Acute generalised exanthematous pustulosis

Background

• A form of severe cutaneous adverse reaction
• Also known as a pustular drug eruption or toxic pustuloderma

Etiologies

• Typically triggered by medications (90% of cases)
  • Antibiotics (most common trigger by far): beta-lactams (most common antibiotic trigger), macrolides, fluoroquinolones, tetracyclines, sulfonamides
  • Other antimicrobials
  • NSAIDs
  • Proton pump inhibitors
  • Long list of other medications
• Possibly also infections, spider bites, allergens, herbal medications, UV therapy
• Can also be idiopathic, without identified trigger

Clinical Manifestations

• Onset typically within 10 days of starting drug (usually within 1 to 3 days), resolving within 2 weeks of drug discontinuation
  • Onset typically faster with antibiotics and iodinated contrast media; long latent periods have been seen with some drugs, up to 40 days for hydroxychloroquine
• Characteristic rash is diffuse, erythematous, with many pinpoint pustules on an erythematous base
  • Lesions typically pinpoint, but can coalesce
  • Rash is pruritic or burning
  • Typically starts in face or intertriginous areas, then spreads centrally
  • Can occasionally involve palms and soles but involvement of oral mucosa is rare
• Followed by desquamation in a collarette pattern over 1-2 weeks
• Can also have systemic symptoms, including subjective or objective fevers
• Typical changes on bloodwork include leukocytosis with neutrophilia, elevated CRP, and occasional mild eosinophilia

EuroSCAR Criteria

Category	Criterion	Value	Score
Morphology	Pustules	Typical	+2
		Compatible	+1
		Insufficient	0
	Erythema	Typical	+2
		Compatible	+1
		Insufficient	0
	Distribution/pattern	Typical	+2
		Compatible	+1
		Insufficient	0
	Post-pustular desquamation	Yes	+1
		No/insufficient	0
Course	Mucosal involvement	Yes	-2
		No	0
	Acute onset (≤10 days)	Yes	0
		No	-2
	Resolution (≤15 days)	Yes	0
		No	-4
	Fever (≥38°C)	Yes	+1
		No	0
	Neutrophils (≥7000)	Yes	+1
		No	0
Histology	Other disease		-10
	Not representative/no histology		0
	Exocytosis of neutrophils		+1
	Subcorneal and/or intraepidermal nonspongiform or NOS pustule(s) with papillary edema or subcorneal and/or intraepidermal spongiform or NOS pustule(s) without papillary edema		+2
	Spongiform subcorneal and/or intraepidermal pustule(s) with papillary edema		+3

Interpretation

Score	Interpretation
≤0	no AGEP
1-4	possible AGEP
5-7	probable AGEP
8-12	definite AGEP

Differential Diagnosis

• Generalized pustular psoriasis is the most similar rash
• DRESS, which can rarely have pustules
• Sneddon-Wilkinson disease
• IgA pemphigus
• Pustular vasculitis
• Pustular Sweet syndrome
• Staphylococcal scalded skin syndrome
• Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE)
• Baboon syndrome

Investigations

• Bloodwork to help rule in: CBC looking for neutrophilia and eosinophilia, creatinine, liver panel, C-reactive protein
• Investigations to exclude other causes: pregnancy test (for pustular psoriasis of pregnancy), SPEP (for Sneddon-Wilksonson disease), procalcitonin, HHV-6/EBV/CMV (if overlap with DRESS), blood cultures, Mycoplasma pneumoniae serology or NP swab, cultures from pustules
• Skin biopsy for histology ± direct immunofluorescence
  • Include a pustule
  • Direct immunofluorescence if bullous disease is on the differential

Management

• Stop offending medication immediately
• Supportive care with mild soap substitutes, moisturizing cream, oral/IV hydration if necessary
• Strong topical corticosteroids (e.g. clobetasol) applied once a day to the whole body except the face, which is typically spared, for 5 to 7 days
• If the syndrome overlaps with DRESS, consider systemic corticosteroids with taper over 3 months

Further Reading

• Acute generalized exanthematous pustulosis: European expert consensus for diagnosis and management. J Eur Acad Dermatol Venereol. 2024;38(1):2073-2081. doi: 10.1111/jdv.20232