What is the pathophysiology, diagnosis, and treatment of DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) syndrome?

DRESS Syndrome: Pathophysiology, Diagnosis, and Treatment

The immediate discontinuation of the suspected causative drug is the first and most crucial step in managing DRESS syndrome, followed by prompt dermatology consultation and initiation of systemic corticosteroids for all suspected cases. 1

Pathophysiology

• DRESS syndrome involves a complex interplay of immunologic and genetic factors through the major histocompatibility complex (MHC), with certain genetic predispositions strongly associated with specific drug reactions 2
• The pathophysiology involves reactivation of herpes family viruses (particularly HHV-6 and EBV) and activation of lymphocytes, leading to a delayed hypersensitivity reaction 3, 4
• T-cell immune-directed toxicity plays a central role, with drug metabolic enzyme defects contributing to the development of the syndrome 1, 4
• The reaction typically occurs after a latent period of 2-6 weeks following exposure to the offending drug, distinguishing it from other drug reactions 1, 3

Common Causative Drugs

• Anticonvulsants (particularly phenytoin, carbamazepine) and sulfonamides are the most common offending agents 3, 4
• Other medications frequently implicated include:
  • Dapsone and vancomycin 5
  • Minocycline and amoxicillin-clavulanic acid 6
  • Abacavir (strongly associated with HLA-B*5701) 2
  • Various antiretroviral drugs 2

Clinical Presentation

• Cutaneous manifestations:

  • Morbilliform (maculopapular) confluent rash is the most common presentation 2, 3
  • Facial edema is characteristic 3
  • Rash typically involves >30% of body surface area 2

• Systemic manifestations:

  • Fever and constitutional symptoms (rigors, myalgias, arthralgias) 2
  • Lymphadenopathy 3, 4
  • Hematologic abnormalities (eosinophilia, atypical lymphocytosis) 2, 3
  • Multi-organ involvement including hepatitis, pneumonitis, myocarditis, pericarditis, and nephritis 2, 4

Diagnostic Criteria

• The diagnosis is clinical, based on the following features:

  • Exposure to causative drug with appropriate temporal relationship (2-6 weeks) 1, 3
  • Cutaneous eruption 2
  • Systemic involvement (fever, lymphadenopathy) 2, 3
  • Hematologic abnormalities (eosinophilia, atypical lymphocytes) 2, 3
  • Internal organ involvement (liver, kidney, lung, heart) 2, 4

• Diagnostic workup should include:

  • Complete blood count with differential 1
  • Liver and kidney function tests 1
  • Urinalysis and blood cultures 1
  • Skin biopsy if diagnosis is uncertain 1

Differential Diagnosis

• DRESS must be distinguished from other severe cutaneous adverse reactions:
  • Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) - characterized by blistering affecting different percentages of body surface area 2
  • Acute Generalized Exanthematous Pustulosis (AGEP) 2
  • Other drug hypersensitivity syndromes 2

Treatment

• First-line management:

  • Immediate discontinuation of the suspected causative drug 1
  • Prompt dermatology consultation 1
  • Admission to burn unit or ICU for severe cases 1

• Systemic therapy:

  • Initiate systemic corticosteroids: IV methylprednisolone 1-2 mg/kg/day 1
  • Wean systemic corticosteroids over at least 4 weeks 1
  • For severe cases unresponsive to initial steroid therapy, consider:
    • Pulse steroid therapy (250 mg/day methylprednisolone for 3 days) 7
    • Intravenous immunoglobulin (IVIG) at 1-2 g/kg total dosage 1, 5
    • Plasmapheresis in cases with impending organ failure 7
    • Cyclosporine for severe or steroid-unresponsive cases 1

• Supportive care:

  • Fluid and electrolyte balance management 1
  • Minimizing insensible water losses 1
  • Infection prevention measures 1
  • Topical treatment and oral antihistamines for symptomatic relief 1, 3

• Monitoring:

  • Serial clinical photography to track skin manifestations 1
  • Regular monitoring of organ function 1
  • Specialist consultation based on organ involvement (ophthalmology, otolaryngology, urology, etc.) 1

Prognosis and Complications

• DRESS syndrome has a mortality rate of approximately 10%, most commonly from fulminant hepatitis with hepatic necrosis 4
• The syndrome may persist and even progress despite standard treatment 7
• Relapse can occur in approximately 12% of cases, particularly with DRESS associated with viral reactivation 2
• Long-term sequelae may include autoimmune diseases and permanent organ damage 3

Special Considerations

• Unlike SJS/TEN, corticosteroids are not contraindicated in DRESS syndrome 1
• Patch testing or intradermal testing should be avoided until at least 6 months after the acute reaction and at least 1 month after discontinuation of systemic corticosteroids 2
• Prophylactic use of corticosteroids when initiating medications known to cause DRESS is not recommended 1
• Genetic testing (e.g., HLA-B*5701 for abacavir) may be useful before prescribing certain medications to prevent hypersensitivity reactions 2