What are the differential diagnoses for a patient presenting with a severe, pruritic, and exudative rash?

Differential Diagnoses for Severe, Pruritic, Exudative Rash

For a patient presenting with a horrible, pruritic, dripping (exudative) rash, the most critical differentials to consider immediately are Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN), bullous drug eruptions, acute generalized exanthematous pustulosis (AGEP), and severe eczematous dermatitis—with SJS/TEN requiring emergency hospitalization due to potential mortality. 1

Life-Threatening Conditions (Exclude First)

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis

• Presents with painful (not just pruritic) rash, skin detachment, and mucosal involvement (eyes, mouth, genitalia) 1
• Look for prodromal fever, malaise, and upper respiratory symptoms 1-3 days before rash onset 1
• Target lesions (particularly atypical targets), purpuric macules, and blisters with positive Nikolsky sign 1
• If suspected, discontinue all potential culprit drugs immediately and arrange emergency hospitalization 1
• Mortality risk is significant without prompt intervention 1

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

• Occurs after 6th week of drug exposure (later than typical eczematous drug reactions) 1
• Presents with diffuse rash affecting >50% body surface, fever, and systemic symptoms 1
• Requires immediate discontinuation of all medications and emergency hospitalization 1

Staphylococcal Scalded Skin Syndrome

• Consider in differential for exudative, dripping presentation 1
• More common in children but can occur in immunocompromised adults 1

Severe Drug-Induced Eruptions

Generalized Bullous Fixed Drug Eruption

• Can present with severe exudation and pruritus 1
• History of medication exposure within 2 months is critical 1
• Discontinue suspected culprit drug immediately 1, 2

Severe Eczematous Drug Dermatitis

• Particularly associated with protease inhibitors (telaprenavir causes eczematous dermatitis in 54% of cases) 1
• Presents with diffuse erythema, xerosis, vesicular lesions, and intense pruritus with excoriations 1
• Neck and axillary creases particularly affected 1
• If Grade 3 (>50% body surface), stop offending drug definitively 1

Immunobullous Disorders

Pemphigus Vulgaris

• Presents with flaccid blisters that rupture easily, leaving painful erosions with exudate 1
• Mucosal involvement is common and often precedes skin lesions 1
• Requires skin biopsy for routine histopathology AND perilesional biopsy for direct immunofluorescence 1

Bullous Pemphigoid

• Tense blisters on erythematous base with intense pruritus 1
• Exudation occurs when blisters rupture 1
• Direct immunofluorescence shows linear IgG and C3 at basement membrane zone 1

Mucous Membrane Pemphigoid

• Predominantly mucosal involvement with skin lesions in some cases 1
• Can present with exudative erosions 1

Systemic Disease-Associated Pruritic Eruptions

Acute Graft-versus-Host Disease

• Consider in any patient with history of bone marrow or stem cell transplantation 1
• Maculopapular rash that can become confluent and exudative 1

Bullous Lupus Erythematosus

• Vesiculobullous eruption in sun-exposed areas 1
• Check ANA, anti-dsDNA, complement levels 3

Severe Infectious Exanthems

Adult-Onset Still's Disease

• Salmon-pink evanescent rash that is intensely pruritic, involving proximal limbs and trunk 3
• Associated with high-spiking fever (≥39°C), arthralgia/myalgia, and sore throat 3
• Serum ferritin typically markedly elevated (4,000-30,000 ng/mL) 3
• Urgent consideration needed as Macrophage Activation Syndrome can complicate presentation 3

Rocky Mountain Spotted Fever

• Fever, rash (starts on ankles/wrists, spreads centrally), and myalgia 3
• Rash becomes petechial by day 5-6 3
• Mortality 5-10% if untreated—requires urgent doxycycline 3

Diagnostic Workup Algorithm

Immediate Assessment (Within Hours)

1. Assess for SJS/TEN red flags: mucosal involvement, skin pain, detachment, fever 1
2. Review ALL medications taken in past 2 months (including OTC and complementary therapies) 1, 2
3. Examine all mucosal sites (eyes, mouth, nose, genitalia) for erosions 1
4. Calculate body surface area involvement using Lund and Browder chart 1

Initial Laboratory Testing

• Complete blood count with differential, ferritin 1, 2
• Liver function tests, total bilirubin, serum bile acids 1, 2
• Urea and electrolytes, creatinine 1
• Inflammatory markers (ESR, CRP) if systemic disease suspected 3
• Serum ferritin and glycosylated ferritin fraction if Adult-Onset Still's Disease considered 3

Skin Biopsy Protocol

• Two biopsies required: one from lesional skin for routine histopathology, one from perilesional skin unfixed for direct immunofluorescence 1
• This distinguishes immunobullous disorders from other causes 1

Additional Testing Based on Clinical Context

• HIV and hepatitis A, B, C serology if risk factors present 1
• Mycoplasma serology 1
• Travel history screening: malaria, strongyloidiasis, schistosomiasis 1
• JAK2 V617F mutation if polycythemia vera suspected 1

Critical Pitfalls to Avoid

• Never delay hospitalization if SJS/TEN or DRESS suspected—these require immediate specialist care and have significant mortality risk 1
• Do not assume all exudative rashes are infectious—immunobullous disorders and drug reactions are common mimics 1
• Do not forget to examine finger webs, anogenital region, nails, and scalp—these areas provide diagnostic clues 4
• Do not overlook drug-induced causes—12.5% of drug reactions present with pruritus, and visible changes may lag behind symptoms 2, 5
• Do not use high-potency topical steroids on face—this causes atrophy and telangiectasia 5

Immediate Management While Awaiting Diagnosis

• Apply emollients liberally to all affected areas using oil-in-water creams or ointments 5
• Low-potency topical corticosteroids (hydrocortisone) for facial involvement, moderate-potency (triamcinolone 0.1%) for body 5
• Non-sedating antihistamines (fexofenadine 180 mg daily or loratadine 10 mg daily) for pruritus 5
• Discontinue all non-essential medications immediately 1, 2