Causes of Interstitial Lung Disease
Interstitial lung disease arises from three major etiologic categories that must be systematically excluded: idiopathic disorders (particularly idiopathic pulmonary fibrosis), connective tissue disease-associated ILD, and environmental/occupational exposures, with smoking representing a critical modifiable risk factor across multiple subtypes. 1
Idiopathic Interstitial Pneumonias
Idiopathic pulmonary fibrosis (IPF) accounts for approximately one-third of all ILD cases and represents the most common idiopathic form. 1, 2 The diagnosis requires exclusion of all known causes including drug toxicities, environmental exposures, and connective tissue diseases. 3 The MUC5B promoter variant is strongly associated with both familial and sporadic IPF, representing a key genetic susceptibility factor. 3, 1
Other idiopathic interstitial pneumonias include:
- Nonspecific interstitial pneumonia (NSIP), which demonstrates a fibrosing pattern distinct from UIP 3
- Cryptogenic organizing pneumonia (COP) 3
- Desquamative interstitial pneumonia (DIP), often smoking-related 3
- Respiratory bronchiolitis-interstitial lung disease (RBILD), virtually always associated with cigarette smoke exposure 3, 4
Connective Tissue Disease-Associated ILD
Connective tissue diseases account for approximately 20-25% of all ILD cases, making systematic exclusion of autoimmune disease mandatory in every patient being evaluated for ILD. 1, 2 This requires checking anti-nuclear antibodies, rheumatoid factor, anti-CCP antibodies, anti-SSA/SSB, anti-topoisomerase-1, anti-centromere, and anti-synthetase antibodies even in the absence of obvious extrapulmonary manifestations. 3
Specific CTD associations include:
- Rheumatoid arthritis accounts for 39% of CTD-ILD cases, with UIP being the most common radiologic pattern 1
- Systemic sclerosis (scleroderma) 3
- Inflammatory myopathies including dermatomyositis, polymyositis, and antisynthetase syndrome 1, 3
- Sjögren's syndrome 3
- Systemic lupus erythematosus 3
- Mixed connective tissue disease 3
A critical pitfall: CTD-ILD may be the first clinical manifestation of connective tissue disease, appearing before other systemic features become apparent. 3 Therefore, accepting an "idiopathic" diagnosis without comprehensive autoimmune serologies represents a diagnostic error.
Environmental and Occupational Exposures
A detailed exposure history is mandatory because 47% of patients presenting with apparently idiopathic ILD actually have hypersensitivity pneumonitis when thoroughly evaluated. 1, 5 This represents the single most common diagnostic pitfall in ILD evaluation—failing to obtain sufficiently detailed exposure history.
Hypersensitivity Pneumonitis
Hypersensitivity pneumonitis accounts for 15% of all ILD cases and results from inhalation of organic antigens including mold, bird proteins, and agricultural dusts. 3, 2 The exposure history must include home environment (humidifiers, water damage, birds), hobbies (woodworking, metalworking), and agricultural exposures. 3, 1
Occupational Pneumoconioses
Metal, silica, and asbestos exposures increase IPF risk with a pooled odds ratio of 1.7 (95% CI 1.42-2.03). 1 Specific occupational causes include:
- Asbestosis from construction, shipbuilding, or insulation work 3, 5
- Silicosis from mining, sandblasting, or stone cutting 3
- Coal worker's pneumoconiosis 3
- Berylliosis from aerospace or electronics manufacturing 5
- Hard metal disease from metalworking with tungsten carbide 5
The occupational history must include specific job tasks, duration of exposure, and use of respiratory protection. 5
Smoking-Related ILD
Smoking represents a major risk factor for multiple ILD subtypes and accelerates disease progression. 3, 6 Smoking-related patterns include:
- Respiratory bronchiolitis-ILD (all cases have smoking history) 3, 4
- Desquamative interstitial pneumonia (majority smoking-related) 3
- Smoking-related interstitial fibrosis with airspace enlargement 3
- Increased risk of IPF in smokers 3
Drug-Induced ILD
Medication-induced ILD must be systematically excluded, particularly in patients with CTD who are receiving immunosuppressive therapy. 1 Approximately 1% of patients receiving immunosuppressive agents develop drug-induced ILD. 1
High-risk medications include:
- Methotrexate 1
- TNF-alpha inhibitors 1
- Cyclophosphamide 1
- Rituximab 1
- Leflunomide 1
- Sulfasalazine and sulfonamides 1
- Amiodarone 3
- Nitrofurantoin 3
- Chemotherapeutic agents 3
Granulomatous Diseases
Sarcoidosis presents with discrete nonnecrotizing granulomas in a lymphatic distribution and can develop coexistent fibrosis. 1, 3 The diagnosis requires exclusion of other granulomatous diseases including hypersensitivity pneumonitis (which shows poorly formed granulomas in a bronchiolocentric distribution). 3
Other Causes
Additional causes that must be considered include:
- Radiation-induced ILD following thoracic radiation therapy 1
- Aspiration with fibrosis, which can closely resemble fibrotic hypersensitivity pneumonitis 3
- Post-infectious ILD 3
- Lymphangioleiomyomatosis (LAM) 3
- Pulmonary Langerhans cell histiocytosis 3
- Eosinophilic pneumonia 3
Critical Diagnostic Algorithm
When evaluating any patient with suspected ILD, the following systematic approach prevents diagnostic errors:
Obtain comprehensive exposure history: occupational exposures (with specific job tasks and duration), home environment (mold, water damage, birds, hot tubs), medications (including over-the-counter and supplements), and smoking history 1, 5
Screen for connective tissue disease: check ANA, RF, anti-CCP, anti-SSA/SSB, anti-Scl-70, anti-centromere, anti-Jo-1, CPK, and aldolase even without obvious systemic symptoms 3, 1
Perform high-resolution CT: this is 91% sensitive and 71% specific for diagnosing ILD subtypes and guides further diagnostic decisions 2, 6
Review all medications systematically: including those prescribed by other physicians and those started within the past 2 years 1
Consider surgical lung biopsy: when clinical, radiologic, and serologic evaluation does not yield a confident diagnosis, particularly to distinguish between IPF and other treatable forms of ILD 3
The most dangerous error is accepting an "idiopathic" diagnosis without systematically excluding medication history, environmental exposures, connective tissue disease, and occupational exposures, as this leads to missed opportunities for disease-modifying interventions. 1