Fixed drug eruption is a drug reaction that has a bullous form in one-third of cases. It can present infrequently as a generalized form, with blisters and erosions, in addition to mucosal involvement, and should therefore be considered in the differential diagnosis of other more common cutaneous drug reactions such as erythema multiforme major, Stevens-Johnson syndrome, and toxic epidermal necrolysis. We present the case of an elderly patient with associated comorbidities, hospitalized for abdominal symptoms requiring antibiotic therapy and analgesia, who developed erythematous-violaceous lesions on the trunk and extremities, with blisters and eroded areas, in addition to mucosal involvement. The patient received a presumptive clinical diagnosis of erythema multiforme major or Stevens-Johnson syndrome, but the pathological findings were consistent with generalized bullous fixed drug eruption.

Bullous fixed drug eruption is a rare clinical variant of fixed drug eruption, accounting for 30% of cases [1,2]. Regarding the pathophysiology of this condition, it is believed that this condition is mediated by CD8+ memory T cells located in the basal layer of the epidermis in latent lesions of fixed drug eruption [2].

It is considered a severe adverse reaction that can lead to significant morbidity and mortality¬¬. According to the Food and Drug Administration Adverse Event Reporting System (FAERS) published by Shrestha P et al, out of 19,604,736 identification reports from 2012 to 2022, 1,393 cases of FDE and 71 cases of GBFDE were identified, representing approximately 0.0075% of the total [3].

It is usually associated with drugs administered topically, orally, or parenterally [4], including trimethoprim/sulfamethoxazole, nonsteroidal anti-inflammatory drugs, azoles, and anticonvulsants [2].

It typically appears minutes to hours after initial exposure [2], in a localized or generalized form [2,5]. Clinically, it presents with classic oval erythematous-violaceous plaques, in addition to a diffuse, generalized rash with blisters and erosions [4]. This generalized form with blisters and erosions can resemble Stevens-Johnson syndrome or toxic epidermal necrolysis, depending on the extent of the lesions [4]. Erythema multiforme is also considered as a differential diagnosis [6]. 

This rare case highlights the clinical, histological, and prognostic differences compared to other more well-known entities that are often considered first-line diagnoses.

A 72-year-old female patient, hypertensive and diabetic, treated with losartan 100 mg/day and metformin 850 mg/day, was hospitalized for acute cholecystitis. She received treatment with amoxicillin-sulbactam, with subsequent coverage adjusted to ciprofloxacin and metronidazole, plus dipyrone due to a fever spike upon admission. Two days after starting medication, she presented with erythematous lesions that began on the trunk and spread to the extremities, as well as the face and mucosal involvement. Physical examination revealed rounded, erythematous-violaceous macules and plaques, some with a vesiculobullous center, appearing as a target, others coalescing, with scaly areas on the face, trunk, and upper and lower extremities, affecting 80% of the surface area. Nikolsky's sign was negative. Petechiae were present in the oral mucosa, and erosions were observed on the hard palate. No other mucous membranes were affected. 

Figure 1: Erythematous-violaceous macules and plaques, some with a blister center, others eroded, on the face and trunk.

Laboratory results: White blood cells 12,5 × 109/L; Neutrophils 73%; Lymphocytes 13%; Eosinophils 10% (1,25 × 109/L) (SI). Renal and liver function tests were unremarkable.

Punched biopsy of macular lesions and plaques with a bullous center using punch number 4 revealed lichenoid dermatitis with subepidermal bullae, isolated basal necrotic keratinocytes, extensive perivascular interstitial eosinophilic infiltrate, superficial melanophores, and erythrocyte extravasation, consistent with fixed bullous drug eruption.

Figure 2: Skin biopsy of the trunk (hematoxylin and eosin) 10X: lichenoid dermatitis with subepidermal bullae (black arrow), isolated basal necrotic keratinocytes, extensive superficial perivascular and interstitial eosinophilic infiltrate (red arrow) with scattered melanophores and erythrocyte extravasation.

Corticosteroid therapy was initiated with prednisone 1 mg/kg/day, with subsequent clinical improvement after one week, followed by a tapering regimen. 

This case highlights the similarities and differences between generalized bullous fixed drug eruption and other pathologies such as erythema multiforme and Stevens-Johnson syndrome or toxic epidermal necrolysis.

The frequency of this condition varies from 6.7% of 30 cases of fixed drug eruption in an Iranian series to 50.8% in a French series [7,8]. In the study by Zaouak et al., [5], no sex predominance was observed, and it can affect any age, from young people to older adults.

Exposure to many drug groups makes etiological diagnosis challenging, but dipyrone is considered the most frequent culprit. Nonsteroidal anti-inflammatory drugs (NSAIDs) were the drug group most frequently associated with generalized bullous fixed drug eruption according to the series by Zaouak et al., [5], Freitas et al., [9] and Paulmann et al., [10]. Similarly, in a study conducted in Taiwan and Tunisia, dipyrone was the most frequent cause, while etoricoxib and paracetamol were the most frequent causes in a series from Singapore; and non-steroidal anti-inflammatory drugs and paracetamol were the most frequent causes in a study from Korea [10]. Ciprofloxacin and metronidazole are also cited as less frequent causes [3]. The timing of administration was taken into account: dipyrone was the drug received on the first day, and lesions developed two days after its administration; while ciprofloxacin and metronidazole were administered later, one day before the skin lesions appeared. It is described that the lesions usually appear between 8 and 24 hours after re-exposure to the causative drug, unlike Stevens-Johnson syndrome or toxic epidermal necrolysis, where exposure occurs 1 to 3 weeks before the appearance of skin lesions [2]. Generalized bullous fixed drug eruption is characterized by erythematous-violaceous and vesiculobullous plaques, with involvement of at least 10% of the body surface area and affecting at least three of six anatomical sites: head, neck, anterior and posterior trunk, upper and lower extremities, and genitals; both the lesions and the extent can be similar to Stevens-Johnson syndrome [5,10], but the clinical and histological differences to consider are:

• The presence of systemic symptoms is mild in generalized bullous fixed drug eruption and erythema multiforme compared to Stevens-Johnson syndrome or toxic epidermal necrolysis;
• Mucosal involvement is rare and mild, unlike Stevens-Johnson syndrome where involvement must be present in at least one mucosa and is usually severe; The patient presented with mild buccal mucosal involvement and no involvement of other mucous membranes [2].
• The histological findings of generalized bullous fixed drug eruption consist of subepidermal blisters or denuded epidermis and vacuolar interface dermatitis with a variable number of necrotic keratinocytes in the epidermis, in addition to inflammatory infiltrate in the dermis. These same findings can also be observed in erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis [5,6]. Eosinophil infiltration is more suggestive of generalized bullous fixed drug eruption, with a higher number of eosinophils compared to Stevens-Johnson syndrome. Melano phages are also more frequently associated with generalized bullous fixed drug eruption and are usually present in later stages [4,10]. These last two findings were observed in the patient, leading to this diagnosis.

Previously, a distinction was thought to be necessary between generalized bullous fixed drug eruption and Stevens-Johnson syndrome because the prognosis and treatment were considered different. However, a case-control study comparing both entities demonstrated that mortality in both groups was not significantly different, with a 22% mortality rate in patients with generalized bullous fixed drug eruption [6].

The mainstay of treatment is discontinuation of the causative drug in addition to supportive care, although topical and systemic corticosteroids are commonly used in generalized bullous fixed drug eruption as treatment in several cases. It rarely requires admission to the intensive care unit, unlike Stevens-Johnson syndrome or toxic epidermal necrolysis [4,10].

Among the main limitations of this report are the descriptive design based on a single case, the impossibility of performing provocation or re-exposure tests to the drug due to the high risk of triggering a severe reaction, and the recall bias since the identification of the causative agent depended largely on the pharmacological history reported by the patient.

This case highlights the clinical and histological similarities between generalized bullous fixed drug eruption, a rare entity, and more common conditions such as erythema multiforme and Stevens-Johnson syndrome/toxic epidermal necrolysis. While certain findings help distinguish between these entities, the prognosis and treatment are similar.

Funding: This Research Received No Esternal Funding

Conflict of interest: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. 

Institutional Review Board Statement: ethical review and approval were waived for this case due to its nature as a single-patient case report, in accordance with institutional policies. 

Informed Consent Statement: written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Data availability statement: data are contained within the article.

Copyrights: the authors of these case report approve the submission and publication of this original and unpublished work.