Interstitial and Restrictive Lung Disease

• Interstitial and Restrictive Lung Disease

Learning Objectives

• Understand the definition, etiologies, and pathogenesis of interstitial lung disease
• Learn the classification of interstitial lung disease
• Recognize the clinical presentation and radiological findings of interstitial lung disease
• Identify the histological features of UIP (Usual Interstitial Pneumonia), Sarcoidosis, Extrinsic Allergic Alveolitis/Hypersensitivity Pneumonia, Wegener's Granulomatosis, Pneumoconiosis (Coalworker's pneumoconiosis, Silicosis, Asbestosis), and Drug-Induced Lung Disease
• Know the prognosis and complications of interstitial lung disease
• Describe the essential histologic and gross features of Adult Respiratory Distress Syndrome (ARDS)
• Outline the pathophysiological consequences and common causes of ARDS
• Describe the mechanisms of lung damage in ARDS

Interstitial Lung Diseases

• Consider key questions such as defining the interstitium, identifying causes and pathophysiological effects, and differentiating between acute and chronic conditions

Definition of Interstitial Lung Diseases

• These diseases involve increased interstitial fibrosis and inflammation of the lung
• The interstitium of the alveolar wall includes the basement membrane of endothelial and epithelial cells, collagen fibers, elastic tissue, fibroblasts, proteoglycans, mast cells, and occasional lymphocytes

Pathogenesis of ILD

• Idiopathic pulmonary fibrosis is thought to be caused by recurrent lung injury or an autostimulating process
• Repeated stimuli increase cytokine production, leading to cytokine dysregulation and fibroblast proliferation
• Fibroblast proliferation increases extracellular matrix deposition and results in physiologic impairment

Restrictive Lung Disease

• Characterized by the destruction of alveolar walls, starting with the epithelium or endothelium and later predominating in the interstitium
• Decreased compliance leads to stiff lungs due to edema or fibrosis
• Diffusion defect is present causing impaired air exchange, dyspnea and hypoxia

Classification of Interstitial Lung Disease - Known Causes:

• Inhalants which include inorganic dusts/pneumoconioses like silicosis and asbestosis, organic dusts causing hypersensitivity pneumonitis, and toxic gases like oxygen
• Drugs and Toxins include antiarrhythmics and chemotherapeutics
• Infections include CMV, TB, and PCP
• Radiation

Classification of Interstitial Lung Disease - Unknown Causes:

• Includes Idiopathic Interstitial Pneumonias like UIP, DIP, RBILD, NSIP, and Acute Interstitial Pneumonia, also known as Hamman Rich Syndrome
• Connective tissue disease associated with ILD
• Sarcoidosis
• Eosinophilic granuloma
• Eosinophilic pneumonia
• Pulmonary hemorrhage syndromes like Goodpasture's syndrome and Wegener's granulomatosis
• Pulmonary alveolar proteinosis

Alternative Classification of Interstitial Lung Disease

• Fibrosing types include UIP, NSIP, collagen vascular disease associated ILD, Pneumoconiosis, drug reaction, and radiation pneumonitis
• Granulomatous types include sarcoidosis and hypersensitivity pneumonitis
• Eosinophilic types of ILD
• Smoking-Related types include DIP and RBILD
• Other: Pulmonary alveolar proteinosis

Diagnosis of Idiopathic Interstitial Pneumonias

• The classification and diagnosis can be difficult for surgical pathologists
• Histologic abnormalities are nonspecific
• Diagnosis requires substantial clinical input

Diagnostic Findings

• X-rays show interstitial markings that may become more prominent and relate to the underlying pathology
• CT scans may show ground glass opacities and subpleural fibrosis

Restrictive Lung Disease - Acute vs Chronic

• Acute conditions include diffuse alveolar damage (DAD/ARDS) with inflammation and edema
• Chronic conditions include diffuse alveolar damage, inflammation, edema, and fibrosis

DAD (Diffuse Alveolar Damage) - Causes:

• Can be caused by idiopathic factors, infections(sepsis, pneumonia), inhalation injuries(smoke, gases, near-drowning, oxygen), trauma(head, fat embolism, burns), aspiration, radiation, hematological abnormalities (DIC), and metabolic abnormalities (uremia, pancreatitis)

Pathogenesis of DAD/ARDS

• Involves multiple pathways leading to the same results
• Capillary endothelium and alveolar epithelium injury
• Neutrophils and macrophages, proinflammatory mediators (IL1, IL6, TNF-alpha)
• Profibrotic mediators (PDGF, IL10 etc)

DAD (Diffuse Alveolar Damage) Phases

• Acute phase lasting from day 1-7 involves Type 1 pneumocyte necrosis, intraalveolar and interstitial edema, hyaline membrane, and fibrin thrombi
• Organizing phase lasting from Day 8-20) involves Type 2 pneumocyte hyperplasia, interstitial fibroblastic proliferation, and thrombi
• End-stage fibrotic phase lasting >21 days involves collagenous fibrosis with architectural remodeling, cyst formation, and honeycombing

Clinical-pathologic correlation

• General symptoms of dyspnea
• Decreased lung volume and diffusing capacity
• Hypoxia
• Normal FEV1:FVC, specific disease symptoms

End Stage Lung

• Characterized by honeycomb lung
• It represents the final pathway of different disease processes with interstitial fibrosis

Current Classification of Idiopathic Interstitial Lung Disease

• Usual Interstitial Pneumonia (UIP) or Idiopathic Pulmonary Fibrosis or Cryptogenic fibrosing alveolitis
• Desquamative Interstitial Pneumonia (DIP)
• Acute Interstitial Pneumonia
• Nonspecific Interstitial Pneumonia (NIP)

Patient Ages

• UIP is more common in patients >50 y
• NSIP is more common in patients <50 y
• DIP and RB-ILD presents approximately in patients 36 and 42 y

Diagnosis

• Patient history focusing on potential exposures
• Physical Exam
• Imaging using High Resolution CT

Usual Interstitial Pneumonia

• Clinical presentation beings insidiously with dynpnea, dry cough, cyanosis, and clubbing (late)
• Gradual deterioration with survival less than 3 years
• Lung transplant is an option

UIP HISTOLOGIC FEATURES

• Patchy lung involvement
• Subpleural, paraseptal, and/or peribronchiolar distribution
• Dense fibrosis with frequent "honeycomb" appearance.
• Fibroblastic foci at the edge of dense scar
• Interstitial inflammation, mild to moderate

Sarcoidosis

• Non-necrotizing granulomatous inflammation composed of tight clusters of epithelioid histiocytes, giant cells, and lymphocytes that may become hyalinized
• Granulomas in interstitium
• Necrotizing granulomas can be seen
• X-ray shows interstitial infiltrate with hilar adenopathy
• Affects the lungs, skin, eye, lymph nodes, and spleen

Extrinsic Allergic Alveolitis/Hypersensitivity Pneumonia

• Immunologic reaction on inhaled agents (fungus, mold, animal proteins); type III/IV immune reaction
• Can be caused from pigeon breeder's lung or humidifier/AC lung
• Clinical presentation is either is either acute; dyspnea, cough, fever, which resolve in 12-18 hours or chronic: dyspnea, cough

Extrinsic Allergic Alveolitis - Histology

• Patchy chronic interstitial pneumonia around bronchioles with uninvolved lung in between
• Predominance of lymphocytes, plasma cells, histiocytes and rare eosinophils/neutrophils
• No vasculitis
• Loosely formed granulomas present in 2/3 of cases

Wegener's Granulomatosis

• Classic form shows Acute necrotizing granulomas of upper and lower respiratory tracts; necrotizing vasculitis in lung; focal necrotizing glomerulonephritis
• Clinical presentation: persistent pneumonitis; chronic sinusitis, nasopharyngeal ulceration and renal disease
• Peak incidence in 40s, male more than female
• Prognosis: if untreated 80% die within 1 year, Treated with immunosuppression
• Marker: Serum antineutrophil cytoplasmic antibodies (ANCA-C)
• Histology: Multiple bilateral nodules of necrosis in the lung, geographic lesions with eosinophils, giant cells (not forming well-defined granulomas), leukocytoklastic angiitis (arteries and veins).

Pneumoconiosis

• Non-neoplastic reaction of the lung to inhaled mineral or organic dust, excluding asthma, bronchitis, and emphysema
• Includes Silicosis, Asbestosis and Coalworker's pneumoconiosis

Silicosis

• Acute cases result from heavy exposure for 1-3 years
• Chronic cases occur after 20-40 years
• Occurs in those involved In occupations: mining, sand blasting, metal grinding, and tunneling
• Histology: hyalinized nodules, peripheral, upper lobe with black pigment (with concomitant exposure to coal dust); concentric lamellated hyaline with rare granulomas; refractile round particles
• Prognosis is poor including TB (10-30X relative risk) and progressive massive fibrosis

Asbestosis

• Occurs 15-20 years after exposure
• Histology: interstitial fibrosis similar to UIP, peribronchial fibrosis (lower lobe), pleural fibrosis/calcifications, and parietal pleural collagenous plaques

Coal Workers Pneumoconiosis

• After years of exposure to coal dust
• Develops dust macule with interstitial dust-filled macrophages around respiratory bronchioles, minimal fibrosis
• Followed by Coal nodule (<1cm): hyalinized collagen and pigmented macrophages
• Then massive fibrosis with large black masses which results in (complicated CWP)

Drug Induced Lung Disease

• Cyclophosphamide: may cause DAD, BOOP, or chronic interstitial pneumonia
• Methotrexate: Hypersensitivity pneumonitis, BOOP, DAD may occur as induced illnesses
• Related drugs include Antiarrhythmics (Amiodarone), Antihipertensive (Hydrochlorthiazide) and certain Antibiotics