A 50-year-old woman was referred because of general malaise, diffuse pruritus, angio-oedema of hands and feet and lowered consciousness and faintness within 5 min of intake of a tablet of 500 mg valacyclovir (Zelitrex ; GSK, Genval, Belgium) for genital herpes simplex. History revealed no prior allergies. Flow cytometric analysis (FACScan; BD, Immunocytometry Systems, San Jose, CA, USA) of activated basophils was performed using quadruple labelling with Alexa 448-coupled anti-IgE (SigmaAldrich, Chemic GmBH, Steinheim, Germany), anti-phospho-p38 MAPK (T180/Y182) conjugated with Alexa Fluor 647 (BD Biosciences), anti-CD203c (kindly provided by HJ Buhring, Department of Internal medicine, University of Tubingen, Germany) and phycoerythrin-conjugated anti-CD63 antibodies [Pharmingen; BD Biosciences, Erembodegem, Belgium; for details: (1)]. The test included a negative control (stimulation buffer), a positive control (anti-IgE; Pharmingen) and stimulation with acyclovir (Zovirax ; GSK, dilution 1 up to 10 lg/ml). The test was also performed in a healthy control individual tolerant for acyclovir. Upon challenge with acyclovir, basophils of the patient showed a manifest dose-dependent phosphorylation of p38 MAPK from 0% to 78% and up-regulated CD63 and CD203c expression from 0% to 43% and 8% to 47%, respectively (Fig. 1). Phosphorylation of p38 MAPK and expression of CD63 and CD203c on basophils from the control individual remained unchanged. A lymphocyte transformation test (LTT) with acyclovir assessed by the incorporation of [methyl-H] thymidine (2) was borderline with a stimulation index (SI), i.e. counts per minute (cpm) of the acyclovir-challenged lymphocytes divided by the cpm cultured with serumfree medium of 2.1 for two consecutive stimulation concentrations of 10 and 100 lg/ml (normal 1.6). Skin prick tests for acyclovir were positive in the patient with a wheal and flare reaction of 5/27 mm for a 10 dilution but negative in an acyclovirtolerant control individual (up to neat solution). There is no serological assay for acyclovir-specific IgE that is readily available. Valacyclovir is the l-valine ester of acyclovir. After oral administration, valacyclovir is rapidly absorbed and extensively metabolized by gut hydroxylases into acyclovir and the essential amino acid l-valine (3). The mode of action and spectrum of anti-viral activity of valacyclovir are thus identical to acyclovir (4). In contrast to valacyclovir, acyclovir is available in a parenteral (intravenous) formulation that can be readily applied for in vitro and in vivo allergy-testing. Acyclovir and valacyclovir are considered effective and safe drugs (4, 5) and severe related immunologic adverse events remain anecdotal. However, systemic reactions, such as urticaria, angio-oedema and wide-spread erythematous dermatoses have been described (6–8). Note that several patients with systemic reactions had already presented an allergic contact dermatitis to topical application of acyclovir and that on several occasions crossreactivity with famcylovir that also contains a 2-aminopurine nucleus has been reported (7, 9, 10). Foscarnet and cidofovir do not contain that core, and might, therefore be considered as potential alternative antiviral drugs. We present a patient in whom the temporal relationship between intake and symptoms and results of additional tests are highly indicative of a valacyclovirrelated adverse event. Finally, our results endorse the basophil activation test (BAT) to be a potential additional tool to diagnose drug allergy [for review: (11)] AL LERGY 2 0 0 8 : 6 3 : 9 4 1 – 9 5 0 • a 2008 THE AUTHORS • JOURNAL COMPILAT ION a 2008 BLACKWELL MUNKSGAARD • CONTRIBUT IONS TO THIS SECT ION WILL NOT UNDERGO PEER REVIEW, BUT WILL BE REV IEWED BY THE ASSOCIATE EDITORS •