What is the step-by-step approach to managing a patient with suspected drug hypersensitivity reaction or DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) syndrome, particularly with medications such as Augmentin (amoxicillin/clavulanate) and Voltaren (diclofenac)?

Step-by-Step Clinical Approach to Drug Hypersensitivity/DRESS Syndrome

History Taking

Document the precise timeline of drug exposure and symptom onset, as DRESS characteristically presents 2-6 weeks after starting the offending medication 1, 2, 3.

Medication History

• List ALL medications taken in the past 8 weeks, including over-the-counter drugs, with exact start dates 4, 5
• Identify high-risk medications: anticonvulsants (phenytoin, carbamazepine), sulfonamides, allopurinol, minocycline, and beta-lactam antibiotics including amoxicillin-clavulanate 1, 4, 6
• Note that amoxicillin-clavulanate (Augmentin) is a documented cause of DRESS syndrome 4, 5
• Document any recent antibiotic changes, as multiple sequential antibiotics can complicate identification of the culprit drug 5

Symptom Timeline

• Record the exact date of rash onset and its progression pattern 2
• Document fever onset (temperature >38°C is typical) 2
• Ask specifically about: facial swelling, lymph node swelling, sore throat, difficulty breathing, dark urine, jaundice, abdominal pain 1, 7
• Inquire about constitutional symptoms: rigors, myalgias, arthralgias, fatigue 7

Past Medical History

• Family or personal history of drug allergies or hypersensitivity reactions 4
• Previous severe cutaneous reactions to any medication 8
• Asthma history (particularly aspirin-sensitive asthma, as NSAIDs like diclofenac can cause cross-reactivity) 8
• Renal or hepatic impairment (increases risk with NSAIDs) 8

Clinical Examination

Perform a complete body surface area assessment, as DRESS typically involves >30% of body surface area 1, 2.

Dermatologic Examination

• Characterize the rash: morbilliform (maculopapular) confluent pattern is most common 1, 2
• Calculate percentage of body surface area involved (typically >30%) 1
• Examine for facial edema (periorbital, perioral swelling) 1
• Inspect mucous membranes (oral, conjunctival, genital) for involvement 7
• Distinguish from Stevens-Johnson Syndrome/TEN: DRESS has maculopapular rash WITHOUT extensive blistering, exfoliation, or mucosal erosions 7, 8

Systemic Examination

• Measure temperature (fever >38°C expected) 2
• Palpate ALL lymph node regions (cervical, axillary, inguinal) for lymphadenopathy 1, 2
• Examine liver: palpate for hepatomegaly, assess for right upper quadrant tenderness 4
• Examine spleen: palpate for splenomegaly 4
• Cardiovascular assessment: auscultate for pericardial rub (pericarditis), signs of myocarditis 1
• Respiratory examination: auscultate for crackles (pneumonitis) 1
• Ophthalmologic examination if vision complaints: check for papilledema 5

Diagnostic Workup

Order comprehensive laboratory testing immediately, as organ involvement determines severity and prognosis 7, 2.

Essential Laboratory Tests

• Complete blood count with differential: look for eosinophilia >700/μL or >10% 2
• Comprehensive metabolic panel 7, 2:
  • ALT, AST, alkaline phosphatase, bilirubin (hepatitis: ALT >2× upper limit normal)
  • BUN, creatinine (nephritis: creatinine >1.5× baseline)
  • Electrolytes (monitor for hyperkalemia with NSAIDs) 8
• Urinalysis: evaluate for nephritis (proteinuria, hematuria, casts) 7
• Blood cultures: rule out infectious causes 7

Additional Diagnostic Studies

• Skin biopsy if diagnosis uncertain: look for lymphocytic CD4+ infiltrates with eosinophils 7
• Serial clinical photography: document progression of skin manifestations 7
• Chest X-ray if respiratory symptoms: evaluate for pneumonitis 1
• ECG and troponin if cardiac symptoms: screen for myocarditis/pericarditis 1

RegiSCAR Scoring System

Calculate RegiSCAR score to classify as "no," "possible," "probable," or "definite" DRESS 2:

• Fever >38°C
• Enlarged lymph nodes (≥2 sites, >1 cm)
• Eosinophilia (>700/μL or >10%)
• Atypical lymphocytes
• Skin involvement >50% body surface area
• Organ involvement (≥2 organs)
• Duration >15 days

Management Plan

Immediately discontinue the suspected causative drug—this is the single most crucial intervention 1, 7.

Immediate Actions

• Stop ALL potentially offending medications immediately 1, 7, 3
• Flag amoxicillin-clavulanate and diclofenac as severe allergies in the medical record 4
• Obtain urgent dermatology consultation for all suspected cases 1, 7

Admission Criteria

• Admit to hospital if: fever >39°C, mucosal involvement, blistering, exfoliation, ALT >5× upper limit normal, intolerable pruritus, or any organ involvement 9, 7
• Consider ICU or burn unit admission for severe cases with multi-organ involvement 7

Pharmacologic Treatment

Initiate systemic corticosteroids for all suspected DRESS cases—unlike Stevens-Johnson syndrome, corticosteroids are NOT contraindicated and are necessary 1, 7.

First-Line Therapy

• IV methylprednisolone 1-2 mg/kg/day for severe cases 1, 7
• Wean over at least 4 weeks (prolonged taper essential to prevent relapse) 1, 7
• Do NOT use prophylactic corticosteroids when initiating high-risk medications, as this increases rash risk 7

Second-Line Therapy (Steroid-Unresponsive Cases)

• Intravenous immunoglobulin (IVIG) 1-2 g/kg total dose 9, 7
• Cyclosporine may be considered 7

Supportive Care

• Fluid and electrolyte management: minimize insensible water losses 1, 7
• Topical corticosteroids and oral antihistamines: for symptomatic relief of pruritus 1, 7
• Infection prevention measures: monitor for secondary infections 7
• Pain management consultation if needed 7

Specialist Consultations

• Dermatology: mandatory for all cases 1, 7
• Ophthalmology: if ocular symptoms or papilledema 7, 5
• Cardiology: if myocarditis/pericarditis suspected 1
• Nephrology: if significant renal dysfunction 7
• Hepatology: if severe hepatitis (ALT >5× upper limit) 9

Monitoring During Treatment

• Daily clinical assessment: track rash progression, fever curve, symptom resolution 7
• Serial laboratory monitoring: CBC with differential, comprehensive metabolic panel every 2-3 days initially 8
• Watch for relapse: occurs in approximately 12% of cases, particularly with viral reactivation 1

Critical Pitfalls to Avoid

• Do NOT rechallenge with the suspected drug, even if patch testing is negative—DRESS can be fatal on re-exposure 9
• Do NOT perform patch testing or intradermal testing until at least 6 months after acute reaction AND at least 1 month after stopping systemic corticosteroids 9, 1
• Do NOT abruptly discontinue corticosteroids—taper slowly over minimum 4 weeks to prevent relapse 1, 7
• Do NOT miss the diagnosis by attributing symptoms to viral infection—DRESS can mimic acute viral illness 1, 8
• Do NOT overlook diclofenac (Voltaren) as a potential cause—NSAIDs are documented DRESS triggers and can cause serious skin reactions including DRESS 8
• Do NOT delay treatment waiting for biopsy results—clinical diagnosis is the gold standard, and treatment should begin immediately 9