Drug-Induced Pneumonitis: Causative Medications
Cancer chemotherapy agents, particularly bleomycin, are the most common cause of drug-induced pneumonitis, followed by drugs for autoimmune diseases (methotrexate), amiodarone, and antibiotics (nitrofurantoin). 1
Major Drug Categories and Specific Agents
Cancer Chemotherapy Agents (Most Common)
- Bleomycin is the classic culprit, causing pulmonary toxicity in 10% of treated patients, with approximately 1% progressing to pulmonary fibrosis and death 2
- Methotrexate causes pneumonitis in approximately 7% of cases when given orally or systemically, and can occur even with intrathecal administration 3
- Cyclophosphamide in combination regimens has been associated with interstitial pneumonitis 4
- Etoposide (VP-16-213) may interact with other agents to increase pneumonitis risk, with rates as high as 24% reported in combination therapy 4
- Carmustine can cause delayed pulmonary fibrosis, sometimes occurring beyond 10 years after treatment completion 1
- Docetaxel causes pneumonitis with a hypersensitivity pattern 1
Molecular Targeting Agents
- EGFR inhibitors (erlotinib, gefitinib, afatinib, osimertinib) cause pneumonitis in 0.55-4.77% of patients, with higher rates in Japanese populations 1
- ALK inhibitors (alectinib, brigatinib, ceritinib, crizotinib) cause pneumonitis in 1.14-6.25% of patients, again with higher rates in Japanese cohorts 1
- mTOR inhibitors (everolimus) cause organizing pneumonia pattern 1
Immune Checkpoint Inhibitors
- PD-1 inhibitors (nivolumab, pembrolizumab) cause pneumonitis in 2.7% of patients on monotherapy and 6.6% on combination therapy 1
- PD-L1 inhibitors (atezolizumab, durvalumab, avelumab) cause pneumonitis in approximately 1.3% of patients 1
- CTLA-4 inhibitors (ipilimumab) are associated with immune-related pneumonitis 1
Immunologic/Rheumatologic Agents
- Methotrexate for autoimmune diseases is a leading cause after cancer drugs 1
- Gold salts were historically common culprits, with pneumonitis developing after approximately 6 months of therapy 5
- Anti-TNF biologics (certolizumab) can cause granulomatous inflammation and organizing pneumonia 6
- IL-6 inhibitors (tocilizumab) cause organizing pneumonia or NSIP patterns 7
- Rituximab (CD20 antibody) caused pneumonitis in 121 reported cases, with 15% mortality and diffuse alveolar damage pattern 1
Cardiovascular Agents
- Amiodarone is a well-established cause, with pulmonary toxicity including pneumonitis, ARDS, and bronchiolitis obliterans organizing pneumonia 1, 8
Antibiotics
- Nitrofurantoin is a common antibiotic culprit 1
- Various antimicrobial agents cause pneumonitis typically within 7-21 days of initiation (mean 12 days) 9
Other Agents
- Chinese herbal medicines have become increasingly recognized causes, with onset typically after 2-3 months 5
- NSAIDs and analgesics cause pneumonitis with eosinophilic features, typically developing 1-2 weeks after starting therapy 5
- Antituberculosis agents cause pneumonitis with intermediate features 5
Important Clinical Patterns by Drug Class
Timing of onset varies dramatically by drug class and is crucial for diagnosis:
Rapid onset (1-2 weeks): Anti-inflammatory drugs, analgesics, and antibiotics typically present with eosinophilic pneumonia pattern, high positive DLST rates, and good outcomes 5
Intermediate onset (2-6 months): Chinese herbal medicines, gold salts, and antituberculosis agents present with eosinophilic pneumonia, BOOP, or interstitial pneumonia patterns 5
Delayed onset (months to years): Anticancer and immunosuppressive agents often present with diffuse interstitial pneumonia and pulmonary fibrosis, low DLST positivity, and poor outcomes 5
Very delayed onset (>10 years): Carmustine-induced pulmonary fibrosis can occur more than a decade after treatment completion 1
Geographic and Population Considerations
Japanese populations demonstrate significantly higher pneumonitis rates with EGFR and ALK inhibitors (4.77% vs 0.55% for gefitinib; 6.25% vs 1.14% for ALK inhibitors in Japanese vs non-Japanese cohorts), suggesting genetic or environmental susceptibility factors 1
Critical Risk Factors
Age ≥55 years, ECOG performance status 2-4, smoking history, pre-existing or concurrent interstitial lung disease, and comorbid pleural effusion are significant risk factors for developing drug-induced pneumonitis, particularly with crizotinib 1