Symptoms of Methotrexate Lung Toxicity
Methotrexate-induced pulmonary toxicity typically presents with a dry, nonproductive cough, progressive dyspnea (shortness of breath), and fever, developing most commonly within the first 32 weeks of treatment but potentially occurring at any time during therapy. 1, 2, 3
Primary Clinical Manifestations
The classic triad of symptoms includes:
- Dry, nonproductive cough occurring in 82.8-93% of patients, typically present for 23-27 days before diagnosis 3, 4
- Progressive dyspnea (shortness of breath) in 93.1% of cases, often worsening over several weeks 3, 4
- Fever in 69% of patients, usually present for approximately 10 days before diagnosis 3, 4
Additional Clinical Features
- Bibasilar crackles on lung auscultation are commonly found on physical examination 3
- Hypoxemia with decreased oxygen saturation may be present 2, 5
- Tachycardia can accompany the respiratory symptoms 5
- Peripheral eosinophilia occurs in approximately one-third of cases (18-33%), which can be a helpful diagnostic clue 3, 5
Temporal Pattern and Onset
- Symptoms most commonly develop subacutely over several weeks, not acutely 3, 4
- Approximately 50% of cases occur within 32 weeks of starting methotrexate therapy 4
- However, methotrexate lung toxicity can occur at any time during treatment, even after 30 years of use, making vigilance necessary throughout therapy 5
- The presentation is not dose-dependent and can occur with low-dose therapy 1, 3
Important Clinical Distinctions
This is a potentially fatal complication that accounts for 30 of 164 reported methotrexate-associated deaths, making it the second most common cause of methotrexate-related mortality after myelosuppression 6, 7. The mortality rate is approximately 17.2-17.6% once pulmonary toxicity develops 4.
The symptoms are nonspecific, which creates a critical diagnostic challenge—they can easily be mistaken for infection, particularly pneumonia or Pneumocystis carinii pneumonia 1, 2. This is why infection must always be excluded before attributing respiratory symptoms to methotrexate toxicity 1, 2.
Risk Factors That Should Heighten Suspicion
- Pre-existing pulmonary disease significantly increases risk 1, 7
- Rheumatoid arthritis patients have higher rates than psoriasis patients 1, 7
- Cigarette smoking and age >40 years increase risk 1
- Renal impairment elevates toxicity risk 7
- Advanced age is an independent risk factor 7
Critical Pitfall to Avoid
Do not assume that long-term tolerance of methotrexate means the patient is safe from pulmonary toxicity. Cases have been documented after 30 years of stable use 5. Respiratory symptoms should never be dismissed in any patient on methotrexate, regardless of treatment duration. The British Association of Dermatologists specifically recommends that enquiry regarding respiratory symptoms should be made at every visit 1.