What causes hypersensitivity pneumonitis?

Causes of Hypersensitivity Pneumonitis

Hypersensitivity pneumonitis (HP) is primarily caused by repeated inhalation of various environmental and occupational antigens in genetically susceptible individuals, leading to an immunologically mediated inflammatory response in the lungs. 1

Types of Inciting Agents

Organic Antigens (Most Common)

• Microorganisms:

  • Fungi (e.g., Aspergillus species, thermophilic actinomycetes)
  • Bacteria (e.g., Saccharopolyspora rectivirgula)
  • Mycobacteria (e.g., in hot tub lung)

• Animal Proteins:

  • Avian proteins (bird droppings, feathers, serum) - causing "bird fancier's lung"
  • Mammalian proteins

• Plant Materials:

  • Wood dust
  • Vegetable dust
  • Grain dust

Non-Organic Antigens

• Low-molecular-weight chemicals:
  • Isocyanates (used in polyurethane foam, paints)
  • Anhydrides
  • Metals (e.g., cobalt, zinc, zirconium, beryllium)

Pharmaceutical Agents

• Antibiotics (penicillins, cephalosporins)
• Immunosuppressive agents (methotrexate)
• Other medications (pravastatin, venlafaxine) 1

Common Exposure Settings

Occupational Exposures

• Farming environments (farmer's lung)
• Bird breeding facilities
• Wood processing plants
• Metal working (exposure to metalworking fluids)
• Swimming pool facilities (lifeguards)
• Automobile manufacturing (exposure to polyurethane)

Household Exposures

• Contaminated humidifiers
• Air conditioning systems
• Hot tubs (hot tub lung)
• Pet birds
• Moldy basements or bathrooms

Recreational Exposures

• Hot tub use
• Bird keeping
• Woodworking hobbies 1, 2

Pathophysiological Mechanisms

The development of HP involves a complex immunological response:

1. Immunological Dysregulation:

   • Combined type III (immune complex) and type IV (cell-mediated) hypersensitivity reactions
   • Formation of antigen-specific IgG antibodies (humoral response)
   • T-helper cell type 1 (Th1) cellular immune responses 1, 3

2. Inflammatory Cascade:

   • Antigen recognition by antigen-presenting cells (APCs)
   • CD4+ T cell differentiation into Th1 cells
   • Production of pro-inflammatory cytokines (IFN-γ, TNF-α, IL-2)
   • Lymphocytic inflammatory pattern and granulomatous inflammation
   • Neutrophilic inflammation in early disease stages 1, 2

Host Susceptibility Factors

• Genetic predisposition:

  • Certain HLA alleles (increased frequency of HLA-DRB11305 and HLA-DQB10501)
  • TNF-α promoter gene polymorphisms 3

• Environmental cofactors:

  • Smoking status (HP occurs mainly in non-smokers, though smoking may promote chronic disease)
  • Intensity and duration of exposure
  • Prior sensitization to the antigen 4

Important Clinical Considerations

• In up to 30-60% of cases, a specific inciting antigen cannot be identified despite thorough investigation 2

• The same antigen can cause different clinical presentations in different individuals, suggesting host factors play a significant role 1

• The presence of serum precipitins (antigen-specific IgG/IgA) indicates exposure but alone is insufficient to confirm or rule out HP diagnosis 2

• Fibrotic progression significantly impacts prognosis and treatment approach 2

• Telomere-related gene mutations are associated with shortened survival in HP 2

Diagnostic Approach

A thorough environmental and occupational history is crucial for identifying potential exposures. Consider using standardized questionnaires tailored to cultural habits and geographical differences to systematically assess exposures at home, work, and frequently visited places 1.

When the source is obscure, involving an occupational medicine specialist and environmental hygienist during the diagnostic workup may be beneficial 2.

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HP is a complex disease with diverse causative agents. Understanding the specific inciting antigen is critical for management, as complete antigen avoidance is the cornerstone of treatment and may lead to complete resolution in early non-fibrotic disease 2.