Acute generalised exanthematous pustulosis

Macmillan (1973), Tan (1974), Beylot (1980)

• Acute generalized pustulosis
• Pustulosis acuta generalista
• Acute generalized pustular bacterid
• Acute generalized exanthematous pustulosis
• Pustular drug eruption
• Pustular drug rush
• Toxic pustuloderma
• AGEP
• PEAG
• Acute generalized exanthematic pustular dermatitis
• Toxic pustuloderma
• Pustuloses exanthématiques aigës généralisés

Acute drug reaction with abrupt onset of sterile, pinhead-sized, non-follicular pustules on an erythematous-edematous base. Usually starts in large flexures, spreads rapidly, fever, neutrophilia. Heals in 1-3 weeks with desquamation after trigger is stopped.

• 1-5/million/year, probably underreported
• Adults (median age 50-60 years), rarely children

Risk factors:

• Psoriasis
• Obesity

• Disseminated, small pustular form
• Large pustular form on erythematous islands
• Targetoid form
• Mixed forms, e.g. with small vessel vasculitis or EEM or DRESS syndrome
• ALEP as a localized form

Working diagnosis in acute cases of sterile pustulosis:

• AGEP / possible GPP

Classification according to triggers: 

• 90% drug-triggered form
• 1% pathogen-triggered form (viruses, bacteria, parasites, vaccinations)
• 10% other triggers

• Exact mechanism still unclear
• Mutation in the IL36RN gene known in 4%
• Increased formation of IL-23, IL-17, and IL-8 detected
• Frequent HLA-B5, HLA-DR11 and HLA-DQ3
• Previous sensitization is assumed. Neutrophilia in the blood and the accumulation of neutrophils in the lesions suggest the release of activating cytokines by membrane-bound specific T lymphocytes. This has a cytotoxic effect on the cells.
• Other data show a T-cell-independent reaction of monocytes and macrophages to the triggering drugs.

• Acute: fever, malaise, pustules on erythema, onset in flexural areas
• Course: rapid spread, targetoid lesions possible, 5-10% mild mucosal involvement
• Laboratory: leukocytosis with neutrophilia, ↑ CRP, ± eosinophilia
• Healing with collar-shaped desquamation (corneal sign)

• Clinical
• Laboratory: pathological inflammation parameters with pronounced leukocytosis (>15,000 leukocytes/ul) and marked neutrophilia, moderate eosinophilia, kidney parameters (transient renal dysfunction), rarely hypocalcemia
• Histology with subcorneal pustules
• Pustule smear to rule out possible infection, especially KOH mycology for Candida folliculitis.
• Patch test/epicutaneous testing is positive for the responsible medication in 50% of cases
• Determine RegiSCAR score. 

Triggers (90% medication-related):

• Antibiotics (especially β-lactams, macrolides, quinolones)
• Terbinafine, hydroxychloroquine (long half-life!), diltiazem, NSAIDs
• <10% infectious (enteroviruses, mycoplasmas, SARS-CoV-2)

Differentiation from GPP:

• Under discussion whether possible at all, transcription profile of AGEP and drug-induced GPP is exactly the same. No history of psoriasis, smaller pustules, eosinophilia → indicates AGEP
• Course, histology, IL36RN testing for differentiation if necessary

• Initially on the face and in 25% predominantly on large body folds (axilla, groin, submammary), then also on the trunk and distal extremities as the disease progresses.
• In 5% also oral, in 12% also lips. 

• Ask about previous drug reactions (present in 86% of patients, known drug allergy in approx. 70%)
• Record medications and the time of their administration
• Clarify psoriasis in the medical history

• Subcorneal sterile pustules with neutrophilic infiltrate, ± eosinophils, ± spongiosis
• No pronounced acanthosis as in GPP

• Superinfection → sepsis
• Transient organ involvement
• Residual pigmentation
• Mortality <5%

• Avoid triggering medications
• Within 1-6 months after healing, perform epicutaneous testing (patch testing) with the medications in question.
• Avoid oral provocation due to risk of recurrence. 

• Spontaneous healing within 10 days to 4 weeks
• If medication-induced: the sooner the medication is discontinued, the better
• Depends on the age and underlying disease of the patient

• Parisi R, Shah H, Navarini AA, et al. Acute generalized exanthematous pustulosis: clinical features, differential diagnosis, and management. Am J Clin Dermatol. 2023;24(4):557-575.
• Tetart F, Walsh S, Milpied B, et al. Acute generalized exanthematous pustulosis: European expert consensus for diagnosis and management. J Eur Acad Dermatol Venereol. 2024;38(11):2073-2081.
• Russo G, Dumont S, Menzinger S, et al. Severe acute generalized exanthematous pustulosis successfully treated by spesolimab. Acta Derm Venereol. 2024;104:adv41311.
• Zhang L, Xu Q, Lin T, et al. Successful treatment of acute generalized exanthematous pustulosis with secukinumab: a case report. Front Med (Lausanne). 2021;8:758354.
• Gualtieri B, Solimani F, Hertl M, et al. Interleukin 17 as a therapeutic target of acute generalized exanthematous pustulosis (AGEP). J Allergy Clin Immunol Pract. 2020;8(6):2081-2084.
• Sussman M, Napodano A, Huang S, et al. Pustular psoriasis and acute generalized exanthematous pustulosis: a diagnostic and therapeutic challenge. Medicina (Kaunas). 2021;57(10):1004.
• Lee EY, Koh MJ. Acute generalized exanthematous pustulosis in children and adolescents: a 10-year review from Singapore. Pediatr Dermatol. 2021;38(2):424-430.
• Fathallah N, Kenani Z, Mokni S, et al. Acute generalized exanthematous pustulosis: analysis of cases in a Tunisian tertiary hospital. Therapie. 2024;79(4):469-474.
• Creadore A, Desai S, Alloo A, et al. Clinical characteristics, disease course, and outcomes of patients with acute generalized exanthematous pustulosis in the US. JAMA Dermatol. 2022;158(2):176-183.
• Matei I, Cohen J, Khalifa N, et al. Evolution of the spectrum of drugs associated with acute generalized exanthematous pustulosis over time: a pharmacovigilance study. J Am Acad Dermatol. 2024;90(5):1023-1032.