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Acute Generalized Exanthematous Pustulosis (AGEP)
Introduction
Acute generalized exanthematous pustulosis is a severe cutaneous adverse reaction characterized by the rapid onset of widespread, non-follicular, sterile pustules on an erythematous base, accompanied by fever and neutrophilic leukocytosis. While generally self-limited with a favorable prognosis (mortality less than 5%), distinguishing AGEP from other pustular dermatoses — particularly acute generalized pustular psoriasis — is a critical diagnostic challenge.
Epidemiology
AGEP occurs at an incidence of approximately 1 to 5 cases per million per year, with a slight female predominance and a mean age of onset of 56 years, though it can occur at any age. Over 90% of cases are drug-induced, with rare cases triggered by infections (enterovirus, parvovirus B19, CMV, Mycoplasma), spider bites, or contact allergens such as mercury.
Pathogenesis
AGEP is a type IVd delayed hypersensitivity reaction mediated by drug-specific CD4+ and CD8+ T cells. Activated T cells release CXCL8 (IL-8), GM-CSF, and IL-17/IL-22, which recruit neutrophils to the epidermis. The resulting neutrophil accumulation in subcorneal and intraepidermal locations leads to sterile pustule formation. IL-36 signaling pathway involvement links AGEP pathogenically to pustular psoriasis, as both involve IL-36-mediated neutrophilic inflammation. However, AGEP lacks the genetic IL-36 receptor antagonist (IL36RN) mutations seen in generalized pustular psoriasis.
The drug-specific T-cell response involves drug antigen presentation via MHC class I and II to T cells. Effector T cells migrate to the skin, produce CXCL8, and directly induce keratinocyte apoptosis via Fas-FasL and perforin-granzyme pathways. The resulting spongiform subcorneal pustules are the histopathologic hallmark.
Common Culprit Drugs
Antibiotics are the most common category, accounting for approximately 80% of cases. Aminopenicillins (amoxicillin, ampicillin) are the single most common culprits, followed by macrolides (azithromycin, erythromycin), quinolones (ciprofloxacin, levofloxacin), sulfonamides, and cephalosporins. Other recognized triggers include hydroxychloroquine, antifungals (terbinafine, fluconazole), calcium channel blockers (diltiazem), and acetaminophen/paracetamol, which is an underrecognized culprit. The latency period is characteristically less than 48 hours for antibiotics (short) and up to 11 to 14 days for non-antibiotic drugs. This short latency for antibiotics is a distinguishing feature from other severe drug reactions.
Clinical Features
Cutaneous Presentation
The hallmark is an acute onset of widespread, non-follicular, sterile pustules (pinpoint, 1 to 3 mm) on a background of diffuse, edematous erythema. The pustules characteristically arise on erythematous skin independent of hair follicles. The eruption typically begins in the intertriginous areas (axillae, groin, neck folds) and face, then rapidly generalizes. Pustules may coalesce into larger purulent collections known as "lakes of pus." Facial edema is common, occurring in 30 to 50% of cases. A positive Nikolsky sign may be present in areas of confluent erythema, which makes it important to distinguish from TEN. Target-like purpuric lesions may occur, creating overlap with SJS/TEN ("AGEP-TEN overlap").
Systemic Features
High fever (above 38 C) is present in approximately 80% of cases. Neutrophilic leukocytosis (above 7000/microL) is present in approximately 90%. Eosinophilia occurs in approximately 30%. Mild hepatic involvement with transaminase elevation is seen in 20 to 30%. Renal insufficiency is uncommon (less than 10%). Mucous membrane involvement is mild in 20 to 25% and is typically limited to one site (oral). Extensive mucosal involvement should prompt reconsideration of the diagnosis (SJS/TEN, pemphigus).
Time Course
Onset is rapid after drug exposure (hours to days for antibiotics). Spontaneous resolution within 1 to 2 weeks after drug withdrawal is the rule. Characteristic "collarette desquamation" during the resolution phase involves superficial peeling in areas of prior pustules and is a helpful retrospective diagnostic clue.
<image>Clinical progression of AGEP showing initial diffuse erythema and edema of the neck and axillary folds, followed by hundreds of pinpoint non-follicular sterile pustules on an erythematous base, and resolution phase with collarette desquamation</image>
Diagnosis
EuroSCAR Validation Score for AGEP
The EuroSCAR score is a standardized scoring system evaluating morphology (pustules, erythema, distribution, post-pustular desquamation), course (mucosal involvement, acute onset, resolution within 15 days, fever above 38 C, neutrophils above 7000/microL), and histology (spongiform subcorneal or intraepidermal pustules, perivascular eosinophils, neutrophils, edema of papillary dermis). Score interpretation ranges from 0 or less (no AGEP), 1 to 4 (possible), 5 to 7 (probable), to 8 to 12 (definite).
Histopathology
The hallmark finding is spongiform subcorneal and/or intraepidermal pustules filled with neutrophils. Marked papillary dermal edema and a perivascular neutrophilic and eosinophilic infiltrate are present. Necrotic keratinocytes may be seen, representing an overlap feature with SJS/TEN. Importantly, there is no acanthosis or tortuous blood vessels, which helps distinguish AGEP from pustular psoriasis. Biopsy should be taken from a pustule on erythematous skin.
Laboratory Studies
CBC shows neutrophilic leukocytosis with possible eosinophilia. Hepatic panel may reveal mild transaminase elevation in 20 to 30%. Renal function is usually normal. Blood cultures should be obtained to exclude bacteremia, as pustules are sterile in AGEP. Pustule culture confirming sterility supports the non-infectious etiology. Patch testing performed retrospectively is positive in 50 to 58% of AGEP cases when performed 6 to 8 weeks after resolution. A pustular reaction at the patch test site is highly specific for AGEP.
Differential Diagnosis
AGEP vs. Generalized Pustular Psoriasis (GPP)
| Feature | AGEP | GPP |
|---|---|---|
| Drug trigger | Yes (>90%) | Rarely drug-triggered |
| Personal/family history of psoriasis | Absent | Often present |
| Latency | Hours to days | Days to weeks |
| Duration | Resolves in <15 days | Chronic/relapsing |
| Histology | No acanthosis, eosinophils present | Acanthosis, tortuous vessels, no eosinophils |
| IL36RN mutations | Absent | Present in familial GPP |
AGEP vs. SJS/TEN
AGEP pustules are non-follicular and sterile, whereas SJS/TEN features targetoid macules with full-thickness necrosis. Mucosal involvement in AGEP is mild and limited, while it is severe in SJS/TEN. AGEP has a much lower mortality (less than 5% versus 10 to 50%). The Nikolsky sign can be positive in both conditions, making histopathology the definitive differentiator.
Other Considerations
Subcorneal pustular dermatosis (Sneddon-Wilkinson) is chronic and relapsing and not drug-related. IgA pemphigus is distinguished by DIF showing intercellular IgA. Bacterial septicemia with cutaneous dissemination is identified by positive blood cultures and pustule cultures.
<image>Histopathologic comparison between AGEP (subcorneal spongiform pustule with dermal eosinophils and papillary dermal edema without acanthosis) and generalized pustular psoriasis (spongiform pustule of Kogoj with acanthosis and tortuous dilated dermal blood vessels)</image>
Management
Acute Management
Identifying and withdrawing the culprit drug is the primary and most important intervention. Supportive care includes maintaining hydration and temperature regulation while monitoring for secondary infection. Topical corticosteroids (medium-to-high potency) provide symptomatic relief of pruritus and erythema. Antipyretics address fever. Systemic corticosteroids are reserved for severe cases with extensive skin involvement, significant systemic symptoms, or delayed resolution, using a short course (0.5 to 1 mg/kg/day with rapid taper over 1 to 2 weeks). Cyclosporine has been used anecdotally for AGEP-TEN overlap cases.
Monitoring
Serial labs (CBC, hepatic and renal panels) should be followed until resolution. Areas of extensive pustulation and desquamation should be monitored for secondary skin infection. Complete resolution should be observed, and failure to resolve within 2 to 3 weeks of drug withdrawal should prompt reassessment of the diagnosis, with particular consideration of GPP.
Follow-Up
Patch testing with the suspected culprit drug is recommended 6 to 8 weeks after complete resolution to confirm the causative agent and guide future drug avoidance. The reaction and culprit drug should be clearly recorded in the medical record. Patients should be counseled about cross-reactivity and advised to avoid structurally related drugs (for example, all aminopenicillins if amoxicillin was the trigger).
Key Clinical Pearls
The short latency period (less than 48 hours for antibiotics) and rapid spontaneous resolution (less than 15 days) are the hallmarks that distinguish AGEP from other severe cutaneous drug reactions. Non-follicular sterile pustules on erythematous, edematous skin beginning in intertriginous folds is the classic presentation; follicular pustules suggest a different diagnosis. Collarette desquamation during the resolution phase is a characteristic and diagnostically helpful finding. AGEP has the best prognosis among severe cutaneous adverse reactions (mortality less than 5%), but AGEP-TEN overlap cases require more intensive management. Patch testing with a pustular reaction is highly specific for confirming the culprit drug and should be pursued 6 to 8 weeks after resolution.
References
- Sidoroff A, Halevy S, Bavinck JN, Vaillant L, Roujeau JC. Acute generalized exanthematous pustulosis (AGEP) — a clinical reaction pattern. J Cutan Pathol. 2001;28(3):113-119.
- Szatkowski J, Schwartz RA. Acute generalized exanthematous pustulosis (AGEP): a review and update. J Am Acad Dermatol. 2015;73(5):843-848.
- Beylot C, Bioulac P, Doutre MS. Acute generalized exanthematous pustuloses (four cases). Ann Dermatol Venereol. 1980;107(1-2):37-48.
- Hotz C, Valeyrie-Allanore L, Haddad C, et al. Systemic involvement of acute generalized exanthematous pustulosis: a retrospective study on 58 patients. Br J Dermatol. 2013;169(6):1223-1232.
