What are the causes of pneumonitis?

Causes of Pneumonitis

Pneumonitis is defined as focal or diffuse inflammation of the lung parenchyma that can be caused by various agents including drugs, environmental exposures, immune checkpoint inhibitors, and other factors. 1

Immune Checkpoint Inhibitor-Related Pneumonitis

• Immune checkpoint inhibitors (ICIs) can cause pneumonitis with an overall incidence of <5% for monotherapy, with higher rates (up to 10%) reported with combination therapies 2
• PD-1 inhibitors have higher incidence of pneumonitis (3.6%) compared to PD-L1 inhibitors (1.3%) 2
• Radiographic patterns include cryptogenic organizing pneumonia (COP), nonspecific interstitial pneumonitis (NSIP), hypersensitivity pneumonitis (HP), or usual interstitial pneumonitis (UIP)/pulmonary fibrosis 2
• Higher risk observed in patients with non-small cell lung cancer compared to melanoma patients 2

Hypersensitivity Pneumonitis

• Caused by inhalation of various environmental antigens leading to an exaggerated immune response 2, 3
• Common inciting agents include:
  • Organic dusts (moldy hay, straw) 3
  • Bird proteins (from pigeons, parakeets) 4
  • Contaminated humidifiers 4
  • Indoor molds 4
• Characterized by CD4+ T cell differentiation into Th1 cells promoting granuloma formation 2
• Can progress to irreversible fibrosis if exposure continues 3, 4

Drug-Induced Pneumonitis

• Methotrexate can cause interstitial pneumonitis, alveolitis, and respiratory failure 5
• Other medications associated with pneumonitis include:
  • Cancer drugs
  • Drugs for autoimmune diseases
  • Amiodarone
  • Antibiotics 1
• Clinical presentation ranges from asymptomatic to life-threatening 1

Chemical Pneumonitis

• Caused by inhalation of organic and nonorganic chemical agents 6
• More soluble agents affect upper respiratory tract, while less soluble agents reach distal airways causing pulmonary edema 6
• Can lead to long-term complications including bronchiectasis, bronchiolitis obliterans, and lung destruction 6

Viral Pneumonitis

• Can affect all age groups and both immunocompetent and immunocompromised hosts 7
• Common viral causes include:
  • Respiratory syncytial virus
  • Adenoviruses
  • Varicella-zoster virus
  • Herpes simplex virus
  • Influenza A and B viruses
  • Cytomegalovirus 7

Sarcoidosis and Sarcoid-like Reactions

• Pulmonary sarcoidosis and sarcoid-like granulomatous reactions can occur following immune checkpoint inhibitor therapy 2
• Characterized by increased numbers of T helper 17 (Th17.1) cells in bronchoalveolar lavage fluid 2
• May present with cough, wheezing, fatigue and/or chest pain 2

Diagnostic Considerations

• Bronchoalveolar lavage (BAL) cellular analysis can help differentiate between causes of pneumonitis 2
• BAL cell differential counts with >15% lymphocytes, >3% neutrophils, >1% eosinophils, and >0.5% mast cells represent different cellular patterns with diagnostic implications 2
• High-resolution CT is essential for diagnosis and should be performed as early as possible when pneumonitis is suspected 1
• Pneumonitis must be distinguished from pneumonia, diffuse alveolar hemorrhage, pulmonary edema, radiation pneumonitis, and pulmonary metastases 1

Clinical Implications and Management

• If unchecked, pneumonitis can lead to pulmonary fibrosis, respiratory insufficiency, and even death 1, 3
• Primary approach is to identify and remove the causative agent 1
• For immune checkpoint inhibitor-related pneumonitis, treatment is based on severity grading, with drug withdrawal as the mainstay for all grades 2
• Corticosteroids are indicated for moderate to severe cases, with additional immunosuppression (infliximab, cyclophosphamide) for recalcitrant disease 2

Early recognition and treatment are essential to prevent progression to chronic, irreversible disease 1.