What are the symptoms and signs of a drug-induced rash and how is it managed?

Drug-Induced Rash: Symptoms, Signs, and Management

The immediate discontinuation of the suspected causative drug is the most critical first step in managing drug-induced rashes, especially for severe reactions like Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN), which can be life-threatening. 1

Clinical Presentation of Drug-Induced Rashes

Common Presentations

• Mild to moderate rashes: Most commonly maculopapular exanthema, typically occurring within the first weeks of therapy 1
• Timing: Usually appears 5-28 days after drug initiation (latent period), but may occur sooner with previous exposure to the same drug 1
• Distribution: Often widespread; certain drugs may have characteristic patterns (e.g., seborrheic areas with EGFR inhibitors) 1

Severe Presentations (Medical Emergencies)

1. Stevens-Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN):

   • Multiple apoptotic keratinocytes throughout the epidermis
   • Epidermal detachment and blistering
   • Mucosal involvement (often severe)
   • Systemic symptoms including fever
   • Can progress to extensive skin sloughing 1

2. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS):

   • Rash with systemic involvement
   • Fever, hematological abnormalities (eosinophilia)
   • Multiple organ involvement
   • Prolonged course 1

3. Acute Generalized Exanthematous Pustulosis (AGEP):

   • Generalized sterile small pustules
   • Often mistaken for infection 2

High-Risk Drugs Associated with Rashes

Severe Reactions (SJS/TEN/DRESS)

• Anticonvulsants
• Allopurinol
• Antibiotics (particularly sulfonamides)
• Non-nucleoside reverse transcriptase inhibitors (NNRTIs) - especially nevirapine 1
• Antifungals - rarely fluconazole 3

Common Culprits for Milder Reactions

• HIV medications:
  • NNRTIs (nevirapine, efavirenz, etravirine)
  • NRTIs (abacavir)
  • Protease inhibitors (amprenavir) 1
• Chemotherapy agents:
  • EGFR inhibitors (acneiform rash)
  • PD-1/PD-L1 inhibitors 1
• Antibiotics 4

Diagnostic Approach

Key Clinical Assessment

• Timeline: Document precise relationship between drug initiation and rash onset 1
• Drug history: Complete medication review from multiple sources (patient, relatives, GP, pharmacist) 1
• Physical examination: Assess for:
  • Extent of skin involvement (% body surface area)
  • Presence of blisters or epidermal detachment
  • Mucosal involvement
  • Systemic symptoms 1, 5

Diagnostic Tests

• Skin biopsy: Gold standard for diagnosis - take from lesional skin adjacent to a blister 1, 2
• Laboratory tests: CBC with differential (eosinophilia), liver function tests, renal function 1
• Documentation: Photographs to document type and extent of lesions 1

Management Algorithm

Step 1: Risk Assessment

• Mild reaction (localized rash, no systemic symptoms):

  • Discontinue suspected drug
  • Administer oral antihistamines
  • Monitor for 2-4 hours 4

• Moderate reaction (widespread rash, mild systemic symptoms):

  • Discontinue suspected drug
  • Administer oral antihistamines
  • Consider oral corticosteroids
  • Monitor for at least 4 hours 4

• Severe reaction (SJS/TEN, DRESS, extensive involvement, mucosal involvement):

  • Immediate drug discontinuation
  • Emergency care/hospitalization
  • Consider transfer to specialized unit (burn unit for SJS/TEN)
  • Supportive care with fluid management
  • Consider systemic corticosteroids (0.5-2 mg/kg/day) 1

Step 2: Symptomatic Treatment

• For pruritus:

  • Non-sedating H1 antihistamines (cetirizine, fexofenadine, loratadine)
  • For nighttime symptoms: Add sedating antihistamine (chlorphenamine 4-12 mg or hydroxyzine 10-50 mg) 4

• For pain:

  • Appropriate pain management, may require pain specialist consultation 1

• For SJS/TEN:

  • Establish peripheral venous access (through non-lesional skin)
  • IV fluid resuscitation
  • Consider nasogastric feeding if oral intake compromised
  • Urinary catheter for urogenital involvement 1

Step 3: Monitoring and Follow-up

• Monitor for 24-48 hours after initial reaction
• Clinical improvement should occur within 48-72 hours
• If symptoms worsen or fail to improve after 72 hours, consider treatment failure and switch to alternative agent 4
• For severe reactions, use SCORTEN to predict mortality risk 1

Special Considerations

Antihistamine Dosing Adjustments

• Adjust doses in renal impairment:
  • Halve cetirizine and levocetirizine doses in moderate renal impairment
  • Avoid cetirizine and levocetirizine in severe renal impairment
  • Use loratadine and desloratadine with caution in severe renal impairment 4

Pregnancy Considerations

• Avoid antihistamines in pregnancy, especially first trimester
• If necessary, chlorphenamine may be preferred due to longer safety record 4

Cross-Reactivity Concerns

• With NNRTIs, cross-hypersensitivity reactions may occur
• Patients with history of SJS/TEN with one NNRTI should avoid other NNRTIs 1
• For antibiotics, consider non-beta-lactam alternatives if severe reaction to beta-lactams 4

Prevention of Future Reactions

• Document drug allergies clearly in medical records
• Provide patient education about avoiding the offending drug
• Consider referral to allergist for formal evaluation 4
• For certain drugs (e.g., nevirapine), using dose escalation schedules may reduce rash incidence 1

Common Pitfalls to Avoid

• Delayed recognition of severe reactions like SJS/TEN or DRESS
• Continuing medication despite early rash development
• Prophylactic use of corticosteroids with high-risk medications (may increase risk)
• Misdiagnosing AGEP as infection, leading to inappropriate treatment
• Failing to consider drug etiology in chronic dermatological conditions 2, 6