Concetti chiave sulle “cosiddette” reazioni allergiche Antonino Romano antoninoromano@h-columbus.it

1. Concetti chiave sulle “cosiddette” reazioni allergiche Antonino Romano antoninoromano@h-columbus.it

2. A revised nomenclature for allergyAn EAACI position statement from the EAACI nomenclature task force Non-allergic drug hypersensitivity Drug hypersensitivity IgE-mediated Drug allergy non-IgE-mediated SGO Johansson et al, Allergy 2001 SGO Johansson et al, J Allergy Clin Immunol 2004

3. Types of allergic reactions to penicillin Immediate(less than 1 hour) - Urticaria - Anaphylactic shock - Laryngeal edema - Local swelling - Bronchospasm Non-immediate(more than 1 hour) - Morbilliform rash - Serum sickness - Urticaria Other non-immediate reactions - Stevens-Johnson syndrome - Vasculitis - Toxic epidermal necrolysis - Hemolytic anemia - AGEP - Neutropenia - Interstitial nephritis - Thrombocytopenia A Saxon et al, Ann Intern Med 1987 (modified)

4. News and commentaries Management of hypersensitivity reactions to iodinated contrast media K Brockow et al, Allergy 2005

5. Classification of adverse events after RCM administration Adverse event Pharmacological toxicity Hypersensitivity Unrelated event Immediate reactions 1 hour Non-immediate reactions 1 hour-7 days Pharmacological effect Non-allergic or IgE-mediated? T-cell-mediated Organ toxicity Allergy-like reactions Exanthematous skin eruptions Unspecific symptoms K Brockow et al, Allergy 2005

6. Pathophysiology New concepts Some immediate reactions, especially severe ones, appear to be IgE-mediated Most non-immediate skin reactions appear to be T-cell mediated Consequence Patients with a previous allergic reaction to RCM are at risk for a repeat reaction of increased intensity

7. WJ Pichler, Ann Intern Med 2003

8. Hypersensitivity reactions to iodinated contrast media R-M Guéant-Rodriguez et al, Curr Pharm Des 2006

9. Clinical symptoms When headache, nausea and vomiting are excluded, most adverse reactions to RCM are allergy-like Non-immediate Immediate 0-60 min 24 h–7 d 1-24 h Cardiovascular reactions, anaphylactic shock Respiratory reactions, urticaria, angioedema Fever, chill, skin eruptions Almost all life-threatening reactions are immediate, anaphylactic reactions C Christiansen, Curr Opin Allergy Clin Immunol 2002

10. Symptoms of immediate and non-immediate hypersensitivity reactions to RCM Immediate reactions Urticaria Pruritus Dyspnea (bronchospasm) Angioedema / facial edema Rhinitis Hypotension Cardiovascular shock Respiratory arrest Cardiac arrest Non-immediate reactions Exanthematous drug eruptions (macular, maculopapular) Urticaria Angioedema Erythema multiforme minor Fixed drug eruption Stevens-Johnson syndrome Toxic epidermal necrolysis Graft-versus-host reaction Vasculitis Pruritus C Christiansen, Curr Opin Allergy Clin Immunol 2002

11. Immediate Non-immediate Urticaria 65-85% Angioedema 5-15% Maculopapular rash >50% Clinical symptoms As for other drugs, cutaneous reactions are the predominant adverse reactions C Christiansen, Curr Opin Allergy Clin Immunol 2002

12. Duration of adverse reactions Most immediate reactions fade within 1 hour. Most non-immediate reactions last from 12 hours to 7 days 40 30 20 Percentage 10 0 0,5 1 2 3 4 5 6 7 >7 Duration of non-immediate reactions (days) T Hosoya et al, Radiat Med 2000

13. IMMEDIATE REACTIONS

14. Diagnostic tests of hypersensitivity reactions to drugs A Romano et al, J Allergy Clin Immunol 2011

15. Diagnosis of anaphylactic reactions Shock (gradation) Cell-mediator assays tryptase + histamine (sensitivity 80%) (serum) (plasma, EDTA) (1 month later) - Consultation in allergology: skin tests - Biology: serum specific IgE assays / BATs

16. Evaluation of immediate reactions to iodinated contrast media by skin tests

17. Pathophysiology New concepts Some immediate reactions, especially severe ones, appear to be IgE-mediated Most non-immediate skin reactions appear to be T-cell mediated Consequence Patients with a previous allergic reaction to RCM are at risk for a repeat reaction of increased intensity

18. NON-IMMEDIATE REACTIONS

19. Diagnostic tests of hypersensitivity reactions to drugs A Romano et al, J Allergy Clin Immunol 2011

20. Evaluation of non-immediate reactions to iodinated contrast media

21. Evaluation of non-immediate reactions to iodinated contrast media

22. Pathophysiology New concepts Some immediate reactions, especially severe ones, appear to be IgE-mediated Most non-immediate skin reactions appear to be T-cell mediated Consequence Patients with a previous allergic reaction to RCM are at risk for a repeat reaction of increased intensity

23. Skin testing in patients with hypersensitivity reactions to iodinated contrast media –a European multicenter study Skin prick, intradermal, and patch tests with a series of contrast media (CM) were conducted in 220 patients with either immediate (122) or non-immediate (98) reactions K Brockow et al, Allergy 2009

24. Skin testing in patients with hypersensitivity reactions to iodinated contrast media –a European multicenter study Positive skin tests were observed in 32 (26%; 95% CI: 18% - 34%) of 122 patients with immediate reactions Positive immediate responses to at least one of the tested CM were observed in 3 of the 71 unexposed controls, but in none of the 11 CM-exposed controls The specificity of the intradermal tests was 96.3% (95% CI: 92% – 100%) K Brockow et al, Allergy 2009

25. Skin testing in patients with hypersensitivity reactions to iodinated contrast media –a European multicenter study The frequency of positive test results was 14/28 (50%) in patients tested within 2 to 6 months, but was only 17/92 (18%) for patients tested at other time points (earlier than 2 months or later than 6 months) K Brockow et al, Allergy 2009

26. Skin testing in patients with hypersensitivity reactions to iodinated contrast media –a European multicenter study Delayed-reading skin tests were positive in 37 (38%; 95% CI: 28% - 47%) of 98 non-immediate reactors Patch tests were positive in 22 (28%) of 79 patients 9 patients presented delayed-reading intradermal-test positivity and patch-test negativity, while 7 patients were positive to patch tests and negative to intradermal ones K Brockow et al, Allergy 2009

27. Skin testing in patients with hypersensitivity reactions to iodinated contrast media –a European multicenter study While 47% (29/62) of patients were skin-test positive when tested within the first 6 months after reactions, only 22% (8/36) were positive when tested at later time points (p = 0.02) K Brockow et al, Allergy 2009

28. Skin test results Immediate reactors More extensive cross-reactivity testing with 8 or more CM was conducted in 11 patients 6 patients were positive to only one product 2 patients were positive to two products more extensive cross-reactivity was observed in the remaining 3 patients

29. Skin test results Non-immediate reactors Twenty-five of the 37 patients with a delayed hypersensitivity were tested with at least 8 CM Cross-reactivity was especially pronounced among the CM with a very similar chemical structure, such as iodixanol, iohexol, iopentol, iomeprol, and ioversol

30. Delayed hypersensitivity reactions caused by iodixanol: An assessment of cross-reactivity in 22 patients F Hasdenteufel et al, J Allergy Clin Immunol in press

31. IgE-mediated reactions to gadolinium-containing intravenous contrast media

32. Diatesi allergica – Come identificare il paziente a rischio? Si richiede la preparazione? Quando e come? Antonino Romano antoninoromano@h-columbus.it

33. Main risk factors Immediate Non-immediate Prior RCM reaction  Bronchial asthma  β-Blocker  Cardiac disease  Severe allergy  A history of drug allergy  A history of contact allergy  Serum creatinine level >2 mg/dl  Interleukin-2 treatment  C Christiansen, Curr Opin Allergy Clin Immunol 2002 K Brockow et al, Allergy 2005

34. Pharmacological prevention of serious anaphylactic reactions due to iodinated contrast media: a systematic review MR Tramèr et al, BMJ 2006

35. Arbitrary symptom combinations (grades) MR Tramèr et al, BMJ 2006

36. MR Tramèr et al, BMJ 2006

37. MR Tramèr et al, BMJ 2006

38. MR Tramèr et al, BMJ 2006

39. What is already known on this topic MR Tramèr et al, BMJ 2006

40. What this study adds MR Tramèr et al, BMJ 2006

42. Repeat contrast medium reactions in premedicated patients: Frequency and severity • Between January 1999 and December 2007, 175 patients experienced 190 breakthrough reactions to intravenous low-osmolality contrast media (LOCM) • Of 128 breakthrough reactions, in which the index reaction severity was known, 103 (81%) were of severity similar to that of the index reaction, 15 (12%) were less severe, and 10 (8%) were more severe MS Davenport et al, Radiology 2009

43. Repeat contrast medium reactions in premedicated patients: Frequency and severity • Of the 175 patients with confirmed breakthrough reactions, 58 underwent 197 subsequent LOCM-enhanced CT examinations during the study period • There was no breakthrough reaction after 174 (88%) of these 197 examinations • Additional breakthrough reactions occurred after 23 (12%) examinations performed in 23 subjects MS Davenport et al, Radiology 2009

44. Repeat contrast medium reactions in premedicated patients: Frequency and severity • Breakthrough reactions were significantly more likely to be moderate or severe in patients with a history of chronic corticosteroid use (P = .01), drug (P = .04) or severe (P < .001) allergies, or allergies to 4 or more allergens (P = .01) MS Davenport et al, Radiology 2009

45. Prevention of recurrence Premedication • Immediate reactions: • Steroids and anti-histamines • Non-immediate reactions: • Cyclosporine and steroids Currently used premedication ineffective in preventing severe immediate reactions