Acute generalized exanthematous pustulosis induced by terbinafine

ARTICLE

Auteur(s) : Rosa TABERNER, Lluis PUIG*, Montserrat GILABERTE*, Agustín ALOMAR*

Department of Dermatology, Hospital de Son Llàtzer, Carretera de Manacor, Km. 4, Son Ferriol, 07198 Palma de Mallorca, Spain 
* Department of Dermatology, Hospital de la Santa Creu i de Sant Pau, Barcelona, Spain

Article accepted on 18/03/2003

Case report

A 36-year-old woman presented a generalized pustular eruption. She had no personal or family history of skin disease including psoriasis, no documented allergies, and took no other medications. Nine days after she started oral therapy with terbinafine 250 mg/day for tinea corporis, she developed an intense and generalized eruption, which caused her referral 7 days later. On physical examination, there were diffuse, confluent, erythematous papules and plaques studded with non-follicular pustules, involving trunk and extremities. Palms, soles and mucous membranes were spared. She had no fever or lymph node enlargement, and general physical examination was normal. Terbinafine was discontinued and treatment was started with topical methylprednisolone aceponate and oral prednisone 60 mg/day, tapered to discontinuation in 2 weeks. Laboratory analyses revealed elevated white blood cell count (12.68 × 10⁹/L) with 83.5% neutrophils. Electrolytes, renal and liver function tests, urinalysis, and sedimentation rate were normal. A skin biopsy specimen showed subcorneal pustules containing neutrophils, spongiosis and a perivascular infiltrate composed of neutrophils, lymphocytes and esosinophils. Results of bacterial and fungal cultures of pustules were negative. The pustules dried and desquamated with postinflammatory hyperpigmentation. Fingernails and toenails exhibited yellow-white discoloration, and longitudinal ridges. Tinea corporis resolved following treatment with oral itraconazole, and the patient refused further tests. The temporal relationship strongly suggested terbinafine as the etiologic agent, and a diagnosis of acute generalized exanthematous pustulosis (AGEP) induced by terbinafine was established.

Discussion

In 1980, Beyot et al. [1] introduced the term acute generalized exanthematous pustulosis (AGEP) to describe pustular eruptions of acute onset after infection or drug ingestion in patients with no history of psoriasis, which healed spontaneously after a single attack. In 1991 Roujeau et al. [2] further delineated the main features of AGEP: (1) numerous small (less than 5 mm), mostly non-follicular pustules arising on a widespread edematous erythema; (2) biopsy showing intraepidermal or subcorneal pustules associated with one or more of the following: dermal edema, vasculitis, perivascular eosinophils or focal necrosis of keratinocytes; (3) fever (temperature more than 38 °C); blood neutrophil count above 7 × 10⁹/L; and (5) acute evolution with spontaneous resolution of pustules in less than 15 days.
Most cases of AGEP are drug-induced. A wide range of drugs has been suspected of causing these reactions, antibacterials being the most frequent triggers. Other reported drugs are antifungal agents, anticonvulsants and calcium channel blockers. Less common reported causes of AGEP included mercury exposure, PUVA, and viral infections [3]. A neutrophilic inflammation as a manifestation of a drug allergic reaction – as in AGEP – is unusual since eosinophilia, but not neutrophilia, is the typical hallmark of drug allergies. Previous reports of patients with AGEP have revealed a high rate of positive patch tests to drugs compared with patients with other drug eruptions [4]. This suggests that T cells are involved in AGEP. They seem to contribute to the accumulation of polymorphonuclear neutrophils (PMNs) at the site of the lesions by the release of PMN-attractive chemokines such as interleukin-8. A positive in vitro proliferative response of T cells from patients with AGEP to the incriminated drugs by lymphocyte transformation tests has recently been demonstrated [5].
Terbinafine is a widely used allylamine fungicidal agent. Adverse effects occur in 10.5% of treated patients, with cutaneous side effects in 2.3% [6]. Rashes, pruritus, urticaria, desquamation, and fixed drug eruption are predominantly reported. Severe and life-threatening cutaneous reactions (erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis) are rare. Terbinafine has been linked to flaring of stable chronic plaque psoriasis and the development of pustular psoriasis de novo [7]. Eight cases of terbinafine-induced AGEP have been reported in the literature [4, 8-13] (Table I). Post-marketing and experimental studies would be required to ascertain if this apparent overrepresentation of terbinafine as a causative agent of AGEP is due to reporting bias or can be associated with a pharmacologic effect of this drug, which has been shown to enhance selected functions of PMNs [14].

Table I. Published cases of terbinafine-associated AGEP

References

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2. Roujeau JC, Bioulac-Sage P, Bourseau C, Guillaume JC, Bernard P, Lok C, et al. Acute generalized exanthematous pustulosis. Analysis of 63 cases. Arch Dermatol 1991; 127: 1333-8.

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14. Vago T, Baldi G, Colombo D, Barbareschi M, Norbiato G, Dallegri F, et al. Effects of naftifine and terbinafine, two allylamine antifungal drugs, on selected functions of human polymorphonuclear leukocytes. Antimicrob Agents Chemother 1994; 38: 2605-11.