Version May 2024
INTRODUCTION — Acute generalized exanthematous pustulosis (AGEP) is a rare, acute eruption characterized by the development of numerous nonfollicular sterile pustules on a background of edematous erythema (picture 1A) [1,2]. Fever and peripheral blood leukocytosis are usually present.
In approximately 90 percent of cases, AGEP is caused by drugs, most often antibiotics (eg, aminopenicillins and macrolides), antifungals, the calcium channel blocker diltiazem, and antimalarials [3,4]. The eruption develops within hours or days of drug exposure and resolves spontaneously in one to two weeks after drug discontinuation. In a large-scale, retrospective study, the median time from medication initiation to AGEP start date was three days [4].
AGEP will be discussed in this topic. Other types of cutaneous drug reactions and pustular eruptions are discussed separately.
●(See "Drug eruptions".)
●(See "Exanthematous (maculopapular) drug eruption".)
●(See "Lichenoid drug eruption (drug-induced lichen planus)".)
●(See "Fixed drug eruption".)
●(See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)
●(See "Approach to the patient with pustular skin lesions".)
●(See "Cutaneous adverse effects of conventional chemotherapy agents".)
EPIDEMIOLOGY — A rough estimate of the incidence of AGEP is one to five per million per year [1,5-8]. AGEP can occur at any age, although it most often affects adults [4]. In a study including 340 validated cases of AGEP, the mean age was 57.8 years [4]. All patients are affected, with a female predominance [4].
ETIOLOGY AND PATHOGENESIS
Eliciting factors — AGEP is caused by drugs in approximately 90 percent of cases [3,4]. There are isolated reports of AGEP associated with viral, bacterial, or parasitic infections (eg, parvovirus B19, cytomegalovirus, coxsackie B4, Mycoplasma pneumoniae); spider bites; herbal medications; and iodine-based intravenous contrast media [3,4,9-19]. However, in some cases, the cause remains undetermined [4].
Anti-infective agents (table 1A), antimalarials, and the calcium channel blocker diltiazem are the most frequently reported triggers of AGEP. In a multinational case-control study, pristinamycin, aminopenicillins, quinolones, hydroxychloroquine, antibacterial sulfonamides, terbinafine, and diltiazem were also strongly associated with the occurrence of AGEP [8]. However, AGEP has been associated with a wide array of medications (table 1B) [20].
Immunologic mechanisms — The pathomechanism of AGEP has been only partially investigated. AGEP is a T cell mediated neutrophilic inflammation involving drug-specific CD4+ T cells, cytotoxic CD8+ T cells, and inflammatory cytokines and chemokines. Drug-specific CD4+ T cells produce large amounts of CXCL8 and GM-CSF. CXCL8, a chemokine inducing neutrophil chemotaxis, and GM-CSF, which reduces neutrophil apoptosis, are both involved in tissue accumulation of neutrophils [21-27]. T helper 17 (Th17) cells also may be involved in the recruitment, activation, and migration of neutrophils in AGEP [28,29]. (See "Drug allergy: Pathogenesis", section on 'IVd'.)
Genetics — Recessively inherited mutations in the IL36RN gene encoding the interleukin-36 receptor antagonist (IL-36Ra) have been found in generalized pustular psoriasis [30]. These mutations in IL36RN lead to uncontrolled IL-36 signaling and enhanced production of proinflammatory cytokines IL-6, IL-8, IL-1-alpha, and IL-1-beta [30]. Mutations in IL36RN have also been found in a very small subset of patients with AGEP (4 of 96 patients in one study) [31-33]. This finding suggests that generalized pustular psoriasis and AGEP may share a common pathogenetic pathway, making it difficult in some cases to distinguish between the two entities. (See "Pustular psoriasis: Pathogenesis, clinical manifestations, and diagnosis".)
In vitro studies demonstrated that the culprit drug specifically induced IL-36-gamma release either directly by the patient's peripheral blood monocytes or indirectly by keratinocytes in the presence of autologous peripheral blood mononuclear cells [33]. This drug-induced IL-36-gamma secretion was specific for AGEP and involved toll-like receptor 4 (TLR4) sensing the drug/albumin complex as a danger signal. Furthermore, IL-36 cytokines, especially IL-36-gamma, are highly expressed in lesional skin of AGEP patients. Keratinocytes and macrophages are major sources of IL-36-gamma.
HISTOPATHOLOGY — The histologic hallmark of AGEP is a spongiform subcorneal and/or intraepidermal pustules (picture 2A-B). Other features include a marked edema of the papillary dermis, necrosis of single keratinocytes, and a superficial, interstitial, and mid-dermal inflammatory infiltrate of neutrophils with perivascular accentuation [34,35]. Eosinophils are often seen in the pustules or dermis.
CLINICAL FEATURES — AGEP typically manifests with the rapid development of dozens to hundreds nonfollicular, sterile, pinhead-sized pustules on a background of edematous erythema with flexural accentuation (picture 1A-C) [1,2]. The eruption usually occurs a few hours to a few days after the administration of the offending drug. In a series of 97 cases of AGEP, the median time between drug exposure and development of symptoms was one day for antibiotics and 11 days for all other drugs [8].
The eruption generally begins on the face or intertriginous areas and rapidly extends to the trunk and limbs with a diffuse or patchy distribution. A localized facial variant has also been described [36-38].
The pustular rash is occasionally accompanied by facial edema and nonspecific lesions such as purpura (especially on the legs), atypical target lesions, blisters, or vesicles. Severe cases of AGEP may present with atypical target lesions and coalescent pustules, resulting in superficial erosions and a clinical picture similar to Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) [39-45]. Involvement of mucous membranes is unusual and, when present, is limited to erosions of the lips.
During the acute phase, fever above 38°C (100.4°F), leukocytosis with a neutrophil count >7000/microL, and mild eosinophilia are often present. In a study of 340 patients with AGEP, 85 percent had absolute neutrophilia, and 52 percent developed either absolute or relative eosinophilia [4].
Organ involvement is not common in AGEP, but can occur, particularly in older or compromised patients. A mild increase in serum transaminases or a reversible reduction in the creatinine clearance have been reported in some patients [1-4,46]. In a retrospective study of 340 patients with AGEP, 25 of 298 patients (8.4 percent) had an acute elevation of aspartate aminotransferase and alanine aminotransferase levels, with a peak at six days. Twenty-five of 319 patients (7.8 percent) experienced acute kidney insufficiency, with the median time to peak creatinine level being four days after the AGEP start date [4]. Another study found that 10 of 58 patients (17 percent) with AGEP had evidence of at least one organ involvement [46]. Liver and/or kidney function tests were abnormal in seven patients, two developed acute respiratory distress, and one developed agranulocytosis.
CLINICAL COURSE — Skin symptoms usually resolve without treatment in one to two weeks after the discontinuation of the offending drug [47]. The pustular eruption is followed by desquamation with characteristic collarettes of scale. Courses longer than two weeks are rare [48]. Complications (eg, secondary skin infection, hypocalcemia) may occur in older or compromised patients [1-3,49].
DIAGNOSIS
Clinical and histologic — The diagnosis of AGEP is suspected in a patient presenting with an acute, febrile pustular eruption a few hours or days after starting a drug treatment, in particular antibiotics or diltiazem (table 1A-B). Histologic examination of a skin biopsy is necessary to confirm the diagnosis and rule out other pustular eruptions. A 4 mm punch biopsy that includes a pustule is appropriate. Gram staining of a pustular smear and culture of pustule exudate may be helpful in excluding a superficial skin infection. (See 'Differential diagnosis' below.)
Clinical and laboratory criteria for the diagnosis of AGEP are as follows:
●Rapid development of a febrile (≥38°C) pustular eruption a few hours or days after beginning a drug treatment
●Clinical finding of dozens to hundreds of pinhead-sized, nonfollicular pustules on a background of edematous erythema (picture 1A-C)
●Leukocytosis with marked neutrophilia (>7000/microL)
●Pustular smear and culture negative for bacteria
●Rapid resolution of the rash after drug discontinuation
Histologic features that support the diagnosis of AGEP include (picture 2A-B) [50] (see 'Histopathology' above):
●Intra- or subcorneal spongiform pustules
●Eosinophils in the pustules or dermis
●Necrotic keratinocytes
●Superficial, interstitial, and mid-dermal infiltrate rich in neutrophils
●Absence of tortuous, dilated blood vessels
Patch testing — Patch testing with one or multiple suspected drugs may be useful in identifying the cause of AGEP [51-55]. Patch testing is generally performed four to six weeks after the disease resolution. A positive test can confirm a suspected drug as the cause of AGEP. However, a negative result does not exclude that a certain drug is the causative agent. Positive patch testing reactions may occur from 18 to 58 percent of cases, depending on the drugs tested and the specific type of severe drug reaction [54,56,57].
A positive patch test reaction is often morphologically similar to AGEP, showing small sterile pustules on an erythematous base. Systemic reactions to patch testing rarely have been reported [55]. (See "Patch testing", section on 'Patch test interpretation'.)
Other tests — Drug-specific in vitro immunologic tests (eg, mast cell degranulation test, macrophage migration inhibition factor test, interferon gamma release test, lymphocyte proliferation response) are only performed in research settings [58-61].
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of AGEP includes [1,2]:
●Generalized acute pustular psoriasis (von Zumbusch type) – Seen at a single time point and without additional information, generalized acute pustular psoriasis (picture 3) and AGEP may be difficult to differentiate both clinically and histologically. Criteria that favor a diagnosis of generalized acute pustular psoriasis include a history of psoriasis; longer duration of fever and pustular eruption; absence of drug exposure; and histologic finding of subcorneal pustules with acanthosis and papillomatosis [1]. Although generalized acute pustular psoriasis can be elicited by drugs, the spectrum of medications known to trigger psoriasis (mainly beta-blockers or lithium) differs from the drugs associated with AGEP [8]. (See "Pustular psoriasis: Pathogenesis, clinical manifestations, and diagnosis".)
●Stevens-Johnson syndrome/toxic epidermal necrolysis – Severe cases of AGEP presenting with atypical target lesions and confluent pustules mimicking a positive Nikolsky sign may be difficult to differentiate from Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) [39-41,62]. Features that favor a diagnosis of SJS/TEN include: a longer latency between drug exposure and clinical manifestations (one to four weeks); involvement of the mucous membranes (in over 90 percent of cases); more severe course; and histologic finding of full thickness epidermal necrosis with a sparse inflammatory dermal infiltrate.
There are isolated reports of overlap cases with clinical and histologic features of both AGEP and SJS/TEN [42-44,63]. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)
●Subcorneal pustular dermatosis (Sneddon-Wilkinson disease) – Subcorneal pustular dermatosis (Sneddon-Wilkinson disease) is a rare, chronic, relapsing pustular eruption characterized by large, flaccid pustules that involve the trunk and the intertriginous areas (picture 4A-B) [64]. Sneddon-Wilkinson has been reported in association with pyoderma gangrenosum, monoclonal IgA gammopathy, IgA myeloma, and other lymphoproliferative diseases. On histology, there is a subcorneal accumulation of neutrophils without spongiosis or keratinocyte damage and a perivascular infiltrate of neutrophils (picture 5A-B) [65-69]. (See "Neutrophilic dermatoses", section on 'Subcorneal pustular dermatosis'.)
●Drug reaction with eosinophilia and systemic symptoms – Pustules can occasionally occur in patients with drug reaction with eosinophilia and systemic symptoms (DRESS) [70]. However, DRESS is characterized by a long latency (two to eight weeks) between drug exposure and appearance of symptoms, a more severe and prolonged clinical course than AGEP, eosinophilia or atypical lymphocytosis in the peripheral blood, and signs and symptoms of visceral involvement (abnormal liver function tests in approximately 80 percent of cases). The histology of DRESS is characterized by mild spongiosis with a lymphocytic infiltrate containing eosinophils in the superficial dermis. However, subcorneal and intraepidermal neutrophilic microabscesses can be seen in pustular DRESS [70]. Cases with features of both DRESS and AGEP have been described [7,63,71,72]. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)
●Bullous impetigo – Bullous impetigo generally occurs in young children. Small vesicles or pustules are usually localized to the head and neck or intertriginous areas (picture 6A-B). Pustules rupture and leave erosions with a honey-colored crust (picture 7). Gram staining of pustule smear reveals Gram-positive cocci. Culture of pustule exudate is positive for Staphylococcus aureus. (See "Impetigo", section on 'Bullous impetigo'.)
MANAGEMENT — AGEP is a self-limiting disease with a favorable prognosis. Management includes withdrawal of the offending drug, supportive care, and symptomatic treatment of pruritus and skin inflammation.
Drug withdrawal and supportive measures — Prompt withdrawal of the causative agent is the mainstay treatment of AGEP. In patients taking multiple drugs, the drugs suspected to be the cause of AGEP (table 1A) should be discontinued. Since re-exposure to the causative agent can induce another episode of AGEP, patients should be counseled to avoid the offending drug and be provided with a written list of the generic and brand names of the offending drug [73,74].
Patients with severe forms of AGEP usually are hospitalized for treatment. Older or compromised patients with fever and widespread eruption may require fluid, electrolyte, and nutritional support.
Symptomatic treatment — For symptomatic relief of pruritus and skin inflammation, we suggest topical rather than systemic corticosteroids. We use medium potency corticosteroids (group four (table 2)). They are applied twice a day for one week. In the desquamation phase, emollients may be helpful in restoring the skin barrier function.
The use of topical corticosteroids for AGEP has not been evaluated in clinical trials. Their use is based upon small case series and clinical experience of efficacy in other pruritic or inflammatory skin conditions [75,76].
Given the natural history of rapid spontaneous resolution following withdrawal of the offending drug, we avoid systemic corticosteroids for the treatment of AGEP. In case series and case reports, systemic corticosteroids have been used to treat AGEP, but evidence that they shorten the disease course is lacking [17,47,75,77].
PROGNOSIS — AGEP resolves spontaneously without sequelae in the majority of patients. Mortality rate of 2 percent has been reported in a pharmacovigilance study in France [20]. In another study from the United States, all-cause mortality within 30 days was 3.5 percent, but no death was suspected to be due to AGEP [4].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Drug allergy and hypersensitivity".)
SUMMARY AND RECOMMENDATIONS
●Definition and etiology – Acute generalized exanthematous pustulosis (AGEP) is a rare, acute hypersensitivity reaction caused in approximately 90 percent of cases by drugs, most often antibiotics, calcium channel blockers, and antimalarials (table 1A-B). (See 'Eliciting factors' above.)
●Clinical presentation and course – AGEP is characterized by the development of numerous nonfollicular, sterile, small pustules on a background of edematous erythema (picture 1A-C) [1,2]. Fever above 38°C (100.4°F) and leukocytosis with a neutrophil count >7000/microL are usually present. The eruption resolves spontaneously in one to two weeks after the discontinuation of the offending drug. (See 'Clinical features' above and 'Clinical course' above.)
●Diagnosis – The diagnosis of AGEP is based upon the clinical presentation and histologic examination of a skin biopsy (picture 2A). The rapid resolution of the eruption after drug discontinuation also supports the diagnosis. (See 'Diagnosis' above and 'Histopathology' above.)
●Management – Prompt withdrawal of the causative agent is the mainstay of treatment of AGEP. Since re-exposure to the causative agent can induce another episode of AGEP, patients should be counseled to avoid the offending drug and be provided with a written list of the generic and brand names of the offending drug. (See 'Drug withdrawal and supportive measures' above.)
For symptomatic relief of pruritus and skin inflammation, we suggest topical corticosteroids (Grade 2C). We generally use medium potency topical corticosteroids (group four (table 2)). They are applied twice a day for one week. (See 'Symptomatic treatment' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Alexis Sidoroff, MD, who contributed to an earlier version of this topic review.
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