Concetti chiave sulle “cosiddette” reazioni allergiche Antonino Romano [email protected].

Concetti chiave sulle “cosiddette” reazioni allergiche

Antonino [email protected]

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


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

WJ Pichler, Ann Intern Med 2003

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


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


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

IMMEDIATE 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)


Pathophysiology

New concepts

Consequence



Most non-immediate skin reactions appear

to be T-cell mediated

NON-IMMEDIATE 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

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)


Pathophysiology

New concepts

Consequence



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



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%)



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)




• 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




• 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)


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


• 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)


• Grade 2 reactions were not significantly

reduced, either with the single dose or with

the double dose methylprednisolone regimen


• 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)


What is already known on this topic


• 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


• 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


• 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



• 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)


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

Concetti chiave sulle “cosiddette” reazioni allergiche Antonino Romano [email protected].

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