N.O.S.G.D.

Allergologia e Immunologia Clinica Ospedale Nuovo San Giovanni di Dio

Azienda Sanitaria di FirenzeResponsabile: Responsabile: Donatella MacchiaDonatella Macchia

Stefania Capretti, Giuseppe Ermini, Maria L Iorno, Elisa Meucci, Elisa Meucci, Sergio TestiSergio Testi

Iodinated contrast media (ICM)

early twentieth century were introduced into clinical practice (however, their application was initially limited owing to poor radiopacity and toxicity)

1950s ICM were increasingly used thanks to new formulations with higher resolution and lower toxicity

1970s nonionic dimeric ICM and derivatives with higher physiological osmolality were developed

Nowadays ICM are administered more than 75 million times per year worldwide

Classificazione dei Mezzi di Contrasto per esami radiografici

La Radiologia Medica – Radiol Med 107 (suppl 1 al N. 4):8-31,2004Edizione Minerva Medica -Torino

Il contrasto negli esami radiologici è generato dall’assorbimento dei raggi X operato dal mezzo presente lungo il decorso del fascio radiante

Sostanze a bassa densità (aria o anidride carbonica) riducono l’assorbimentodelle radiazioni

Sostanze che contengono elementi ad elevato numero atomico (bario o iodio) aumentano l’assorbimento delle radiazioni

La Radiologia Medica – Radiol Med 107 (suppl 1 al N. 4):8-31,2004Edizione Minerva Medica -Torino

• Anello benzenico

• Tre atomi di Iodio in posizione 2-4-6

• Catene laterali in posizione 1-3-5, (a cui sono affidate le proprietà fisico-chimiche e biologiche)

Struttura di base e classificazione dei Mezzi di Contrasto iodati

1

2

3

4

5

6

Jeffrey J Mayo Clin Proc 2012

Properties of the 4 classes of Iodinate Contrast Agents

Non vengono più usati per via e.v. per l’alto rischio di reazioni avverse

Non vengono più usati per via e.v. per l’alto rischio di reazioni avverse

Classification of adverse events after contrast medium administration

Brockow K Allergy 2005

The prevalence of nonimmediate reactions, however, has increased in the last decade, to the extent that they are now more common than immediate reactions

Rosado Ingelmo A J Investig Allergol Clin Immunol 2016

Risk Factors for Immediate and Nonimmediate Reactions

• Female gender

• Acute or chronic kidney failure. Serum creatinine >2 mg/dL

• Other diseases with renovascular involvement, eg, diabetes, myeloma, dehydration

• Cardiopulmonary disease

• Previous reaction with ICM

• Repeated administration of ICM

• Using ionic monomeric high hosmolality ICM

•Treatment with IL-2

• Previous drug allergy

Rosado Ingelmo A J Investig Allergol Clin Immunol 2016

Additional risk factors for immediate reactions(common to allergic drug reactions)

• poorly controlled bronchial asthma

• concomitant medications (eg, ß-blockers, ACE inhibitors)

• mastocytosis

• viral infections

• autoimmune diseases

• rapid administration of the drug

Epidemiology

The prevalence of allergic reactions to ICM is estimated to be 1:170 000, that is,

0.05%-0.1% of patients undergoing radiologic studies with ICMThese percentages are generally higher for ionic ICM (0.16%-12.66%) than for nonionic ICM (0.03%-3%) Rosado Ingelmo A et al. J Investig Allergol Clin Immunol 2016

Even the newer generation CM cause immediate and nonimmediate reactions in

about 1–3% of applications Brockow K et al. Allergy 2009

Total CM adverse reaction was 1.05% Pradubpongsa P et al. Asian Pac J Allergy Immunol 2013

As low osmolality nonionic contrast agents replaced high-osmolality ionic ones, the incidence of immediate RCM hypersensitivity diminished remarkably from

3.8–12.7% to 0.7–3.1% Kim MH et al. PLOS ONE 2014

The incidence of these reactions is difficult to establish (1–25% according to various sources) Mruk B et al. Pol J Radiol 2016

The risk of reactions to ICM in children is lower Rosado Ingelmo et al. J Investig Allergol Clin Immunol 2016

Reazioni da Ipersensibilità immediata da Mezzi di Contrasto

Prevalenza

MORTALITA’

1 – 3/100.000 somministrazioni(non dovute ad un particolare tipo di M. di C.)1 – 3/100.000 somministrazioni

(non dovute ad un particolare tipo di M. di C.)

75 milioni di trattamenti/anno75 milioni di trattamenti/anno

a causa della frequenza con cui i RCM vengono utilizzati, questi agenti diagnostici sono tra ifarmaci che più frequentemente causano anafilassi fatale.

Pumphrey RS Clin Exp Allergy 20000

a causa della frequenza con cui i RCM vengono utilizzati, questi agenti diagnostici sono tra ifarmaci che più frequentemente causano anafilassi fatale.

Pumphrey RS Clin Exp Allergy 20000

Ingelmo R J Investig Allergol Clin Immunol 2016

Clinical Manifestations

Immediate Reactions

Nonimmediate Reactions

Nonallergic Reactions(can occur immediately after administration of ICM and usually resolve spontaneously)

• erythema and urticariawith or without angioedema(more than 70%)

• maculopapular rash (30-90%),• delayed urticaria, with or without angioedema(40%-60%)

• heat• facial flushing• dizziness • nausea

• dyspnea, • nausea• vomiting• hypotension• anaphylactic shock• acute coronary syndrome (Kounis syndrome)

• contact dermatitis• fixed drug eruption•Stevens-Johnson syndrome• toxic epidermal necrolysis • acute generalized pustulosis• vasculitis

Rosado Ingelmo A J Investig Allergol Clin Immunol 2016

Time to onset of reactionImmediate reactorsImmediate reactors

Time to onset of the reaction was known for 107 patients in the immediate group

Reaction after CM injection: • within 1–5 min 72 (67.2%)• after 10–15 min 19 (17.7%)• after 20–30 min 13 (12.1%)• after 45–60 min 3 (2.8%)

Time to onset of immediate reactions for patients with ( ) or without ( ) previous contrast medium exposure.

Brockow K Allergy 2009

84.9%84.9%

Grade I …………………………………..in 38 patients (31%), Generalized cutaneous and/or mucocutaneous symptoms

Grade II …………………………………..in 55 patients (45%), Mild systemic reactions

Grade III ………………………………… in 27 patients (22%) Life-threatening systemic reactions

Grade IV ………………………………….in 2 patients (1.6%)Cardiac and/or respiratory arrest

Grade I …………………………………..in 38 patients (31%), Generalized cutaneous and/or mucocutaneous symptoms

Grade II …………………………………..in 55 patients (45%), Mild systemic reactions

Grade III ………………………………… in 27 patients (22%) Life-threatening systemic reactions

Grade IV ………………………………….in 2 patients (1.6%)Cardiac and/or respiratory arrest

Severity of the immediate reactions (122 patients)

Severity of the immediate reactions (122 patients)

The scoring system of Ring and MessmerThe scoring system of Ring and MessmerBrockow K Allergy 2009

76%76%

Time to onset of reactionNonimmediate reactorsNonimmediate reactors

Time to onset of the reaction was known for 95 patients in the nonimmediate group

• 1–6 h 18 (18.9%)• 7–12 h 21 (22.1%)• 13–24 h 21 (22.1%)• >1–2 days 14 (14.7%) • >2–3 days 9 (9.4%)• >3 days 12 (12.6%)

Time to onset of nonimmediate reactions for patients with ( ) or without ( ) previous contrast medium exposure.

Brockow K Allergy 2009

78%78%

Mild When non treatmen was required

ModerateWhen the patient responded readly to appropriate tretment and no hospitalization was nedeed

Severe When the reaction required hospitalization or was life-threatening

Mild When non treatmen was required

ModerateWhen the patient responded readly to appropriate tretment and no hospitalization was nedeed

Severe When the reaction required hospitalization or was life-threatening

Severity of the nonimmediate reactions (98 patients)

Severity of the nonimmediate reactions (98 patients)

Brockow K Allergy 2009

Occasionally, more severe skin eruptions were observed. (bullous exanthema, flexuralexanthema, palpable purpura, purpura/maculopapular eruption combined with eosinophilia, psoriasis-like exanthema, acute generalized exanthematous pustulosis (AGEP), exfoliative eruption)

Occasionally, more severe skin eruptions were observed. (bullous exanthema, flexuralexanthema, palpable purpura, purpura/maculopapular eruption combined with eosinophilia, psoriasis-like exanthema, acute generalized exanthematous pustulosis (AGEP), exfoliative eruption)

Were mainly mild to moderate skin eruptions (81%) that were often treated with either antihistamines (12%), corticosteroids (29%) or a combination of the two (40%)

Were mainly mild to moderate skin eruptions (81%) that were often treated with either antihistamines (12%), corticosteroids (29%) or a combination of the two (40%)

Severity of the nonimmediate reactions (98 patients)

Severity of the nonimmediate reactions (98 patients)

Diagnosis

(acute phase)

Immediate reactions Nonimmediate reactions

measurements of serum tryptase (at the onset of the reaction and 2 and 24 hours later)

complete blood count and serum chemistry - detection of peripheral blood eosinophilia - evaluation of renal and hepatic function

biopsy of the affected skin

Rosado Ingelmo A J Investig Allergol Clin Immunol 2016

Clinical Historyshould be taken carefully, as with any adverse drug reaction

• time interval between reaction and allergological study

• the symptoms • the interval between administration of the ICM and the onset of symptoms,

• the ICM administered

• treatment required to control symptoms

• possible previous administration of ICM

• subsequent tolerance to this ICM or others

Rosado Ingelmo RA J Investig Allergol Clin Immunol 2016

Skin TestsICM (300–320 mgI/ml) diluted 10-fold in sterile saline

immediate reactions(Sensitivity 4.2% to 73% )

(Specificity 96.3%)

nonimmediate reactions

Skin Prick Test undiluted undilutedreading after 20 min

Intradermal Test 1:10 1:10reading after 20 min (Undiluted)

Torres MJ et al. Allergy 2012

reading should be taken at 48, 72, and 96 hours and occasionally at 7 days

Patch Test undilutedreading should be taken at 48, 72, and 96 hours and occasionally at 7 days

Brockow K et al Immunol Allergy Clin North Am 2009

Rosado Ingelmo A J Investig Allergol Clin Immunol 2016

Tot: 122 Pos: 32 (26%)

Tot: 122 Pos: 32 (26%)

FREQUENCY OF POSITIVE TESTStime period between reaction and skin testing

Tot: 98 Pos: 37 (38%)

Tot: 98 Pos: 37 (38%)

Tot: 28 Pos: 14 (50%)

Tot: 28 Pos: 14 (50%)

Tot: 62 Pos: 29 (47%)

Tot: 62 Pos: 29 (47%)

Brockow K Allergy 2009

Clinical Historyshould be taken carefully, as with any adverse drug reaction

• time interval between reaction and allergological study

• the symptoms • the interval between administration of the ICM and the onset of symptoms,

• the ICM administered

• treatment required to control symptoms

• possible previous administration of ICM

• subsequent tolerance to this ICM or others(should be performed 2-6 months

after the reaction)

(should be performed 2-6 months

after the reaction)

In Vitro Methods

immediate reactions nonimmediate reactions

Basophil Activation Test (BAT)

Lymphocyte Transformation Test (LTT)

to detect basophil activation markers (CD45, CD18, and CD63) by means of flow cytometry

ability of T cells to proliferate upon contact with ICM in sensitized patientsBAT was positive in 62.5% of cases confirmed

as having hypersensitivity, showing a good correlation with the ST and DPT results, thus indicating that BAT may be a useful method for confirming the diagnosis, especially in severe cases

Salas M Allergy 2013

BAT was positive in 62.5% of cases confirmed as having hypersensitivity, showing a good correlation with the ST and DPT results, thus indicating that BAT may be a useful method for confirming the diagnosis, especially in severe cases

Salas M Allergy 2013

The basophil activation test is increasingly used with drugs

• ß-lactams Torres MJ Clin Exp Allergy 2004

• quinolones Aranda A Allergy 2011

• protein pump inhibitorsPérez-Ezquerra PR Allergol Immunopathol (Madr) 2011

• corticosteroids Aranda A Allergy 2010

• ICM Salas M Allergy. 2013

The basophil activation test is increasingly used with drugs

• ß-lactams Torres MJ Clin Exp Allergy 2004

• quinolones Aranda A Allergy 2011

• protein pump inhibitorsPérez-Ezquerra PR Allergol Immunopathol (Madr) 2011

• corticosteroids Aranda A Allergy 2010

• ICM Salas M Allergy. 2013

Skin test resultsImmediate reactors

More extensive cross-reactivity testing with 8 or more CM was conducted in 11 patients

• six patients were positive to only one product

• two patients were positive to two products

• more extensive cross-reactivity was observed in the remaining three patients

• six patients were positive to only one product

• two patients were positive to two products

• more extensive cross-reactivity was observed in the remaining three patients

Brockow K Allergy 2009

Skin test resultsNonimmediate reactors

Twenty-five of the 37 delayed skin test positive patients were tested with at least8 CM (Table 5).

Cross-reactivity was especially pronounced among the CM of very similar chemical structure such as iodixanol, iohexol, iopentol, iomeprol and ioversol.

The positive results in skin tests and lymphocyte proliferation tests indicated that an important cross-reactivity exists Torres MJ et al. Clinical and Experimental Immunology 2008

The positive results in skin tests and lymphocyte proliferation tests indicated that an important cross-reactivity exists Torres MJ et al. Clinical and Experimental Immunology 2008

VISIPAQUEVISIPAQUE

OPTIRAYOPTIRAY

IOMERONIOMERON

Brockow K Allergy 2009

An alternative skin test–negative ICM could be eligible for future testing --- however --- tolerability is uncertain, since the negative predictive value of skin testing remains unknown.

Prieto-García et al. JIACI 2013

Confirmation of a presumptive diagnosis by a DPT is often the only reliable way to establish a diagnosis, if other diagnostic procedures such as in vivo skin testing and in vitro laboratory tests do not lead to conclusive results. Aberer W et al. Allergy 2003

DRUG PROVOCATION TEST

Prieto-García A et al. JIACI 2013

Drug provocation testalternative skin test–negative ICMwas administered intravenously

day 1 5-30-60 mL

if this was well tolerated

day 2 120 mL

106 patients with IHR to ICM

11 patients had positive skin test results with the culprit contrast agent (10.4%)

7 tolerated subsequent exposure to an alternative skin test–negative ICM with no premedication.

Torres MJ et al. Allergy 2012

Drug provocation testCM was administered intravenously diluted in saline at different doses at 1-h intervals

first run 5, 10 and 15 cc of CM

if this was well tolerated

1 week later 20, 30 and 50 cc (cumulative dose = 100 cc)

48.4%

a DPT was carried out with the CM

Involved

DPT was carried out selecting a CM

with a negative skin test

21%

Reazioni immediateSomministrazione endovenosa del mezzo di contrasto alternativo, negativo alle prove cutanee

1a somm. 5-30-60 mL (in fisiologica)Somministrazione in 30 minuti100ml Flusso 200 ml/h

se ben tollerato

in radiologia Successiva somministraz.

Reazioni non immediateSomministrazione endovenosa del mezzo di contrasto alternativo, negativo alle prove cutanee

1a somm. 5-30 mL (in fisiologica)Somministrazione in 30 minuti100ml Flusso 200 ml/h

se ben tollerato

2° somm. dopo una settimana

30-60 mL (in fisiologica)Somministrazione in 30 minuti100ml Flusso 200 ml/h

se ben tollerato

in radiologia(almeno dopo una settimana)

Successiva somministraz.

Allergologia e Immunologia Clinica Ospedale Nuovo San Giovanni di Dio

Azienda Sanitaria di Firenze

Diagnostic algorithmThe guidelines were developed by a panel of allergy specialists from the Drug Allergy Committee of the Spanish Society of Allergy and Clinical Immunology (SEAIC) with extensive clinical expertise in the evaluation and management of hypersensitivity reactions and broad research experience.

Rosado Ingelmo A J Investig Allergol Clin Immunol 2016

1

Kemp SF et al. Allergy 2008

Physicians and other healthcare professionals who perform procedures or administer medications should have availableshould have available the basic therapeutic agents used to treat anaphylaxis:

• stethoscope and sphygmomanometer;

• tourniquets, syringes, hypodermic needles, large-bore needles (e.g. 14- or 16-gauge);

• equipment and supplies for administering supplemental oxygen;

• equipment and supplies for administering intravenous fluids;

• oral or laryngeal mask airway;

• an automatic defibrillator, and one-way valve facemask with oxygen inlet port (and other supplies that some clinicians might find desirable depending on the individual clinical

setting);

• injectable aqueous epinephrine 1 : 1000 (1 mg in 1 ml);

• diphenhydramine or similar injectable antihistamine;

• ranitidine or other injectable H2 antihistamine;

• corticosteroids for i.v. injection;

• vasopressor (e.g. dopamine or norepinephrine);

• glucagon;

Le reazioni generali da MCR sono principalmente reazioni tossiche dipendenti sia dalla elevata osmolalità (relativamente ai MCR ionici), sia dalla chemotossicità, cioè dalla proprietà di legarsi alle proteine come ad esempio agli enzimi, sia da reazioni

pseudoallergiche ed (eccezionalmente) allergiche.Memoranda S.I.A.I.C 1992

The fact that up to 50% of patients up to 50% of patients had positive skin testshad positive skin tests when tested 2–6 months after the reaction2–6 months after the reaction, indicates that a significant fraction of the CM-induced immediate and nonimmediate hypersensitivity reactions are immunologic reactionsimmunologic reactions, involving CM-reactive IgE antibodies and CM-reactive T cells, respectively

Brockow K et al Allergy 2009

CONCLUSIONIPer quanto riguarda i Mezzi di Contrasto Radiologici, allo stato attuale delle conoscenze scientifiche è consigliabile, in un soggetto con pregressa reazione avversa al MC, - non esporre di nuovo il paziente al MC responsabile della pregressa RA (quando noto), - usare un MC risultato negativo alle prove cutanee, - effettuare la procedura diagnostica radiologica in ambiente idoneo (attrezzatura e farmaci di pronto intervento), - essere consapevoli dei fattori di rischio per le reazioni da ipersensibilità ai M di C (r. immediate: precedente

reazione avversa al M. di C., asma bronchiale, malattie cardiache, trattamento con beta-bloccanti; r. ritardate: precedente reazione

avversa al M. di C., trattamento con interleuchina-2, pregressa allergia farmaci e allergia da contatto).- evitare la nuova somministrazione di MC in pazienti con precedenti severe reazioni cutanee (bollose) ritardate.

Per quanto riguarda i Mezzi di Contrasto Radiologici, allo stato attuale delle conoscenze scientifiche è consigliabile, in un soggetto con pregressa reazione avversa al MC, - non esporre di nuovo il paziente al MC responsabile della pregressa RA (quando noto), - usare un MC risultato negativo alle prove cutanee, - effettuare la procedura diagnostica radiologica in ambiente idoneo (attrezzatura e farmaci di pronto intervento), - essere consapevoli dei fattori di rischio per le reazioni da ipersensibilità ai M di C (r. immediate: precedente

reazione avversa al M. di C., asma bronchiale, malattie cardiache, trattamento con beta-bloccanti; r. ritardate: precedente reazione

avversa al M. di C., trattamento con interleuchina-2, pregressa allergia farmaci e allergia da contatto).- evitare la nuova somministrazione di MC in pazienti con precedenti severe reazioni cutanee (bollose) ritardate.

We propose controlled challenge testing based on skin test results to identify a safe ICM for future diagnostic procedures.

Prieto-García A et al. JIACI 2013 Torres MJ et al. Allergy 2012

Rosado Ingelmo A J Investig Allergol Clin Immunol 2016

• Prevalenza 0.05% - 25%!

• Percentuale positività prove cutanee con quale R.A. pregressa

• Prove cutanee con M di C I non diluito nelle RA di tipo non immediato (nelle immediate?)

• Cross reazioni, veramente così significative?

• Valore predittivo negativo (necessari altri casi!)

In our study, the rate of a positive skin test result for immediate HSR

was 13.5%. This result agrees with the literature: 17% from a

recent metaanalysis (Yoon SH et al. Allergy 2015) and 10.4% from another study (Prieto-Garcıa A et al. J Investig Allergol Clin Immunol 2013)…………. our rate of positive

skin test results increased to 20% when skin tests were performed during the year after the HSR. Sesé L et al. Clinical & Experimental Allergy 2016

Le reazioni avverse a mezzi di contrasto: dalle evidenze cliniche alla proposta di un Position Paper

elisa.meucci@uslcentro.toscana.it

Grazie per l’attenzione