Original article Skin test evaluation in nonimmediate allergic reactions to penicillins Maculopapular exanthemas, followed by urticaria, are the most common manifestation of cutaneous drug reactions (1–3). Other skin reactions induced by drugs include erythema multiforme, Stevens Johnson syndrome, toxic epidermal necrolysis, fixed drug eruptions, erythro- derma (exfoliative dermatitis), hypersensitivity syndrome or drug rash with eosinophilia and systemic syndrome, pseudolymphoma, generalized or localized eczema, ba- boon syndrome, systemically induced contact dermatitis, flexural cutaneous adverse drug reactions, acute general- ized exanthematic pustulosis, purpura, leucocytoclastic vasculitis, lichenoid dermatosis and eczematous photo- sensitivity reaction (4). For maculopapular exanthema and urticaria, a number of studies indicate that aminopenicillins (AP) is the most common drug involved (5–7). These cutaneous reactions are reproducible and an immunological mechanism seems to be involved (8, 9). They can be induced after re-administration of the culprit drug (5, 6), and the application of the drug to the skin may also induce localized erythema and induration, often associated with the formation of vesicles and bullae, with the presence of a lymphocyte infiltrate consisting mainly of CD4 and CD8 cells (6–8, 10–12). Further support for an immuno- logical mechanism is that specific T cells and T-cell clones have been raised from both peripheral blood and affected skin (12–14). Originally, Levine reported delayed positive intrader- mal tests (IT), consisting of erythema and variable induration, in patients with skin rashes (15). Since then, a number of studies have reported that patch tests (PT) (6, 10, 16) or IT (5, 6, 17) can be used as a diagnostic procedure for studying nonimmediate reactions (NIR) to drugs. Although several comparisons between PT and IT have been carried out, considerable heterogeneity exists in their performance, including the preparation of the reagents (4–6, 18–20). These differences hinder compar- ison of the results and are a source of disagreement (4). Our group, for example, mainly uses IT, because this is part of a standardized protocol for evaluating patients claimed to be allergic to betalactams (5, 21). Background: Nonimmediate reactions (NIR) to aminopenicillins (AP) are frequent. Although patch testing (PT) and intradermal testing (IT) are used for diagnosis, comparative results have never been adequately performed. We compared PT and IT in subjects with NIR to AP. Methods: Twenty-one subjects with NIR to AP and positive IT were re-evalu- ated. Skin tests were performed with amoxicillin (AX) and ampicillin (AM) at different concentrations in petrolatum, 50, 25, and 5% w/w, for PT and in saline, 20, 2, and 0.2 mg/ml for both PT and IT. Skin biopsies from the site of the positive response were studied with haematoxylin–eosin and immunohisto- chemistry. Results: In the re-evaluation, one case was IT and PT negative and was excluded; 20 were IT positive and 18 PT positive for both AX and AM. Decreasing concentrations of AP induced a reduction in positivity in both methods when diluted in saline, but not when mixed in petrolatum (PT only). With both PT and IT, immunohistochemical studies showed a perivascular mononuclear infiltrate with CD4 and CD8 memory cells expressing perforin and granzyme B. Conclusions: Both tests appear valuable for the diagnosis of NIR to AP. How- ever, IT diagnosed more patients than PT. The vehicle (saline or petrolatum) had no influence on the response, although in the former the concentration was critical. The immunohistochemical analysis showed skin infiltrates compatible with a T-cell drug reaction. M.-J. Torres 1 , E. Sµnchez-SabatØ 2 , J. lvarez 3 , C. Mayorga 1 , J. Fernµndez 4 , A. Padial 2 , J.-A. Cornejo-García 1 , T. Bellón 2 , M. Blanca 1 1 Research Unit for Allergic Diseases, Carlos Haya Hospital, Mµlaga; 2 Allergy Unit, La Paz Hospital, Madrid; 3 Pathology Unit, La Paz Hospital, Madrid; 4 Allergy Unit, Elche Hospital, Alicante, Spain Key words: amoxicillin; ampicillin; intradermal test; nonimmediate reactions; patch test; skin tests; T cells. Maria Jose Torres Jaen, MD PhD Laboratorio de Investigación Hospital Civil, pabellón 5 sótano 29009 Malaga Spain Accepted for publication 26 May 2003 Abbreviations: AP, aminopenicillins; PT, patch test; IT, intradermal test; NIR, nonimmediate reactions to drugs; AX, amoxicillin; PPL, penicilloyl-poly-l-lysine; MDM, minor determinant mixture; AM, ampicillin. Allergy 2004: 59: 219–224 Printed in UK. All rights reserved Copyright Ó Blackwell Munksgaard 2004 ALLERGY 219