What are the causes of interstitial lung disease in adults?

Causes of Interstitial Lung Disease in Adults

Interstitial lung disease in adults arises from three major etiologic categories: idiopathic disorders (particularly idiopathic pulmonary fibrosis representing one-third of cases), connective tissue disease-associated ILD (accounting for 25% of cases), and environmental/occupational exposures (including hypersensitivity pneumonitis at 15% of cases). 1, 2, 3

Idiopathic Interstitial Pneumonias

• Idiopathic pulmonary fibrosis (IPF) with usual interstitial pneumonia (UIP) pattern represents approximately one-third of all ILD cases and is the most common form. 2, 3
• Nonspecific interstitial pneumonia (NSIP) has a differential diagnosis that must exclude autoimmune disease, hypersensitivity pneumonitis, and drug reactions. 2
• Other idiopathic forms include cryptogenic organizing pneumonia (COP), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis-ILD (RBILD), acute interstitial pneumonia (AIP), pleuroparenchymal fibroelastosis (PPFE), and lymphoid interstitial pneumonia (LIP). 1, 2
• Familial interstitial pneumonia occurs in 2-20% of cases, with heterozygous mutations in SFTPC, SFTPA2, TERT, and TERC accounting for 20% of familial cases. 2
• The MUC5B promoter variant is strongly associated with both familial and sporadic IPF. 2

Connective Tissue Disease-Associated ILD

Connective tissue diseases account for approximately 20-25% of all ILD cases, making this a critical category to systematically exclude. 4, 5, 3

• Rheumatoid arthritis (RA-ILD) accounts for 39% of CTD-ILDs, with UIP being the most common pattern in RA patients. 2, 6
• Systemic sclerosis (SSc-ILD) accounts for 31% of CTD-ILDs. 2, 4
• Sjögren's syndrome causes autoimmune-mediated lymphocytic infiltration with characteristic patterns including NSIP, respiratory bronchiolitis, UIP, and lymphoid interstitial pneumonia. 2
• Idiopathic inflammatory myopathies including dermatomyositis, polymyositis, and antisynthetase syndrome (which may be amyopathic) are associated with CTD-ILD. 1, 2
• Systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD) should be considered in the differential diagnosis. 1, 2

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. 2, 4

Hypersensitivity Pneumonitis

• Results from immune reactions to inhaled organic antigens, characterized by centrilobular nodules, mosaic air-trapping, upper lobe distribution on HRCT, and poorly formed granulomas with bronchiolocentric distribution on biopsy. 2
• Accounts for approximately 15% of ILD cases. 5, 3

Occupational Inorganic Dust Exposures

• Metal, silica, and asbestos exposures increase IPF risk with a pooled odds ratio of 1.7 (95% CI 1.42-2.03). 2, 7
• Specific occupational ILDs include asbestosis, silicosis, coal worker's pneumoconiosis, and berylliosis. 1
• The proportion of HP cases related to workplace exposure is 17% (95% CI 7-28%). 7

Tobacco Smoke

• Environmental tobacco smoke increases ILD risk and specifically causes respiratory bronchiolitis-ILD and desquamative interstitial pneumonia. 2, 5
• RBILD is a consequence of cigarette smoke exposure in virtually all patients, though RBILD and DIP often coexist. 1
• DIP is related to cigarette smoke in the majority of patients but can also occur in connective tissue disease without smoke exposure. 1

Drug-Induced ILD

Medication-induced ILD carries significant risk and must be systematically excluded, particularly in CTD patients who progress despite appropriate therapy, as the immunosuppressive medications themselves may be causative. 2, 4

• Immunosuppressive agents including methotrexate, TNF-alpha inhibitors, cyclophosphamide, rituximab, leflunomide, sulfasalazine, and sulfonamides carry approximately 1% risk of drug-induced ILD. 2
• Nitrofurantoin toxicity causes unclassifiable interstitial fibrosis patterns with patchy fibrosis, subpleural and bronchiolocentric accentuation, and prominent lymphoid aggregates. 2
• A comprehensive review of all current and recent medications is mandatory to exclude medication-induced ILD. 4

Other Causes

• Sarcoidosis with discrete nonnecrotizing granulomas and lymphatic distribution can develop coexistent fibrosis. 1
• Radiation-induced ILD following thoracic radiation therapy. 1
• Post-infectious ILD following severe pulmonary infections. 1
• Illicit drug use can cause various ILD patterns. 1
• Langerhans cell histiocytosis (LCH) and lymphangioleiomyomatosis (LAM) represent ILDs with cysts and/or airspace filling. 1
• Pulmonary alveolar proteinosis (PAP) and lymphoproliferative disorders. 1
• Inborn errors of metabolism, surfactant protein disorders, and pulmonary involvement by systemic disorders. 1

Critical Diagnostic Pitfalls to Avoid

• Failing to obtain sufficiently detailed exposure history is a critical error, as nearly half of patients initially thought to have idiopathic disease actually have hypersensitivity pneumonitis when properly evaluated. 2, 4
• Relying solely on patient recall without standardized questionnaires tailored to cultural habits and geographical differences misses occupational and environmental exposures. 2
• Accepting "idiopathic" diagnosis without systematic exclusion of medication history, environmental exposures, connective tissue disease, and occupational exposures, because identification and removal of causative factors may result in improved clinical outcomes. 2, 4
• Not considering drug-induced ILD in CTD patients who progress despite therapy, as the medications treating the underlying disease can themselves cause ILD. 2, 4
• Failing to question family history to identify genetic predisposition that may guide management of other family members. 2