RESTRICTIVE LUNG DISEASES Interstitial Lung Diseases

LECTURE GOALS: Restrictive lung disease 1&2 (Pathology) 1.Define restrictive lung disease. 2.Be familiar with the principles, cause & mechanisms in acute restrictive lung disease identifying Acute Respiratory Distress Syndrome in adults and newborn. 3.Discuss the pathology of idiopathic pulmonary fibrosis. 4.List the commoner cause of pulmonary fibrosis with emphasis on the pathology of Sarcoidosis. 5.Be familiar with causes and pathology of pneumoconiosis. 6.Identify causes and pathology of Asbestosis & Mesothalioma. 7.List the pulmonary hemorrhage syndromes, which may lead to pulmonary fibrosis.

 Include diseases which interfere with lung expansion. Chest wall defects & severe obesity. Pulmonary diseases. Restrictive Pulmonary diseases  Stiff non compliant lung  Dyspnea & Hypoxia. Destruction of alveolar walls with FIBROSIS in the chronic phase.

Kyphosis/Scoliosis

Restrictive pulmonary diseases : Predominantly diffuse. Acute or chronic. Acute is represented by ARDS. Chronic is involvement of the pulmonary connective tissue  FIBROSIS. Principally involves the alveolar walls.

PATHOGENESIS : Alveolar septae structure

Pulmonary Function Tests :  Forced Vital Capacity ( FVC ) and ( FEV1 ) in the same ratio.  FEV1 / FVC near normal in Restrictive lung diseases.

Characteristics : Decreased lung compliance (stiff lung). Increase in effort to breath → (inspiratory dyspnea). Damage to alveolar epithelium & vasculature leads to abnormalities in ventilation- perfusion ratio & hypoxemia. X-ray : Bilateral diffuse pulmonary infiltrates. Progression to respiratory failure, Pulmonary hypertension, ± Honey Comb Lung

LATER stage of ARDS: Macrophage derived fibrogenic factors ( TGF-B, PDGF, IL-1, TNF) Recruitment of fibroblasts → Fibrogenesis All previous can be counteracted by endogenous antiproteases, antioxidants, & anti - inflammatory cytokines(IL-10) Clotting cascade is also triggered

Pathogenesis : Whatever the cause, the lesion is an ‘alveolitis’ Lymphocytes, macrophages & neutrophils Macrophage activation → leukotrines recruit neutrophils & Fibrogenic Cytokines induce FIBROSIS.

Major types of Interstitial Lung Diseases with different patterns : Fibrosing: Idiopathic Pulmonary Fibrosis (UIP) Nonspecific Interstitial Pneumonia Cryptogenic Organizing Pneumonia ( BOOP ) Associated with Collagen Vascular Dis. Pneumoconiosis Drug Related & Radiation Induced

Granulomatous : Sarcoidosis Hypersensitivity Pneumonitis Eosinophilic: Pulmonary Eosinophilia Smoking Related

Fibrosing Reaction

1- Idiopathic Pulmonary Fibrosis : (Cryptogenic Fibrosing Alveolitis) M  F. Two thirds of patients are older than 60 years of age at presentation. Diagnosed only after exclusion of all other causes. Severe hypoxemia & cyanosis. Histological pattern of Usual Interstitial Pneumonia ( UIP)

- IPF is caused by “repeated cycles” of epithelial activation/injury by unknown causes until now. - Inflammation by many cell types will lead to initiate the process of healing, but in IPF instead of complete healing, there will be activation of macrophages  which will initiate fibrosis.

Clinical Features & Examination : Insidious presentation Nonproductive cough & progressive dyspnea Examination : Cyanosis, clubbing, dry ‘crackles’ at inspiration Chest X ray  bilateral basal nodular infiltrates Pulmonary function tests  restrictive result Lung biopsy ± Bronchoalveolar lavage Prognosis : Death in 2-4 years

Morphology : Cobblestones because of the retraction of scars along the interlobular septa. Interstitial chronic inflammation with cellular fibroblastic proliferation OR Interstitial collagenous acellular process

- Not all areas affected equally: ‘Temporal heterogeneity’. - Peripheral location, basal, along pleura & septae. - Patchy fibrosis  collapse alveolar walls  irregular cystic spaces lined by hyperplastic type II pneumocytes or bronchiolar lining (Honeycomb Lung).

Cobblestone Appearance

2- Nonspecific Interstitial Pneumonia: Similar to previous, but more diffuse & without heterogeneity Better prognosis than UIP. WASTEBASKET DIAGNOSIS, of ANY pneumonia (pneumonitis) of any known or unknown etiology. Mature FIBROSING Pattern * CELLULAR Pattern : INFILTRATE (LYMPHS & PLASMA CELLS)

3 -Cryptogenic Organizing Pneumonia : Bronchiolitis Obliterans Organizing Pneumonia (BOOP) Many causes (inflammatory, vascular…) but mainly cryptogenic Interstitial inflammation,not temporal heterogeneity. Polypoid plugs of fibrosis in bronchioles & alveolar ducts & alveoli No destruction of lung architecture Recovery within 6 months with steroids

BOOP

4- “COLLAGEN” VASCULAR DISEASES Rheumatoid Arthritis SLE (“Lupus”) Progressive Systemic Sclerosis (Scleroderma) + Any interstitial pattern

5- Pneumoconiosis : Environmental /occupational diseases Pneumoconiosis is a term originally coined to describe the non- neoplastic lung reaction to inhalation of mineral dusts. The three most common forms of pneumoconiosis result from exposure to coal dust, silica, and asbestos—nearly always result from exposure in the workplace. The reaction of the lung to mineral dusts depends on many variables, including size, shape, solubility, and reactivity of the particles.

- Particles that are 1 to 5 μm in diameter are the most dangerous, because they get lodged at the bifurcation of the distal airways. - The pulmonary alveolar macrophage is a key cellular element in the initiation and perpetuation of lung injury and fibrosis. - Tobacco smoking worsens the effects of all inhaled mineral dusts, more so with asbestos than with any other particle.

A- Anthracosis ( Coal miner’s lung) Pulmonary anthracosis is the most common pattern of Coal related diseases. Seen in tobacco smokers. Inhaled carbon pigment is engulfed by macrophages, which then accumulate in the connective tissue.

1- Simple CWP: macule and nodule. 1- The coal macule consists of dust-laden macrophages. 2- The coal nodule is larger and contains collagen. - Upper lobes involved more than lower lobe. - Centrilobular emphysema might occur. **CWP: Coal Workers pneumoconiosis.

- 2- Complicated CWP : - Occurs on a background of simple CWP by coalescence of coal nodules cm. - Requires many years to develop. 3- Progressive Massive Fibrosis:increasing pulmonary dysfunction, pulmonary hypertension, and cor pulmonale. No increase in risk for lung cancer.

Anthracosis with Fibrosis

B- Silicosis Commonest occupational lung disease Inhalation of crystalline silica (Quartz: most common) & amorphous types. Workers in sandblasting,ceramics, glass and stone cutting, construction….etc Acute heavy exposure  ARDS Chronic after yrs exposure

Pathogenesis : Silica in macrophages  injury to cell membrane. Release silica +fibroblast stimulating factor. Free silica re-engulfed in macrophages. The cycle is repeated  Progressive Fibrosis

Pathology : Silicotic small nodules (2-4 mm),in upper lobe. Later large nodules (1-10cm) silicotic nodule demonstrates concentrically arranged hyalinized collagen fibers surrounding an amorphous acellular center. Examination of the nodules by polarized microscopy reveals weakly birefringent silica particles, primarily in the center of the nodules Fibrotic calcified nodules in hilar lymph nodes → X ray : Egg shell calcification Progressive Massive Fibrosis & Honey comb

Clinical picture : Many patients are asymptomatic. Most patients do not develop shortness of breath until late in the course, after PMF is present. Shortening of breath Silicosis is associated with an increased susceptibility to tuberculosis.  risk lung cancer with crystalline silica.

Silicotic Nodule: concentrically arranged hyalinized collagen fibers surrounding an amorphous acellular center

C-Asbestos induced lesions  Workers in installation & insulation materials, ship builders………  Family members also at risk.  Long latency ( yrs.)  Two forms of asbestos :  Most common: Serpentine ~ ʅ Ϛ  Amphibole : straight & stiff

 Asbestos Bodies (Ferruginous Bodies)  Found in sputum & bronchial wash & lung tissue, composed of : Asbestos fibers + protein + iron ( positive Perl’s stain) May be even in normal !

Asbestos body in macrophage

Ferruginous Asbestos Body

Lesions include : 1- Asbestosis : chronic diffuse interstital fibrosis lower lobe  Honey comb lung & cor pulmonale 2- Pleural effusion 3- Pleural fibrosis 4- Pleural plaques most common & parietal pleura 5- Malignant Mesothelioma 6-  risk lung CA,larynx, stomach & colon

Pleural Plaques

6- Drug & Radiation Induced Pulmonary Diseases Cancer Chemotherapy (Bleomycine) Anti-arrythmic agents (amiodarone) Radiation pneumonitis mainly anticancer: Acute or chronic

Granulomatous Reaction :

1- Sarcoidosis :  in US blacks, Scandinavians and nonsmokers Multisystem disorder Lungs & hilar LNs Skin Eye & lacrimal glands Salivary glands Liver, Spleen, Bone marrow Adults younger than 40 years

Etiology : Disordered immune response Genetic predisposition (HLA-A1 & HLA-B8) Environmental antigen ??? Atypical mycobacteria Pollen Virus

Immune mechanisms :  Type IV hypersensitivity reaction  T lymphocytes subsets abnormalities - Oligoclonal expansion of T cell subsets - Blood :  CD4 /CD8 ( NR ). - Alveolar lavage :  T- cells. -  level IL-8, TNF, MIP-1  locally Polyclonal hypergammaglobulinemia

Pathology : Lesions are noncaseating granulomas with giant cells containing Schaumann & Asteroid bodies (not specific) Lymph nodes 75-90% hilar, 30%peripheral Lung : 90%Interstitium, parabronchioles, paravenules and pleura. 5-15% progress to honey comb lung Spleen, liver, BM : often involved without organ enlargment.

Skin, eyes, lacrimal & salivary glands Occular involvement + Lacrimal Gland= SICCA Syndrome + Parotid involvement = MIKULICZ Syndrome

Sarcoid Granuloma

Schaumann Bodies

NON-Caseating Granulomas are the RULE “Asteroid” bodies within these granulomas are virtually diagnostic

Clinical picture : May be asymptomatic or insidious onset of fever, malaise, cough & dyspnea Majority recover ( ± steroid therapy ) 20% have respiratory dysfunction % progress to interstitial fibrosis Some patients may have additional obstructive symptoms

Diagnosis: By exclusion of all other granulomas Radiological picture : Bilateral hilar lymphadenopathy Ground glass miliary shadows in both lung Hypercalcemia Skin test : KVEIM test

2- Hypersensitivity Pneumonitis : Syndrome caused by a variety of inhaled organic dust or chemicals Inflammatory response in alveoli & terminal bronchioles, accompanied by systemic symptoms Type III & type IV reactions. Presentation depends on duration & intensity of exposure : - Acute - Subacute - Chronic

Hypersensitivity pneumonitis Immunologically mediated disorder affecting airways and interstitium. Farmer’s lung Thermophilic actinomycetes in hay Pigeon breeder’s Air-condition lung Thermophilic bacteria

Phases of Hypersensitivity Pneumonitis : Acute : direct irritant effect  asthmatic attack with dyspnea, fever,…4-8 hr. after exposure Chronic : delayed hypersensitivity reaction. Morphology in chronic cases : Patchy interstitial inflammatory infiltrate in terminal bronchioles & alveolar walls 75% show noncaseating granuloma in alveolar walls in peribronchial t.  FIBROSIS

Extrinsic allergic alveolitis with granuloma

Smoking –Related Interstitial Diseases Desquamative Interstitial Pneumonia(DIP) Interstitial inflammation + macrophages in alveolar spaces Respond to steroids Bronchiolocentric respiratory bronchiolitis with peribrochial fibrosis