3.3.05/06 Pathophysiology of Interstitial Lung Disease 1 & 2

What is the difference between obstructive and restrictive lung disease?

- Reduced lung volumes, total lung capacity (TLC) < 80% - Diseases in which the expansion of the lung is restricted either because of alterations in the lung parenchyma, or because of diseases of the pleura, chest wall or neuromusculature

What are the 5 steps in assessing a patient with suspected ILD?

1. A detailed history and exam: duration and severity of symptoms, any systemic features or manifestations of connective tissue disease (current or previous), occupation, home environment (rural, mould, chooks), medications, smoking, family history 2. Lung function testing: confirm restriction (low FEV1, low FVC, normal or elevated FEV1/FVC ratio; decreased lung volumes; decreased DLCO) 3. HRCT: look at pattern of ILD (honeycombing vs ground glass, nodules, plaques; distribution) 4. Blood tests: evidence of autoimmune process or hypersensitivity 5. Lung biopsy: consider if diagnosis not certain from steps 1-4 and well enough

What are the 3 components of the blood-gas barrier? What is the ECM/interstitium composed of?

1. Alveolar epithelium 2. Interstitium - ECM consisting of cellular attachments and lamina dense collagen IV 3. Capillary endothelium

MCQ? What is bronchoscopy used for? When is it usually performed?

1. BAL (broncho-alveolar lavage for sample) 2. Transbronchial lung biopsy - usually when sarcoid or neoplasm suspected** 3. EBUS (endo-bronchial ultrasound) - nodal aspirate ** Need lung surgery biopsy for other ILD

What is granulomatous lung disease? What are the 3 main pathologies?

1. Chronic inflammation 2. Lymphocytes and macrophages 3. Non-caseating (non-necrotising) granuloma

What are the 3 subtypes of ILDs of known association?

1. Connective tissue disease-associated 2. Drug-associated 3. Occupational exposure-associated

What is organising pneumonia? What are the types?

1. Cryptogenic Organising Pneumonia (formerly BOOP) 2. Fibrosing Organising Pneumonia

What are the 2 types of smoking-associated idiopathic interstitial pneumonias?

1. DIP - Desquamative Pneumonia (smoking-associated) 2. RB-ILD - Respiratory Bronchiolitis Interstitial Lung Disease (smoking-associated)

What are the radiological findings of hypersensitivity pneumonitis?

1. Fibrosis 2. Mosaiscism

What are the 7 classifications of ILD? How are they now grouped?

1. Idiopathic Interstitial Pneumonia 2. Collagen-Vascular Disease 3. Granulomatous disease 4. Occupational/environmental 5. Iatrogenic/drug induced 6. Inherited 7. Unique Entities 4 groups of ILD 1. Idiopathic Interstitial Pneumonias a. Idiopathic Pulmonary Fibrosis b. Non-IPF IIP i. NSIP - Non-Specific Interstitial Pneumonia ii. COP (BOOP) - Cryptogenic Organising Pneumonia iii. AIP - Acute Interstitial Pneumonia iv. LIP - Lymphocytic Interstitial Pneumonia v. DIP - Desquamative Pneumonia (smoking-associated) vi. RB-ILD - Respiratory Bronchiolitis Interstitial Lung Disease (smoking-associated) 2. Miscellaneous ILD a. Lymphangioleiomyomatosis (LAM) b. Histiocuytosis X 3. Granulomatous ILD a. Sarcoidosis b. Hypersensitivity pneumonitis (Extrinsic allergic alveolitis) 4. ILD of known association a. Connective tissue disease b. Drugs c. Occupational exposure

What are the 3 groups that restrictive lung disease can be divided into?

1. Intrinsic lung diseases, which cause inflammation or scarring of the lung tissue (interstitial lung disease) or fill the airspaces with exudate or debris (acute pneumonitis) 2. Extrinsic disorders, such as disorders of the chest wall or the pleura, which mechanically compress the lungs or limit their expansion 3. Neuromuscular disorders, which decrease the ability of the respiratory muscles to inflate and deflate the lungs

What is the radiological pattern of NSIP?

1. Lower Zone 2. Often symmetrical 3. Ground Glass Opacity (predominant) 4. Reticular changes 5. Traction Bronchiectasis 6. No Honeycombing

What is the Usual Intersitial Pneumonia histopathological pattern?

1. Patchy interstitial fibrosis with alternating areas of normal lung 2. Temporal heterogeneity of fibrosis - scattered fibroblastic foci in the background of dense acellular collagen 3. Architectural distortion due to chronic scarring or honeycomb change

What sorts of connective tissue diseases are associated with ILD? Which comes first? What sort of pattern does it present with? What tests do we order for diagnosis? What is the prognosis compared to IIPs? What is the treatment?

1. Rheumatoid Arthritis 2. Systemic Sclerosis (scleroderma) 3. Dermatomyositis/ polymyositis 4. Sjogren's syndrome 5. Systemic Lupus Erythematosis 6. Mixed Connective Tissue Disease Chronic (autoimmune) inflammation leads to fibrosis (but sometimes ILD can pre-date the other manifestations NSIP pattern Screen of serum autoantibodies (ANA, ENA, ds-DNA, RF, myositis-specific antibodies Better prognosis than IIPs Anti-inflammatory drugs

What are the characteristic findings of Usual Intersitial Pneumonia on imaging?

1. Symmetrical bilateral reticulations 2. Architectural distortion 3. Honeycomb change 4. Involving mainly subpleural regions and lower lobes

What is the histological pattern of NSIP?

1. Temporally Uniform 2. Absence of honeycomb change 3. Minimal or no fibroblast foci 4. Cellular or fibrotic

Define interstitial lung disease.

A disease entity that goes by many names: Pulmonary fibrosis Interstitial pneumonia Diffuse parenchymal lung disease

What is IPF? What is the prevalence? What are the clinical features?

A specific form of chronic, severe, progressive fibrosing interstitial pneumonia Unknown aetiology Most common of the idiopathic interstitial pneumonias: Prevalence 7-20/100,000 More common in men; age >50 Median survival 3-5 years No current effective treatment Clinical features: Dyspnoea Dry cough Fine "velcro" crackles on inspiration Fingernail clubbing

What is hypersensitivity pneumonitis? What is it caused by? What are the subtypes? What is the treatment?

Also known as Extrinsic Allergic Alveolitis (EAA) A complex syndrome of varying intensity, clinical presentation, and natural history rather than a single, uniform disease Caused by repeat inhalation of dusts containing organic antigens (>300 aetiologies reported) Most common: Farmer's lung, Bird Fancier's lung Blood tests can reveal positive Farmer's lung or Avian IgG (precipitin) antibodies Acute HP, subacute HP, chronic HP Treatment: Removal from exposure to inciting antigen (although difficult if none identified; also less effective in chronic form) Immunosuppression with prednisone (sometimes stronger agents needed)

What are the typical radiological findings of pulmonary sarcoidosis?

Chest CT: 1. Typical micronodular infiltrates 2. Distributed in a bronchovascular pattern 3. Often predominating in the mid to upper lung zones

How is IPF diagnosed? What is the UIP pattern?

Diagnosis requires 1. Exclusion of all other known causes of ILD (occupational, drug-associated, connective tissue disease-associated) 2. "Usual Interstitial Pneumonia" (UIP) pattern on radiology (HRCT) and/or surgical lung biopsy

What is non-specific interstitial pneumonia? What are the 3 types? What are the causes?

Has a non-specific histological pattern Younger (mean 40-50), women Usually slowly progressive (variable) Non-Specific histological pattern: • No detectable cause (idiopathic NSIP) • Collagen vascular disease • Hypersensitivity pneumonitis • Drug-induced pneumonitis • Infection • Immunodeficiency (HIV) 3 types 1. Cellular (inflammatory) 2. Mixed 3. Fibrotic (fibrosis) May be idiopathic but often associated with underlying systemic disease

Which diseases have the UIP pattern?

ILDs of known association (CT disease, Drugs, Occuptional) Hypersensitivity pneumonitis IPF

What was the traditional concept of IPF? Why is it not true? Which cells are predominant on histology?

Insult --> Inflammatory --> Scarring is WRONG due to very few inflammatory cells AND anti-inflams DON'T WORK Fibroblastic foci: fibroblasts and myofibroblasts, smooth muscle cells, undifferentiated cells (mesenchymal cells) Deposition of type I collagen into ECM

What are the clinical features of sarcoidosis? Does it resolve?

Multisystem disease (eyes, skin, heart, neurologic, lungs) May be clinically silent Classical pulmonary features: Bilateral Hilar lymph nodes Airway involvement Interstitial Fibrosis Spontaneous resolution occurs within 5 years in approximately two thirds of patients, without specific treatment

What is the prognosis of IPF versus NSIP?

NSIP prognosis better than IPF

Which lung volumes are affected in RLD versus OLD? How does this affect lung compliance in restrictive?

Obstructive - decreased FEV1, decreased ratio Restrictive - decreased FEV1 AND FVC, normal or elevated ratio Reduced lung compliance due to increased stiffness = less volume change for same pressure change

What can ILD associated with occupation or iatrogenic be caused by?

Occupational - Classical Dust/ Fibre Exposures (Pneumoconioses) Asbestos - Asbestosis Silica - Silicosis Coal - CWP Beryllium - Berylliosis Iatrogenic - Radiotherapy involving the lung fields Drugs (100's associated with ILD) - Amiodarone, Bleomycin, Methotrexate

What is sarcoidosis? What is the pathological mechanism?

Perilymphatic, peribronchial concentration of granulomas Sarcoid granuloma: Core of epithelioid histiocytes + multinucleated giant cells, surrounded by T cells Inflammation in sarcoidosis is dependent on persistent stimulation by CD4+ T cells It is still unknown whether a single agent triggers the disease or if sarcoidosis represents a stereotyped immune response to diverse etiologies.

What are the radiological features of asbestosis?

Pleural plaques - but often asymptomatic

What is the lung interstitium? What are the components?

Space between endothelium and epithelium. But interstitial disease also involves alveoli airspaces, epithelium, capillaries, fibroblasts

Why are the other types of idiopathic interstitial pneumonias different to IPF?

The pathogenic processes follow the traditional inflammatory paradigm (Anti-inflams often work, prognosis usually much better)

What is the pathological mechanism involved in ILD?

Thickening of interstitium --> Inflammatory infiltrate (lymphocytes and plasma cells) --> Type I collagen deposition by fibroblasts --> Extensive scarring --> Architectural distortion --> Obliteration of capillary bed (microscopic honey combing) = IMPARIED GAS EXCHANGE

Why does the blood-gas barrier have a thin and thick side?

Thin for gas exchange Thick for strength and fluid exchange

What are the main differences in UIP and NSIP on imaging?

UIP (has 95% correlation with IPF) - HONEYCOMBING, PATCHY DISTRIBUTION NSIP - no honeycombing, GROUND GLASS OPACITY, SYMMETRICAL/HOMOGENEOUS, SUBPLEURAL SPARING

What are the main differences in UIP and NSIP on histology?

UIP - heterogeneity, fibrotic foci, honeycombing NSIP - homogeneous, cellular, inflammatory picture (can progress to fibrosis)

How does RLD affect a) gas exchange b) control of ventilation c) pulmonary vasculature?

a) Reduced PaO2 Normal (or low) PaCo2 Exercise-induced oxygen desaturation Impaired diffusing capacity (DLCO) b) Rapid shallow breathing Small tidal volumes Increased dead space ventilation c) Obliteration of capillaries Increased pulmonary vascular resistance = pulmonary hypertension