concetti chiave sulle “cosiddette” reazioni allergiche antonino romano...
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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
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 - ThrombocytopeniaA Saxon et al, Ann Intern Med 1987 (modified)
Management of hypersensitivity
reactions to iodinated contrast media
K Brockow et al, Allergy 2005
News and commentaries
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
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
Hypersensitivity reactions to iodinated contrast media
R-M Guéant-Rodriguez et al, Curr Pharm Des 2006
Immediate0-60 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
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
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
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
Per
cen
tag
e
0,5 1 2 3 4 5 6 7 >7
Duration of non-immediate reactions (days)
Duration of adverse reactions
Diagnostic tests of hypersensitivity reactions to drugs
Type of reaction Type of tests
Immediate In vitro Specific IgE assaysFlow cytometric BATs
In vivo Skin testsProvocation tests
Non-immediate In vitro LTTs or LATsELISPOT assays for analysis ofantigen-specific, cytokine-producing cells
In vivo Delayed-reading intradermal testsPatch testsProvocation tests
A Romano et al, J Allergy Clin Immunol 2011
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)
Evaluation of immediate reactions to iodinated contrast media by skin tests
AuthorNo. of
patients
Reagents’ highest
concentration
No. of positive
patients (%)
V Kvedariene et al, Clin Exp Allergy 2006
32 1:10 9 (28.1)
J Trcka et al,Am J Roentgenol 2008
96 1:10 4 (4.2)
K Brockow et al,Allergy 2009
122 1:10 32 (26.2)
K Dewachter et al,Eur J Radiol 2011
26 1:1 19 (73.1)
O Goksel et al,Int Arch Allergy Immunol 2011
24 1:10 5 (20.8)
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
Diagnostic tests of hypersensitivity reactions to drugs
Type of reaction Type of tests
Immediate In vitro Specific IgE assaysFlow cytometric BATs
In vivo Skin testsProvocation tests
Non-immediate In vitro LTTs or LATsELISPOT assays for analysis ofantigen-specific, cytokine-producing cells
In vivo Delayed-reading intradermal testsPatch testsProvocation tests
A Romano et al, J Allergy Clin Immunol 2011
Evaluation of non-immediate reactions to iodinated contrast media
AuthorNo. of
patientsMethod
No. of positive
patients (%)
L Vernassiere et al,Contact Dermatitis 2004
15Skin tests, patch tests, challenges
11 (73.3)
T Nakada et al, Clin Exp Dermatol 2006
117Patch tests,
intradermal tests69 (58.9)
V Kvedariene et al,Clin Exp Allergy 2006
11 Intradermal tests 1 (9)
Y Delgado-Jimenez et al,Contact Dermatitis 2006
11 Patch tests 3 (27.2)
Evaluation of non-immediate reactions to iodinated contrast media
AuthorNo. of
patientsMethod
No. of positive
patients (%)
MJ Torres et al,Clin Exp Immunol 2008
14Skin tests, patch tests, challenges
6 (42.8)
K Brockow et al,Allergy 2009
98Skin tests, patch tests
37 (37.7)
CS Seitz et al, Eur J Radiol 2009
32Skin tests,patch tests
6 (18.7)
F Hasdenteufel et al,J Allergy Clin Immunol in press
22Skin tests,patch tests
11 (50)
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
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
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
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
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
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
Skin test resultsImmediate 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
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
Skin test resultsNon-immediate reactors
Twenty-five of the 37 patients with a delayed hypersensitivity were tested with at least8 CM
Cross-reactivity was especially pronounced among the CM with a very similar chemical structure, such as iodixanol, iohexol, iopentol, iomeprol, and ioversol
Delayed hypersensitivity reactions caused by iodixanol: An assessment of cross-reactivity in 22 patients
F Hasdenteufel et al, J Allergy Clin Immunol in press
IgE-mediated reactions to gadolinium-containing intravenous contrast media
AuthorNo. of
patientsResponsible compound
Method
DC Kalogeromitros et al,Int Arch Allergy Immunol 2007
1Gadobenate dimeglumine
Intradermal test
F Hasdenteufel et al, J Allergy Clin Immunol 2008
2Gadoterate
dimeglumineSkin tests,
LHRT
C Galera et al,Allergy 2010
2Gadoteridol,Gadobenate dimeglumine
Intradermal tests
Diatesi allergica – Come identificare il paziente a rischio?
Si richiede la preparazione? Quando e come?
Antonino [email protected]
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 2002K Brockow et al, Allergy 2005
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
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
• 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
• 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
• 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
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
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
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
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
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
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