What is the classification and management of interstitial lung disease (ILD)?

Classification of Interstitial Lung Disease

Interstitial lung diseases should be classified using the 2013 ATS/ERS multidisciplinary framework that divides ILD into four major categories: ILDs of known cause (drugs, collagen vascular disease, exposures), idiopathic interstitial pneumonias (IIPs), granulomatous lung diseases (sarcoidosis, fungal, mycobacterial), and unique entities (pulmonary alveolar proteinosis, lymphangioleiomyomatosis, eosinophilic pneumonia). 1

Primary Classification Framework

The classification system organizes ILD into distinct categories based on etiology and pathologic patterns 1:

Known Causes

• Drug-induced ILD: Requires detailed medication history including chemotherapeutic agents, antibiotics, and antiarrhythmics 1
• Collagen vascular disease-associated ILD: Represents approximately 20% of all ILD cases, with rheumatoid arthritis (39%) and systemic sclerosis (31%) being most common 2
• Environmental/occupational exposures: Includes hypersensitivity pneumonitis, asbestosis, and hard metal pneumoconiosis 1

Idiopathic Interstitial Pneumonias (IIPs)

The IIPs comprise seven distinct entities with varying prognoses 1:

• Idiopathic Pulmonary Fibrosis (IPF): Accounts for 55% of IIPs, characterized by usual interstitial pneumonia (UIP) pattern with 5-year survival worse than many cancers 1
• Nonspecific Interstitial Pneumonia (NSIP): Represents 25% of IIPs, with variable prognosis depending on cellular versus fibrotic pattern 1
• Respiratory Bronchiolitis-ILD (RB-ILD): Comprises 10-15% of IIPs, typically smoking-related 1
• Cryptogenic Organizing Pneumonia (COP): Accounts for 5% of IIPs 1
• Desquamative Interstitial Pneumonia (DIP): Strongly associated with cigarette smoking 1
• Acute Interstitial Pneumonia (AIP): Represents <2% of IIPs 1
• Lymphoid Interstitial Pneumonia (LIP): Comprises <1% of IIPs, frequently secondary to autoimmune disease or immunodeficiency 1

Granulomatous Lung Diseases

• Sarcoidosis
• Fungal infections
• Mycobacterial infections 1

Unique Entities

• Pulmonary alveolar proteinosis (PAP)
• Lymphangioleiomyomatosis (LAM)
• Eosinophilic granulomatosis and eosinophilic pneumonia 1

Complementary Classification by Disease Behavior

When specific diagnosis remains uncertain after multidisciplinary discussion, classify by disease behavior pattern to guide management strategy. 1

The ATS/ERS guidelines provide five behavioral patterns 1:

Reversible and Self-Limited

• Example: Many RB-ILD cases
• Management goal: Remove causative exposure
• Monitoring: 3-6 month observation to confirm regression 1

Reversible with Risk of Progression

• Examples: Cellular NSIP, some fibrotic NSIP, DIP, COP
• Management goal: Achieve initial response, then rationalize long-term therapy
• Monitoring: Short-term assessment for treatment response, long-term observation to preserve gains 1

Stable with Residual Disease

• Example: Some fibrotic NSIP
• Management goal: Maintain current status
• Monitoring: Long-term observation to assess disease course 1

Progressive but Potentially Stabilizable

• Example: Some fibrotic NSIP
• Management goal: Achieve stabilization
• Monitoring: Long-term observation for disease trajectory 1

Progressive Despite Therapy

• Examples: IPF, some fibrotic NSIP
• Management goal: Slow progression, consider transplant evaluation
• Monitoring: Long-term assessment for transplant timing or effective palliation 1

Unclassifiable ILD Category

The 2002 ATS/ERS classification formally recognized that 10-15% of ILD cases remain unclassifiable even after thorough multidisciplinary evaluation. 1

Circumstances Leading to Unclassifiable Status

• Inadequate clinical, radiologic, or histologic information 1
• Overlapping histologic patterns that may indicate connective tissue disease or drug-induced disease rather than idiopathic process 1
• Discordant findings between clinical, radiologic, and pathologic assessments 1

Management Approach for Unclassifiable Cases

Base management on the most probable diagnosis after multidisciplinary discussion and the expected disease behavior pattern. 1

This behavioral classification should complement, not replace, attempts at specific diagnosis and should not justify delaying surgical lung biopsy when indicated 1

Diagnostic Integration Requirements

Accurate ILD classification mandates multidisciplinary discussion integrating pulmonology, radiology, and pathology expertise. 1

Essential Diagnostic Elements

• High-resolution CT (HRCT): Central role in diagnostic pathway with formal UIP pattern criteria 1
• Surgical lung biopsy: Gold standard for definitive diagnosis when HRCT is non-diagnostic 1, 2
• Bronchoalveolar lavage: Useful for differential diagnosis, particularly lymphocytic pattern (>15% lymphocytes) suggesting hypersensitivity pneumonitis or NSIP 2

Common Pitfalls

• HRCT misdiagnosis: Particularly by less experienced radiologists interpreting UIP patterns 1
• Premature closure: Failing to exclude secondary causes (drugs, exposures, connective tissue disease) before labeling as "idiopathic" 1
• Delayed biopsy: Increases surgical complications and may result in sampling of end-stage fibrosis rather than diagnostic tissue 1

Treatment Implications by Classification

IPF-Specific Therapy

• Antifibrotic agents: Pirfenidone or nintedanib slow FVC decline in IPF 2, 3
• Pirfenidone demonstrated mean treatment difference of 193 mL in FVC decline at 52 weeks versus placebo 3

NSIP and Other IIPs

• Mycophenolate: Preferred first-line therapy for NSIP pattern (1000-1500 mg twice daily) 4
• Rituximab: Alternative for NSIP, particularly with autoimmune features 4
• Nintedanib: Consider adding to immunosuppression for progressive fibrotic disease 4

Progressive Fibrosing ILD

Regardless of underlying diagnosis, progressive fibrosing phenotype may warrant antifibrotic therapy. 2, 4