Acetaminophen-induced cellulitis-like fixed drug eruption.

Acetaminophen is a widely used analgesic drug. Its adverse reactions are rare but severe. An 89-year-old man developed an indurated edematous and erythematous plaque on his left arm 1 day after acetaminophen ingestion. Cellulitis was suspected and antibiotictherapy was started but there was no improvement of the rash; there was a spectacular extension of the lesion with occurrence of flaccid vesicles and blisters in the affected sites. The diagnosis of generalized-bullous-fixed drug eruption induced by acetaminophen was considered especially with a reported history of a previous milder reaction occurring in the same site. Acetaminophen was withdrawn and the rash improved significantly. According to the Naranjo probability scale, the eruption experienced by the patient was probably due to acetaminophen. Clinicians should be aware of the ability of acetaminophen to induce fixed drug eruption that may clinically take several aspects and may be misdiagnosed.

Introduction

Acetaminophen is among the most commonly prescribed medications.[1] Its cutaneous adverse effects are rare, varying from transient pruritis or maculopapular rash to Stevens–Johnson syndrome and even fatal toxic epidermal necrolysis.[23] Only few cases of acetaminophen-induced generalized-bullous fixed drug eruption have been reported in literature.[45] We report a case of generalized-bullous-fixed drug eruption induced by acetaminophen and presenting initially like cellulitis.

Case Report

An 89-year-old man presented with a one-day history of painful erythematous and edematous eruption affecting his left arm.

The patient's medical history was significant for hypertension treated with furosemide (40 mg/day). Moreover, there was a notion of self-medication by acetaminophen for recent arthralgia in the latest 48 h.

On physical examination, the patient was febrile with an axillar temperature of 39°C. He had also a wet cough with expectorations of thick yellowish sputum. Vital signs were within normal range. His left arm was red, glossy, and warm to the touch. The plaque was tender and indurated with definite borders, covering the left forearm and extending to the upper arm [Figure 1]. Clinically, the lesion's aspect mimicked a cellulites, and the patient was initially treated with intravenous cefapirine (4 g/day).

Figure 1

On the left thigh, two superficial blisters and a ruptured bulla roof are seen on an erythematous base with epidermal detachment: generalized-bullous-fixed drug eruption

Laboratory investigations showed the following values: white blood cell count of 8.3×109/L (normal range, 4.5–11×109/l); hemoglobin 16 g/dl (normal range, 12–16 g/dl); blood urea nitrogen 9.6mg/dl (normal range, 6–21 mg/dl); and a creatinine level of 1.6 mg/dl (normal range, 0.5–1.3 mg/dl).

Two days later, superficial flaccid blisters appeared at the affected site and a varying size of multiple well-circumscribed erythematous and hyperpigmented patches were observed on the right arm, the abdomen, and both legs. Some of them were studded with flaccid vesicles and blisters [Figure 2]. The mucous membranes and the face were not involved.

Figure 2

A large erythematous, edematous, and shiny plaque with determinate borders covering the left arm: Cellulitis-like fixed drug eruption

In view of this skin disorder, the diagnosis of generalized-bullous-fixed drug eruption and Stevens–Johnson syndrome were considered.

Meanwhile, the patient gave history of similar but a more localized reaction following acetaminophen ingestion occurring 2 years earlier. A skin biopsy was carried out. Histopathological examination of the lesional biopsy specimen taken from a flaccid blister overlying a purplish-livid patch on the left arm revealed a thin epidermis with necrosis of epidermal keratinocytes. The dermis was edematous with a mixed inflammatory infiltrate consisting of mononuclear cells and few eosinophils. Direct immunofluorescence revealed no IgG, IgE, or IgA and C3 deposition at the basement membrane zone.

The diagnosis of acetaminophen-induced generalized-bullous-fixed drug eruption was confirmed based on the clinical and histological findings. Acetaminophen was then withdrawn. The blisters and vesicles disappeared few days later.

Discussion

Fixed drug eruption is a specific cutaneous adverse reaction induced by an ever-expanding list of drugs. It usually consists of solitary or multiple lesions occurring after the drug exposure. The reactions vary in severity from localized lesions to generalized eruptions. Acetaminophen-induced fixed drug eruption is reported in literature in less than 1.5% of all cases of fixed drug eruption.[6] This adverse reaction rarely progresses to a generalized bullous fixed drug eruption. It can exceptionally appear under a clinical shape, which mimes cellulitis.[7] In our review of the literature and according to data from a MEDLINE search for over the past 40 years, we identified only one publication regarding a case of cellulitis-like fixed drug eruption induced by acetaminophen. In this case, the fixed drug eruption, which was developed in a 65-year-old woman clinically seemed like cellulitis. There was absence of development of blisters even after rechallenge of acetaminophen.[7]

Our case is original in the sense that the eruption took several aspects in the same patient and changed from a cellulitis-like eruption to a generalized-bullous one. In fact, our patient developed at first an eruption clinically mimicking cellulitis and initially treated as such. However, the exacerbation of clinical manifestation under antibiotictherapy and with continued exposure to acetaminophen suggested the diagnosis of fixed drug eruption especially with the reported history of a previous milder reaction occurring in the same site. The clinical aspect of the eruption with the flaccid vesicles and blisters was unusual in fixed drug eruption. After a repeated exposure to the offending drug, the severity of fixed drug eruption may increase and may progress rarely to a generalized bullous-fixed drug eruption, which is an extensive form of fixed drug eruption. It is characterized by multiple, large, well-defined, purplish-livid patches eroded by flaccid blisters.[8] The clinical aspect may be misdiagnosed as Stevens–Johnson syndrome, which is an important differential diagnosis that can be separated by clinical means, but not in terms of the histopathology. In generalized-bullous-fixed drug eruption, lesions occur quite early within few hours of drug intake. It generally involves the same sites, which were affected in the previous episodes. By contrast, recurrent lesions in Stevens–Johnson syndrome show no predilection for previously affected sites. The epidermal changes in generalized-bullous-fixed drug eruption and Stevens–Johnson syndrome vary from few scattered necrotic keratinocytes to full thickness epidermal necrosis and the histopathological differentiation cannot be easily distinguished in all conditions. In fixed drug eruption, a mixed inflammatory infiltrate is noted around superficial and deep plexuses, which mainly contain neutrophilis and eosinophilis in addition to lymphocytes and histocytes. Presence of intraepidermal vesiculation with keratinocyte necrosis makes the diagnosis of fixed drug eruption more likely.[9]

In our case, there are many arguments in favor of generalized-bullous-fixed drug eruption induced by acetaminophen. In fact, there is a temporal correlation between the drug introduction and the rash appearance, previous history of milder reaction, favorable evolution and rapid recovery after acetaminophen withdrawal. Skin biopsy was also consistent with this diagnosis. According to the objective causality assessment by the Naranjo probability scale,[10] acetaminophen-induced bullous-fixed drug eruption was probable.The patient was firmly instructed to avoid self-medication, particularly with acetaminophen.

Conclusions

Physicians should be aware of the risk of the occurrence of cutaneous adverse reactions under acetaminophen, especially fixed drug eruption that may clinically appear with variable aspects and may be misdiagnosed.