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Observation
June 20, 2011

Acute Generalized Exanthematous Pustulosis Simulating Toxic Epidermal NecrolysisA Case Report and Review of the Literature

Author Affiliations

Author Affiliations: Division of Dermatology, University of Calgary, Calgary, Alberta, Canada (Dr Haber). Mr Peermohamed is a medical student at the University of Calgary.

Arch Dermatol. 2011;147(6):697-701. doi:10.1001/archdermatol.2011.147
Abstract

Background  Both acute generalized exanthematous pustulosis (AGEP) and toxic epidermal necrolysis (TEN) are adverse cutaneous reactions. Despite the fact that these 2 cutaneous reactions differ in presentation, prognosis, pathologic features, and treatment, overlap can exist between them, creating a diagnostic challenge.

Observations  We describe a patient who presented with clinical features of both AGEP and TEN, and we summarize overlapping cases of AGEP-TEN that have been reported in the literature. It is essential to be able to differentiate between AGEP and TEN, as these conditions are clinically and morphologically distinct entities. They also differ considerably in their prognosis and treatment.

Conclusions  Because overlap exists, AGEP should be considered in the differential diagnosis of widespread blistering and erosive conditions. A greater understanding of how to differentiate AGEP and TEN can lead to quicker diagnosis as well as more effective case management and treatment.

We describe a patient who presented with clinical features of both acute generalized exanthematous pustulosis (AGEP) and toxic epidermal necrolysis (TEN), and we review reports of overlapping cases of AGEP and TEN.

REPORT OF A CASE

A 25-year-old man was admitted to an intensive care unit and underwent an emergency laparotomy because of widespread abdominal trauma. Tazocin, which is a combination of piperacillin sodium and tazobactam sodium, was administered intravenously as prophylaxis. After 24 hours, the patient developed a widespread eruption consisting of diffuse erythema on his chest, abdomen, and arms along with superimposed nonfollicular pustules (Figure 1) as well as diffuse vesicles and bullae, which coalesced and then sloughed on his back (Figure 2) and legs (Figure 3). A positive Nikolsky sign was present on his back and legs. There was no mucous membrane involvement.

Figure 1.
Close-up of pustules of acute generalized exanthematous pustulosis.

Close-up of pustules of acute generalized exanthematous pustulosis.

Figure 2.
Close-up of blistering on the patient's back and a positive Nikolsky sign.

Close-up of blistering on the patient's back and a positive Nikolsky sign.

Figure 3.
Hemorrhagic bullae on the patient's ankle.

Hemorrhagic bullae on the patient's ankle.

The differential diagnosis was thought to be between TEN and AGEP or possibly an overlap of these 2 conditions based on clinical findings. The Tazocin therapy was discontinued after 3 days, and the patient received 1 intravenous immunoglobulin 80-g infusion once a day on 2 consecutive days for suspected TEN, pending the results of his skin biopsies.

A skin biopsy specimen was obtained from a pustule and a bulla (Figure 4 and Figure 5), and both specimens were thought to be entirely compatible with AGEP, with no evidence of TEN. Based on the biopsy results, the intravenous immunoglobulin infusions were discontinued, and intravenous hydrocortisone sodium succinate therapy (100 mg every 8 hours for 4 days) was initiated. The pustulation and blistering gradually resolved over 2 weeks, and the patient was left with postinflammatory hyperpigmentation but no scarring.

Figure 4.
Higher magnification of a pustule. Intraepidermal pustules contain neutrophils but no eosinophils. The results of a Gram stain were negative (hematoxylin-eosin, original magnification ×100).

Higher magnification of a pustule. Intraepidermal pustules contain neutrophils but no eosinophils. The results of a Gram stain were negative (hematoxylin-eosin, original magnification ×100).

Figure 5.
Biopsy specimen from a bulla. There was widespread intraepidermal bulla formation but no epidermal necrosis (hematoxylin-eosin, original magnification ×100).

Biopsy specimen from a bulla. There was widespread intraepidermal bulla formation but no epidermal necrosis (hematoxylin-eosin, original magnification ×100).

COMMENT

Acute generalized exanthematous pustulosis is an adverse and potentially severe cutaneous reaction that usually occurs in response to drug therapy but has also been reported to develop after viral infections (eg, enteroviruses), UV radiation, and heavy metal exposure (eg, mercury).1,2 It is usually characterized by sterile pinhead-sized nonfollicular pustules, erythema, edema, fever, and leukocytosis with neutrophilia.3 This immunologically mediated reactive process is most commonly caused by the use of drugs such as antimicrobial agents, most frequently β-lactams (including penicillins and cephalosporins).24 The onset of AGEP is rapid, often occurring hours to days after drug exposure.3,4

Acute generalized exanthematous pustulosis usually resolves once the causative drug is no longer used. One case report, however, describes how AGEP can evolve into a TEN-like picture, illustrating how AGEP is not always mild and self-limited.5 Additional cases describe the clinical overlap of AGEP and TEN, cases in which cessation of the causative drug and systemic corticosteroid treatment did not lead to resolution.6 Instead, the pustular exanthema continued to progress along with bullae formation.6 Treatment with a tumor necrosis factor inhibitor, infliximab, stopped this rapid progression and led to complete resolution.6 One of the most recent cases of AGEP-TEN overlap describes how discontinuation of the drug therapy along with intravenous hydration and treatment with analgesics and antihistamines did not improve the condition, despite the fact that the histologic findings were more consistent with AGEP.7 While the use of steroids in TEN is controversial, current data are not sufficient to suggest that steroids are necessary in the treatment of AGEP.2

Toxic epidermal necrolysis is another adverse and severe cutaneous reaction that has also been reported in response to antibiotic therapy as well as to the use of numerous other systemic medications.2 The latent period between the intake of the drug and the onset of TEN symptoms is usually 2 to 3 weeks, which is longer than that of AGEP.2 While AGEP often improves after the use of the offending agent is discontinued, TEN is a life-threatening condition with a much poorer prognosis. It is also characterized by mucous membrane involvement in more than 1 area, low white blood cell counts, and skin sloughing.2 Secondary infections, ocular complications, and sepsis are significant concerns in patients with TEN.2 The differences between AGEP and TEN are further summarized in Table 1.

Table 1. 
Comparison of Acute Generalized Exanthematous Pustulosis (AGEP) and Toxic Epidermal Necrolysis (TEN)
Comparison of Acute Generalized Exanthematous Pustulosis (AGEP) and Toxic Epidermal Necrolysis (TEN)

While the distinctions between AGEP and TEN have been described, clinical pictures often can be complicated and can display the features of both AGEP and TEN. This blurring of distinctions creates diagnostic challenges, as in the present case. Acute generalized exanthematous pustulosis can present with morphological features that are similar to those of TEN, including diffuse erythema, edema, oral mucuous membrane involvement, and a positive Nikolsky sign. While mucous membrane involvement in TEN can include the mouth, vagina, and conjunctiva, mucous membrane involvement in AGEP, if present, is usually limited to the mouth. Biopsy specimens should be obtained to make a definitive diagnosis in cases with overlapping morphological features. Histopathologic findings can help to differentiate between AGEP and TEN; however, 1 case has been described in which the biopsy specimens showed histologic features of both AGEP and TEN.1 Therefore, it is possible that there can be both clinical and histologic overlap with these 2 cutaneous reactions. The particular exanthema that emerges in a patient may depend on a variety of factors, such as the type and duration of stimulus exposure and that individual's specific T-cell subset population.9 A summary of case reports describing overlapping features of AGEP and TEN is provided in Table 2.

Table 2. 
Summary of Case Reports of Acute Generalized Exanthematous Pustulosis and Toxic Epidermal Necrolysis Overlap
Summary of Case Reports of Acute Generalized Exanthematous Pustulosis and Toxic Epidermal Necrolysis Overlap

Acute generalized exanthematous pustulosis is characterized by the following histopathologic features: spongiform subcorneal or intraepidermal pustules, perivascular leukocytosis with mostly neutrophils and some eosinophils, and edema of the papillary dermis.5,7,10 In contrast, TEN is commonly characterized by necrotic keratinocytes, scarce cell infiltration with mainly lymphocytes, and full-thickness epidermal necrosis with separation from the dermis.5,7,10 The histologic features will usually provide evidence in support of either AGEP or TEN, but there is 1 reported case in which histopathologic analysis showed features of both reactions.1

Both AGEP and TEN are thought to be type IV hypersensitivity reactions that are mediated by T cells but with important distinctions.7,10 Preferential activation of different types of T cells can lead to different delayed drug hypersensitivity reactions.10 According to the revised Coombs and Gell classification, AGEP is characterized largely as a type IVd T-cell reaction, involving the recruitment and activation of neutrophils by interleukin 8.10 In contrast, TEN is a type IVc T-cell reaction, in which keratinocyte apoptosis is dependent on cytotoxic CD8+ T cells that produce perforin and granzyme B.10 While overlap of such immune-mediated reactions can occur, 1 type is usually most prominent.10

In both AGEP and TEN, initial keratinolysis may be mediated by keratolytic cytokines. Immunophenotyping in the early stages of AGEP reveals more perforin, granzyme B, and Fas ligand staining of T cells than it does in the later stages.1 In the later stages of AGEP, more interleukin 8 is produced by T cells, attracting neutrophils, which fill the intraepidermal vesicles, producing pustules.11 The TEN-like appearance of AGEP is attributed to coalescent intraepidermal pustulation producing bullae and resulting in denudation.1 This histopathologic finding was demonstrated in the biopsy specimen from a bulla in our case that showed widespread intraepidermal bulla formation with neutrophils (Figure 5).

It is possible for AGEP to simulate TEN, although these cases are rare. Acute generalized exanthematous pustulosis can display both clinical and histologic features of TEN. These diagnostic similarities pose a challenge for dermatologists and other physicians when they are determining diagnosis, treatment, and prognosis. When there are overlapping morphological features and the clinical presentation is unclear, biopsies should be performed to help make a definitive diagnosis. It is important for dermatologists to be aware that, unlike TEN, most cases of AGEP have an excellent prognosis once treatment with the precipitating agent is discontinued.

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Article Information

Correspondence: Richard M. Haber, MD, FRCPC, Division of Dermatology, University of Calgary, Richmond Road Diagnostic and Treatment Centre, 1820 Richmond Rd SW, Calgary, AB T2T 5C7, Canada (richard.haber@albertahealthservices.ca).

Accepted for Publication: August 24, 2010.

Author Contributions: Both authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Haber. Acquisition of data: Peermohamed and Haber. Analysis and interpretation of data: Peermohamed. Drafting of the manuscript: Peermohamed. Critical revision of the manuscript for important intellectual content: Peermohamed and Haber. Administrative, technical, and material support: Haber. Study supervision: Haber. Literature reviews: Peermohamed.

Financial Disclosure: None reported.

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