Introduction

Drug-induced fixed urticaria (DIFU) is an immediate-type reaction, characterized by isolated pruritic wheals that always appear in the same site after exposure to the responsible drug. DIFU was first described by Barbarroja-Escudero and colleague s in 2015 in two adult patients with atypical fixed drug eruption (FDE), caused by local anesthetics, and by paracetamol and metamizole, respectively. A suspected IgE-mediated mechanism was considered by the results of skin biopsies in both of them.¹ Another two adult patients with DIFU because of cross-reactive NSAID intolerance were described in 2019, being considered as a type of FDE that resembled a local form of NSAID-induced urticaria/angioedema (NIUA).² A fifth case in an adult caused by nivolumab has just been newly reported.³ We are aware of only two recently published p ediatric cases, caused by NSAID and by plasma-derived activated prothrombin complex concentrate, respectively.^4,5 We are reporting a third pediatric case (eight in adults and children) that presented at our center.

Clinical Case

This case concerns a 10-year-old girl who reported three episodes of localized urticaria on the dorsal side of both upper arms (Figure 1) and on the eyelid in the last 2–3 months, which occurred approximately 1 hour after taking ibuprofen. The wheals faded without treatment after 1 hour, although they did reappear with less intensity in the subsequent hours. She had previously taken ibuprofen, paracetamol, and metamizole with no adverse reaction. Her medical history included allergic rhinitis with sensiti zation to house dust mites. Her father also suffers hypersensitivity to NSAIDs, presenting with urticaria on his arms and other sites, as well as eyelid edema after taking ibuprofen, acetylsalicylic acid, and metamizole, but with good tolerance to paracetamol.

An oral provocation test (OPT) was performed with ibuprofen (1/10, 1/4, and 1/1 of the therapeutic dose in intervals of 1 hour; total cumulative dose 540 mg), which gave a positive result with the immediate appearance of a wheal on the left eyelid which disappeared and, 2 hours after administration, the appearance of itchy erythematous wheals on the dorsal surface of both upper arms that resolved spontaneously without treatment. Subsequently, OPT was conducted with acetylsalicylic acid (total cumulative dose 785 mg) and with metamizole (total cumulative dose 810 mg), which caused the appearance of the same wheals on the dorsal surface of her arms between 1 and 3 hours after administration, which resolved spontaneously. The wheals were completely similar to those occurring in previous episodes (Figure 1). No other skin manifestations or systemic symptoms were noted. The girl continues tolerating paracetamol, and also tolerated an OPT with meloxicam. Other laboratory tests or the performance of a biopsy were not considered useful nor convenient for this patient.

Figure 1 Three different episodes of urticaria from the patient. Wheals appear in the same location in both upper arms 1–3 hours after the intake of different NSAIDs. The wheals faded away without treatment in about an hour and flared up again mildly some hours later. Pictures captured and supplied by her mother.

Discussion

Our case adds to the rare reports of patients with DIFU. The eight published cases to date, including the one presented in this report, are summarized in Table 1. Common characteristics of these patients are the mild course with the absence of systemic symptoms, the short interval between drug administration and urticarial lesions, usually 1 hour or less, and fast resolution even without treatment, in normally less than 1 to a few hours. DIFU may be more frequent than supposed, if patients and doctors are not worried about such a mild disorder.

Cross-intolerance to NSAID was the main cause of DIFU in four of the eight patients. In our patient, the father suffers from generalized urticaria because of hypersensitivity to NSAIDs. Although this familial aggregation is not reported in other cases of DIFU, a genetic component has been reported in both FDE⁶ and NSAID hypersensitivity.⁷

Allergy skin tests are mostly useless. Provocation tests should be performed for confirmation because they are safe and produce mild urticarial lesions in the same location as the index reaction. Provocation tests are also useful to find alternative drugs for the patient.

The biopsy performed in three of the patients shows findings of typical urticaria. Some authors consider DIFU as an atypical variant of FDE, with which it shares the recurring location of the wheals in the same site after exposure to the drug involved. However, FDE is a late hypersensitivity reaction that usually presents as erythematous-violaceous wheals with well-defined edges that appear between hours to days after administration of the causative drug. The wheals subsequently heal leaving a residual post-inflammatory hyperpigmentation.^6,8 In contrast, in all cases reported in the literature with DIFU, the typical wheals developed and faded rapidly, without leaving residual lesions nor skin pigmentation. Patients with DIFU seem to share characteristics that are halfway between FDE and acute drug urticaria, and are also similar to some rare cases of food-induced fixed eruption.^9,10 Therefore, DIFU may be considered either as an atypical variant of FDE or as a peculiar form of acute drug-induced urticaria.

Although the treatment consists in avoiding the drug or drugs involved, repeated administration or desensiti zation have been performed when the drug was essential.^3,5

Conclusions

DIFU is a mild disorder characterized by repeated episodes of wheals in the same location after the administration of the same drug(s). DIFU is frequently associated with NSAID hypersensitivity, although its underlying physiopathology and long-term outcomes remain unknown because of the scarce number of patients who have reported to date. Provocation tests are safe and necessary for diagnosis.