Version July 2025
INTRODUCTION —
Acute generalized exanthematous pustulosis (AGEP) is a rare, acute, severe cutaneous adverse reaction characterized by the development of numerous nonfollicular, sterile pustules on a background of edematous erythema [1-3]. In most cases, AGEP is caused by drugs, most often antibiotics, antifungals, the calcium channel blocker diltiazem, and antimalarials [4,5]. The eruption develops within hours or days of drug exposure and resolves spontaneously in one to two weeks after drug discontinuation.
AGEP will be discussed in this topic. Pustular eruptions and other types of cutaneous drug reactions are discussed separately.
●(See "Approach to the patient with pustular skin lesions".)
●(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 "Cutaneous adverse effects of conventional chemotherapy agents".)
●(See "Hand-foot skin reaction induced by multitargeted tyrosine kinase inhibitors".)
●(See "Toxic erythema of chemotherapy (hand-foot syndrome)".)
●(See "Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors".)
EPIDEMIOLOGY —
A rough estimate of the incidence of AGEP is one to five per million per year [1,6-9]. AGEP can occur at any age, although it most often affects adults [5]. In a study including 340 validated cases of AGEP, the mean age was 57.8 years, with a female predominance [5].
ETIOLOGY AND PATHOGENESIS
Eliciting factors — AGEP is caused by a drug in approximately 90 percent of cases [4,5,10]. 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, and terbinafine were also strongly associated with the occurrence of AGEP [9]. However, AGEP has been associated with a wide array of medications (table 1B) [11].
There are isolated reports of AGEP associated with viral, bacterial, or parasitic infections (eg, parvovirus B19, cytomegalovirus, coxsackie B4, severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2], Mycoplasma pneumoniae); spider bites; herbal medications; and iodine-based intravenous contrast media [4,5,12-24]. However, the cause remains undetermined in some cases [5].
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 [25]. Drug-specific CD4+ and CD8+ T cells produce large amounts of CXCL8 and granulocyte-macrophage colony-stimulating factor (GM-CSF). CXCL8, a chemokine inducing neutrophil chemotaxis, and GM-CSF, which reduces neutrophil apoptosis, are both involved in tissue accumulation of neutrophils [26-32]. T helper 17 (Th17) cells, which produce interleukin (IL) 22, may also be involved in the recruitment, activation, and migration of neutrophils in AGEP [33,34].
IL36RN gene — AGEP shares clinical, histopathologic, and transcriptomic features with pustular psoriasis [35] (see "Pustular psoriasis: Pathogenesis, clinical manifestations, and diagnosis"). Recessively germline variants in the IL36RN gene encoding the IL-36 receptor antagonist (IL-36Ra) have been found in generalized pustular psoriasis [36]. These pathogenic variants lead to uncontrolled IL-36 signaling and enhanced production of the proinflammatory cytokines IL-6, IL-8, IL-1-alpha, and IL-1-beta [36].
Variants in IL36RN have also been found in a very small subset of patients with AGEP (4 of 96 patients in one study) [37-39].
This finding suggests that generalized pustular psoriasis and AGEP may share a common pathogenetic pathway, making it difficult to distinguish between the two entities in some cases.
An in vitro study demonstrated that the causative 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 [39]. The 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.
HISTOPATHOLOGY —
The histologic hallmark of AGEP is spongiform subcorneal and/or intraepidermal pustules (picture 1A-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 [40,41]. Eosinophils are often seen in the pustules or dermis.
CLINICAL PRESENTATION
Typical features
●Skin lesions – AGEP typically manifests with the sudden development of dozens to hundreds of nonfollicular, sterile, pinhead-sized pustules on a background of edematous erythema with flexural accentuation (picture 2B and picture 2A and picture 2C) [1,2].
●Latency – The eruption usually occurs hours to days after the administration of the offending drug. Antibiotics have a short lag time, although some drugs (eg, diltiazem, terbinafine, hydroxychloroquine) may show a prolonged latency time of up to several weeks [9]. 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 [9]. In a large-scale retrospective study, the median time from medication initiation to AGEP start date was three days [5].
●Areas involved – The eruption generally begins on the face or intertriginous areas and rapidly extends to the trunk and limbs with a diffuse or patchy distribution. The pustular rash is occasionally accompanied by facial edema. Involvement of mucous membranes is unusual and limited to erosions of the lips when present (picture 3).
●Systemic symptoms – During the acute phase, fever above 38°C (100.4°F) is often present.
Atypical presentations
Localized variant — A very rare localized clinical subtype (acute localized exanthematous pustulosis [ALEP]) has also been described [42-44]. ALEP presents with the sudden onset of multiple small pustules on a background of edematous erythema, most often located on the face (picture 4).
Severe AGEP — Atypical features such as purpura (especially on the legs), blisters, or vesicles may be seen in some patients.
Severe cases of AGEP may present with atypical target lesions and coalescent pustules, resulting in superficial erosions and a clinical picture that can be mistaken for Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) [45-51].
Rare cases of AGEP associated with hemodynamic instability and multiorgan involvement simulating septic shock or systemic inflammatory response syndrome have been reported [47,52-56].
Laboratory findings — Leukocytosis with a neutrophil count >7000/microL and mild eosinophilia are common. In a study of 340 patients with AGEP, 85 percent had absolute neutrophilia, and 52 percent developed either absolute or relative eosinophilia [5].
Organ involvement — 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 [1,2,4,5,57].
●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 [5]. Twenty-five of 319 patients (7.8 percent) experienced acute kidney insufficiency, with the median time to peak creatinine level being four days after disease onset.
●Another study found that 10 of 58 patients (17 percent) with AGEP had evidence of at least one organ involvement [57]. Liver and/or kidney function tests were abnormal in seven patients, two developed acute respiratory distress, and one developed agranulocytosis.
CLINICAL COURSE AND COMPLICATIONS —
Skin symptoms usually resolve without treatment in one to two weeks after the discontinuation of the offending drug [58]. The pustular eruption is followed by desquamation with characteristic collarettes of scale (picture 5). Courses longer than two weeks are rare [59].
Complications (eg, secondary skin infection, hypocalcemia) may occur in older or compromised patients [1,2,4,60].
DIAGNOSIS
Clinical suspicion — 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).
Diagnostic criteria — Clinical and laboratory criteria for the diagnosis of AGEP are as follows [61]:
●Rapid development of a febrile (≥38°C [100.4°F]) 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 2A-C)
●Leukocytosis with marked neutrophilia (>7000/microL)
●Pustular smear and culture negative for bacteria
●Rapid resolution of the rash after drug discontinuation
Biopsy — Histologic examination of a skin biopsy can help confirm the diagnosis and rule out other pustular eruptions. A 4 mm punch biopsy that includes a pustule is appropriate. Histologic features that support the diagnosis of AGEP include (picture 1A-B) [62] (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
Additional testing for the identification of the causative drug
●Patch testing – Patch testing with one or multiple suspected drugs may be useful in identifying the cause of AGEP [63-66]. (See "Patch testing".)
Patch testing is generally performed at least six weeks after the resolution of the rash. 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. Moreover, the optimal concentration of the specific drugs and vehicles for patch testing have not been determined.
Positive patch testing reactions range between 18 to 75 percent of cases depending on the specific drugs tested and the specific type of drug reaction [63,66-69]. Drugs with high patch test positivity rates include beta-lactam antibiotics, aromatic anticonvulsants, phenytoin, and corticosteroids [66]. A positive reaction is often morphologically similar to AGEP, showing small sterile pustules on an erythematous base.
Little is known about the safety of patch testing in the setting of AGEP and other severe cutaneous drug reactions. Reactivation of the original reaction has been rarely reported [66,67,70].
●In vitro 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 [71-74].
DIFFERENTIAL DIAGNOSIS —
The differential diagnosis of AGEP includes [1,2,75]:
●Generalized acute pustular psoriasis (von Zumbusch type) – Seen at a single time point and without additional information, generalized acute pustular psoriasis (picture 6) 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) overlaps with, but is distinct from, the drugs associated with AGEP [9]. (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) [45-47,76]. Features that favor a diagnosis of SJS/TEN include a longer latency between drug exposure and clinical manifestations (one to four weeks), nearly universal involvement of two or more mucous membranes, 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 [48-50,77]. (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 7A-B) [78]. Sneddon-Wilkinson disease has been reported in association with pyoderma gangrenosum, monoclonal immunoglobulin A (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 8A-B) [79-83]. (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) [84]. 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 [84]. Cases with features of both DRESS and AGEP have been described [8,77,85,86]. (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 9A-B). Pustules rupture and leave erosions with a honey-colored crust (picture 10). 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 —
The management of AGEP involves 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. Patients with severe AGEP and older or immunocompromised patients with fever and widespread eruption should be hospitalized for fluid, electrolyte, and nutritional support.
Symptomatic treatment — For symptomatic relief of pruritus and skin inflammation, we suggest topical, rather than systemic, corticosteroids. In case series and case reports, systemic corticosteroids did not shorten the disease course [20,58,87,88].
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 evidence of efficacy in other pruritic or inflammatory skin conditions [88,89].
Severe AGEP — For patients with atypical, severe disease, a short course of systemic corticosteroids (methylprednisolone or prednisone 1 mg/kg for 7 to 14 days with variable taper) may be indicated. (See "Glucocorticoid withdrawal", section on 'Tapering regimens'.)
Low-dose oral cyclosporine at the dose of 3 to 5 mg/kg/day tapered over two weeks has also been used in a few patients with severe disease [90]. A single 900 mg dose of spesolimab, a monoclonal antibody that targets the IL-36 receptor approved for the treatment of generalized pustular psoriasis, has been successfully used in two patients with refractory AGEP [91,92].
Evidence supporting the use of systemic corticosteroids or other immunosuppressants or immunoregulators for the treatment of severe AGEP is limited to case reports and small case series. In a single-institution retrospective study that included 31 hospitalized patients with severe AGEP, systemic corticosteroids (methylprednisolone or prednisone 1 mg/kg) or oral cyclosporine 3 mg/kg daily were similarly effective in inducing rapid clinical improvement and cessation of pustule formation [90].
PROGNOSIS —
In most patients, AGEP resolves spontaneously without sequelae. Mortality rate of 2 percent has been reported in a pharmacovigilance study in France [11]. 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 [5].
FUTURE DRUG AVOIDANCE —
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 [93,94]. The offending drug(s) should be listed as a cause of severe cutaneous adverse reaction in the patient's medical record.
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 in most cases caused 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 a few hours to a few days after the administration of the offending drug (picture 2A-C) [1,2]. Fever above 38°C (100.4°F) and leukocytosis with a neutrophil count >7000/microL are usually present. Severe cases may present with atypical target lesions and coalescent pustules that result in superficial erosions and a clinical picture resembling Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). The eruption resolves spontaneously in one to two weeks after the discontinuation of the offending drug. (See 'Clinical presentation' above and 'Clinical course and complications' above.)
●Diagnosis – The diagnosis of AGEP is based on the clinical presentation and histologic examination of a skin biopsy (picture 1A). The rapid resolution of the eruption after drug discontinuation also supports the diagnosis. (See 'Diagnostic criteria' above and 'Biopsy' above.)
●Management
•Drug withdrawal and supportive treatment – Prompt withdrawal of the causative agent is the mainstay of treatment of AGEP. Patients with severe AGEP and older or immunocompromised patients with fever and widespread eruption should be hospitalized for fluid, electrolyte, and nutritional support. (See 'Drug withdrawal and supportive measures' above.)
•Symptomatic treatment – For symptomatic relief of pruritus and skin inflammation, we suggest topical, rather than systemic, corticosteroids (Grade 2C). We generally use medium- to high-potency topical corticosteroids (groups 1 to 4 (table 2)). They are applied twice a day for one week. (See 'Symptomatic treatment' above.)
•Severe AGEP – For patients with atypical, severe disease, we suggest a short course of systemic corticosteroids in addition to supportive measures (Grade 2C). Oral prednisone can be given at the dose of 1 mg/kg for 7 to 14 days with variable taper. Low-dose oral cyclosporine at the dose of 3 to 5 mg/kg/day tapered over two weeks is an alternative treatment option. (See 'Severe AGEP' above.)
●Prognosis and prevention – In most patients, AGEP resolves spontaneously without sequelae. 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 'Prognosis' above and 'Future drug avoidance' above.)
ACKNOWLEDGMENT —
The editorial staff at UpToDate acknowledge Alexis Sidoroff, MD, who contributed to an earlier version of this topic review.
