Which medications are most likely to cause eosinophilia?

Which Drugs Most Commonly Cause Eosinophilia

NSAIDs (particularly ibuprofen, naproxen, and celecoxib), beta-lactam antibiotics, nitrofurantoin, anticonvulsants (especially phenytoin), and sulfonamide-containing antibiotics are the most common medication classes that cause eosinophilia. 1, 2, 3, 4

High-Risk Medication Classes

NSAIDs - Most Common Culprits

• Ibuprofen is among the most frequently implicated NSAIDs, causing not only isolated eosinophilia but also Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome and pulmonary infiltrates with eosinophilia (PIE syndrome) 3, 5, 6
• Naproxen causes PIE syndrome with fever, cough, dyspnea, infiltrates on chest radiograph, and absolute peripheral eosinophilia 6
• Celecoxib (selective COX-2 inhibitor) can trigger DRESS syndrome, though this is rare and may present without eosinophilia initially 7
• Oxicam derivatives (meloxicam, piroxicam) and acetic acid NSAIDs (diclofenac) have higher associations with severe cutaneous adverse drug reactions including DRESS 1

Antibiotics

• Beta-lactam antibiotics are common causes of drug-induced eosinophilia 2
• Sulfonamide-containing antibiotics are among the most common offenders for DRESS syndrome 4, 5
• Nitrofurantoin is specifically noted as a common cause 2
• Vancomycin can trigger DRESS syndrome 5

Anticonvulsants

• Phenytoin historically was the first recognized cause of DRESS (initially called "phenytoin hypersensitivity syndrome") 4
• Anticonvulsants as a class are among the most common offenders for DRESS syndrome 1, 4

Clinical Presentation Patterns

Isolated Asymptomatic Eosinophilia

• Most cases of drug-induced eosinophilia are asymptomatic 8
• This is a diagnosis of exclusion after ruling out helminthic infections and allergic conditions 8
• One study showed increased rates of hypersensitivity reactions in patients with higher eosinophil counts and earlier onset of eosinophilia 8

DRESS Syndrome - Life-Threatening Presentation

• DRESS has a characteristic latent period of 2-6 weeks after drug initiation 4
• Classic triad: fever, rash (morbilliform cutaneous eruption), and lymphadenopathy 4
• Systemic manifestations include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis 3, 4
• Eosinophilia is often present but not always - the celecoxib case demonstrates DRESS can occur without eosinophilia 7
• Early manifestations may include fever or lymphadenopathy even when rash is not evident 3

Pulmonary Infiltrates with Eosinophilia (PIE Syndrome)

• NSAIDs (particularly naproxen and ibuprofen) cause PIE syndrome with fever, cough, dyspnea, infiltrates on chest roentgenogram, and absolute peripheral eosinophilia 6
• Pathologic examination reveals poorly defined granulomas with infiltrating eosinophils 6
• The prevalence is likely underestimated given extensive NSAID use and relatively benign course 6

Critical Management Algorithm

Step 1: Immediate Drug Discontinuation

• The most important step is early diagnosis and immediate cessation of the suspected offending drug 4
• If DRESS is suspected based on signs/symptoms (fever, lymphadenopathy, rash), discontinue the drug immediately and evaluate the patient urgently 3

Step 2: Risk Stratification

• Asymptomatic isolated eosinophilia: Monitor after drug discontinuation 8
• Any patient with eosinophilia and evidence of end-organ damage requires urgent medical evaluation 9
• DRESS syndrome patients should be managed in intensive care for appropriate supportive care and infection control 4

Step 3: Treatment Based on Severity

• Asymptomatic eosinophilia: Drug discontinuation alone may suffice 8
• DRESS syndrome: Topical corticosteroids for symptomatic relief, but systemic steroids and other immunosuppressants are usually required 4
• Multi-organ involvement requires intensive supportive care 4

Critical Pitfalls to Avoid

• Do not assume eosinophilia is drug-related without first excluding helminthic infections, especially in travelers or migrants where helminths cause 19-80% of eosinophilia cases 9, 2
• Do not wait for eosinophilia to appear before diagnosing DRESS - early manifestations may include only fever or lymphadenopathy without rash or eosinophilia 3, 7
• Do not underestimate NSAID-induced eosinophilia as benign - it can progress to life-threatening DRESS or PIE syndrome 3, 6
• Ibuprofen is frequently falsely implicated in Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) cases due to protopathic effect (started for prodromal fever/symptoms before rash appears) 1

Medication Review Priorities

When evaluating eosinophilia, focus medication review on:

• Recent additions within the past 2-6 weeks (DRESS latency period) 4
• NSAIDs (especially ibuprofen, naproxen, celecoxib, meloxicam, piroxicam, diclofenac) 1, 3, 6, 7
• Beta-lactam antibiotics 2
• Nitrofurantoin 2
• Anticonvulsants 4
• Sulfonamide-containing antibiotics 4, 5
• Vancomycin 5