Bullous nonpigmenting multifocal fixed drug eruption due to pseudoephedrine in a combination drug: clinical and diagnostic observations

Abstract

Nonpigmenting fixed drug eruption (NPFDE) is a clinically recognizable entity first reported in 1987 as a variant of FDE characterized by large and well-circumscribed erythematous plaques, rarely bullous, appearing repeatedly in the same area and shortly after drug readministration without residual pigmentation. In NPFDE, the site of lesions does not remain heavily pigmented after resolution because of the absence of hydropic degeneration of the basal cell layer and of pigmentary incontinence. Among the reported causes of NPFDE, pseudoephedrine hydrochloride (Ph) is the drug most commonly associated and the bullous form was described only in 1 of the 3 patients reported by Shelley and Shelley. As in patients with classic FDE, a challenge test with the suspected drug is the gold standard in establishing the diagnosis. In fact, a patch test with the offending drug, especially when applied on the previous lesions, may help diagnosis of NPFDE, but its sensitivity and its diagnostic value are unknown. However, this diagnostic algorithm is not easy to perform when the culprit drug is in a combination tablet and when it is not available individually on the market, as in the case reported below. A 38-year-old woman affected by allergic rhinoconjunctivitis was referred to us in April 2015 for many round, large, and itchy scarlet-colored edematous multifocal plaques symmetrically localized on the upper and lower limbs, lower back, and buttocks (Figure 1, A), and on the right-hand palm (Figure 1, B), and the nape. In the latter, the plaque was centered by a serous blister (Figure 1, C ). All lesions developed 6 hours after the single administration of a combination tablet containing Ph (60 mg), triprolidine hydrochloride (Th) (2.5 mg), and paracetamol (P) (300 mg). Lesions spontaneously disappeared within 2 weeks with no residual pigmentation. The patient reported that the same drug was administered several times during the last 5 years and that 1 year before similar lesions had appeared 10 hours after the administration of the same drug (second tablet on day 2). Two months later, we carried out patch tests both on uninvolved skin (upper back) and on previously involved skin (buttock) with the combination tablet as is. This was diluted 25% and 50% w/v in petrolatum (pet) and in dimethyl sulfoxide (DMSO) (Table I). No positive reactions were observed. Although we warned the patient not to take Ph-, Th-, and P-based drugs, in July 2015, she self-administered a combination tablet containing Ph (60 mg) and Th (2.5 mg). Five hours after, all the plaques relapsed in all previous sites and with the same clinical features. The lesions spontaneously resolved in 10 days with no residual pigmentation. In view of this positive self-rechallenge and according to the patient, we subsequently performed an oral challenge test with P (day 1: 0.3 mg, and 3.0 mg 12 hours later; day 2: 30.0 mg, and 300.0 mg 12 hours later) to definitely exclude this antiinflammatory drug, with negative result. Only in September 2015 we were able to obtain separately Ph and Th to clarify the etiological role of these 2 compounds and to specify the culprit drug. The 2 chemicals were patch tested as reported in Table I. Strong positive reaction to Ph 10% in DMSO on previous buttock plaque was observed. Diagnosis of multifocal bullous NPFDE due to Ph was made. The reported case presents some atypical clinical features. To our knowledge, among the cases of NPFDE due to pseudoephedrine reported in the literature, ours is the second bullous form described. Moreover, compared with multifocal classic FDE, our patient was younger (third decade vs sixth decade of life), the latency time was shorter (5-10 hours vs 24 hours to some days), and clinical course was shorter (10-14 days vs 1-6 weeks). Our patient raises the problem of the methodology and diagnostic value of allergological tests in NPFDE caused by Ph in a combination tablet. Ph is marketed in Italy only in combination with 2 or more active ingredients. For this reason, we first patch tested the combination tablet with false negative result, likely due to Ph low concentration in a tablet that is not able to elicit a positive patch test response. Positive self-rechallenge with PhþTh in a combination tablet allowed us to confirm the clinical but not the precise etiological diagnosis of NPFDE; the latter was possible only when Ph was singularly patch tested. In conclusion, our findings support the diagnostic utility of the patch test in NPFDE when performed (i) with the culprit drug, (ii) on the previously affected area, and (iii) employing DMSO as a vehicle with the function of a penetration enhancer. Moreover, this diagnostic procedure performed by us is relevant because it is well known that serious generalized, bullous, mucosal, and cutaneous reactions may be elicited by the challenge test in cases of FDE.