Which of the following medications - ammonium lactate, gabapentin, hydroxyzine hydrochloride, latanoprost, quetiapine, mirtazapine, naproxen, tamsulosin, and levetiracetam - is most likely to cause drug-induced lung injury?

Drug-Induced Lung Injury: Identifying the Most Likely Culprit

Among the medications listed, naproxen is most likely to cause drug-induced lung injury due to its established association with pulmonary toxicity, particularly hypersensitivity pneumonitis and eosinophilic reactions. 1, 2

Evaluation of Each Medication's Pulmonary Toxicity Risk

High Risk:

• Naproxen
  • Documented cases of pulmonary infiltrates with eosinophilia, cough, fever, and respiratory symptoms 2
  • Listed specifically in guidelines as a non-steroidal anti-inflammatory drug (NSAID) that can cause bronchospasm with or without cough 1
  • Multiple case reports show resolution of symptoms after drug discontinuation 2

Moderate Risk:

• Amiodarone (not in the list but mentioned for comparison)
  • Known for causing significant pulmonary toxicity
  • Often used as a reference standard for drug-induced lung injury

Low to Minimal Risk:

• Gabapentin: No significant evidence of pulmonary toxicity in the provided literature
• Hydroxyzine hydrochloride: Not associated with significant pulmonary toxicity
• Latanoprost: No documented pulmonary toxicity
• Quetiapine: Not associated with significant pulmonary toxicity
• Mirtazapine: Not associated with significant pulmonary toxicity
• Tamsulosin: Not associated with significant pulmonary toxicity
• Levetiracetam: Not associated with significant pulmonary toxicity
• Ammonium lactate: Topical agent with no documented pulmonary toxicity

Mechanisms of NSAID-Induced Pulmonary Toxicity

NSAIDs like naproxen can cause lung injury through several mechanisms:

• Hypersensitivity reactions leading to eosinophilic pneumonia 3
• Bronchospasm, particularly in susceptible individuals 1
• Organizing pneumonia pattern on imaging 1
• Non-cardiogenic pulmonary edema in some cases 4

Clinical Presentation of Naproxen-Induced Lung Injury

Patients typically present with:

• Dry cough (most sensitive symptom) 1
• Progressive dyspnea 1
• Low-grade fever 2
• Fatigue and weakness 2
• Eosinophilia in blood and/or sputum 2
• Symptoms typically develop within 1-2 weeks of starting the medication 3

Diagnostic Approach

1. Imaging findings:

   • High-resolution CT is the preferred imaging modality 1
   • Common patterns include ground-glass opacities, organizing pneumonia, or eosinophilic pattern 1, 5

2. Laboratory evaluation:

   • Complete blood count may show eosinophilia 2
   • Drug lymphocyte stimulation test (DLST) often positive with anti-inflammatory drugs 3

3. Temporal relationship:

   • Symptoms typically appear 1-2 weeks after starting naproxen 3
   • Improvement within days after drug discontinuation strongly supports the diagnosis 2

4. Exclusion of other causes:

   • Infections, particularly respiratory infections
   • Progression of underlying disease
   • Other pulmonary conditions

Management

1. Immediate discontinuation of the suspected medication (naproxen) 1

2. Corticosteroid therapy may be necessary in severe cases 2

   • Prednisone 0.5-1 mg/kg for 1-2 weeks followed by gradual tapering

3. Supportive care as needed for respiratory symptoms

4. Avoid rechallenge with the same medication or similar NSAIDs

Key Considerations and Pitfalls

• Drug-induced lung injury is a diagnosis of exclusion that relies heavily on temporal relationships and exclusion of other causes 1
• Multiple medications taken simultaneously can complicate identification of the culprit drug
• Symptoms may persist or worsen temporarily even after drug discontinuation
• Some patients may develop cross-reactivity with other NSAIDs
• The clinical and radiological patterns of drug-induced lung injury are often non-specific 1

Conclusion

When evaluating these medications for potential lung toxicity, naproxen stands out as the most likely culprit based on documented cases of pulmonary infiltrates, established mechanisms of toxicity, and inclusion in clinical guidelines as a medication associated with drug-induced cough and pulmonary reactions 1, 2.