What is the updated protocol for the approach and management of drug eruptions, including differentiation between maculopapular drug eruption, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Stevens-Johnson syndrome, Toxic Epidermal Necrolysis (TEN), and Acute Generalized Exanthematous Pustulosis (AGEP)?

Updated Protocol for Drug Eruption Management

Immediate Assessment and Triage

Immediately discontinue all suspected causative drugs upon presentation of any drug eruption, as this is the single most critical intervention affecting morbidity and mortality. 1, 2

Initial Clinical Evaluation

Obtain detailed medication history:

• Document all medications taken in the previous 2 months, including over-the-counter and complementary therapies with exact start dates 1
• Determine the index date (first symptom onset: sore throat, rash, skin pain, sore eyes/mouth) 1
• Note timing between drug initiation and symptom onset (critical for differentiation) 1, 3

Assess severity immediately using these danger signs:

• Skin pain or burning sensation 1
• Mucosal involvement (eyes, mouth, genitalia) 1
• Fever >38.5°C 1, 4
• Facial edema or infiltrated skin 1
• Respiratory symptoms (dyspnea, cough, bronchial hypersecretion) 1
• Systemic symptoms (malaise, lymphadenopathy) 2, 4

Morphologic Differentiation Protocol

Step 1: Assess Body Surface Area (BSA) and Skin Detachment

Document percentage of BSA with erythema AND percentage with epidermal detachment separately using Lund and Browder chart—detachment percentage determines prognosis, not erythema. 1

• <10% BSA detachment = Stevens-Johnson Syndrome (SJS) 5
• 10-30% BSA detachment = SJS-TEN overlap 5
• >30% BSA detachment = Toxic Epidermal Necrolysis (TEN) 5

Step 2: Examine Skin Morphology

Maculopapular Drug Eruption:

• Confluent erythematous macules and papules 6
• No blisters, pustules, or epidermal detachment 6
• Typically involves <30% BSA 4
• No mucosal involvement 6
• Minimal systemic symptoms 1

DRESS Syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms):

• Morbilliform (maculopapular) confluent rash involving >30% BSA 2, 4
• Latency period of 2-6 weeks after drug exposure 2, 3
• Fever >38°C with constitutional symptoms 4, 3
• Facial edema common 1, 4
• Lymphadenopathy present 4, 3
• NO epidermal detachment or blistering 2

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis:

• Painful skin with burning sensation 1
• Atypical target lesions or purpuric macules 1
• Flaccid blisters and areas of epidermal detachment 1
• Positive Nikolsky sign (skin shearing with minimal trauma) 1
• Hemorrhagic erosions of mucous membranes (eyes, mouth, genitalia) 1, 5
• Grey-violaceous or dusky color of lesions 1
• Shorter latency (days to 2 weeks) 7

Acute Generalized Exanthematous Pustulosis (AGEP):

• Exanthema with numerous small, non-follicular sterile pustules 1
• Pustules on erythematous base 1
• Rapid onset (typically <24-48 hours after drug exposure) 8
• Fever >38.5°C 1
• Neutrophilia (not eosinophilia) 8
• NO mucosal involvement 8

Step 3: Mandatory Laboratory Workup

Order immediately for all suspected severe reactions:

• Complete blood count with differential (assess for eosinophilia >700/μL or >10% in DRESS; neutrophilia in AGEP) 1, 4, 3
• Comprehensive metabolic panel including liver function tests (ALT, AST, alkaline phosphatase, bilirubin) and renal function (BUN, creatinine) 1, 4, 3
• Electrolytes, magnesium, phosphate, bicarbonate, glucose 1
• Coagulation studies 1
• Urinalysis to evaluate for nephritis 4, 3
• Mycoplasma serology 1
• Chest X-ray 1

DRESS-specific additional testing:

• Viral serologies for herpes family virus reactivation (EBV, HHV-6) 2, 4

Step 4: Obtain Skin Biopsy

Perform skin biopsy from lesional skin adjacent to a blister (for SJS/TEN) or from representative lesion (for other eruptions) to confirm diagnosis and exclude differential diagnoses. 1, 4

Differentiation Summary Table

Feature	Maculopapular	DRESS	SJS/TEN	AGEP
Latency	Days to weeks [6]	2-6 weeks [2,3]	Days to 2 weeks [7]	<48 hours [8]
Primary lesion	Macules/papules [6]	Maculopapular rash [2]	Blisters/detachment [1]	Pustules [1]
BSA involvement	Variable [6]	>30% [4]	Variable [5]	Diffuse [8]
Mucosal involvement	Absent [6]	Rare [2]	Prominent [1]	Absent [8]
Fever	Absent/low [1]	>38°C [4]	Present [1]	>38.5°C [1]
Eosinophilia	Absent [6]	>700/μL [4]	Absent [5]	Absent [8]
Organ involvement	Absent [6]	Hepatitis, nephritis [4,3]	Respiratory, GI [1]	Minimal [8]
Skin pain	Absent [6]	Absent [2]	Prominent [1]	Absent [8]

Management Protocols by Diagnosis

Maculopapular Drug Eruption (Non-severe)

Outpatient management is appropriate:

• Discontinue causative drug 1, 6
• Oral H1-antihistamines for symptomatic relief 1
• Topical corticosteroids for pruritus 6
• Monitor for progression to severe reaction 1

DRESS Syndrome

Admit to hospital immediately for all suspected cases: 2, 4

First-line treatment:

• IV methylprednisolone 1-2 mg/kg/day 1, 2, 4
• Taper over minimum 4 weeks (prolonged taper required due to T-cell immune mechanism and risk of relapse) 1, 2
• Do NOT use short steroid courses—this is a common pitfall leading to relapse 2

Supportive care:

• Fluid and electrolyte management 2, 4
• Topical emollients and high-strength topical corticosteroids 1, 2
• Oral antihistamines for pruritus 1, 2
• Monitor for infection 2

Steroid-refractory cases:

• IVIG 1-2 g/kg total dose 1, 4
• Cyclosporine as alternative 1, 4

Follow-up:

• Monitor for relapse (occurs in 12% of cases) 2
• Avoid patch testing until at least 6 months after acute reaction and 1 month after stopping corticosteroids 2

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis

Transfer immediately to burn unit or intensive care unit: 1

Critical initial management:

• Discontinue ALL potential culprit drugs immediately 1
• Consult dermatology, ophthalmology, and wound care services urgently 1
• If respiratory symptoms or hypoxemia present, perform fiberoptic bronchoscopy 1

Supportive care (primary treatment):

• Warming of environment 9
• Fluid and electrolyte replacement (manage as major burn) 1, 9
• High caloric intake 9
• Infection prevention 1, 9
• Topical emollients (white soft paraffin or petrolatum) every 4 hours 1
• Silicone dressings (e.g., Mepitel) to eroded areas 1
• Pain management 1

Ocular care:

• Daily ophthalmology review mandatory 1
• Topical corticosteroid ointment to noneroded surfaces once daily 1
• Prevent synechiae formation 1

Urogenital care:

• Daily urogenital review 1
• White soft paraffin ointment every 4 hours 1
• Potent topical corticosteroid ointment to involved noneroded surfaces 1

Controversial systemic therapy:

• Systemic corticosteroids are CONTRAINDICATED in advanced TEN (shown to be deleterious) 9
• Early-stage SJS may benefit from IV methylprednisolone 0.5-1 mg/kg, but evidence is controversial 1, 9
• IVIG or cyclosporine may be considered in severe or steroid-unresponsive cases 1
• Thalidomide is CONTRAINDICATED (increased mortality in clinical trial) 9

Prognosis assessment:

• Calculate SCORTEN score to predict mortality 5
• Mortality: SJS 1-5%, TEN 25-35% 5

Acute Generalized Exanthematous Pustulosis (AGEP)

Hospital admission for monitoring: 8

Management:

• Discontinue causative drug 8
• Supportive care with topical corticosteroids 1, 8
• Oral antihistamines for symptomatic relief 8
• Monitor for secondary infection 8
• Self-limited course—pustules typically resolve within 2 weeks after drug withdrawal 8
• Systemic corticosteroids rarely needed 8

Discharge and Long-term Management

For all severe cutaneous adverse reactions:

• Provide written documentation of drug(s) to avoid (include chemically related compounds) 1, 9
• Encourage MedicAlert bracelet 1
• Document drug allergy in medical records and inform all treating physicians 1
• Report to national pharmacovigilance authorities 1
• Arrange dermatology follow-up within 2-4 weeks of discharge 1
• Arrange ophthalmology follow-up if ocular involvement occurred 1

Drug hypersensitivity testing:

• Routine testing NOT recommended after SJS/TEN 1
• Consider specialist testing only when: culprit drug unknown, medication avoidance detrimental, or accidental exposure possible 1
• Lymphocyte drug-induced IFN-γ assay has best evidence for identifying culprit drugs 1

Common Pitfalls to Avoid

• Do not delay drug discontinuation while awaiting test results or specialist consultation 1, 2
• Do not use short corticosteroid courses for DRESS (minimum 4-week taper required) 2
• Do not give systemic corticosteroids in advanced TEN (harmful) 9
• Do not perform oral drug challenge testing to confirm causative agent (risk of severe exacerbation) 7
• Do not confuse erythema percentage with detachment percentage in SJS/TEN—only detachment has prognostic value 1
• Do not miss DRESS diagnosis by focusing only on rash—systemic involvement and eosinophilia are key features 2, 4