Exposure-related ILD

Exposure-related ILDs are responsible for 20% of all ILDs.¹ These ILDs impact individuals of all ages, with the causative agent often differing between adults and children.²

• Exposure-related pediatric ILD is thought to be underestimated²
• Misdiagnosis or underestimation of pediatric ILD often leads to diagnosis when the disease is already chronic²
• Most cases of pediatric ILD are due to environmental or avocational hypersensitivity pneumonitis, radiation exposure, or are drug induced²
• Adults are often exposed within the workplace¹

DRUG-ASSOCIATED ILD³

• Drug-induced lung injury can involve multiple parts of the lung:
  • Airways
  • Lung parenchyma
  • Mediastinum
  • Pleura
  • Vasculature
  • Neuromuscular system
  • Most common form is ILD
• Route of drug administration associated with ILD is often oral or parenteral, but can also be from nebulized or intrathecal medication
• Direct (often seen with chemotherapeutics) or indirect actions of certain drugs can lead to ILD

CAUSATIVE AGENTS

Over 450 drugs from a variety of classes have been associated with ILD:³

• Cytotoxic (e.g., bleomycin, carmustine, busulfan, cyclophosphamide)³
• Cardiovascular (e.g., amiodarone, statins)^2,3
• Anti-inflammatory or immunosuppressive (e.g., aspirin, methotrexate, azathioprine, NSAlDs)^2,3
• Antibiotics or antimicrobials (e.g., nitrofurantoin, amphotericin B, sulfonamides, sulfasalazine)^2,3
• Biological agents (e.g., tumor necrosis factor-α (TNF-α) blockers, anti-CD20 antibodies, interferon-α (INF-α)³
• Miscellaneous (e.g., bromocriptine)³

EPIDEMIOLOGY³

• An estimated 2.5%-3% of ILD cases are thought to be drug-induced
• ILD is most commonly found among patients exposed to known ILD—causing agents, particularly in populations such as:
  • Patients receiving chemotherapy
  • Patients with inflammatory conditions such as rheumatoid arthritis or inflammatory bowel disease
  • Patients receiving concurrent toxic therapeutic agents

DISEASE PROGRESSION⁴

Drug-specific pathways:

• With chemotherapeutics, the release of cytokines is directly related to the causative drug and can cause capillary leakage and pulmonary edema
• Methotrexate-associated ILD is thought to induce release of free oxygen radicals
  • A similar mechanism may underlie bleomycin, nitrofurantoin, and mitomycin C-induced ILD
    • The lung is particularly sensitive to bleomycin toxicity as the drug is preferentially distributed to the lung, and has lower levels of the detoxifying enzyme
• Gefitinib impairs alveolar repair mechanisms and impacts epithelial proliferation underlying pulmonary fibrosis
• Amiodarone disrupts lysosomal membranes, leading to release of oxygen radicals and the activation of caspase-mediated apoptosis in lung epithelial cells

RISK FACTORS

General Risk Factors³

• Age
  • Children and the elderly are associated with a higher risk³
• Gender
  • Higher incidence in females³
• Ethnicity
• Dosage
• Oxygen
  • Drugs inducing reactive oxygen species and oxidative stress may contribute to ILD³
• Drug interactions
  • Certain drug combinations can elicit, or increase the risk of ILD³
• Radiation
• Underlying drug disease

Risk for Immune Reactions⁴

• Drug structure
• Genetics
• Environment
• Nature of drug exposure