What is DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) syndrome?

What is DRESS Syndrome?

DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) syndrome is a rare, potentially life-threatening drug-induced hypersensitivity reaction characterized by a morbilliform rash involving >30% of body surface area, fever >38°C, eosinophilia, lymphadenopathy, and multi-organ involvement (most commonly liver, kidney, heart, and lung) that typically occurs 2-6 weeks after exposure to the offending medication. 1, 2

Key Clinical Features

Timing and Presentation

• The reaction occurs after a characteristic latent period of 2-6 weeks following drug exposure, distinguishing it from other immediate drug reactions 1, 2, 3
• This delayed presentation has earned DRESS the moniker "the great mimicker," often leading to diagnostic delays and increased morbidity 4

Cutaneous Manifestations

• The most common skin finding is a morbilliform (maculopapular) confluent rash that typically involves more than 30% of body surface area 1, 2
• The rash is accompanied by fever and constitutional symptoms including rigors, myalgias, and arthralgias 5

Systemic Involvement

• Internal organ involvement occurs in close to 90% of patients, with multiple organs affected in approximately half of cases 4
• Hepatitis is the most common organ manifestation, with ALT >2 times the upper limit of normal 2
• Kidney involvement presents as nephritis with creatinine >1.5 times baseline 2
• Pulmonary manifestations occur in 50% of cases with interstitial infiltrates, and 31% may develop acute respiratory distress syndrome (ARDS) 4
• Cardiac involvement can include myocarditis and pericarditis 1

Hematologic Abnormalities

• Eosinophilia is a hallmark feature, defined as >700/μL or >10% of white blood cells 2
• Lymphadenopathy is commonly present 1, 3
• Skin biopsy shows lymphocytic CD4+ infiltrates with eosinophils and papillary edema 5

Pathophysiology

The syndrome involves reactivation of herpes family viruses (particularly EBV and HHV-6) and activation of lymphocytes, leading to T-cell immune-directed toxicity 1, 6

• Genetic predispositions through the major histocompatibility complex (MHC) play a significant role, with specific HLA associations linked to particular drug reactions (e.g., HLA-B*58:01 with allopurinol-induced DRESS) 1, 2

Common Causative Medications

Anticonvulsants and sulfonamides are the most frequent offending agents, though many other drugs have been implicated 3, 7

• Anticonvulsants (historically phenytoin, but also carbamazepine, lamotrigine)
• Sulfonamides and other antibiotics (including minocycline and amoxicillin-clavulanic acid) 6
• Allopurinol 2
• Immune checkpoint inhibitors (anti-PD-1, anti-CTLA-4) can cause DRESS as a rare but potentially lethal adverse event 8

Diagnostic Approach

The diagnosis is clinical, based on the RegiSCAR scoring system that classifies cases as "no," "possible," "probable," or "definite" based on clinical and laboratory findings 2

Essential Diagnostic Workup

• Complete blood count with differential to assess for eosinophilia 2
• Comprehensive metabolic panel evaluating liver function (ALT, AST, alkaline phosphatase, bilirubin) and kidney function (BUN, creatinine) 2
• Urinalysis to evaluate for nephritis 5, 2
• Blood cultures to rule out infectious causes 5
• Skin biopsy if diagnosis is uncertain 5

Critical Differential Diagnoses

DRESS must be distinguished from other severe cutaneous adverse reactions (SCARs) 8, 2:

• Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN): Distinguished by the presence of eosinophilia, longer latency period, and organ involvement in DRESS 5
• Acute Generalized Exanthematous Pustulosis (AGEP) 1
• Viral infections and autoimmune disorders 2

Clinical Significance and Prognosis

DRESS syndrome carries a mortality rate of approximately 10%, making early recognition critical 6

• Pulmonary involvement is associated with more severe clinical course and potentially worse outcomes 4
• In multivariate analysis, latency of 30 days or less and age of 60 or less were associated with development of ARDS 4
• Relapse can occur in approximately 12% of cases, particularly with DRESS associated with viral reactivation 1

Management Principles

Immediate discontinuation of the suspected causative drug is the first and most crucial step, followed by prompt dermatology consultation 1, 5

Severity Assessment

• Early evaluation is essential to identify severe presentations requiring immediate intervention, including SJS, TEN, bullous lesions, and DRESS syndrome that necessitate immediate interruption of therapy, specialist treatment, and monitoring 8
• 45% of cases are initially misdiagnosed as pneumonia and inappropriately treated with empiric antimicrobials 4

Treatment Approach

• Systemic corticosteroids are first-line therapy (IV methylprednisolone 1-2 mg/kg/day), with weaning over at least 4 weeks required due to T-cell immune-directed toxicity 1, 5
• Severe cases require admission to burn unit or ICU with dermatology and wound care services consultation 5
• Unlike in Stevens-Johnson syndrome, corticosteroids are not contraindicated in DRESS syndrome 5
• For steroid-unresponsive cases, consider intravenous immunoglobulin (IVIG) at 1-2 g/kg total dosage or cyclosporine 5, 9
• Supportive care includes fluid and electrolyte management, infection prevention, topical corticosteroids, and oral antihistamines 1, 5

Important Caveats

• Prophylactic corticosteroids when initiating medications known to cause DRESS are not effective and may increase the risk of skin rash 5
• 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 1
• Genetic testing (such as HLA-B*5701 for abacavir) may be useful before prescribing certain medications to prevent hypersensitivity reactions 1