Delayed onset of acute generalised exanthematous pustulosis following phenytoin administration

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Acute generalised exanthematous pustulosis (AGEP) is a serious adverse event affecting the skin, usually characterised by fever and an elevated white blood cell count. It is characterised by a sudden onset of diffuse, pinhead-sized, non-follicular, sterile pustules on an erythematous, oedematous base.¹ About 90% of the cases are drug-induced; others are triggered by viral and bacterial infections, mercury exposure, or spider bites.²

An 81-year-old woman with a history of epilepsy, obesity, and type 2 diabetes mellitus was admitted to the hospital with a pruritic rash on her trunk, associated with fever. There was no personal or familial history of psoriasis. Phenytoin had been initiated for epilepsy 2-weeks prior to presentation, and no other medications were introduced in the preceding 6 months.

Physical examination revealed a diffuse, confluent erythematous plaques covered by sheets of non-follicular, millimetre-sized pustules on the trunk, upper limbs, and thighs [Figures 1a and b]. There were no mucosal lesions, and Nikolsky sign was negative. Laboratory investigations revealed marked leukocytosis with neutrophil predominance, an elevated creatinine level of 103 µmol/L (reference range: 44-88 µmol/L), and increased C-reactive protein levels. Eosinophil count and liver function tests were within normal limits. Skin swabs and blood cultures were negative. Viral serology was negative for cytomegalovirus, Epstein-Barr virus, hepatitis B and C, HIV, parvovirus B19. Histopathological examination of a skin biopsy revealed subcorneal pustules, spongiosis, perivascular and dermal mixed infiltration composed of lymphocytes, neutrophils and eosinophils, and eosinophilic exocytosis [Figure 2a-b]. Based on clinical presentation, laboratory results, and histopathological evidence, AGEP was diagnosed. According to the objective causality assessment using the Naranjo adverse drug reaction probability scale, phenytoin-induced AGEP was classified as probable. Patch testing for phenytoin was not available. RegiSCAR scoring ruled out DRESS syndrome.

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Figure 1a:

Confluent, erythematous, scaly plaques on the trunk, upper limbs, and thighs.

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Figure 1b:

Pinhead-sized, non-follicular pustules on an erythematous and oedematous base.

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Figure 2a:

Subcorneal spongiform pustule (black arrow), accompanied by spongiosis and a dermal infiltrate composed of lymphocytes, neutrophils, and eosinophils (Haematoxylin & eosin, 40x).

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Figure 2b:

Subcorneal neutrophilic pustule (Haematoxylin & eosin, 400x).

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Phenytoin was immediately discontinued, and she received intravenous prednisolone (1 mg/kg/day) for 3 days, leading to near-complete resolution of the rash within 48 hours [Figure 3]. At the 2-year follow-up, she remained asymptomatic, with no evidence of recurrence.

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Figure 3:

Resolution of skin lesions following intravenous prednisolone administration.

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Although rare, AGEP can be triggered by anticonvulsants like phenytoin.^3-5 Literature reports a time-to-onset range between 5 days and 8 weeks after drug exposure of this group.⁶ Choon et al. described two phenytoin-induced AGEP cases where symptoms appeared 21 and 28 days after initiation.³ Similarly, Ben Salem et al. reported a young woman who developed AGEP 3 weeks after starting phenytoin.⁵

The reason this variable and sometimes delayed onset is possible lies in the complex immunological mechanisms behind AGEP. It is generally considered a type IV (delayed) hypersensitivity reaction, involving drug-specific CD4⁺ and CD8⁺ T-cells that activate an inflammatory cascade. These T-cells produce interleukin-8 (IL-8), a key chemokine that recruits neutrophils to the skin, leading to the pustular rash characteristic of AGEP. Some patients also show elevated Th17 cells and IL-22, which further stimulate keratinocytes to produce more IL-8, amplifying the response.⁷ Therefore, a delay of several weeks is immunologically plausible, particularly with drugs like phenytoin that are metabolised slowly and may persist in the system.

The close differential diagnosis includes acute generalised pustular psoriasis (GPP); however, most GPP cases are associated with a personal or family history of psoriasis. Histopathological differentiation between AGEP and GPP remains challenging due to overlapping features such as subcorneal and intraepidermal spongiform pustules. However, the presence of eosinophils, necrotic keratinocytes, and a mixed interstitial and mid-dermal perivascular inflammatory infiltrate is more suggestive of AGEP, whereas prominent psoriasiform acanthosis is more characteristic of GPP.⁸ Other less common differentials are bacterial, viral, or fungal cutaneous infections, neutrophilic dermatosis, and Sneddon-Wilkinson disease.⁴

Discontinuation of the offending drug is the cornerstone of AGEP management and often results in symptom resolution within approximately 2 weeks. In addition, topical corticosteroids are considered the first-line therapy.⁷ In more severe cases, systemic corticosteroids may be administered and have been associated with a reduction in both hospital stay and overall morbidity.⁴ In the present case, extensive cutaneous involvement and associated acute kidney injury led to the initiation of high-dose corticosteroid pulse to achieve a rapid therapeutic effect.

This case highlights the therapeutic strategy used, which enabled prompt clinical improvement, reduced the need for prolonged corticosteroid exposure, particularly important given the patient’s underlying diabetes, and contributed to a shortened duration of hospitalisation. Early recognition and prompt withdrawal of the culprit drug, combined with appropriate systemic therapy when indicated, are essential to minimise morbidity, especially in elderly patients with comorbid conditions.