What is the etiopathogenesis of interstitial lung disease (ILD), particularly in older adults over 50 with idiopathic pulmonary fibrosis (IPF)?

Etiopathogenesis of Interstitial Lung Disease

Interstitial lung diseases represent a heterogeneous group of disorders characterized by inflammation and/or fibrosis of the lung parenchyma, with etiology broadly categorized into three main groups: those associated with underlying systemic disorders (autoimmune diseases), those linked to antigenic or toxic exposures (occupational, environmental, or drug-related), and idiopathic disorders such as idiopathic pulmonary fibrosis. 1

Classification by Etiology

The etiopathogenesis of ILD can be systematically understood through the following framework 1:

Known Causes and Associations

• Systemic autoimmune diseases: Rheumatoid arthritis, systemic sclerosis, idiopathic inflammatory myopathies, Sjögren's syndrome, and systemic lupus erythematosus account for approximately 25% of ILD cases 1, 2
• Antigenic or toxic exposures: Hypersensitivity pneumonitis (15% of cases), pneumoconioses (asbestosis, silicosis, coal worker's pneumoconiosis, berylliosis), drug-induced ILD, radiation-induced injury, and illicit drug exposure 1, 2
• Occupational and environmental factors: Mold exposure, air pollution, and various occupational dusts 1

Idiopathic Disorders

• Idiopathic pulmonary fibrosis represents approximately one-third of all ILD cases and is the most common form 2
• Other idiopathic interstitial pneumonias: Nonspecific interstitial pneumonia (NSIP), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis with interstitial lung disease (RBILD), acute interstitial pneumonia (AIP), cryptogenic organizing pneumonia (COP), and lymphoid interstitial pneumonia (LIP) 1
• Sarcoidosis represents another major idiopathic category 1

Pathogenesis of Idiopathic Pulmonary Fibrosis

For IPF specifically, the pathogenesis involves functional up-regulation of sensory neurons in the lung, with increased sensitivity to substance P and capsaicin, and elevated sputum levels of nerve growth factor and brain-derived neurotrophic factor. 1

Genetic Susceptibility

• Heritable factors play a substantial role, with 20% of patients having familial pulmonary fibrosis (defined as two or more genetically related individuals with fibrotic ILD) 1
• MUC5B promoter variant is strongly associated with ILD risk, particularly in older adults over 50 years 1
• Telomerase mutations and shortened telomere length increase susceptibility, with 15-30% of asymptomatic first-degree relatives of IPF patients showing interstitial lung abnormalities on CT 1
• At least 30% of patients with sporadic or familial pulmonary fibrosis have known genetic predisposing factors 1

Environmental and Host Interactions

• Cigarette smoking represents a major risk factor, with the majority of IPF patients having a smoking history 1
• Gene-environment interactions: The combination of genetic susceptibility (particularly MUC5B variant) with environmental exposures (smoking, mold, air pollution) drives disease development 1
• Gastroesophageal reflux is associated with IPF development 1
• Chronic viral infections: Epstein-Barr virus and hepatitis C have been implicated 1

Epidemiology and Demographics

IPF occurs primarily in older adults, typically presenting in the sixth and seventh decades of life, with higher incidence in men than women. 1

• Overall ILD prevalence ranges from 25-74 per 100,000 population, with 80.9 per 100,000 in men and 67.2 per 100,000 in women 1
• IPF and other pulmonary fibrotic diseases account for >45% of ILD diagnoses, with incidence of 31.5 per 100,000 in men and 26.1 per 100,000 in women 1
• Patients younger than 50 years with IPF are rare and may subsequently manifest subclinical connective tissue disease or have familial IPF 1

Pathologic Features

The pathologic process extends beyond the microscopic interstitium to involve the alveolar space, small airways, vessels, and pleura, with accumulation of inflammatory and immune effector cells accompanied by abnormal extracellular matrix deposition. 1

• In IPF, the histopathologic pattern is usual interstitial pneumonia (UIP), though UIP and NSIP patterns may coexist in the same patient when multiple lung regions are biopsied 1
• The pathologic patterns are not disease-specific and can occur in other disorders such as connective tissue disease-associated ILD 1

Clinical Pitfalls

A critical caveat is that up to 10% of patients with ILD may have normal chest radiograph findings; therefore, normal chest X-ray cannot rule out clinically significant disease. 1 High-resolution CT scanning is essential for diagnosis, with approximately 91% sensitivity and 71% specificity for diagnosing ILD subtypes 2.