Drug-Induced Interstitial Lung Disease (ILD)

1. Introduction and Epidemiology

2. General Principles of Drug-Induced Lung Injury

3. Mechanisms of Pulmonary Injury

1. Oxidant injury - best established for nitrofurantoin, mitomycin C, and bleomycin. Biotransformation generates reactive oxygen species (H₂O₂, hydroxyl radical •OH, superoxide O₂⁻•), promoting lipid peroxidation, glutathione depletion, and cell death.
2. Immunologic / inflammatory cell-mediated injury - lymphocytic or neutrophilic alveolitis and interstitial infiltrates; drug metabolite-protein adducts act as immunogens causing hypersensitivity; complement-mediated injury is implicated for opiates and β-agonists causing noncardiogenic pulmonary edema (ARDS).
3. Interference with matrix formation or alveolar repair - impairs normal healing after injury.
4. Abnormal protease/antiprotease balance - promotes parenchymal destruction.
5. Interference with lipid (phospholipid) metabolism - best established for amiodarone, which impairs phospholipid catabolism by phospholipases, leading to cellular phospholipidosis and lamellar inclusions.

4. Diagnostic Criteria

1. History of drug exposure
2. Clinical signs, symptoms, radiologic findings, and histopathology are consistent with previously reported toxicity for that drug
3. Alternate diagnoses excluded - infection, systemic disease, malignancy
4. Findings regress with drug discontinuation and/or treatment

5. Histopathologic Patterns

• Nonspecific interstitial pneumonia (NSIP) - most common pattern with many drugs
• Organizing pneumonia (OP/BOOP) - e.g., sulfasalazine (upper lobe opacities), nitrofurantoin, amiodarone
• Diffuse alveolar damage (DAD) - acute/subacute, high mortality
• Eosinophilic pneumonia - nitrofurantoin (acute form), sulfasalazine
• Pulmonary fibrosis (UIP-like pattern) - bleomycin, cyclophosphamide, busulfan, nitrofurantoin (chronic)
• Hypersensitivity pneumonitis (HP) - methotrexate, nitrofurantoin
• Sarcoid-like granulomatosis - anti-TNF agents (etanercept, infliximab, adalimumab)
• Lipoid pneumonia with foamy macrophages - amiodarone (characteristic but not pathognomonic of toxicity alone)

6. Key Causative Drugs and Their Specific Features

A. Amiodarone (Cardiovascular)

• Mechanism: Impairs phospholipid catabolism by phospholipases → cellular phospholipidosis → accumulation of phospholipids → direct cellular injury + reactive oxygen species formation + immune-mediated hypersensitivity. Affects type 2 pneumocytes, endothelial cells, and fibroblasts.
• Histology: Lamellar inclusions + lipid-laden foamy macrophages on BAL and biopsy - characteristic of amiodarone exposure but only indicative of toxicity when accompanied by a lung injury pattern.
• Clinical: Incidence 1-6% of patients on long-term therapy; dose >400 mg/day associated with higher risk; presents as progressive dyspnea, cough, pleuritic pain, fever. CT shows bilateral ground-glass opacities, consolidation, or interstitial infiltrates, often in the upper lobes. High-density opacities due to iodine deposition are characteristic on CT.
• Management: Drug discontinuation + corticosteroids; resolution is slow and may take months given the long half-life.

B. Nitrofurantoin (Antibiotic)

• Acute reaction (most common): Onset within hours to weeks of first dose. Fever, dyspnea, cough, hypoxemia; chest X-ray shows bilateral infiltrates, often with pleural effusion. Eosinophilia may be present. Thought to be immune/hypersensitivity mediated. Responds rapidly to drug withdrawal.
• Chronic reaction: Insidious onset after months to years of continuous use; presents with progressive dyspnea and fibrosis. Histology shows NSIP or UIP pattern with fibrosis. May not fully resolve even after drug discontinuation.

C. Methotrexate

• Presentation: Cough, dyspnea, fever, widespread crackles, bilateral pulmonary opacities on CXR/CT. Onset is typically subacute (symptoms evolve for up to 2 months before diagnosis); 50% of cases diagnosed within 4 months of initiation.
• Histology: Nonspecific, but a prominent lymphocytic infiltration increases the likelihood of methotrexate pneumonitis.
• Preexisting lung disease does not constitute an absolute contraindication, but caution is warranted when pulmonary reserve is grossly compromised.
• Management: Immediate methotrexate withdrawal + early corticosteroid therapy. Retreatment after prior toxicity is contraindicated.

D. Bleomycin (Chemotherapy)

• Mechanism: Direct oxidant injury via generation of reactive oxygen species; bleomycin-iron complexes generate free radicals that cleave DNA and damage endothelial cells and type 1 pneumocytes.
• Risk factors: Cumulative dose >400 units, age >70 years, concurrent or prior thoracic radiation, renal insufficiency (bleomycin excreted renally), and high inspired oxygen concentration (synergistic oxidant injury - this is a major clinical concern perioperatively and during anesthesia).
• Histology: Organizing pneumonia progressing to UIP/pulmonary fibrosis.

E. Immunotherapy / Checkpoint Inhibitors (PD-1/PD-L1 inhibitors)

• Presentation: Cough, dyspnea, hypoxemia; CT shows ground-glass opacities, organizing pneumonia, or NSIP pattern.
• Grading (CTCAE): Grade 1 (radiographic only) - hold ICI; Grade 2 (symptomatic) - hold ICI + oral corticosteroids; Grade 3-4 (severe/life-threatening) - permanently discontinue ICI + high-dose IV corticosteroids; if refractory, add infliximab or mycophenolate.

F. Targeted Therapies (TKIs) and Other Oncologic Agents

• mTOR inhibitors (everolimus, temsirolimus): Pneumonitis in 13-36% of patients, typically presents as OP or NSIP pattern; often manageable with dose reduction or corticosteroids.
• PI3K inhibitors (idelalisib, copanlisib, duvelisib): Pneumonitis in 5-13%; also risk of opportunistic infections including Pneumocystis jirovecii.
• VEGF inhibitors (sorafenib): Very low incidence of pneumonitis (0.44%) but case fatality rate is high (41%) when it does occur (Fishman, Ch. 64).
• Bevacizumab: Pulmonary hemorrhage rather than ILD, especially with cavitary tumors or squamous cell histology.
• Busulfan: Insidious-onset pulmonary fibrosis after high cumulative doses, median onset 3.5 years; called "busulfan lung."
• Cyclophosphamide: Two patterns: early-onset (< 6 months) pneumonitis (reversible) and late-onset (> 6 months) fibrosis (often irreversible).

G. Biologic DMARDs / Anti-TNF Agents

• Etanercept, infliximab, adalimumab: Associated with sarcoid-like granulomatosis - cough, chest pain, dyspnea; hilar/mediastinal adenopathy; noncaseating granulomas on biopsy. Also risk of infection (especially TB reactivation - a true and important association). Resolves in majority with drug discontinuation; corticosteroids used in some (Fishman, Ch. 65).
• Rituximab (anti-CD20): Associated with rapidly progressive ILD, particularly in RA patients.
• Leflunomide: Associated with pulmonary rheumatoid nodules and interstitial disease (Murray & Nadel, Ch. 99).
• Gold therapy: Pulmonary disease in the form of alveolar opacities adjacent to bronchovascular bundles, best seen on HRCT; often associated with fever, skin rash, relatively low rheumatoid factor titers, and BAL lymphocytosis. Largely regresses with withdrawal and corticosteroids.
• Sulfasalazine: Organizing pneumonia with upper lobe opacities (most cases reported in ulcerative colitis, rare in RA); largely reversible.

7. Drug-Induced Pulmonary Hypertension

• Fenfluramine/dexfenfluramine (appetite suppressants): Odds ratio of 23.1 for PAH with use >3 months (International Primary Pulmonary Hypertension Study Group, 1996). Withdrawn from market in 1995. Estimated incidence 1-2 cases per million users per year.
• Interferon-α and interferon-β (for hepatitis C/multiple sclerosis): PAH through release of endothelin-1.
• L-tryptophan contaminated preparations: Eosinophilic myalgia syndrome with acute lung injury and PAH.

8. Investigations

• HRCT chest: Most sensitive imaging; patterns guide diagnosis (ground-glass opacity, consolidation, reticular, honeycombing).
• BAL: May show lymphocytosis (hypersensitivity pattern), eosinophilia, or foamy macrophages (amiodarone). Primarily useful to exclude infection.
• Pulmonary function tests: Typically restrictive pattern with reduced DLCO; may precede symptoms.
• Lung biopsy (surgical/transbronchial): Histopathology confirms pattern of injury but is rarely pathognomonic for a specific drug.
• Serum biomarkers: KL-6 and SP-D may be elevated but are nonspecific.
• Drug-specific: Serum amiodarone levels, drug history, temporal correlation.

9. Management

1. Identify and discontinue the offending drug - the single most important step.
2. Corticosteroids - first-line for most immune-mediated patterns; dose ~1 mg/kg/day prednisolone, tapered over weeks to months.
3. Supportive care - supplemental oxygen (with caution in bleomycin-exposed patients given oxygen synergy), mechanical ventilation if needed.
4. Do NOT rechallenge - risk of severe recurrence.
5. For checkpoint inhibitor pneumonitis: graded response per CTCAE - add infliximab or mycophenolate for steroid-refractory cases.

10. Summary Table: Key Drugs and Their Pulmonary Toxicity Patterns

• Fishman's Pulmonary Diseases and Disorders, 5th Ed. - Chapter 64 (Pulmonary Toxicity Related to Systemic Treatments for Cancer) and Chapter 65 (Drug-induced Pulmonary Disease Due to Nonchemotherapeutic Agents)
• Murray & Nadel's Textbook of Respiratory Medicine - Chapters 92 and 99 (Drug-Induced Pulmonary Disease, Rheumatoid Arthritis and the Lung)