What are the causes of Interstitial Lung Disease (ILD)?

Causes of Interstitial Lung Disease

Interstitial lung diseases can be classified into three major etiologic categories: those associated with underlying systemic disorders (particularly autoimmune diseases), those caused by antigenic or toxic exposures (including drugs, occupational, and environmental factors), and idiopathic disorders without identifiable cause. 1

Primary Etiologic Categories

1. Connective Tissue Disease-Associated ILD (CTD-ILD)

CTD-ILD accounts for approximately 20% of all ILDs and represents a substantial subset of cases. 1

Specific autoimmune conditions causing ILD include:

• Systemic sclerosis (SSc-ILD) - accounts for approximately 31% of CTD-ILDs 1
• Rheumatoid arthritis (RA-ILD) - accounts for approximately 39% of CTD-ILDs 1
• Idiopathic inflammatory myopathies (IIM-ILD) - including dermatomyositis, polymyositis, and antisynthetase syndrome 1
• Sjögren's syndrome - causes autoimmune-mediated lymphocytic infiltration of lung parenchyma 2
• Systemic lupus erythematosus 1
• Mixed connective tissue disease 1

2. Environmental and Occupational Exposures

A detailed exposure history is mandatory, as 47% of patients presenting with apparently idiopathic ILD may actually have hypersensitivity pneumonitis when thoroughly evaluated. 1

Critical exposures to investigate include: 1

• Organic antigens: Mold, birds, down feathers, animals, vegetable dust, livestock exposure
• Inorganic dusts: Metal dusts (brass, lead, steel), silica, wood dust (pine)
• Occupational factors: Hair dressing, farming, metalworking
• Hobbies: Bird keeping, woodworking, hot tub use

Occupational exposures to metal, silica, and environmental tobacco smoke increase IPF risk with a pooled odds ratio of 1.7 (95% CI 1.42-2.03), and workplace exposure accounts for 17% (95% CI 7-28%) of hypersensitivity pneumonitis cases. 3

3. Drug-Induced ILD

Medication-induced ILD must be systematically excluded, particularly in patients with CTD already receiving immunosuppressive therapy. 1, 2

High-risk medications include: 2

• TNF-alpha inhibitors - approximately 1% risk
• Methotrexate
• Leflunomide
• Cyclophosphamide
• Rituximab
• Sulfasalazine
• Sulfonamides

This is particularly important because drug-induced ILD can mimic disease progression in patients being treated for CTD-ILD. 2

4. Idiopathic Interstitial Pneumonias

Idiopathic pulmonary fibrosis (IPF) accounts for approximately one-third of all ILD cases and represents over 45% of pulmonary fibrotic disease diagnoses. 1, 4

Other idiopathic forms include nonspecific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia, and lymphoid interstitial pneumonia when no underlying cause is identified. 1

Critical Diagnostic Approach

Before diagnosing idiopathic ILD, you must systematically exclude:

1. Medication history - comprehensive review of all current and recent drugs 1
2. Environmental exposures - using structured questionnaires for home, work, and frequently visited locations 1
3. Connective tissue disease - through serologic testing and clinical evaluation 1
4. Occupational exposures - including mineral particles and specific workplace hazards 2

The American Thoracic Society emphasizes that this exclusion process is mandatory because identification and removal of causative factors may result in improved clinical outcomes. 1

Common Pitfalls to Avoid

The most critical error is failing to obtain a sufficiently detailed exposure history. Nearly half of patients initially thought to have idiopathic disease actually have hypersensitivity pneumonitis when properly evaluated. 1

Do not rely solely on patient recall - use standardized questionnaires tailored to cultural habits and geographical differences, as patients often fail to recognize relevant exposures without specific prompting. 1

Consider drug-induced ILD in any patient with CTD-ILD who progresses despite appropriate therapy - the medications used to treat the underlying CTD can themselves cause ILD. 2

Remember that up to 10% of patients with clinically significant ILD may have normal chest radiographs, so HRCT is essential when clinical suspicion exists. 1