1. Clinical Manifestations

Recognizing the classic triad—fever, polymorphous rash, and lymphadenopathy—is the first step in DRESS diagnosis. Onset is typically 2–8 weeks after drug exposure, and overlapping features with infection demand careful differentiation.

A. Fever: Patterns & Duration

• Persistent high-grade fever (>38 °C), often spiking daily.
• Onset occurs 2–8 weeks post-drug exposure; intermittent patterns reflect cytokine waves.
• Fever lasting more than 7 days despite broad-spectrum antimicrobials strongly favors a DRESS diagnosis.

B. Rash: Morphology & Distribution

• Typically begins as a widespread, pruritic maculopapular eruption that can evolve into confluent erythematous plaques.
• Variants include urticarial lesions, pustules, and target-like lesions. Facial edema is a common and important sign.
• The rash often starts on the face and upper trunk, spreading centrifugally. Mucosal involvement is usually mild or absent, which helps differentiate it from Stevens-Johnson syndrome.

C. Lymphadenopathy: Sites & Detection

• Typically involves two or more nodal regions, most commonly cervical, axillary, and inguinal.
• Nodes are often tender and mobile. Point-of-care ultrasound can be valuable for detecting occult nodes in sedated or obese patients.
• Lymphadenopathy generally resolves with the withdrawal of the offending drug and initiation of therapy.

2. Laboratory Evaluation

A structured panel—including a complete blood count (CBC) with differential, liver function tests (LFTs), renal function markers, and viral assays—is essential to confirm the diagnosis and assess severity.

A. Hematology

• Eosinophilia: The hallmark finding, defined as ≥700 cells/µL or >10% of total leukocytes. Severe cases may exceed 1,500 cells/µL.
• Atypical Lymphocytes: Present on the peripheral smear in 25–50% of patients.
• Trend Counts: Eosinophils typically rise during the acute phase and decline with effective immunosuppression.

B. Hepatic Markers

• AST/ALT elevation is common, often >3 times the upper limit of normal (ULN). A direct bilirubin predominance suggests cholestatic injury.
• GGT and ALP may also be elevated.
• Monitor liver panels every 48–72 hours. Worsening enzymes despite drug cessation are a clear indication for therapy escalation.

C. Renal Markers

• Acute kidney injury (AKI) occurs in 20–30% of cases, defined as a creatinine increase of ≥0.5 mg/dL or ≥50% from baseline. Oliguria may ensue.
• Urine eosinophils, if present, support a diagnosis of acute interstitial nephritis (AIN) as the cause of AKI.

D. Viral Assays

• Human Herpesvirus 6 (HHV-6) reactivation is found in 40–60% of cases. A quantitative PCR >10,000 copies/mL is associated with more severe disease.
• While EBV and CMV serologies may be positive, they are less specific for DRESS pathogenesis.

3. Diagnostic Algorithms

Standardized scoring systems like the RegiSCAR criteria and established ICU pathways help streamline diagnosis, ensure a complete workup, and facilitate timely treatment.

A. RegiSCAR Criteria

The RegiSCAR scoring system is the most widely used tool for diagnosing DRESS. A score is calculated based on the presence of key clinical and laboratory findings.

Scoring: A final score of ≥5 indicates a “definite” case, 4 is “probable,” and 2–3 is “possible.”

B. Japanese Consensus Criteria

This system includes similar clinical and laboratory parameters but places additional weight on HHV-6 reactivation and specific histopathology findings. It is particularly useful when the RegiSCAR score is equivocal but there is strong evidence of HHV-6 reactivation.

C. ICU Rapid Diagnostic Pathway

For critically ill patients, a structured pathway is crucial to accelerate diagnosis and treatment.

4. Severity Stratification & Urgency

Classifying DRESS severity is critical for directing therapy intensity—from topical agents for mild disease to high-dose IV steroids and adjunctive immunosuppression for severe cases.

A. Mild vs. Severe Cutoffs

Distinguishing between mild and severe DRESS guides the initial therapeutic choice and intensity of monitoring.

B. Immunosuppressive Trigger Points

• Indications: A “probable” or “definite” RegiSCAR score plus any of the following: AST/ALT >3x ULN with jaundice; creatinine ≥1.5x baseline; severe pneumonitis or myocarditis; HHV-6 viral load >10,000 copies/mL.
• First-line Therapy: Methylprednisolone 1–2 mg/kg/day IV or equivalent.
• Escalation: Consider cyclosporine or IVIG after 5–7 days of inadequate response to high-dose steroids.