Acute generalized exanthematous pustulosis induced by topical diphenhydramine

ARTICLE

ejd.2011.1500

Auteur(s) : Takaaki Hanafusa, Ken Igawa igawa@derma.med.osaka-u.ac.jp, Hiroaki Azukizawa, Ichiro Katayama

Department of Dermatology, Osaka University, Graduate School of Medicine, 2-2 Yamada-oka Suita-city, Osaka 565-0871, Japan

Acute generalized exanthematous pustulosis (AGEP) is characterized by the rapid onset of many sterile erythematous pustules, often accompanied by leukocytosis and fever. In almost all cases, systemic administration of drugs is causative, but AGEP can sometimes be induced by the application of topical medicines, such as bufexamac [1, 2]. To our knowledge, this is the first case report of AGEP probably induced by the application of diphenhydramine cream.

A 67-year-old woman presented with itchy erythematous plaques at the site of insertion of a catheter on the left arm for intravenous hyperalimentation, 15 days after partial pancreatic resection for serous cystadenoma. A low-grade fever of approximately 37.0̊C had persisted for several days, but no infectious symptoms were noted as she had a normal white blood cell (WBC) count and normal C-reactive protein levels. On the following day, the adhesive film for the catheter was removed since we hypothesized that the dressing might induce contact dermatitis. Treatment with topical diphenhydramine cream was subsequently begun for the erythema. The pruritic erythemas were exacerbated; 2 days later, she presented with developing erythematous patches and scattered pustules, extending to the site of the diphenhydramine cream application on both the trunk and extremities (figure 1A, B). No mucosal involvement was noted. Physical examination revealed a high body temperature of 38.4̊C. Laboratory findings showed leukocytosis (WBC count, 15,850/μL) with 89.0% neutrophilia, but neither were infectious symptoms observed nor were bacterial infections identified in a bacteriological culture of the contents of one of the pustules. A drug lymphocyte stimulation test (DLST), performed 2 days after the erythematous pustules appeared, was positive for diphenhydramine (stimulation index: 480%). A skin biopsy from a left femoral pustule revealed subcorneal neutrophilic pustules and perivascular infiltration of neutrophils, lymphocytes, and eosinophils (figure 1C, D). The AGEP validation score (EuroSCAR group criteria) was 9 (8-12: definite) [1]. Therefore, we diagnosed the patient with AGEP mostly likely induced by diphenhydramine cream application. Replacement of diphenhydramine cream with betamethasone ointment dramatically improved her erythematous skin reactions within 3 days, with post-pustular desquamation. Her leukocytosis and high fever also improved. A patch test, performed 3 days after the erythematous pustules resolved, was negative for diphenhydramine cream (as is) (diphenhydramine 1%) at both the 48- and 72-hour time points.

Diphenhydramine, one of the most effective sedating antithistamines, is often used in topical medicines [3]. Nevertheless, it can induce contact sensitization and photodermatitis [4]. In this case, we concluded that the preceding low-grade fever was non-specific and temporary under post-operative conditions, but the concurrent high fever was closely related to diphenhydramine cream application, because she did not present any symptoms of infection and her body temperature rose after drug application and fell rapidly after drug stoppage, corresponding to the clinical course of the erythematous pustular reactions. Localized pustular contact dermatitis as a differential diagnosis could be ruled out, since it does not accompany either leukocytosis or high fever. Histologically, spongiotic changes were rarely found in the epidermis, as commonly seen in contact dermatitis. Recently, the definition of acute localized exanthematous pustulosis (ALEP) was introduced [5], which may be an appropriate diagnosis in our case, because the skin reaction was limited to the application site. On the other hand, a patch test after resolution of the pustules was negative in our case. One reason for our findings could be a false-negative result or inflammasome signaling of IL-1β from some preceding post-operative inflammation, which would convert diphenhydramine cream into a sensitizer, inducing neutrophilic and eosinophilic reactions through IL-8 and IL-5 [6].

Disclosure

Financial support: none. Conflicts of interest: none.

References

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