Keywords

Synonyms::

Toxic pustuloderma, pustular drug rash, pustular psoriasiform eruption with leukocytosis

Etiology::

Drugs, infectious triggers, spider bites, exposure to mercury

Incidence::

1–5 cases/1 million/year

Clinical::

Acute onset of numerous sterile pinhead-sized pustules accompanied by fever and leukocytosis

Distribution::

Main flexural folds, face

Histology::

Subcorneal, intracorneal, and intraepidermal pustules, spongiosis, necrotic keratinocytes, eosinophils in pustules and within the dermis, erythrocyte extravasation, leukocytoclasia, interstitial and dermal infiltrate of neutrophils, papillary edema, perivascular lymphocytic inflammation

Adverse variables::

Significant comorbidities, secondary infection

Treatment::

Self-resolving; topical/oral/systemic corticosteroids for symptomatic relief or for severe cases with or without organ involvement

Prognosis::

Favorable prognosis; resolution within 15 days following withdrawal of the offending drug

Mortality rate::

5 %

Acute generalized exanthematous pustulosis (AGEP) is a rare clinical entity characterized by an acute onset of numerous sterile, nonfollicular, pinhead-sized pustules arising on an erythematous, edematous base accompanied by fever (>38 C), neutrophilia, and occasionally eosinophilia. In 1968, Baker and Ryan reported 104 cases of pustular psoriasis and specifically detailed five patients whom they diagnosed as having “exanthematic pustular psoriasis” most likely due to a drug or infectious etiology [1]. These five patients did not have a history of psoriasis and were characterized as having pustular skin reactions of acute onset that quickly resolved and did not recur. Subsequently, in 1980, Beylot et al. reviewed the existing literature regarding pustuloses and reported four additional cases; they are responsible for coining the name of this distinct entity as “acute generalized exanthematic pustulosis” [2]. Additional literature reports by Macmillan in 1973 and Staughton and Harper in 1984 denote pustular skin eruptions most likely representing AGEP which they termed as “generalized pustular drug rash” and “toxic pustuloderma,” respectively [3, 4].

The vast majority (>90 %) of AGEP cases are attributable to drugs. A large-scale multinational case-control study, the EuroSCAR study, reported 97 cases of AGEP highly associated with pristinamycin, ampicillin/amoxicillin, quinolones, hydroxychloroquine, anti-infective sulfonamides, terbinafine, and diltiazem. Additional suspected drugs with less strong associations include corticosteroids, macrolides, oxicam nonsteroidal anti-inflammatory drugs (NSAIDs), and antiepileptic drugs [5]. Atypical medications in association with AGEP include atenolol, nifedipine, itraconazole, minocycline, clindamycin, paracetamol, allopurinol, dexamethasone, icodextrin (a peritoneal dialysate), and IV radiocontrast media [6].

Additional suspected causes of AGEP include infectious etiologies such as enteroviruses, adenovirus, cytomegalovirus, Epstein-Barr virus, hepatitis B virus, Mycoplasma pneumoniae, parvovirus B19, Chlamydia pneumoniae, Escherichia coli of the urinary tract, cystic echinococcosis of the liver, exposure to mercury, and spider bites [7–13]. The influence of infectious agents as a cause of AGEP has been described with contrasting theories in the literature. The role of infection in causing AGEP has been demonstrated to lack stringent evidence; rather, the use of anti-infective drugs to treat the infectious agent has been reported as the primary cause of AGEP [5]. Contrastingly, another theory suggests that infectious agents may trigger the AGEP response to the offending drug via priming of the Th1 immune response, leading to release of CXCL8 (IL-8) and GM-CSF and subsequent neutrophilia [6].

The pathogenesis of AGEP is largely a T-cell-mediated phenomenon involving CD4 and CD8 T cells. The pathogenesis of the disease is hypothesized to occur from drug-specific CD4 and CD8 T cells that are activated in lymph nodes following APC presentation of the drug. Once activated, the CD4 and CD8 T cells expand and infiltrate the dermis and epidermis. Keratinocytes within the epidermis are killed by CD8 T cells via granzyme and perforin release in addition to the Fas/FasL mechanism. These initial steps result in the formation of a subcorneal vesicle filled mainly with CD4 T cells which subsequently release CXCL8 (IL-8) and GM-CSF. These chemokines attract neutrophils and occasionally eosinophils to the epidermis, converting the subcorneal vesicle into a sterile pustule [14].

AGEP is a rare clinical entity with an incidence rate of approximately 1–5 cases out of every 1 million individuals per year [15]. While previous literature demonstrates an equal distribution of AGEP between men and women [15], the more recent EuroSCAR study reported a female predominance, with a male to female ratio of 0.8 [5]. The EuroSCAR study also reported a mean age of AGEP at 56 years with a SD of 21 years. AGEP has also been reported in children [16]. While reports of AGEP have been reported in North America, the majority of cases are represented in European literature.

AGEP is characterized by the rapid development (within a few hours) of dozens to hundreds of sterile, nonfollicular pinhead-sized (less than 5 mm in diameter) pustules on an erythematous, edematous background commonly on the main flexural folds. Additional dermatologic manifestations include edema of the face, purpura, atypical targets, blisters, and vesicles. A small percentage of cases (20 %) involve mucous membranes, however; the involvement is mild and commonly occurs in one site, most frequently oral mucous membranes. Systemic features of the disorder include a high fever usually above 38 C and marked leukocytosis, from a predominance of neutrophils (greater than 7,000 neutrophils/μL) and occasionally eosinophils (in approximately 1/3 of patients). While internal organ involvement is not usually observed, atypical presentations of AGEP have reported systemic involvement including renal insufficiency, hepatocellular involvement, acute respiratory failure, hemodynamic instability, and bone marrow involvement [17]. Following discontinuation of the drug, spontaneous resolution of the disorder occurs within 15 days and is characterized by resolution of the pustules followed by postpustular desquamation.

It is important to note that atypical presentations of AGEP with clinical similarity to toxic epidermal necrolysis (TEN) and drug-induced hypersensitivity syndrome (DIHS) have been reported. While the clinical presentation of these cases resemble TEN and DIHS, histopathologically, the cases are typical of AGEP. Cases simulating TEN were described as having mucosal involvement, diffuse exfoliation with bullae formation, and occasionally atypical target formation [6]. In most AGEP-TEN overlap cases, the prognosis of patients clinically modeled AGEP with complete recovery; however, some cases resulted in end-organ dysfunction requiring aggressive treatment, and another case was recently reported to result in mortality [18]. AGEP-DIHS cases have been reported to have systemic involvement including organ dysfunction, most frequently hepatic and renal involvement. These cases resulted in complete recovery (resolution of dermatological manifestation, transaminitis, and renal dysfunction) following drug discontinuation, supportive measures, and topical corticosteroids [6]. Atypical localized presentations of AGEP have also been reported including AGEP resembling contact dermatitis in association with methylchloroisothiazolinone and hydrocortisone butyrate, and photodistributed AGEP following sertraline administration [6].

AGEP is characterized histologically by subcorneal, intracorneal, and intraepidermal pustules often large in size with greater than 15 keratinocytes; pustules may also contain eosinophils. Spongiform features are common in the intraepidermal pustules as compared to subcorneal or intracorneal pustules. Follicular pustules may also be observed. Perivascular lymphocytic inflammation is also typical with neutrophils and some eosinophils. Epidermal features recognized in AGEP include necrotic keratinocytes with segmental necrosis and spongiosis with exocytosis of neutrophils. Dermal characteristics include papillary edema, mixed superficial, interstitial, and middle to deep dermal infiltrates of neutrophils and eosinophils. While vasculitis has rarely been observed, erythrocyte extravasation and leukocytoclasia are more frequently noted. Additional histologic features of AGEP include parakeratosis, rete ridge elongation, fusion of rete ridges, mild clubbing, and the presence of a granular cell layer [19].

AGEP has similar clinical and histological features to generalized pustular psoriasis, specifically the most severe form of generalized pustular psoriasis – the von Zumbusch type, which is marked clinically by an abrupt generalized onset of pustules on an erythematous background lasting for up to several weeks and frequently accompanied by fever and leukocytosis. Distinguishing the histopathological features of these two diseases may pose a challenge; thus, reliance on clinical information such as association with drugs and quick resolution following drug withdrawal, nonrecurrence, a lack of family history of psoriasis, and a lack of arthritis favor a diagnosis of AGEP. Differentiating features between AGEP and generalized pustular psoriasis may include eosinophils in the pustules or dermis, necrotic keratinocytes, an interstitial and dermal infiltrate of neutrophils, and the absence of tortuous, dilated blood vessels which are frequently noted in AGEP as compared to generalized pustular psoriasis [20].

The EuroSCAR study group developed the AGEP validation score, a standardized scoring system based upon clinical features including morphology (pustules, erythema, distribution, postpustular desquamation), course of the disease (mucosal involvement, acute onset of less than 10 days, resolution in less than 15 days, fever >38 C, neutrophils >7000/mm), and histopathologic data. The scoring system ranges from 0 to 12 and categorizes cases into one of four categories: no AGEP (<0), possible AGEP (1–4), probable AGEP (5–7), and definite AGEP (8–12).

The course of AGEP typically features spontaneous resolution following withdrawal of the offending agent; thus treatment for AGEP includes supportive measures during the acute pustular reaction phase. Treatments include disinfectant solutions to prevent infection and moist dressings with drying. During the postpustular desquamation phase, emollients have been used to promote the integrity of the skin barrier. Topical corticosteroids may provide symptomatic relief; systemic corticosteroids may be appropriate in severe cases of AGEP such as those with organ involvement.

AGEP has a favorable prognosis, with most patients experiencing resolution of dermatologic and/or systemic involvement within 15 days of onset if the offending drug is removed. The mortality rate of AGEP is approximately 5 %; mortality most frequently occurs in elderly individuals with secondary infections or in those with significant comorbidities.