-8
  24. 24. <ul><ul><li>After recovery </li></ul></ul><ul><ul><ul><li>Skin test </li></ul></ul></ul><ul><ul><ul><ul><li>Positive tests were rarely reported and only in patients with severe reactions </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Standardization is not yet established </li></ul></ul></ul></ul><ul><ul><ul><li>Specific IgE </li></ul></ul></ul><ul><ul><ul><ul><li>No commercial assay is available </li></ul></ul></ul></ul><ul><ul><ul><li>Basophil activation test </li></ul></ul></ul><ul><ul><ul><ul><li>Not widely available and no defined standardization </li></ul></ul></ul></ul><ul><ul><ul><li>Provocation test </li></ul></ul></ul><ul><ul><ul><ul><li>May induce severe reactions in high risk patients </li></ul></ul></ul></ul>Brockow K et al. Allergy 2005;60:150-8
  25. 25. Skin test was positive in 50% of patients who were skin tested within 2-6 months Specificity of skin test was 96.3% 32 (26%) (4 by SPT, 30 by IDT) 122 Brockow K et al (Allergy 2009) BAT was positive in 3 patients 4 (4%) by IDT 96 Trcka J et al (Am J Roentgenol 2008) Median time to skin test was 3 and 48 months in positive and negative skin test patients (p <0.05) Respiratory allergy was more frequent in the positive skin test patient 9 (28%) (1 by SPT, 8 by IDT) 32 Kvedariene V et al (Clin Exp Allergy 2006) 9.3% cross-reactivity rate 19 (73%) by IDT 26 Laroche D et al (Contrast Mol Med Imaging 2006) Note Positive results Number of patients References
  26. 27. <ul><ul><li>Skin tests were positive in 14/28 (50%) of patients tested within 2-6 months while only 17/92 (18%) of patients tested at other time were positive skin test (p = 0.0003) </li></ul></ul><ul><ul><li>43% of positive skin tested patients had reacted to a ICM on first exposure </li></ul></ul>
  27. 29. Treatment <ul><ul><li>Majority of patients recover if they are treated quickly and appropriately </li></ul></ul><ul><ul><li>The proper training personnel, first line drugs and equipments should be readily available </li></ul></ul><ul><ul><li>Patients should never be left alone for at least 30 minutes after ICM administration </li></ul></ul><ul><ul><li>Patients should be given a MedicAlert bracelet </li></ul></ul>Christensen C. in Pichler WJ Drug hypersensitivity 2007
  28. 30. Prevention <ul><ul><li>Contrast media selection </li></ul></ul><ul><ul><ul><li>10 fold reduction in severe repeat reactions with non-ionic ICM in patients with a previous reaction to ionic ICM </li></ul></ul></ul><ul><ul><ul><li>No available data of repeat reactions to non-ionic ICM </li></ul></ul></ul><ul><ul><ul><li>Patients with previous severe reactions should avoid re-exposure to ICM </li></ul></ul></ul><ul><ul><ul><li>Role of skin testing and in vitro tests to prevent repeat reactions remains to be established </li></ul></ul></ul>Brockow K et al. Allergy 2005;60:150-8
  29. 31. <ul><ul><li>Premedication </li></ul></ul><ul><ul><ul><li>Remains controversial </li></ul></ul></ul><ul><ul><ul><li>Marked variable prophylactic protocol </li></ul></ul></ul><ul><ul><ul><li>The estimated recurrence rate despite steroid administration is almost 10% </li></ul></ul></ul><ul><ul><ul><li>Severe reactions have been reported despite optimal premedication </li></ul></ul></ul>Gueant-Rodriguez RM et al. Curr Pharm Des 2006;12:3359-72
  30. 32. Idee JM et al. Fundam Clin Pharmacol 2005;19:263-81
  31. 33. Idee JM et al. Fundam Clin Pharmacol 2005;19:263-81
  32. 34. <ul><ul><li>Premedication may help to lessen reactions caused by non-specific histamine release, but may not be as effective in preventing IgE-mediated reactions </li></ul></ul><ul><ul><li>ANDEM-ANAES stated that ‘the limited number of relevant information in humans does not allow to establish the efficacy of a systemic premedication intended to prevent anaphylactoid reactions’ </li></ul></ul>Gueant-Rodriguez RM et al. Curr Pharm Des 2006;12:3359-72 Christensen C. in Pichler WJ Drug hypersensitivity 2007
  33. 35. Delayed hypersensitivity reaction
  34. 36. Prevalence <ul><ul><li>The frequency of delayed reactions varies from 0.5-23% </li></ul></ul><ul><ul><li>There seems to be a higher incidence of delayed reactions associated with non-ionic dimer </li></ul></ul><ul><ul><li>Severe delayed reactions are extremely rare </li></ul></ul><ul><ul><li>Only 6 cases have been reported </li></ul></ul>Gueant-Rodriguez RM et al. Curr Pharm Des 2006;12:3359-72
  35. 37. Idee JM et al. Fundam Clin Pharmacol 2005;19:263-81
  36. 38. Clinical manifestations <ul><ul><li>MP rash is the most frequent presentations (> 50%) </li></ul></ul><ul><ul><li>Usually mild to moderate in severity, transient and self-limiting </li></ul></ul><ul><ul><li>Most reactions occurs between 3 hr-2 days and disappear after 1-7 days </li></ul></ul><ul><ul><li>Immediate type symptoms and biphasic reactions have been reported </li></ul></ul>Brockow K et al. Allergy 2005;60:150-8
  37. 39. Risk factors <ul><ul><li>Previous reactions to ICM </li></ul></ul><ul><ul><ul><li>The most important risk factor </li></ul></ul></ul><ul><ul><li>IL-2 treatment </li></ul></ul><ul><ul><li>Serum Cr > 2 mg/dl </li></ul></ul><ul><ul><li>History of drug and contact allergy </li></ul></ul>Brockow K et al. Allergy 2005;60:150-8
  38. 40. Pathophysiology <ul><ul><li>T-cell mediated reactions </li></ul></ul><ul><ul><ul><li>The frequently reported positive patch tests and delayed IDTs to the culprit CM in previous reactors </li></ul></ul></ul><ul><ul><ul><li>The presence of dermal infiltrates of T cells in affected skin and positive skin test sites </li></ul></ul></ul><ul><ul><ul><li>The reappearance of the eruption after provocation testing </li></ul></ul></ul><ul><ul><ul><li>The ability of CM to simulate proliferation of peripheral T cells from patients with CM-induced skin eruptions </li></ul></ul></ul>Brockow K et al. Allergy 2005;60:150-8 Gueant-Rodriguez RM et al. Curr Pharm Des 2006;12:3359-72
  39. 41. <ul><ul><li>ICM might stimulate memory T cells directly via their TCR, in absence of a peptide antigen (direct metabolism-independent T-cell stimulation) </li></ul></ul>Gueant-Rodriguez RM et al. Curr Pharm Des 2006;12:3359-72
  40. 42. Diagnosis <ul><ul><li>During or immediately after the reaction </li></ul></ul><ul><ul><ul><li>CBC (eosinophilia) </li></ul></ul></ul><ul><ul><ul><li>Liver and renal function tests </li></ul></ul></ul><ul><ul><ul><li>Presence of lymphocyte activation markers (CD25, CD69, HLA-DR by flow cytometry or soluble CD25 by enzyme immunoassay) </li></ul></ul></ul><ul><ul><ul><li>Skin biopsy </li></ul></ul></ul>Brockow K et al. Allergy 2005;60:150-8 Gueant-Rodriguez RM et al. Curr Pharm Des 2006;12:3359-72
  41. 43. <ul><ul><li>After recovery </li></ul></ul><ul><ul><ul><li>Patch tests with undiluted ICM and IDT with diluted ICM appear to be specific and useful for diagnosis </li></ul></ul></ul><ul><ul><ul><li>Frequent cross-reactivity has been observed </li></ul></ul></ul><ul><ul><ul><li>The sensitivity of both PT and IDT has to be investigated </li></ul></ul></ul><ul><ul><ul><li>LTT cannot be recommended for routine use </li></ul></ul></ul>Brockow K et al. Allergy 2005;60:150-8 Gueant-Rodriguez RM et al. Curr Pharm Des 2006;12:3359-72
  42. 44. <ul><ul><li>Delayed skin tests were positive in 37/98 (38%) </li></ul></ul><ul><ul><li>32% had positive delayed IDTs and 28% were positive to patch tests </li></ul></ul><ul><ul><li>47% (29/62) were skin test positive when tested within 6 months after reactions while 22% (8/36) were positive when tested at other time (p = 0.02) </li></ul></ul><ul><ul><li>33% of positive skin tested patients had reacted on first ICM exposure </li></ul></ul>
  43. 45. Prevention <ul><ul><li>Contrast medium selection </li></ul></ul><ul><ul><ul><li>Change of ICM is no guarantee against repeat reactions due to frequent cross-reactivity </li></ul></ul></ul><ul><ul><ul><li>The value of skin testing to selective an alternative ICM remains to be established </li></ul></ul></ul><ul><ul><li>Premedication </li></ul></ul><ul><ul><ul><li>Delayed reactions have been reported despite steroid premedication </li></ul></ul></ul>Brockow K et al. Allergy 2005;60:150-8 Gueant-Rodriguez RM et al. Curr Pharm Des 2006;12:3359-72
  44. 46. Conclusion <ul><ul><li>Hypersensitivity reactions to ICM remain a significant problem for both the patients and physicians involved </li></ul></ul><ul><ul><li>Most delayed reactions are T-cell mediated while new data indicate that many of immediate reactions are IgE-mediated </li></ul></ul><ul><ul><li>Skin testing may be a useful tool for diagnosis and selection of an alternative ICM to prevent repeat reaction </li></ul></ul>
  45. 47. Thank You

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