What is the pathophysiology of interstitial lung disease (ILD)?

Pathophysiology of Interstitial Lung Disease

Interstitial lung disease (ILD) involves three primary pathophysiological mechanisms: inhalation injury/airway inflammation, alveolar inflammation, and abnormal senescence, which lead to progressive inflammation and fibrosis of the lung parenchyma, resulting in impaired gas exchange and respiratory failure. 1

Core Pathophysiological Mechanisms

1. Bronchiolocentric Fibrosis

• Results from centrilobular injury due to:
  • Inhalation of fumes, dust, or antigens
  • Aspiration
  • Systemic diseases with airway inflammation 1
• Classic examples include:
  • Respiratory bronchiolitis from smoking
  • Hypersensitivity pneumonitis
  • Asbestosis
  • Systemic diseases (Sjögren syndrome, inflammatory bowel disease) 1

2. Nonspecific Interstitial Pneumonia-Fibrosis

• Results from diffuse alveolar inflammation followed by fibrosis
• Characteristic of:
  • Autoimmune connective tissue diseases
  • Drug reactions
  • Some cases of hypersensitivity pneumonitis
  • Organizing phase of diffuse alveolar damage 1
• Often driven by circulating factors affecting alveolar tissue diffusely 1

3. Usual Interstitial Pneumonia (UIP)

• Characterized by aberrant senescence
• Key features:
  • Fibrosis accentuated at the periphery of pulmonary lobules and subpleural regions
  • Microscopic honeycombing with irregular airspaces lined by bronchial epithelium
  • Fibroblast foci at the interface between fibrotic and less-involved regions 1
• Molecular mechanisms:
  • Significantly shorter telomeres than matched controls
  • Mutations in telomerase pathway (TERC and TERT)
  • Oldest type 1 pneumocytes located in distal peripheral acinar tissues
  • Increased tractional stress during normal inspiration and coughing 1

Cellular and Inflammatory Patterns

• Bronchoalveolar lavage (BAL) reveals characteristic cellular patterns:
  • Lymphocyte count >25%: suggests granulomatous disease, cellular NSIP, drug reaction, LIP, COP, or lymphoma 1

  • 15% lymphocytes, >3% neutrophils, >1% eosinophils, and >0.5% mast cells represent lymphocytic, neutrophilic, eosinophilic cellular patterns, and mastocytosis, respectively 2

Disease Progression and Fibrosis

• Progressive pulmonary fibrosis is defined by at least two of the following criteria within the past year:

  • Worsening respiratory symptoms
  • Physiological evidence of disease progression
  • Radiological evidence of disease progression 2

• Fibrosis progression leads to:

  • Reduced lung volumes
  • Impaired pulmonary gas exchange
  • Decreased cardiovascular function 3
  • A 5% decline in forced vital capacity (FVC) over 12 months is associated with approximately 2-fold increase in mortality 4

Common Complications

• Pulmonary hypertension develops in up to 85% of individuals with end-stage fibrotic ILD 2, 4
• Acute exacerbations can occur following lung procedures and are associated with high mortality, particularly in IPF 2
• Progressive respiratory failure is common in fibrotic ILDs 5

Clinical Behavior Patterns

ILDs can be categorized into five clinical behavior patterns based on their pathophysiology:

1. Reversible and self-limited
2. Reversible disease with risk of progression
3. Stable with residual disease
4. Progressive, irreversible disease with potential for stabilization
5. Progressive, irreversible disease despite therapy 2

Diagnostic Challenges

• Approximately 10-25% of ILD cases remain unclassifiable even after multidisciplinary discussion 2
• Up to 10% of patients with ILD may have normal chest radiograph findings 2
• Certain lung pathology patterns occur in multiple ILD subtypes and thus are not disease-specific 2

Pitfalls and Caveats

• Overlapping histological features often make classification difficult
• Small biopsy samples may lead to misdiagnosis due to sampling error
• Advanced interstitial fibrosis may obscure the underlying pattern
• Pre-biopsy treatment can alter histological findings 1
• Delayed diagnosis is common due to subtle presentation and similarity to atypical pneumonia 6

Understanding these pathophysiological mechanisms is crucial for accurate diagnosis, classification, and appropriate management of ILD to improve morbidity, mortality, and quality of life outcomes.