skin tests in immediate type drug induced allergy

Prick and intradermal skin tests in immediate type drug induced

hypersensitivity reactions

Author Nadia GhermanMDPhD Allergology and Clinical Immunology consultant physician Clinical Emergency County Hospital ClujUniversity Teaching Assistant Dept of Allergology and Immunology ldquoIuliu Hațieganurdquo University of Medicine and Pharmacy Cluj-Napocanadiaghermanionicayahoocom

Classification of drug allergies

P Demoly N F Adkinson K Brockow et al International Consensus on drug allergy Allergy 2014 Apr69(4)420-37

Grade of severity of the immediate HSR (and clinical features)

Mertes PM1 Malinovsky JM Jouffroy L Working Group of the SFAR and SFA Aberer W Terreehorst I Brockow K Demoly P ENDA EAACI Interest Group on Drug Allergy Reducing the risk of anaphylaxis during anesthesia 2011 updated guidelines for clinical practice J Investig Allergol Clin Immunol 201121(6)442-53

Selecting diagnostic tests in the immediate type HSR to drugs

Romano A1 Torres MJ Castells M Sanz ML Blanca M Diagnosis and management of drug hypersensitivity reactions J Allergy Clin Immunol 2011 Mar127(3 Suppl)S67-73

The skin tests in the diagnosis of drug allergy

Skin test is the most commonly used procedure to confirm a sensitization in drug hypersensitivity for many drugs in vitro tests are not available or sufficiently validated

Their diagnostic value has not been fully evaluated for all drugs

The tests should follow standard procedures and should be performed by trained staff

Skin tests have to be applied depending on the suspected pathomechanism of the DHR

Sensitivity and predictive values vary depending on the culprit drug and the clinical presentation

They appear to be lsquogoodrsquo for immediate DHRs to β-lactam antibiotics NMBA platin salts and heparins but moderate to low for most other drugs


Brockow K Garvey LH Aberer Wet al Skin test concentrations for systemically administered drugs -- an ENDAEAACI DrugAllergy Interest Group position paper Allergy 2013 Jun68(6)702-12

The skin tests in the diagnosis of immediate type drug allergy



PM Mertes1 JM Malinovsky2 L Jouffroy3 and the Working Group of the SFAR and SFA and W Aberer4 I Terreehorst5 K Brockow6 P Demoly7 for ENDA and the EAACI Interest Group on Drug Allergy Reducing the Risk of Anaphylaxis During Anesthesia 2011 Updated Guidelines for Clinical Practice J Investig Allergol Clin Immunol 2011 Vol 21(6) 442-453

Skin prick tests (SPT) and intradermal tests (IDT) with immediate readings are used for investigation of immediate hypersensitivity reactions

Intradermal tests are undertaken when skin prick tests are negativeIntradermal testing begins with 11000 dilution of the non-reactive concentration to avoid a test-induced anaphylaxis (severe history)

Compared to skin prick tests intradermal tests provide an enhanced sensitivity for drug-specific IgE

The parenteral preparation of the suspected drug preferably the intravenous form at the recommended concentration should be used for SPT and IDT

Tests should be performed 4ndash6 weeks after the reaction


Brockow K Romano A Skin tests in the diagnosis of drug hypersensitivity reactions Curr Pharm Des 200814(27)2778-91 Mirakian R1 Leech SC Krishna MT Richter AG Huber PA Farooque S Khan N Pirmohamed M Clark AT Nasser SM Management of allergy to penicillins and other beta-lactams Clin Exp Allergy 2015 Feb45(2)300-27

Only 20ndash30 of patients positive on a penicillin skin test remain positive after 10 years

Five years after a positive skin test 100 of amoxicillinallergic patients lost skin test reactivity compared to 40 of patients who reacted to a beta-lactam determinant

More than half of patients with both penicillin- and cephalosporin-positive allergy tests (non-selective reactors) remain positive after 5 years

Optimally a time interval between the reaction and the skin test of 1 and 6 months has been suggested

It is not known whether the loss of skin test reactivity corresponds to a loss of allergy


Brockow K Romano A Skin tests in the diagnosis of drug hypersensitivity reactions Curr Pharm Des 200814(27)2778-91

Leysen J1 Uyttebroek A Sabato V Bridts CH De Clerck LS Ebo DG Predictive value of allergy tests for neuromuscular blocking agents tackling an unmet need Clin Exp Allergy 2014 Aug44(8)

The specificity of skin tests with all β-lactam drugs is very good reaching 97 to 100 The sensitivity of skin testing was 22 for PPL 21 for MDM 43 for amoxicillin and 33 for ampicillin and the combination of all four haptens gave a sensitivity of 70

NMBA skin test and BAT have an excellent negative predictive value negative skin test and negative BAT assisted the selection of alternative NMBA which were well tolerated


P Demoly N F Adkinson K Brockow et al International Consensus on drug allergy Allergy 2014 Apr69(4)420-37Brockow K Garvey LH Aberer Wet al Skin test concentrations for systemically administered drugs -- an ENDAEAACI DrugAllergy Interest Group position paper Allergy 2013 Jun68(6)702-12

Skin tests should use nonirritant concentrations of the drug

The non-reactive concentrations can be established using different dilutions of increasing drug concentration

The nonirritant drug concentration should ideally be established in healthy controls A positive skin test to nonirritating drug concentrations is consistent with an allergic mechanism although the precise test accuracy (sensitivityspecificity) remains unknown

Where the drug is available only in tablet capsule or topical form only SPT andor patch test can be performed

The skin tests in the diagnosis of immediate type drug allergy- determination of the maximum non reactive concentrations

For skin testing the criteria for positivity are based on dilutions of drugs that do not cause wheal and flare in people with no history of reactionFisher MM Doig GS Prevention of anaphylactic reactions to anaesthetic drugs Drug Saf 200427(6)393-410

Interpretation of skin tests requires verification of the patientlsquos normal skin reactivity with negative (normal saline solution) and positive controls (1 histamine 9 codeine phosphate solutions)

The criteria of a positive prick test are the appearance after 20 min of a wheal with a diameter at least 3 mm greater than the negative control and equal or larger than half the diameter of the positive control

The criteria for positivity of an intradermal test are the appearance after 20 min of a wheal with a diameter at least double the diameter of the injecting bleb (8 mm for an injecting bleb of 4 mm) Mertes PM Laxenaire MC Lienhart A Aberer W Ring J Pichler WJ Demoly P Working Group for the SFAR ENDA EAACI Interest Group on Drug Hypersensitivity Reducing the risk of anaphylaxis during anaesthesia guidelines for clinical practice J Investig Allergol Clin Immunol 200515(2)91-101

An increase in weal size of more than 3 mm from the initial bleb with flare is considered positive

P Demoly N F Adkinson K Brockow et al International Consensus on drug allergy Allergy 2014 Apr69(4)420-37Mirakian R1 Leech SC Krishna MT Richter AG Huber PA Farooque S Khan N Pirmohamed M Clark AT Nasser SM Management of allergy to penicillins and other beta-lactams Clin Exp Allergy 2015 Feb45(2)300-27


NMBAs

Skin reactions to intradermal neuromuscular blocking agent injections a randomized multicenter trial in healthy volunteersMertes PM Moneret-Vautrin DA Leynadier F Laxenaire MCAnesthesiology 2007 Aug107(2)245-52 (accept 5 positivities with maximal non-reactive concentations)

Weal and flare responses to intradermal rocuronium and cisatracurium in humansLevy JH Gottge M Szlam F Zaffer R McCall CBr J Anaesth 2000 Dec85(6)844-9

Rocuronium and cisatracurium-positive skin tests in non-allergic volunteers determination of drug concentration thresholds using a dilution titration techniqueBerg CM Heier T Wilhelmsen V Florvaag EActa Anaesthesiol Scand 2003 May47(5)576-82


midazolam ketamine metamizol

Maximum non-reactive concentration of midazolam and ketamine for skin testing study in non-allergic healthy volunteersHagau N Bologa RO Indrei CL Longrois D Dirzu DS Gherman-Ionica NAnaesth Intensive Care 2010 May38(3)513-8

Proposal for use of two reading concentrations for metamizol to intradermal testingGherman-Ionică N Bologa R Cocu S Cristea C Dicircrzu D Hagău N Farmacia 2011 59(4) 578-589

Recommended maximum non-reactive drug concentrations for prick and intradermal testing

Skin test concentrations for systemically administered drugs -- an ENDAEAACI Drug Allergy Interest Group position paper

Brockow K Garvey LH Aberer W Atanaskovic-Markovic M Barbaud A Bilo MB Bircher A Blanca M Bonadonna B Campi P Castro E Cernadas JR Chiriac AM Demoly P Grosber M Gooi J Lombardo C Mertes PM Mosbech H Nasser S Pagani M Ring J Romano A Scherer K Schnyder B Testi S Torres MTrautmann A Terreehorst I ENDAEAACI Drug Allergy Interest GroupAllergy 2013 Jun68(6)702-12







Skin tests in immediate type drug allergy


Skin tests in immediate type drug allergy-concentrations controversies

For midazolam intradermal test a concentration of 025 mgml does not produce the doubling of the diameter of the injecting bleb so does not produce positive results and at a concentration of 01 mgml were no changes (wheal and flare) in the test area at 20 min interval for the recommended concentration (05 mgml) 50 of controls presented positive reactions

For ketamine intradermal test at the recommended concentration of 1 mgml 85 of controls developped positive reaction at 025 mgml the test does not produce positive results (bleb diameter doubling) and at 01 mgml the test area does not present any wheal and flare reactions at the reading time

Hagau N1 Bologa RO Indrei CL Longrois D Dirzu DS Gherman-Ionica N Maximum non-reactive concentration of midazolam and ketamine for skin testing study in non-allergic healthy volunteers Anaesth Intensive Care 2010 May38(3)513-8

In our population the recommended concentrations for midazolam and ketamine seems to be to high leading to false positive results


Guyer AC Saff RR Conroy M Blumenthal KG Camargo CA Jr Long AA Banerji A Comprehensive allergy evaluation is useful in the subsequent care of patients with drughypersensitivity reactions during anesthesia J Allergy Clin Immunol Pract 2015 Jan-Feb3(1)94-100

Ketamine 025 mgml


For intradermal testing with metamizol a concentration of 50 mgml does not produce positive results (bleb doubling) and at a concentration of 5 mgml no wheal and flare are observed a 20 min

The concentration of 5 mgml respect the definition of the maximal non-reactive concentration beeing the greatest concentration that does not produce wheal and flare in controls

Gherman-Ionică N Bologa R Cocu S Cristea C Dicircrzu D Hagău N Proposal for use of two reading concentrations for metamizol to intradermal testing Farmacia 2011 59(4) 578-589

In our population the recommended concentration of 01 mgml is to low increasing the risk of a false negative test

Of 130 intradermal tests to metamizol only 4 (3) were positive at 5 mgml (CAATI II database)

Skin tests in immediate type drug allergy cross-reactivities NMBAs (QAI epitope)

Cross-reactivity has been reported between neuromuscular blocking agents in up to 60ndash70 of casesIt is recommended that in the investigation of the suspected drug also other available neuromuscular blocking agents should be tested simultaneously to rule out cross-reactivity and to identify a safe alternativeBrockow K Garvey LH Aberer Wet al Skin test concentrations for systemically administered drugs -- an ENDAEAACI DrugAllergy Interest Group position paper Allergy 2013 Jun68(6)702-12

Multiple sensitizations are observed in the majority of patientsMonosensitization is more common with succinylcholineSensitization to all NMBAs are uncommonDong SW Mertes PM Petitpain N Hasdenteufel F Malinovsky JM GERAP Hypersensitivity reactions during anesthesia Results from

the ninth French survey (2005-2007) Minerva Anestesiol 2012 Aug78(8)868-78

A positive result to more than one NMBA (crossreactivity) was observed in 56 of patients with positive prick and intradermal tests in 42 with positive BAT and in 63 with positive specific IgEs Nadia Gherman-Ionica Erika Susana Brezoszki Manuela Sfichi Ramona Bologa Natalia Hagau Perianaesthetic anaphylaxis Initial results of the first Romanian allergo-anaesthesia centerRomanian Journal of Anaesthesia and Intensive Care 2011 Vol18 Nr2 87-94

Skin tests in immediate type drug allergycross-reactivities β-lactams

Mirakian R1 Leech SC Krishna MT Richter AG Huber PA Farooque S Khan N Pirmohamed M Clark AT Nasser SM Management of allergy to penicillins and other beta-lactams Clin Exp Allergy 2015 Feb45(2)300-27

Allergenic epitopes The beta-lactam ring the thiazolidinedihydrothiazine rings and the side group are all potentially immunogenic

Skin tests in immediate type drug allergycross-reactivities β-lactams side chains

Kim MH Lee JM Diagnosis and management of immediate hypersensitivity reactions to cephalosporins Allergy Asthma Immunol Res 2014 Nov6(6)485-95



Particular situationSkin tests in penicillin allergy-role in the diagnosis algorithm


Skin tests in perioperative allergy-role in the diagnosis algorithm


Skin tests in immediate type drug allergyConclusions

The skin test is the most commonly used procedure to confirm a sensitization in drug hypersensitivity



The sensitivity of skin tests decrease with time and it is not known whether the loss of skin test reactivity corresponds to a loss of allergy

Skin tests should use nonirritant concentrations of the drug determined in healthy controls for many drugs the non-reactive concentration is still debatable

Specificity sensitivity predictive value is not well established for all drugs

All in all skin testing represent an important step in the diagnostic algorithm of drug allergy mainly when the drug provocation test is not advisable (NMBAs) or in vitro tests are not available or sufficiently validated






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The skin tests in the diagnosis of immediate type drug allergy- determination of the maximum non reactive concentrations NMBAs

The skin tests in the diagnosis of immediate type drug allergy- determination of the maximum non reactive concentrations midazolam ketamine metamizol


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Skin tests in immediate type drug allergy cross-reactivities β-lactams

Skin tests in immediate type drug allergy cross-reactivities β-lactams side chains

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Particular situation Skin tests in penicillin allergy-role in the diagnosis algorithm


Skin tests in immediate type drug allergy Conclusions



















































NMBAs


























Ketamine 025 mgml




































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Ketamine 025 mgml




































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skin tests in immediate type drug induced allergy

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