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

2. A revised nomenclature for allergy An 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. Management of hypersensitivity reactions to iodinated contrast media K Brockow et al, Allergy 2005 News and commentaries

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

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

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. Immediate 0-60 min Cardiovascular reactions, anaphylactic shock Respiratory reactions, urticaria, angioedema Fever, chill, skin eruptions Clinical symptoms Almost all life-threatening reactions are immediate, anaphylactic reactions When headache, nausea and vomiting are excluded, most adverse reactions to RCM are allergy-like Non-immediate 1-24 h 24 h–7 d 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. T Hosoya et al, Radiat Med 2000 Most immediate reactions fade within 1 hour. Most non-immediate reactions last from 12 hours to 7 days 0 10 20 30 40 Percentage 0,51234567>7 Duration of non-immediate reactions (days) Duration of adverse reactions

13. IMMEDIATE REACTIONS

14. Diagnostic tests of hypersensitivity reactions to drugs Type of reaction Type of tests ImmediateIn vitroSpecific IgE assays Flow cytometric BATs In vivoSkin tests Provocation tests Non-immediateIn vitroLTTs or LATs ELISPOT assays for analysis of antigen-specific, cytokine- producing cells In vivoDelayed-reading intradermal tests Patch tests Provocation tests 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) - Consultation in allergology: skin tests - Biology: serum specific IgE assays / BATs (1 month later)

16. Evaluation of immediate reactions to iodinated contrast media by skin tests Author No. of patients Reagents’ highest concentration No. of positive patients (%) V Kvedariene et al, Clin Exp Allergy 2006 321:109 (28.1) J Trcka et al, Am J Roentgenol 2008 961:104 (4.2) K Brockow et al, Allergy 2009 1221:1032 (26.2) K Dewachter et al, Eur J Radiol 2011 261:119 (73.1) O Goksel et al, Int Arch Allergy Immunol 2011 241:105 (20.8)

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

18. NON-IMMEDIATE REACTIONS

19. Diagnostic tests of hypersensitivity reactions to drugs Type of reaction Type of tests ImmediateIn vitroSpecific IgE assays Flow cytometric BATs In vivoSkin tests Provocation tests Non-immediateIn vitroLTTs or LATs ELISPOT assays for analysis of antigen-specific, cytokine- producing cells In vivoDelayed-reading intradermal tests Patch tests Provocation tests A Romano et al, J Allergy Clin Immunol 2011

20. Evaluation of non-immediate reactions to iodinated contrast media Author No. of patients Method No. of positive patients (%) L Vernassiere et al, Contact Dermatitis 2004 15 Skin tests, patch tests, challenges 11 (73.3) T Nakada et al, Clin Exp Dermatol 2006 117 Patch tests, intradermal tests 69 (58.9) V Kvedariene et al, Clin Exp Allergy 2006 11Intradermal tests1 (9) Y Delgado-Jimenez et al, Contact Dermatitis 2006 11Patch tests3 (27.2)

21. Evaluation of non-immediate reactions to iodinated contrast media Author No. of patients Method No. of positive patients (%) MJ Torres et al, Clin Exp Immunol 2008 14 Skin tests, patch tests, challenges 6 (42.8) K Brockow et al, Allergy 2009 98 Skin tests, patch tests 37 (37.7) CS Seitz et al, Eur J Radiol 2009 32 Skin tests, patch tests 6 (18.7) F Hasdenteufel et al, J Allergy Clin Immunol in press 22 Skin tests, patch tests 11 (50)

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

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 Author No. of patients Responsible compound Method DC Kalogeromitros et al, Int Arch Allergy Immunol 2007 1 Gadobenate dimeglumine Intradermal test F Hasdenteufel et al, J Allergy Clin Immunol 2008 2 Gadoterate dimeglumine Skin tests, LHRT C Galera et al, Allergy 2010 2 Gadoteridol, Gadobenate dimeglumine Intradermal tests

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 Nine of 64 potentially relevant reports, published between 1975 and 1996, met inclusion criteria

35. Arbitrary symptom combinations (grades) Grade 1 Single episode of emesis, nausea, sneezing, or vertigo Grade 2 Hives, erythema, emesis more than once, and fever or chills (or both) Grade 3 Clinical “shock”, bronchospasm, laryngospasm or oedema, loss of consciousness, convulsions, fall in blood pressure, increase in blood pressure, cardiac arrhythmia, angina, angio-oedema, or pulmonary oedema MR Tramèr et al, BMJ 2006

36. Grade 1 reactions were significantly reduced with the double dose, but not with the single dose methylprednisolone regimen: 87/3,093 (2.8%) patients who received the double dose regimen had a grade 1 reaction compared with 89/2,178 (4.1%) controls (odds ratio 0.62, 0.46 to 0.84) MR Tramèr et al, BMJ 2006

37. Grade 2 reactions were not significantly reduced, either with the single dose or with the double dose methylprednisolone regimen MR Tramèr et al, BMJ 2006

38. Grade 3 reactions were significantly reduced only with the double dose regimen: 7/3,093 (0.2%) patients who received the double dose regimen had a grade 3 reaction compared with 20/2,178 (0.9%) controls (odds ratio 0.28, 0.13 to 0.60) MR Tramèr et al, BMJ 2006

39. What is already known on this topic MR Tramèr et al, BMJ 2006 Premedication with steroids, antihistamines, and other drugs, alone or in combination, is widely used before injection of iodinated contrast media Premedication is thought to reduce the risk of life- threatening anaphylactic reactions

40. What this study adds MR Tramèr et al, BMJ 2006 Life-threatening anaphylactic reactions due to iodinated contrast media are rare In unselected patients, the usefulness of premedication is doubtful, as a large number of patients need to receive premedication to prevent one potentially serious reaction Data supporting the use of premedication in patients with a history of allergic reactions are lacking

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 Currently used premedication ineffective in preventing severe immediate reactions Premedication Immediate reactions: Steroids and anti-histamines Non-immediate reactions: Cyclosporine and steroids