General considerations for skin test procedures in …

1 RostrumGeneral considerations for skin test procedures in the diagnosis ofdrug hypersensitivityK. Brockow1, A. Romano2,M. Blanca3, J. Ring1, W. Pichler4,P. Demoly5*1 Klinik und Poliklinik fu r Dermatologie undAllergologie, Muenchen, Germany;2 Department ofInternal Medicine and Geriatrics, UCSC, Allergy Unit,CI Columbus, Rome and IRCS Oasi Maria SS, Troina,Italy;3 Research Unit for Allergic Diseases, Carlos HayaHospital, Malaga, Spain;4 Clinic for Rheumatology andClinical Immunology/Allergology, Inselspital, Bern,Switzerland;5 Maladies Respiratoires, Ho pital Arnaudde Villeneuve, Montpellier, FrancePascal DemolyMaladies RespiratoiresINSERM U454Ho pital Arnaud de VilleneuveCHU de Montpellier34295 Montpellier cedex 5 FranceAccepted for publication 20 August 2001 Diagnostic procedures in allergy diagnosis can beclassified into the patient s history,in vivoskin testing,in vitrolaboratory tests and provocation tests (1). Indrug hypersensitivity, a reliable diagnosis is particularlydifficult.

2 The history is often not reliable since differentdrugs are often taken simultaneously. Test reagents areneither standardized forin vitronor forin vivo( skin ) tests and provocation tests are cumbersome, possiblyharmful for the patient and possibly not sensitiveenough since crucial cofactors might be absent duringthe procedure. Finally, the clinical picture of drughypersensitivity is very heterogeneous, mirroring manydistinct pathophysiological events. When immunologicmechanisms have been shown, either antibody or cellmediated, the reactions are referred as drug allergy (20).Drug allergy is in the vast majority due to IgE-mediatedimmediate-type reactions or T-cell mediated delayed-type reactions. In a large number of patients, no allergycan be proven, which may be either due to the lack ofadequate test reagents or procedures , or may indicate anon-allergic pathomechanism. Thus, many doctors relyon history and some reference manuals for drug adverseevent diagnosis, without attempting to prove therelationship between drug intake and symptoms or toclarify the underlying pathomechanism of the an attitude leads to a misunderstanding of theepidemiology and the pathophysiology of this highlyrelevant tests can be used for the evaluation of a drughypersensitivity (2 5).

3 The diagnostic value of skintests has not been fully evaluated and the experience indifferent centres has rarely been exchanged during the*ENDA: European Network for Drug Allergy, the EAACI interestgroup on drug hypersensitivity with the following additional members:Drs W. Aberer, B. K. Ballmer-Weber, A. Barbaud, A. Bircher, , P. Campi, A. de Weck, M. Drouet, J. Fernandez, T. Fuchs, , J. L. Gue ant, C. Gutgesell, A. Kapp, M. Kowalski, G. Marone,H. Merk, D. Moneret-Vautrin, C. Pascual-Marcos, B. Przybilla, , F. Rueff, A. Sabbah, J. Sainte Laudy, M. J. Torres, , B. WediAllergy 2002: 57: 45 51 Printed in UK. All rights reservedCopyright#Munksgaard 2002 ALLERGYISSN 0105-453845last decades. Thus, reliable skin test procedures for thediagnosis of drug hypersensitivity are generally missingand test concentrations are unknown or poorlyvalidated for most tests have to be applied according to thesuspected pathomechanism of thedrughypersensitivity (2 5).

4 In immediateb-lactam drugallergy an IgE-mediated reaction can be demonstratedby a positive skin prick and/or intradermal test after20 min (6, 7). On the other hand, non-immediatereactions tob-lactams manifesting by cutaneoussymptoms occurring more than one hour after lastdrug intake, are often T-cell mediated and a positivepatch test and/or a late-reading intradermal test isfound after several hours or days (8). Moreover, skintests have the additional capability to give insightsconcerning the immunologic harmonize our drug hypersensitivity diagnosticprocedures in Europe, members of ENDA (the corepart of the EAACI interest group on drug hypersensi-tivity) have first developed a questionnaire based on adetailed history of the reaction (9). It also includes someprocedures for skin tests , provocation tests andbiological tests . It is available in various languagesand thus utilized in different regions of Europe. Ournext aim is to develop useful test procedures for thediagnosis of drug hypersensitivity, procedures whichare simple and can be used in centres not specialized indrug a first step, we define General principles for skintesting of drugs, to establish the best skin testconcentrations to be used for already well-studied sub-stances.

5 For other substances and through collaborativestudies, we will be able to provide sensitivity andspecificity data for each drug and drug of patients for skin testingA list of common clinical symptoms, for which skintesting is recommended is listed 1. For thepractising allergist, skin testing with SPT, IDT and/orpatch test is especially recommended in adverse drugreactions to beta-lactam antibiotics (mainly penicillins,cephalosporins). SPT and IDT are often positive tomyorelaxants, insulin, protamine, heparin, streptoki-nase and chymopapain. It is also recommended toperform patch tests and IDT in delayed local orexanthematic adverse reactions to other antibiotics,carbamazepine, practolol, pyrazonolines and tetraze-pam. skin tests and provocation tests to localanesthetics should be performed; however, in this casethe purpose is to exclude a reaction to a preparationunder test conditions, rather than to confirm and signs generally indicating drugallergy, as opposed to non-immunologic adversereaction, are the presence of a sensitization period,reaction to low dosages of the drug, and typicalsymptomatology such as urticaria and anaphylaxisimmediately after administration of a drug (Table 1).

6 However, in adverse reactions to drugs, this generalscheme is often unreliable, as sensitization may not beapparent and some reactions may mimic symptoms ofallergy. Thus, centres with a special interest on drugallergies are encouraged to test patients with otherdrugs to gain and publish experience on the value ofskin testing under different are other diseases where immunologicalreactions to drugs could be involved, but skin testinghas generally not been found helpful. For example,renal or hepatic manifestations may occur as a part of ageneralized allergic reaction ( , in Drug Reactionwith Eosinophilia and Systematic Symptoms). How-ever, the value of skin tests in hematological (anemia,thrombocytopenia, leukopenia), renal ( , glomerulo-nephritis) or hepatic manifestations ( , hepatitis) hasnot been proven. Also skin testing is not consideredto be helpful in autoimmune diseases like systemiclupus erythematosis, bullous pemphigoid, pemphigusvulgaris, and interstitial lung algorithm for the use of skin tests is given immediate, possibly drug-related symptoms ofurticaria/angioedema, rhinitis, conjunctivitis, broncho-spasm or other anaphylactic symptoms, skin prick testsand intradermal tests are recommended.

7 However, it hasto be considered that systemic reactions during skintesting might occur (seeTesting of patients at higher risk;below).In non-immediate, possibly drug-related reactions ofcontact dermatitis, photo-contact dermatitis, exanthe-matous drug eruptions, urticaria/angioedema, purpurapigmentosaprogressiva,leucocytocl asticvasculitis,fixeddrugeruptions(testi nginpreviouslyinvolvedareasandinunaffect ed skin ), Stevens Johnson Syndrome, erythemamultiforme, and toxic epidermal necrolysis, patch testsand/or late readings of the intradermal tests after 24, 48and 72 h are recommended (2 5, 8, 10 12). Also in non-immediate drug hypersensitivity, systemic reactionsfollowingskintestingareknown(13 ).Inseveresituationsespecially, skin testing has to be performed with caution(see specific chapter,Testing of patients at higher risk). Arecurrence or elicitation of a toxic epidermal test methodsStandardized skin test methods considered in thisdocument are the skin prick test (SPT), the intradermaltest (IDT), the patch test and the photopatch tests are used in some centres, but will not befurther considered in this et prick tests and intradermal tests (1) SPT is done by pricking the skinpercutaneously with a prick needle through anallergen solution (14).

8 It is the safest and easiest test,but only moderately sensitive, for immediate drugreactions. An intradermal test is accomplished byinjecting ml of an allergen intradermally,raising a small bleb measuring 3 mm in diameter. TheIDT is more sensitive than the SPT, but also carries ahigher risk for inducing an irritative, falsely positivereaction and might even lead to an anaphylacticreaction in IgE-dependent drugs have to be discontinued prior to skintesting.(Table 2). The patient should be free ofinfectious diseases, fever or inflammatory reactions atthe time of testing, unless the skin test is urgentlyneeded. The intake ofb-adrenergic blocking agentsshould be discontinued (usually for 48 h,) according totheir half-life of elimination, if the drug to be tested hadinduced an anaphylactic reaction, as these drugs mayinterfere with treatment of a possible systemic reactionelicited by the skin should be performed on the volar aspect of theforearm.

9 If this is negative after 15 20 min, anintradermal test can be performed on the volar forearm,although other regions can be tested (however, there isno comparison for drug allergens). The pain ofintradermal tests may limit their use in young these tests are well tolerated, but in highlyIgE sensitized patients generalized symptoms (urticariaand anaphylaxis) might appear.(2) Documentation and should betaken after 15 20 min if immediate reactions areanalyzed, and after 24 and 72 h for evaluation ofnon-immediate (late) reactions. In selected cases,additional readings ( , after 96 h) are sometimesrecommended, as time intervals between testing andpositive test reactions may reactions are documented by measuringthe mean diameter of the wheal (and erythema) of thetest preparations and the negative control directly afterthe injection and after 15 20 min. Different qualitativescoring systems are available and used in differentcentres (14).

10 In order to compare the results, amorphological score should be applied as well, enablinga later comparison of different scoring systems. Thepreferred documentation manner is by outlining the sizeof the injected area and of the reaction at 15 20 min ona translucent cellophane tape. As a criterion forTable 2 Drug-free interval demanded for drugs decreasing reactivity of skin tests (adapted from (14))MedicationRouteImmediate reactionNon-immediate reactionFree intervalH1-antihistamines Imipramines, phenothiazinesb-adrenergic drugsGlucocorticosteroids**Long-termShor t-term, high doseShort-term,<50 mg pred*Topical corticosteroidsOral, intravenousOral, intravenousOral, intravenousOral, intravenousOral, intravenousOral, intravenousTopical**++ttttt ++ +5d5d**3 weeks1 week3d>2 weeks*Prednisolone equivalent; ** no clinical relevance; ** withdrawal may not be possible; ** at the site of testing 1 Common clinical indications for skin testing in the diagnosis of drughypersensitivityPatch tests can be usedas first line of investigationSkin prick tests andintradermal testsAcute generalizedexanthematous pustulosisContact dermatitisErythema multiformeExanthematous drugeruptionFixed drug eruptionPhotoallergic reactionsPurpura/LeucocytoclasticVasculi tisStevens Johnson SyndromeAnaphylaxisBronchospasmConjuncti vitisRhinitisUrticaria/angioedemaToxic epidermal necrolysisFigure for the use of skin tests in the diagnosis ofdrug hypersensitivities.