What is the etiology of interstitial pneumonia?

Etiology of Interstitial Pneumonia

Interstitial pneumonia encompasses multiple distinct etiologies that must be systematically identified, including connective tissue disease (25% of cases), hypersensitivity pneumonitis (15%), idiopathic pulmonary fibrosis (33%), drug-induced disease, occupational exposures, and genetic causes—with accurate identification being critical because treatment differs fundamentally between inflammatory and fibrotic patterns. 1, 2

Major Etiologic Categories

Connective Tissue Disease-Associated ILD (CTD-ILD)

• Rheumatoid arthritis accounts for 39% of all CTD-ILD cases, making it the single most common autoimmune cause, followed by systemic sclerosis at 31%. 1
• Sjögren's syndrome causes lymphocytic infiltration with patterns including NSIP, respiratory bronchiolitis, UIP, and lymphoid interstitial pneumonia. 1
• Idiopathic inflammatory myopathies (dermatomyositis, polymyositis, antisynthetase syndrome) are critical to identify because they frequently present with NSIP pattern and may develop after initial IIP diagnosis. 1, 3
• Systemic lupus erythematosus and mixed connective tissue disease must be considered in the differential diagnosis. 1

Environmental and Occupational Exposures

• 47% of patients presenting with apparently "idiopathic" ILD actually have hypersensitivity pneumonitis when thoroughly evaluated with detailed exposure history, making this the most commonly missed diagnosis. 1
• 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. 1
• Occupational inorganic dust exposures to metal, silica, and asbestos increase IPF risk with pooled odds ratio of 1.7 (95% CI 1.42-2.03). 1
• Environmental tobacco smoke causes respiratory bronchiolitis-ILD and desquamative interstitial pneumonia, with smoking-related inclusions visible on BAL showing predominance of macrophages. 4, 1

Drug-Induced ILD

• Immunosuppressive agents carry approximately 1% risk of drug-induced ILD, including methotrexate, TNF-alpha inhibitors, cyclophosphamide, rituximab, leflunomide, sulfasalazine, and sulfonamides. 1
• Nitrofurantoin toxicity causes unclassifiable interstitial fibrosis patterns with patchy fibrosis, subpleural and bronchiolocentric accentuation, and prominent lymphoid aggregates. 4, 1
• CTD patients who progress despite appropriate therapy must be evaluated for drug-induced ILD, as the medications treating the underlying disease can themselves cause ILD. 1

Idiopathic Interstitial Pneumonias

• Idiopathic pulmonary fibrosis (IPF) with usual interstitial pneumonia pattern represents one-third of all ILD cases, characterized by peripheral lobular fibrosis with temporal heterogeneity. 1, 2
• Nonspecific interstitial pneumonia (NSIP) shows temporally uniform alveolar and interstitial inflammation and/or fibrosis with preserved alveolar architecture, but this pattern requires exclusion of CTD, hypersensitivity pneumonitis, and drug reactions before being labeled "idiopathic." 5, 6
• Acute interstitial pneumonia (AIP) presents with rapidly progressive hypoxemia and bilateral patchy ground-glass opacities with mortality exceeding 50%. 7
• Cryptogenic organizing pneumonia (COP), desquamative interstitial pneumonia (DIP), and respiratory bronchiolitis-ILD (RBILD) represent additional idiopathic forms. 4, 1

Familial and Genetic Causes

• Familial interstitial pneumonia occurs in 2-20% of cases, with heterozygous mutations in SFTPC, SFTPA2, TERT, and TERC accounting for 20% of familial cases. 1
• The MUC5B promoter variant is associated with both familial and sporadic IPF. 1

Diagnostic Algorithm to Identify Etiology

Step 1: Detailed Exposure and Medication History

• Obtain standardized questionnaire for environmental exposures (birds, hot tubs, humidifiers, mold, hay, grain dust) because patient recall alone misses hypersensitivity pneumonitis in nearly half of cases. 5, 1
• Document all current and past medications, particularly immunosuppressives, antibiotics (especially nitrofurantoin), and chemotherapy agents. 5, 1
• Record occupational history including metal work, silica exposure, asbestos, and organic dust exposures. 1
• Quantify smoking history in pack-years to identify smoking-related ILD. 4, 1

Step 2: Screen for Connective Tissue Disease Features

• Systematically assess for Raynaud's phenomenon, arthralgias, myalgias, skin changes, dry eyes/mouth, and muscle weakness because subtle autoimmune features may be the only clue to CTD-ILD. 5
• Obtain comprehensive autoimmune serologies including ANA, rheumatoid factor, anti-CCP antibodies, and myositis panel (anti-Jo-1 and other anti-synthetase antibodies). 5
• Never diagnose idiopathic NSIP without excluding CTD, even with subtle autoimmune features or positive serologies, as this fundamentally changes treatment from antifibrotics to immunosuppression. 5

Step 3: High-Resolution CT Pattern Recognition

• UIP pattern (bibasilar reticular abnormalities, honeycombing, peripheral distribution) suggests IPF but can occur in CTD-ILD, chronic hypersensitivity pneumonitis, and asbestosis. 7, 8
• NSIP pattern (bilateral symmetric ground-glass opacities) has differential including CTD-ILD, chronic hypersensitivity pneumonitis, drug-induced disease, and idiopathic NSIP. 5, 7
• Small airway abnormalities with fibrosis on HRCT (centrilobular nodules, mosaic air-trapping) strongly suggest hypersensitivity pneumonitis over idiopathic NSIP. 5, 1

Step 4: Bronchoalveolar Lavage Cellular Analysis

• BAL lymphocyte count >25% suggests granulomatous disease, cellular NSIP, drug reaction, or lymphoid interstitial pneumonia. 5
• BAL lymphocyte count >50% strongly suggests hypersensitivity pneumonitis or cellular NSIP. 5
• BAL neutrophils >3% or eosinophils >1% suggest acute lung injury, drug reaction, or eosinophilic pneumonia. 4
• Predominance of macrophages with smoking-related inclusions is compatible with DIP, RBILD, or Langerhans cell histiocytosis. 4

Step 5: Histopathologic Confirmation When Needed

• Transbronchial lung cryobiopsy is first-line for tissue diagnosis when clinical, radiologic, and BAL findings are inconclusive. 5
• Surgical lung biopsy is reserved for atypical presentations or when cryobiopsy is non-diagnostic. 7
• Histologic patterns with overlapping features (UIP with bronchiolocentric fibrosis, NSIP with organizing pneumonia) should prompt consideration of hypersensitivity pneumonitis, CTD-ILD, or additional injury patterns. 4

Step 6: Family History Assessment

• Question family history of ILD to identify genetic predisposition that may guide management of other family members. 1

Critical Pitfalls to Avoid

• Missing hypersensitivity pneumonitis by accepting "idiopathic" diagnosis without standardized exposure questionnaires—this is the most common diagnostic error, occurring in 47% of cases initially labeled idiopathic. 1
• Failing to recognize drug-induced ILD in CTD patients on immunosuppressives who progress despite therapy, as the treatment itself may be causative. 1
• Diagnosing idiopathic NSIP without comprehensive CTD screening, as identification of underlying autoimmune disease changes treatment from antifibrotics to immunosuppression. 5
• Relying solely on patient recall for exposures rather than using structured questionnaires, which misses critical environmental and occupational exposures. 1
• Recognizing that fever persisting >15 days is NOT characteristic of NSIP or IPF and should prompt evaluation for infection, drug-induced disease, organizing pneumonia, or other systemic conditions. 5
• Confusing NSIP pattern (histologic finding) with NSIP diagnosis (clinical entity), as the histologic pattern occurs in multiple diseases including CTD-ILD, hypersensitivity pneumonitis, and drug reactions. 5, 6