What is the differential diagnosis of a maculopapular rash in a 39-year-old female, post right lung decortication, with eosinophilia, following the use of Augmentin (amoxicillin/clavulanate) and Voltaren (diclofenac)?

Differential Diagnosis and Clinical Approach

Primary Diagnosis: Drug-Induced Maculopapular Rash with Eosinophilia

The most likely diagnosis is a drug hypersensitivity reaction to either Augmentin (amoxicillin-clavulanate) or Voltaren (diclofenac), with DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) syndrome being the critical diagnosis to rule out given the eosinophilia and leukocytosis. 1, 2

Key Differential Diagnoses to Consider

1. DRESS Syndrome (Most Critical)

• Characterized by maculopapular rash, eosinophilia (present in your patient at 1.23), fever (absent in your case), lymphadenopathy, and internal organ involvement 3, 4
• Critical timing: Typically develops 2-6 weeks after drug initiation, though can occur earlier 3, 4
• Your patient is on day 16 post-surgery, which fits the temporal window if antibiotics were started perioperatively 3
• Mortality rate is significant (2-6.7% of drug reactions can become life-threatening), making this the priority diagnosis to exclude 5
• Amoxicillin can trigger DRESS even without clavulanate, and the combination with other drugs increases risk 3, 4

2. Simple Drug Hypersensitivity (Maculopapular Exanthem)

• Most common cutaneous adverse drug reaction pattern 5
• Both amoxicillin-clavulanate and diclofenac are well-documented causes 1, 2
• Typically presents with widespread erythematous maculopapular rash without systemic involvement 6
• Usually self-limited and resolves within 1-2 weeks after drug discontinuation 6

3. Diclofenac-Induced DRESS

• NSAIDs including diclofenac can cause DRESS syndrome with fever, rash, lymphadenopathy, and eosinophilia 2
• FDA labeling specifically warns about Drug Reaction with Eosinophilia and Systemic Symptoms with diclofenac 2

4. Viral Exanthem Mimicking Drug Reaction

• Post-surgical patients can develop viral infections that present similarly 7
• However, the temporal relationship with drug exposure and eosinophilia make drug reaction more likely 7

Immediate Clinical Assessment Algorithm

Step 1: Assess for DRESS Syndrome Features (URGENT)

Calculate RegiSCAR Score to stratify severity 3, 7:

• Fever ≥38.5°C (absent = 0 points)
• Enlarged lymph nodes (check neck, axillae, groin)
• Eosinophilia: 1.23 (>0.7 = 1 point; >1.5 = 2 points) - your patient scores 1 point
• Atypical lymphocytes on blood smear (order if not done)
• Skin involvement >50% body surface area
• Organ involvement (check below)

Immediately check for organ involvement 3:

• Liver: AST, ALT, alkaline phosphatase, bilirubin (hepatitis is common in DRESS)
• Kidney: Creatinine, BUN, urinalysis (nephritis can occur)
• Cardiac: ECG, troponin if any chest symptoms (myocarditis is life-threatening)
• Pulmonary: Given her continuous air leak and post-decortication status, obtain chest X-ray to assess for new infiltrates (eosinophilic pneumonitis) 3

Step 2: Examine for Severe Cutaneous Adverse Reaction Features

Examine entire skin surface including 6:

• Mucosal involvement (oral, genital, conjunctival) - if present, suggests Stevens-Johnson Syndrome/TEN rather than simple drug reaction 8, 2
• Facial edema - prominent feature in DRESS 7
• Skin detachment or blistering - indicates severe reaction requiring immediate hospitalization 8
• Distribution pattern: Widespread vs. localized 6
• Lymphadenopathy: Palpate cervical, axillary, and inguinal nodes 3

Step 3: Determine Severity Grade

Grade 1-2 (Mild-Moderate) 8, 6:

• Rash <30% BSA, no systemic symptoms, no organ involvement
• Eosinophilia alone without other features

Grade 3 (Severe) 8:

• Rash >30% BSA, systemic symptoms, or any organ involvement
• RegiSCAR score ≥2 for possible DRESS

Grade 4 (Life-threatening) 8:

• Mucosal involvement, skin detachment, multi-organ failure
• Confirmed DRESS with severe organ involvement

Management Algorithm

If DRESS Syndrome is Suspected (RegiSCAR ≥2 or organ involvement)

1. Immediately discontinue both Augmentin and Voltaren 1, 2, 3
2. Initiate systemic corticosteroids: Prednisone 0.5-1 mg/kg/day (or methylprednisolone equivalent) 8, 3
3. Monitor closely for progression: Daily labs (CBC with differential, liver enzymes, renal function) 3
4. Avoid rechallenge: Both drugs should be permanently contraindicated 1, 2
5. Consider viral reactivation testing: HHV-6, EBV (can be associated with DRESS) 4
6. Coordinate with cardiothoracic surgery: Given her continuous air leak, ensure pulmonary complications are not worsening 3

If Simple Drug Hypersensitivity (No DRESS features)

1. Discontinue the offending drug(s) - stop both Augmentin and Voltaren 1, 2
2. Topical management 8, 6:
   • High-potency topical corticosteroids (clobetasol propionate 0.05%) for body
   • Medium-potency (hydrocortisone 2.5%) for face if involved
3. Oral antihistamines for pruritus: Cetirizine 10 mg daily or hydroxyzine 25 mg QID 8
4. Consider short course of oral corticosteroids if >30% BSA: Prednisone 0.5 mg/kg/day tapered over 2 weeks 8, 6
5. Monitor for progression: Daily assessment for first 3-5 days 6

Critical Pitfalls to Avoid

Pitfall 1: Assuming Eosinophilia Alone = DRESS

• Mild eosinophilia (0.7-1.5) can occur in simple drug reactions 7
• DRESS requires additional features: fever, lymphadenopathy, organ involvement, or RegiSCAR score ≥2 3, 7
• Your patient's eosinophilia of 1.23 is borderline and requires close monitoring but doesn't confirm DRESS alone 7

Pitfall 2: Continuing Either Drug "To See What Happens"

• Both drugs must be stopped immediately given the temporal relationship and eosinophilia 1, 2
• Amoxicillin can trigger DRESS in patients on other medications (documented with sulfasalazine, NSAIDs) 4
• Diclofenac FDA labeling explicitly warns about DRESS syndrome 2

Pitfall 3: Missing Organ Involvement

• In post-surgical patients, new liver enzyme elevations or renal dysfunction may be attributed to other causes 3
• Always obtain baseline organ function tests when drug reaction is suspected 3
• Hepatotoxicity from amoxicillin-clavulanate is well-documented and can be severe 1

Pitfall 4: Inadequate Follow-up

• Even if DRESS is ruled out initially, symptoms can evolve over days to weeks 3
• Schedule follow-up within 48-72 hours to reassess for progression 6
• Repeat eosinophil count and liver enzymes in 3-5 days 3

Pitfall 5: Ignoring the Continuous Air Leak Context

• Your patient has ongoing pulmonary issues post-decortication 8
• Drug-induced pneumonitis can complicate the clinical picture and worsen respiratory status 8, 3
• Consider chest imaging if respiratory symptoms change 8

Specific Diagnostic Testing

Immediate Labs (Today)

• Complete metabolic panel (liver and kidney function) 3
• CBC with manual differential (confirm eosinophilia, check for atypical lymphocytes) 3
• Lactate dehydrogenase (elevated in DRESS) 3

If DRESS Suspected

• Viral serologies: HHV-6, EBV, CMV 4
• Chest X-ray or CT (assess for pulmonary infiltrates) 3
• ECG (rule out myocarditis) 2

Skin Biopsy (If Diagnosis Unclear)

• Shows lymphocytic infiltrate with eosinophils in drug hypersensitivity 6
• Can help differentiate from viral exanthem 7
• Not required if clinical diagnosis is clear 6

Prognosis and Timeline

• Simple drug hypersensitivity: Expect resolution within 1-2 weeks after drug discontinuation with supportive care 6
• DRESS syndrome: Requires prolonged steroid taper (4-6 weeks minimum), with potential for relapse if tapered too quickly 8, 3
• Monitor for late complications: DRESS can cause autoimmune sequelae (thyroiditis, diabetes) months later 3

Documentation for Future Care

• Label patient as allergic to both amoxicillin/clavulanate AND diclofenac in medical record 1, 2
• Document reaction type as "maculopapular rash with eosinophilia, possible DRESS syndrome" 3
• Cross-reactivity considerations: Other beta-lactams may be tolerated, but formal allergy testing recommended before rechallenge 1
• NSAIDs as a class should be used cautiously; consider COX-2 selective agents if anti-inflammatory needed 2