Terbinafine‐induced generalized pustular psoriasis (GPP) of von Zumbusch simulating toxic epidermal necrolysis (TEN)

Dear Editors, A 69-year-old man with a history of post-angioplasty myocardial infarction, hypertension, and chronic renal dysfunction presented with a five-day history of progressive erythema that began over the chest before becoming generalized and involving most of the skin surface. Two days prior, he also reported facial swelling, cutaneous pustules, generalized skin sloughing, along with progressive skin tenderness. In addition, he complained of mild oral pain, fatigue, and malaise. Fifteen days prior to the onset of symptoms, his family physician prescribed him a three-week course of terbinafine 250 mg daily for an itchy groin rash. Three days before the onset of symptoms, he was started on a five-day course of prednisone 50 mg daily for a syncopal episode at the emergency department. His other long-term medications included ezetimibe, clopidogrel, aspirin, and metoprolol. In addition to his past medical history, he reported chronic erythematous, thick scaly plaques over his elbows for the past four years. On examination, he presented with an extensive eruption (Figure 1a–c). Notably, Nikolsky's sign was positive revealing areas of skin detachment (Figure 1d, e). The Asboe-Hansen sign was also positive. The total area of skin detachment was over 30% of the body surface area. He also had mucosal erosions of his hard palate. Further examination revealed diffuse nail pitting of his fingernails (Figure 1f). Lab work demonstrated significant neutrophilia of 22.1 × 109/l (4.0–10.0) with toxic granules and vacuoles on microscopy, elevated C reactive protein of 84.1 mg/l (< 10.0), elevated creatinine of 550 μmol/l (58–110), and mild hypocalcemia of 2.09 mmol/ml (2.10–2.55). Streptolysin O antibody, autoimmune serologies, urinalysis, and liver function were all unremarkable. Two skin biopsies, one each of a targetoid lesion and pustule, were taken, revealing intracorneal neutrophilic pustules, hypogranulosis and epidermal hyperplasia, and dilated dermal blood vessels, with notable absence of eosinophils (Figure 2a–c). Direct immunofluorescence of perilesional skin was negative. A thorough discussion of the treatment options, including systemic and topical corticosteroids and cyclosporine A, was completed with the patient. In the context of the patient's significant chronic renal dysfunction, consideration of the patient preference, and acknowledgement that we could initiate more aggressive treatment at any time if needed, we proceeded to begin initial treatment with generous application of clobetasol 0.05% ointment coupled with the immediate withdrawal of terbinafine. Gradual but significant improvement was then noted. Given the clinical history and the presence of extensive pustules, the differential diagnoses primarily included terbinafine-induced generalized pustular psoriasis (GPP) of von Zumbusch or severe terbinafine-induced acute generalized exanthematous pustulosis (AGEP) with the unique presentation of extensive skin detachment. Generalized pustular psoriasis and AGEP can be very difficult to differentiate clinically given the significant overlap of clinical, and even histological, features. The acute onset in the setting of the initiation of a high-risk medication (terbinafine) without other infectious triggers raised the suspicion of AGEP.1 However, in our case, the diagnosis of GPP was preferred given the patient's history of chronic thick scaly plaques over the extensor surfaces suggestive of plaque psoriasis, the physical finding of nail pitting, laboratory findings of hypocalcemia and severe neutrophilia, in addition to the histological features of hypogranulosis and dilated dermal blood vessels without eosinophils. The literature on cases of AGEP and GPP simulating toxic epidermal necrolysis (TEN) was reviewed to further understand the characteristic of the unique phenotype of skin detachment with each condition. First, a total of 21 reported cases of AGEP simulating TEN revealed female predominance without tendency towards a specific age group.2 Many classes of medications, with a notable exception for terbinafine, have been reported to be the causative agents for of the unique presentation of AGEP with significant skin detachment (also known as AGEP with TEN-like desquamation), most commonly beta-lactam antibiotics.2 The eruption started an average of eight days (range of 1–19 days) after drug initiation.2 Patients presented with generalized erythema, pustules, skin blisters, and skin detachment.2 Skin histology showed typical features of AGEP including subcorneal pustules, perivascular inflammatory infiltrate, and most importantly eosinophils.2 On the other hand, a literature search for GPP cases simulating TEN found two cases.3, 4 Varman et al. reported a 42-year-old male with spontaneous onset of extensive skin desquamation simulating TEN, and skin histology showed classic features of GPP.3 Pomahac et al. reported a 55-year-old female presented with pustular eruption with skin desquamation after pre-operative antibiotic use, and the diagnosis was more ambiguous.4 The authors favored the diagnosis of GPP over AGEP, despite the presence of eosinophils on skin histology.4 This again emphasizes the challenge of differentiating GPP from AGEP in certain cases. In addition, a review of all reported cases of GPP triggered by terbinafine revealed the eruption started on an average of 23 days (range of 4–35 days) after drug initiation, which is longer than that of the AGEP simulating TEN.5-9 In summary, the diagnosis of terbinafine-induced GPP is favored in this case. We hope that this case further emphasizes the importance for clinicians to consider not only AGEP but also drug induced GPP when patients present with generalized pustular eruptions with positive Nikolsky's sign and skin detachment in the context of drug eruptions. Timely histological confirmation of the diagnosis and discontinuation of the medication are crucial. We would like to thank Dr. Richard Crawford for providing us with the histology figures and Dr. Jeffrey Toy for his assistance in the preliminary search of the literature. We would like to acknowledge Dr. Brian Kumimoto's involvement in the clinical management this patient. None.

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