DRESS Syndrome: Clinical Overview
DRESS syndrome is a severe, potentially life-threatening drug-induced hypersensitivity reaction that presents 2-6 weeks after drug exposure with a characteristic triad of morbilliform rash (>30% body surface area), fever (>38°C), and multi-organ involvement with eosinophilia—immediate drug discontinuation and systemic corticosteroids are the cornerstones of management. 1, 2
Clinical Presentation
Timing and Onset
- The hallmark latency period is 2-6 weeks after initial drug exposure, which distinguishes DRESS from immediate hypersensitivity reactions 1, 2, 3
- Symptoms typically begin around 3.7 weeks (median) after drug initiation 4
Cutaneous Manifestations
- Morbilliform (maculopapular) confluent rash involving more than 30% of body surface area is the most common skin finding 1, 2
- Facial edema occurs in approximately 58% of patients 4
- The rash is typically erythematous, maculopapular, and widespread 5
Constitutional Symptoms
- Fever >38°C is present in virtually all cases 1, 2
- Rigors, myalgias, and arthralgias commonly accompany the fever 1, 2
- Lymphadenopathy is a frequent finding 1, 2
Organ Involvement
- Hepatitis is the most common organ manifestation, defined as ALT >2 times the upper limit of normal (occurs in 74% of cases) 1, 4
- Nephritis presents with creatinine >1.5 times baseline (occurs in 32% of cases) 1, 4
- Cardiac involvement includes myocarditis and pericarditis (occurs in 4-21% of cases, with troponin elevation in 42%) 1, 4
- Pulmonary manifestations occur in approximately 50% with interstitial infiltrates, and 31% may develop ARDS 6
- Internal organ involvement occurs in close to 90% of patients, with multiple organs affected in approximately half 6
Hematologic Abnormalities
- Eosinophilia (>700/μL or >10% of white blood cells) is a hallmark feature, present in 95% of patients 1, 4
- Eosinophilia typically peaks around 10 days after skin manifestations appear 4
- Leukocytosis occurs in 84% of patients 4
- Reactive (atypical) lymphocytes are present in 26% of cases 4
Common Causative Drugs
Primary Culprits
- Antibiotics account for 74% of DRESS cases, including vancomycin, sulfonamides, and beta-lactams 1, 4
- Anticonvulsants account for 21% of cases, particularly phenytoin, carbamazepine, and phenobarbital 1, 4
- Allopurinol is a well-documented cause, with strong HLA-B*58:01 genetic association 1, 2, 6
Antiretroviral Agents
- Nevirapine causes DRESS in 17-32% of exposed patients, often accompanied by fever and hepatitis 5
- Abacavir is associated with hypersensitivity reactions in 2.3-9% of patients 1
- Nevirapine-induced reactions occur within 3 months of treatment initiation and are more severe with rechallenge 5
NSAIDs
- NSAIDs are among the most common causes of delayed drug hypersensitivity reactions, though they comprise <5% of all DRESS cases 5
- Oxicam derivatives (meloxicam, piroxicam) and acetic acid NSAIDs (diclofenac) are more highly associated with severe cutaneous adverse drug reactions 5
Diagnostic Approach
Clinical Diagnosis
- Diagnosis is primarily clinical, based on the RegiSCAR scoring system that classifies cases as "no," "possible," "probable," or "definite" (score ≥6 indicates definite DRESS) 1, 2, 4
Essential Laboratory Evaluation
- Complete blood count with differential to assess for eosinophilia and atypical lymphocytes 1, 2
- Comprehensive metabolic panel evaluating liver function (ALT, AST, alkaline phosphatase, bilirubin) and kidney function (BUN, creatinine) 1, 2
- Urinalysis to evaluate for nephritis 1, 2
- Blood cultures if febrile to rule out infectious mimics 1
- Troponin if cardiac involvement is suspected 4
Adjunctive Testing
- Skin biopsy if diagnosis is uncertain, showing perivascular lymphocytic infiltration with eosinophils and dermal edema 1, 7
- Delayed intradermal testing (dIDT) or patch testing may support drug causality, but only after ≥6 months following complete resolution and ≥4 weeks after discontinuing systemic steroids (>10 mg prednisone equivalent) 5, 1
- Testing parameters: dIDT uses 0.02-0.05 mL volume with reading at 24 hours for induration; patch testing uses 10-30% trade product or 1-10% pure substance, removed at 48 hours with readings at 24-72 hours, 96 hours, and 7 days 5, 1
Critical Diagnostic Pitfall
- 45% of DRESS cases are initially misdiagnosed as pneumonia when pulmonary manifestations are present, leading to inappropriate empiric antimicrobial therapy 6
- The long latency period and variable presentation have earned DRESS the moniker "the great mimicker" 6
Treatment Recommendations
Immediate Management
- Discontinue the suspected causative drug immediately—this is the first and most crucial step 1, 7
- Prompt dermatology consultation for all suspected cases 1, 7
Corticosteroid Therapy (First-Line)
- IV methylprednisolone 1-2 mg/kg/day for severe cases 1
- Minimum 4-week taper is required to prevent relapse (relapse occurs in 12% of cases with premature taper) 1, 7
- Unlike Stevens-Johnson syndrome, corticosteroids are NOT contraindicated in DRESS 1, 7
- Systemic steroids were used in 84% of cases (16 of 19 patients) in one retrospective series 4
Hospitalization Criteria
- Severe cases require admission to burn unit or ICU with dermatology and wound care services consultation 1, 7
- Patients with severe symptoms or organ involvement should be hospitalized 7
Supportive Care
- Fluid and electrolyte management 1, 7
- Infection prevention measures 1, 7
- Topical corticosteroids for skin manifestations 1
- Oral antihistamines for pruritus 1
- Pain or palliative care consultation for symptom management 7
- Serial clinical photography to track skin manifestations 7
Second-Line Therapies
- Intravenous immunoglobulin (IVIG) at 1-2 g/kg total dosage for steroid-unresponsive cases 1, 7
- Cyclosporine may be considered in severe or steroid-unresponsive cases 1, 7
- Additional options include cyclophosphamide and N-acetylcysteine 8
Specialist Consultation
- Consult appropriate specialists based on organ involvement: ophthalmology, otolaryngology, urology, or gynecology for mucous membrane involvement 7
- Cardiology consultation if myocarditis or pericarditis is suspected 1
- Nephrology consultation for significant renal involvement 1
Critical Management Pitfalls
What NOT to Do
- Never rechallenge with the suspected drug except in extreme circumstances where benefit outweighs risk—DRESS involves severe T-cell-mediated delayed reactions with long-lasting memory responses 1
- Do not perform patch testing or delayed intradermal testing until at least 6 months after complete resolution and at least 4 weeks after discontinuing systemic steroids 5, 1
- Do not taper steroids prematurely—minimum 4 weeks required due to T-cell immune-directed toxicity 1, 7
- Avoid prophylactic corticosteroids when initiating medications known to cause DRESS, as this has not proven effective and may increase the risk of skin rash 7
Prognosis and Long-Term Considerations
Mortality and Recovery
- Mortality rate is approximately 5-10% 4, 9
- Mean recovery time is 2 weeks (interquartile range 2-3.5 weeks) with appropriate treatment 4
- All patients in one pulmonary manifestations series recovered with parenteral steroids and supportive care 6
Prognostic Indicators
- Elevated serum creatinine and ferritin levels at presentation predict fatal outcomes 1
- Latency of ≤30 days and age ≤60 years are associated with development of ARDS 6
- Higher lymphocyte counts indicate the need for systemic corticosteroids 1
Long-Term Sequelae
- Risk of relapse with premature steroid taper 1, 7
- Long-term sequelae primarily relate to organ dysfunction and autoimmune diseases 3
- Prolonged immunosuppression may be necessary due to T-cell immune-directed toxicity 7