What is fibrotic hypersensitivity pneumonitis (HP)?

Fibrotic Hypersensitivity Pneumonitis: Definition and Characteristics

Fibrotic hypersensitivity pneumonitis (HP) is a form of HP characterized by inflammatory and fibrotic changes in the lung parenchyma and small airways, resulting from an immune-mediated reaction to inhaled antigens in susceptible individuals, with radiographic or histopathological evidence of fibrosis that significantly impacts prognosis. 1

Definition and Classification

Hypersensitivity pneumonitis was historically categorized as acute, subacute, or chronic based on disease duration. However, current guidelines from the American Thoracic Society (ATS), Japanese Respiratory Society (JRS), and Asociación Latinoamericana del Tórax (ALAT) recommend classifying HP into two main phenotypes:

• Nonfibrotic HP: Purely inflammatory changes
• Fibrotic HP: Mixed inflammatory and fibrotic changes or purely fibrotic changes 1

This classification is more clinically relevant as the presence of fibrosis is the primary determinant of prognosis.

Pathophysiology of Fibrotic HP

Fibrotic HP develops through several key mechanisms:

• Immune dysregulation: In sensitized individuals, repeated exposure to inciting antigens triggers both humoral (antigen-specific IgG antibodies) and cellular (Th1) immune responses 1
• Genetic susceptibility: Several genetic factors are associated with fibrotic HP:
  • MUC5B promoter variant rs35705950
  • Mutations in telomere-related genes
  • Polymorphisms in major histocompatibility complex class II, proteasomes, and tissue inhibitors of matrix metalloproteinases 1
• Progression to fibrosis: Associated with:
  • Shift from Th1 to Th2 or Th17 cytokine patterns
  • Impaired regulatory T cells
  • Decreased γδT-cell activity
  • Fibroblast and fibrocyte migration
  • Epithelial-to-mesenchymal transition 1

Radiological Features

Fibrotic HP has distinctive radiological features on high-resolution CT (HRCT):

• Early fibrotic changes:

  • Ground-glass opacities
  • Poorly defined centrilobular nodules (<3mm)
  • Mosaic attenuation with "three-density sign" (previously called "headcheese sign")
  • Air trapping on expiratory imaging 1

• Advanced fibrotic changes:

  • Reticular opacities
  • Traction bronchiectasis
  • Volume loss
  • May mimic nonspecific interstitial pneumonia (NSIP) or usual interstitial pneumonia (UIP) patterns 1

Histopathological Features

Fibrotic HP demonstrates characteristic histopathological findings:

• Cellular and/or fibrosing interstitial pneumonia with bronchiolocentric accentuation
• Poorly formed non-necrotizing granulomas with or without giant cells
• Peribronchiolar metaplasia
• Small foci of organizing pneumonia
• In advanced cases, may show NSIP or UIP-like patterns 1

Diagnostic Challenges

Diagnosing fibrotic HP can be challenging because:

1. An inciting antigen is not identified in 30-50% of cases evaluated at ILD referral centers 1
2. Fibrotic HP can mimic other interstitial lung diseases, particularly IPF 2
3. Histopathological findings may show atypical patterns like NSIP or UIP 1

Prognosis

Fibrotic HP has a worse prognosis compared to nonfibrotic HP:

• Patients with fibrotic HP, particularly those with a UIP-like pattern, have reduced survival 1
• Negative prognostic factors include:
  • Cigarette smoking
  • Lower baseline vital capacity
  • Lack of BAL lymphocytosis
  • Persistent exposure to inciting agents
  • Inability to identify an inciting agent
  • Presence of honeycombing on HRCT 1, 3
  • Telomere-related gene mutations 4

Management Approach

Management of fibrotic HP should focus on:

1. Complete antigen avoidance: The most effective treatment strategy

   • May involve remediation or relocation for home exposures
   • Workplace modifications or job change for occupational exposures
   • Complete cessation of hobby-related exposures 4

2. Pharmacological therapy:

   • Systemic corticosteroids for patients with physiologic impairment
   • Early transition to steroid-sparing agents (azathioprine or mycophenolate mofetil)
   • Nintedanib for progressive fibrotic disease despite treatment 4, 5

3. Supportive care:

   • Oxygen therapy for hypoxemic patients
   • Pulmonary rehabilitation
   • Consideration of lung transplantation for end-stage disease 4

Fibrotic HP represents a significant diagnostic and therapeutic challenge that requires a multidisciplinary approach involving pulmonologists, radiologists, and pathologists for optimal management.