Interstitial Lung Diseases Dr. C. Lai

Objectives Describe the normal interstitium & the pathological changes in cells & lung architecture that may occur in interstitial lung disease. Describe the key pathological features of the common idiopathic interstitial lung diseases. Describe the pathological features of common secondary interstitial lung diseases (pneumoconiosis & collagen vascular disease) & compare & contrast their pathological features. Describe the key pathological features of pulmonary vascular diseases.

Air Exchange Diseases Infectious pneumonias Interstitial lung diseases Bacterial, mycobacterial, viral, fungal Interstitial lung diseases Pneumoconiosis, sarcoidosis, idiopathic interstitial fibrosis Pulmonary “vascular” diseases Pulmonary embolism, pulmonary edema, ARDS

Interstitial Lung Diseases Pulmonologist, radiologist, & pathologist have different approaches to ILDs Each approach provides unique insight, but can be confusing due to use of own terminology Clinician: disease causing dyspnea, tachypnea, & restrictive lung disease Radiologist: disease producing irregular lines, small nodules (dots), or ground glass shadows on CXRs Pathologist: disease characterized predominantly by inflammation & fibrosis of pulmonary interstitium

Pulmonary Interstitium

Axial Interstitium

Peripheral Interstitium Pleural Interstitium Interlobular Interstitium

Septal Interstitium

Pathophysiology Impaired lung mechanics Impaired gas exchange Reduces lung compliance Increases work of breathing Reduces lung volumes Impaired gas exchange Smaller lung volumes results in less surface area for gas exchange Interstitial thickening impedes transfer of oxygen from alveoli to pulmonary capillaries

Interstitial lung diseases Acute vs chronic Known vs unknown etiology Primary vs secondary Pathologic patterns 10

Interstitial Lung Diseases Primary Sarcoidosis (20%) Idiopathic pulmonary fibrosis - IPF (15%) Secondary Congestive heart failure/pulmonary edema Infection (pneumonia) Malignancy (lymphangitic carcinomatosis) Pneumoconiosis (25%) Connective tissue disease (10%) Hypersensitivity pneumonitis (5%) Drugs/radiation (5%)

Secondary ILDs

Pneumoconioses Nonneoplastic lung reaction to inhalation of mostly inorganic particulate matter (mineral dusts) encountered in the workplace Usually fibrogenic: Silica Asbestos Usually non-fibrogenic Coal Beryllium (granulomatous)

Silicosis Common lung disease caused by inhalation of crystalline proinflammatory silicon dioxide (silica) Quartz most commonly implicated Subacute presentation (rare) Heavy exposure over months to few years Intra-alveolar accumulation of lipoproteinaceous material Chronic presentation (most common) Usually presents after decades of exposure Slowly progressive, nodular, fibrosing interstitial lung disease 14

Pulmonary Silicosis Early stage Later stage Advanced stage Tiny, barely palpable, discrete pale to blackened nodules in hilar lymph nodes & upper lung zones Later stage Coalescence of nodules into hard, collagenous scars Advanced stage Expansion and coalescence of lesions to produce progressive massive fibrosis

Silicotic Nodule Central area of whorled collagen fibers (arrow) with peripheral zone of dust-laden macrophages Intra-histiocytic, short, needle- shaped, birefringent silicate particles Histiocytic aggregates along lymphatic routes & within lymph nodes

Asbestosis Asbestos Asbestosis Pro-inflammatory crystalline hydrated silicates Asbestosis Asbestos-related disease Chronic presentation (20 to 30 yrs after first exposure) Progressive peribronchiolar & alveolar septal fibrosis Presence of multiple asbestos bodies (long slender fibers coated by iron, AKA ferruginous bodies) Predominantly involves lung bases & subpleural lung 17

Asbestos Body

Pulmonary Fibrosis Septal thickening

Pleural Plaques

Collagen Vascular Diseases Autoimmune diseases can involve the lungs & cause interstitial pneumonitis at some point in their course Rheumatoid arthritis, progressive systemic sclerosis (scleroderma), systemic lupus erythematosus, Sjögren syndrome, dermatomyositis-polymyositis, mixed connective tissue disease Histological features are indistinguishable from idiopathic forms of interstitial lung diseases Most have better prognoses than idiopathic pulmonary fibrosis

Hypersensitivity Pneumonitis Immune-mediated interstitial lung disease due to exposure to inhaled organic antigens Thermophilic bacteria, fungi, animal proteins (birds) Acute, subacute or chronic presentation Peribronchiolar interstitial pneumonitis (centrilobular lymphoplasmacytic inflammation) Presence of poorly-formed, nonnecrotizing granulomas Interstitial fibrosis in chronic presentation (late stages) 22

Hypersensitivity Pneumonitis Septal thickening

Hypersensitivity Pneumonitis Giant cell

Primary ILDs

Sarcoidosis Systemic granulomatous disease of unknown etiology Often involves lung & lymph nodes but can involve many other tissues & organs Immune dysregulation in genetically predisposed individuals Type IV hypersensitivity reaction to unidentified antigen with granulomatous inflammation along lymphatic routes Unpredictable clinical course 65% to 70% recovery with minimal or no residual sequelae 20% permanent loss of some lung function or visual impairment 10% to 15% progressive pulmonary fibrosis and cor pulmonale

Sarcoidosis Interlobular septum Granulomata

Sarcoidosis Artery Bronchiole Granulomata

Sarcoidal Granuloma Granuloma Histiocytes Giant cell

Idiopathic Pulmonary Fibrosis Clinicopathological syndrome of unknown etiology characterized by progressive interstitial pulmonary fibrosis & eventually respiratory failure AKA cryptogenic fibrosing alveolitis (Europe) Middle aged-to-elderly individuals (rare before 50 yrs old) Insidious clinical course with gradually increasing exertional dyspnea & dry cough Median survival is ~3 years after diagnosis Lung transplantation is only definitive therapy

Idiopathic Pulmonary Fibrosis

End-Stage Lung (Honeycombing) Fibrous septa Honeycombing (circled areas)

Idiopathic Pulmonary Fibrosis Cystic spaces (*) Septal fibrosis * Bronchioles

Idiopathic Pulmonary Fibrosis Normal septum Septal fibrosis Inflammatory cells

Pulmonary Vascular Diseases

Types of Diseases Obstruction to venous outflow (pulmonary congestion ) Congestive heart failure → pulmonary edema Increase in pulmonary artery resistance (pulmonary hypertension) Primary or secondary (e.g. systemic sclerosis) Pulmonary artery obstruction (pulmonary thromboembolism) Emboli (common) or thrombosis (uncommon) Vascular inflammation (vasculitis) Granulomatosis with polyangiitis (Wegener’s granulomatosis), Churg-Strauss syndrome

Pulmonary Thromboembolism Pulmonary artery embolism (common) More than 95% associated with deep venous thrombosis of lower limbs Predisposing factors include bedridden, leg surgery, severe trauma, oral contraceptives, cancer, genetic hypercoagulability) Pulmonary artery thrombosis (uncommon) Large vessels: rare, associated with pulmonary hypertension, pulmonary atherosclerosis, heart failure Small vessels: vasculitis, inflammation, diffuse intravascular coagulation (DIC)

Pulmonary Embolism Acute changes Chronic changes Luminal obstruction with endothelial damage Small vessels: alveolar hemorrhage in corresponding irrigated area & possible infarct (especially in those with compromised cardiovascular function) Larger vessels: wedge-shaped, hemorrhagic infarction in center & hemorrhage in periphery Chronic changes Infarcted areas become fibrotic Chronic pulmonary embolism (multiple small emboli) can lead to pulmonary hypertension and chronic cor pulmonale

Thrombosis

Pulmonary Embolism

Pulmonary Embolism Artery Embolus Respiratory bronchiole

Pulmonary Infarct PA thrombus Infarct

Pulmonary Infarct Alveolar septa * Intra-alveolar hemorrhage (*)

Complete Obstruction Organized thrombus Internal elastic layer (short arrows)

Recanalized Thrombus New lumen Organized thrombus

ARDS Acute Respiratory Distress Syndrome Manifestation of severe acute lung injury (abrupt onset of significant hypoxemia & bilateral pulmonary infiltrates in absence of heart failure) Diffuse alveolar damage is histologic manifestation of ARDS Complication of diverse conditions Sepsis, diffuse pulmonary infections, mechanical trauma (including head injuries), & gastric aspiration account for >50% of ARDS cases Numerous other causes: extensive burns, ionizing radiation, fat embolism, pancreatitis, inhaled irritants (toxic fumes), chemical injury, uremia, cardiopulmonary bypass, etc.

Pathogenesis of ARDS ARDS initiated by injury to alveolar septal pneumocytes & endothelial cells Endothelial activation from pneumocyte injury or circulating inflammatory mediators (e.g. sepsis) Adhesion & extravasation of neutrophils into interstitium & alveoli  degranulation & release of more inflammatory mediators  increased recruitment & adhesion of leukocytes  more endothelial injury Increased vascular permeability  interstitial & intra-alveolar edema  fibrinous exudate & hyaline membrane formation Difficult repair, frequently evolving to death or fibrosis

Diffuse Alveolar Damage

Diffuse Alveolar Damage Hyaline membranes (small arrows) Early septal fibrosis