Lung pathology BY:Dr Banchi Dhaba(MD,Pathologist 8/29/2024 1 Outline • Atelectasis • ACUTE RESPIRATORY DISTRESS SYNDROME • Obstructive Versus Restrictive Pulmonary Diseases • Pulmonary Diseases of Vascular Origin • Pulmonary Infections • Lung Tumors • Pleural Lesions 8/29/2024 2 ATELECTASIS (COLLAPSE) Resorption /Obstructive /Atelectasis Compression Atelectasis Contraction atelectasis (or cicatrization atelectasis) 8/29/2024 3 • Atelectasis, also known as collapse, is loss of lung volume caused by inadequate expansion of air spaces • Resulting in reduced or absent gas exchange 8/29/2024 4 • Resorption /Obstructive /Atelectasis: • This is the most common type and occurs when something blocks the airway, such as: • Mucus: Thick mucus can clog the airways, especially in people with respiratory illnesses like chronic obstructive pulmonary disease (COPD). • Tumor: A tumor in the airway can obstruct airflow. • Foreign object: Inhaling a small object, like a toy or food particle, can block the airway 8/29/2024 5 • Compression Atelectasis: • This happens when pressure on the lungs prevents them from expanding, su • Fluid: Pleural effusion (Commonly caused by heart failure ) • Air: Pneumothorax • Tumor: A tumor in the chest can put pressure on the lung. 8/29/2024 6 • Contraction atelectasis (or cicatrization atelectasis) • Occurs when the lung tissue itself can't expand properly • Scarring: Lung scarring (fibrosis) from conditions like pneumonia or tuberculosis can restrict lung expansion. • Surfactant deficiency: Surfactant is a substance that helps the alveoli stay open. A lack of surfactant can lead to atelectasis, especially in premature infants. 8/29/2024 7 ACUTE RESPIRATORY DISTRESS SYNDROME 8/29/2024 8 ACUTE RESPIRATORY DISTRESS SYNDROME Acute and rapidly progressive hypoxia with bilateral pulmonary edema due to alveolar injury caused by pulmonary or systemic insults • Respiratory failure occurring within 1 week of a known clinical insult with bilateral opacities on chest imaging • Severe ARDS is characterized by rapid onset of life threatening respiratory insufficiency, cyanosis, and severe arterial hypoxemia that is refractory to oxygen therapy • The histologic manifestation of ARDS in the lungs is known as diffuse alveolar damage (DAD). 8/29/2024 9 Causes: • Infection: Pneumonia, sepsis, and viral infections (like COVID-19) are common causes. • Trauma: Severe injuries, like those from a car accident or a fall, can cause ARDS. • Aspiration: Inhaling stomach contents or other foreign substances into the lungs. • Blood transfusions: Rarely, ARDS can occur as a reaction to blood transfusions. • Pancreatitis: Inflammation of the pancreas can lead to ARDS. • Drug overdose: Certain drug overdoses can cause ARDS. 8/29/2024 10 Pathophysiology/DAD/ • Exudative (acute) phase: 1 - 7 days • Neutrophil mediated inflammation destroys the alveolar capillary barrier (alveolar epithelium and endothelium), increases its permeability and causes intra-alveolar hemorrhage and edema • Protein rich edema interacts with alveolar surfactants, resulting in decreased pulmonary compliance • Hyaline membranes develop on alveolar wall where epithelium is denudated and disrupted • Proliferative / organizing (subacute) phase: 1 - 3 weeks • Proliferation of type II pneumocytes and subsequent differentiation into type I pneumocytes • Proliferation of myofibroblasts • Drainage of alveolar edema by restored type II pneumocytes • Fibrotic (chronic) phase: after 3 weeks • Collagenous fibrosis in alveolar spaces and interstitium • Refractory rigidity of alveoli due to architectural remodeling 8/29/2024 11 8/29/2024 12 Pathophysiology of acute lung injury and the acute respiratory distress syndrome • The normal alveolus (left) • The injured alveolus in the early phase of acute lung injury and the acute respiratory distress syndrome. • Under the influence of proinflammatory cytokines such as interleukins IL-8 and IL-1 and tumor necrosis factor (TNF) (released by macrophages), neutrophils are sequestered in the pulmonary microvasculature and then egress into the alveolar space, where they undergo activation. • Activated neutrophils release leukotrienes, oxidants, proteases, and plateletactivating factor (PAF), which contribute to local tissue damage, accumulation of edema fluid, surfactant inactivation, and hyaline membrane formation. • Subsequently, the release of macrophage-derived fibrogenic cytokines such as transforming growth factor-β (TGF-β) and platelet-derived growth factor (PGDF) stimulate fibroblast growth and collagen deposition associated with the healing phase of injury. 8/29/2024 13 • Dyspnea and tachypnea , followed by cyanosis, hypoxemia, and respiratory failure refractory to oxygen therapy. • Arterial blood gas test • Hypoxemia • Ratio of pulse oximetry oxygen saturation to FIO2 (SpO2 / FiO2) may be helpful for instant follow up • Chest x-ray films reveal diffuse bilateral infiltrates. 8/29/2024 14 Diagnosis • Diagnosis of ARDS is based on clinical manifestation and its severity is evaluated with ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2 / FiO2) 8/29/2024 15 Therapy • involves mechanical ventilation and treatment of the underlying • cause (e.g., infection) • The overall mortality rate is 40%, primarily secondary to sepsis or multi-organ failure. 8/29/2024 16 OBSTRUCTIVE VERSUS RESTRICTIVE PULMONARY DISEASES Obstructive lung disease Chronic obstructive lung disease Asthma Bronchiectasis Restrictive lung disease Poor breathing mechanics Interstitial lung disease 8/29/2024 17 Overview • Diffuse pulmonary diseases can be classified into two categories: 1. obstructive (airway) disease: characterized by an increase in resistance to air flow caused by partial or complete obstruction at any level 2. Restrictive disease :characterized by reduced expansion of lung parenchyma and decreased total lung capacity 8/29/2024 18 OBSTRUCTIVE LUNG (AIRWAY) DISEASES • Key points: Air trapping, slow flow out, less air out • Reduced FEV1 (slow flow out) • Reduced FEV1/FVC (hallmark) • FEV1/FVC is the ratio of FEV1 to FVC. In healthy adults this should be approximately 70–80% (declining with age) 8/29/2024 19 Residual & Total Lung Volume Both go up in obstructive disease • From air trapping Both fall in restrictive disease • Less air fills the lungs due to restriction 8/29/2024 20 Obstructive Pulmonary Disease • Emphysema • Chronic bronchitis • Asthma • Bronchiectasis 8/29/2024 21 Emphysema • Permanent enlargement/diltation/ of the air spaces distal to the terminal bronchioles, accompanied by destruction of their walls without significant fibrosis. 8/29/2024 22 The four major types of emphysema: anatomic distribution within the lobule 1. Centriacinar 2. Panacinar 3. Distal acinar 4. Irregular 8/29/2024 23 Centriacinar Emphesema • Affect the central or proximal parts of the acini, formed by respiratory bronchioles,distal part spared • More common and severe in the upper lobes apical segment • Most common in cigarette smokers • Often associated with chronic bronchitis 8/29/2024 24 Panacinar emphysema • The acini are uniformly enlarged,from the level of the respiratory bronchiole to the terminal alveoli/entire acini/ • Lower lobe predominant • Associated with α1-anti-trypsin deficiency. 8/29/2024 25 Distal acinar (paraseptal) emphysema • The proximal portion of the acinus is normal but the distal part is primarily Involved along the lobular connective tiissue septa • Typically near the pleura and adjacent to fibrosis or scars • More severe in the uper half of the lung • Cause of this type of emphysema is unknown • Most often seen in young adults who present with spontaneous pneumothorax. 8/29/2024 26 Irregular emphysema • Irregular emphysema, so named because the acinus is irregularly involved • Is almost invariably associated with scarring, such as that resulting from healed inflammatory diseases. • Although clinically asymptomatic, this may be the most common form of emphysema. 8/29/2024 27 Major patterns of emphysema. (A) Diagram of normal structure of the acinus, the fundamental unit of the lung. (B) Centriacinar emphysema with dilation that initially affects the respiratory bronchioles. (C) Panacinar emphysema with initial distention of all the peripheral structures (i.e., the alveolus and alveolar duct); the disease later extends to affect the respiratory bronchioles. 8/29/2024 28 Etiology • Inhalation • Cigarette smoking and environmental pollutants, especially for centriacinar emphysema • However, there is individual susceptibility/genetic predisposition/ • Infections • Genetic factors • Alpha-1 antitrypsin deficiency is well known risk factor, especially for panacinar emphysema) 8/29/2024 29 Pathophysiology • Destruction of lung parenchymal tissue due to chronic inflammation and imbalance of ant protease and protease enzymes • Protease mediated destruction of elastin is an important feature • Morphological progression • Increase in size and number of small fenestrae in alveolar walls (pores of Kohn), which leads to loss of elastic recoil • Breakdown and merging of fibrovascular trabeculae (framework) • Remodeling of acini results in airspace enlargement 8/29/2024 30 8/29/2024 31 Clinical Features • Dyspnea usually is the first symptom; it begins insidiously • Cough/less sputum than chronic bronchitis • Wheezing • Hyperventilation • Weight loss • Barrel chest • Pulmonary function tests reveal reduced FEV1 with normal or nearnormal FVC. • The FEV1 toFVC ratio is reduced.<0.7 8/29/2024 32 Pink Puffer • Loss of alveoli • Loss of surface area for O2 absorption (dead space) • Hyperventilation to compensate (puffer)/expiration done through pursed lips/ • Initially this maintains O2 level (pink) 8/29/2024 33 Radiology description • XRay: overinflation of the lung but it may not be seen in early stages • Chest CT: emphysematous regions are represented by low attenuation areas 8/29/2024 34 Gross and Microscopic Features • Hyperinflation or ballooning due to entrapment of the air from airway obstruction • Lungs may be overlapping the heart • Upper lobes are more involved • Large alveoli. • Thin septa (no interstitial thickening). • Bullous emphysema: descriptive term regarding emphysematous lung with visible bullae upon gross examination • Bulla: an air filled space of 1 cm in diameter within the lung which has developed because of emphysematous destruction of the lung parenchyma 8/29/2024 35 8/29/2024 36 Moderately progressed centriacinar emphysema. Photograph of an inflated and fixed lung demonstrating that the surrounding lung parenchyma is compressed with enlargement of the dilated air spaces, producing a clear border of the emphysematous space (arrows). 8/29/2024 37 Chronic Bronchitis • Diagnosed on clinical grounds Chronic cough Productive of sputum At least 3 months over two consecutive years No other cause of cough present • Strongly associated with smoking 8/29/2024 38 Pathogenesis 8/29/2024 39 • Hypertrophy of mucous secreting glands • Reid Index • Thickness of glands/total wall /normal - <0.4 • >50% in chronic bronchitis • Lungs can plug with mucous “mucous plugging” • Increased risk of infection 8/29/2024 40 Physiologic consequences • Poor ventilation of lungs • Increased CO2 • Decreased O2 • Hypoxic vasoconstriction • Pulmonary hypertension • Right heart failure (cor pulmonale 8/29/2024 41 Clinical Feature • Cough • Wheezing • Crackles • Dyspnea • Cyanosis (shunting )/Blue/ • Blue Bloater /(carbon dioxide retainers)/ • Air trapping (bloated) 8/29/2024 42 Microscopic (histologic) description • Early: hypersecretion of mucus in large airways with hypertrophy of submucosal glands in tracheobronchial tree • Later: increase in goblet cells in small airways contributes to excessive mucus production and airway obstruction • Increased percentage of bronchial wall is occupied by submucosal mucous glands, as measured by Reid index; this directly correlates with sputum production, variable dysplasia, squamous metaplasia, bronchiolitis obliterans • Chronic inflammatory infiltrates range from absent to prominent 8/29/2024 43 CHRONIC OBSTRUCTIVE PULMONARY DISEASE WHO definition • Common preventable, an treatable disease • Characterized by persistent pulmonary symptoms and airflow limitation • Due to airway and/or alveolar abnormalities • Caused by exposure to noxious particles or gases • 4th leading cause of death in the world 8/29/2024 44 Cont…. Underlying pulmonary pathology usually include • Chronic bronchitis and emphysema • Most common in long-standing tobacco smokers (typically >40 packyears); air pollutants also contribute • Often fatal due to development of heart failure or of respiratory failure due to superimposed infection. 8/29/2024 45 Predominant Features of Emphysema and Chronic Bronchitis 8/29/2024 46 8/29/2024 47 Asthma • Hetrogenous disease with Chronic inflammatory disorder of the airways • Reversible bronchoconstriction • Usually due to allergic stimulus • Type I hypersensitivity reaction • Airways are HYPERresponsive • Common in children • Associated with other allergic (atopic) conditions • Rhinitis, eczema • May have family history of allergic reactions 8/29/2024 48 Type of Asthma • Atopic or Extrinsic Asthma • Non atopic • Occupational • Drug induced 8/29/2024 49 Atopic or Extrinsic Asthma • Type I hypersensitivity, generally due to allergens • Begins in childhood • triggered by environmental allergens (dander, dust, pollen, food) • Often has positive family history • More common in African American children 8/29/2024 50 Nonatopic or Intrinsic Asthma • Nonimmune • Due to pneumonia, cold, stress, exercise; follows respiratory infection (rhinovirus, parainfluenza virus) • Not familial • No evidence of allergen sensitization • Normal serum IgE • Viral induced inflammation may lower threshold of subepithelial vagal receptors to irritants 8/29/2024 51 Occupational asthma • Due to repeated exposure to fumes, dusts, gases, chemicals 8/29/2024 52 Drug induced asthma: • Patients are sensitive to small doses of aspirin • Due to direct effects of aspirin on cyclooxygenase pathway 8/29/2024 53 Common asthma triggers include: • URI/ Viral infection/: Colds and flu • Allergens: Pollen, dust mites, pet dander, mold, cockroaches, and certain foods • Irritants: Smoke, fumes, strong odors, air pollution, cold air, and dry air • Exercise: Physical activity can trigger asthma in some people • Stress: Emotional stress can sometimes worsen asthma symptoms • Medications: aspirin 8/29/2024 54 Asthma Symptoms • Episodic symptoms • Dyspnea, wheezing, cough • Hypoxia during episodes • Mucous plugging (airway obstruction/shunt) • Death: Status asthmatics 8/29/2024 55 Pathogenesis • Atopic asthma most often is caused by a TH2 and IgE-mediated immunologic reaction to environmental allergens • Characterized by early-phase (immediate) and late-phase reactions. • The TH2 cytokines IL-4, IL-5, and IL-13 are important mediators. 8/29/2024 56 Pathogenesis 8/29/2024 57 Inhaled allergens (antigen) elicit a TH2-dominated response favoring IgE production and eosinophil recruitment 8/29/2024 58 8/29/2024 59 Asthma Pathology • Classic sputum findings • Curschmann’s spirals /thick, tenacious mucous plugs containing whorls of shed epithelium/ • Charcot-Leyden crystals /crystalloids made up of the eosinophil protein galectin-10/ 8/29/2024 60 • Mic: may show airway remodeling in patient with longstanding asthma • Hypertrophy/hyperplasia of submucosal glands • Hypertrophy/hyperplasia of bronchial smooth muscle • Thickening o basement membrane 8/29/2024 61 Bronchiectasis • Bronchiectasis means a permanent dilatation of one or more bronchi. • Caused by destruction of smooth muscle and elastic tissue • Result of chronic, recurrent airway inflammation • There are 2 main subdivisions 1. Obstructive due to tumour, foreign body or enlarged lymph nodes 2. Post-infective due to repeated respiratory infection, e.g. Cystic Fibrosis or immunodeficiency syndromes 8/29/2024 62 Etiology • Idiopathic /50%/ • Congenital • Cystic fibrosis: most common cause in children • Primary ciliary dyskinesia and other mucociliary disorders • Infection/severe necrotizing / • Autoimmune • Other causes • Chronic obstructive pulmonary disease / smoking • Aspiration • Extremes of age • Immune dysfunction: HIV • Foreign body / obstruction (i.e., tumor) • Malnutrition 8/29/2024 63 Pathophysiology • Obstruction (i.e., due to tumor, foreign body, inspissated mucus) • Causes resorption of air distal to the obstruction • Causes atelectasis and accumulation of intraluminal secretions • Nonobstructive bronchiectasis (i.e., due to pneumonia and atelectasis) • Increased negative intrapleural pressure creates a force on bronchial walls, leading to dilation • Infectious bronchiectasis • Enhanced cellular and mediator responses lead to destruction of tissue • Biopsies have shown infiltration by neutrophils and T lymphocytes • Chemoattractants have been detected 8/29/2024 64 8/29/2024 65 Clinical features • Cough and chronic sputum production • Sputum is typically mucoid to mucopurulent, thick • Can be bloody due to erosive airway damage • Dyspnea and wheezing • Pleuritic chest pain 8/29/2024 66 Morphological Subtypes • cylindrical bronchiectasis • bronchi have a uniform caliber, do not taper and have parallel walls (tram track sign and signet ring sign) • commonest form 14 • varicose bronchiectasis • relatively uncommon • beaded appearances where dilated bronchi have interspersed sites of relative narrowing • cystic bronchiectasis • severe form with cyst-like bronchi that extend to the pleural surface • air-fluid levels are commonly present 8/29/2024 67 Diagnosis • Physical exam • Abnormal breath sounds: crackles, wheezing, rhonchi • Digital clubbing • CT(most accurate modality for diagnosis) scan to differentiate between bronchiectasis and COPD (can overlap) • Radiology description • Tram track opacities • Air fluid levels 8/29/2024 68 CHRONIC INTERSTITIAL (RESTRICTIVE, INFILTRATIVE) LUNG DISEASES 8/29/2024 69 Overview • Key points: Can’t get air in --- less air out • Reduced FEV1 • Reduced FVC (less air in/out) • Normal (>80%) FEV1/FVC(hallmark) 8/29/2024 70 Causes of Restrictive lung diseases • Extrinsic /Poor Breathing Mechanics/ • Not a primary pulmonary issue • Under-ventilation of lungs • Neuromuscular • ALS, Polio, myasthenia gravis • Structural • Scoliosis,kymphosis • Morbid obesity • Intrinsic/Interstitial lung diseases/ 8/29/2024 71 Interstitial lung diseases • Chronic interstitial diseases are a heterogeneous group of disorders by bilateral, often patchy, pulmonary fibrosis mainly affecting the walls of the alveoli. • The hallmark of these disorders is reduced compliance (stiff lungs). • Chest radiographs show small nodules, irregular lines, or “groundglass shadows.” • When advanced all the group result in diffuse scarring and gross destruction of the lung, referred to as end-stage or “honeycomb” lung. 8/29/2024 72 8/29/2024 73 Idiopathic Pulmonary Fibrosis • Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, fibrosing interstitial lung disease (ILD) of unknown cause, associated with histologic and radiological features of usual interstitial pneumonia (UIP) • One of the most common interstitial lung diseases and the most lethal entity • Characterized by bibasilar patchy fibrosis and honeycomb change • Usual interstitial pneumonia (UIP) is the name of morphological pattern in histology and radiology 8/29/2024 74 • Commonly affect In patients older than 50 years old • Male predominance • Several potential risk factors: • Genetic factors, including several mutations • Cigarette smoking • Gastroesophageal reflux 8/29/2024 75 Pneumoconiosis Occupational lung diseases • Coal miner’s lung • Silicosis • Asbestosis 8/29/2024 76 Coal miner’s lung/Anthracosis/ • Inhalation of coal dust particles • Carbon particles are relatively inert and usually don't elicit reactive fibrosis • When extensive, may cause coal workers' pneumoconiosis • CXR or Chest CT: • Small, rounded, nodular opacities • Preference for the upper lobes 8/29/2024 77 Silicosis • Most prevalent chronic occupational disease in the world, due to foundry work, sandblasting, stone cutting and coal mining • Decades of exposure usually required for symptoms • Causes a progressive, nodular fibrosing pneumoconiosis • 8/29/2024 78 • Macrophages react to silica • Inflammation----- fibroblasts……. collagen • High prevalence of TB • Impaired macrophage killing • Affects upper lobe • Eggshell calcifications of lymph nodes 8/29/2024 79 Asbestosis • Inhalation of asbestos fibers • Shipbuilding, roofing,plumbing • Classically affects lower lobes • Three clinical problems: • Interstitial lung disease (asbestosis) • Pleural plaques • Lung cancer 8/29/2024 80 • CXR: Calcified pleural plaquespathognomonic • Path: Asbestos bodies (ferruginousbody) • Asbestos fibers surrounded by a coating of iron and protein 8/29/2024 81 8/29/2024 82 DISEASES OF VASCULAR ORIGIN Pulmonary Embolism and Infarction Pulmonary Hypertension Diffuse Pulmonary Hemorrhage Syndromesn 8/29/2024 83 Pulmonary Embolism and Infarction • Pulmonary embolus (PE) is a blockage of the pulmonary artery or one of its branches due to material (solid, gaseous or liquid) that has traveled through the circulation from elsewhere in the body • Usually are Blood clots/thrombus/ • Most emboli originate in the deep veins of the lower extremities (iliac, femoral and popliteal) • Travels to lung via IVC RA RV • Rarely formed in heart or pulmonary vasculature • Third most common acute cardiovascular condition worldwide, trailing only myocardial infarction and stroke 8/29/2024 84 • Risk factors can be divided into genetic versus acquired • Genetic factors include hypercoagulable conditions, such as factor V Leiden mutation, protein C and S deficiency, prothrombin mutations, antiphospholipid syndrome, etc. • Acquired risk factors include : pregnancy, hospitalization, obesity, oral contraceptive use, malignancy, long bone fracture, stroke, indwelling central venous lines, acute spinal cord injury and patients who have had joint arthroplasty or repair 8/29/2024 85 Pathogenesis • Pathogenesis of pulmonary embolism is similar to that of thrombus formation (i.e., Virchow's triad) • Virchow's triad includes • venous stasis • endothelial damage • hypercoagulability 8/29/2024 86 • Size of the embolus determines the pulmonary vessel (PV) tributary that is occluded. • (1) Large emboli occlude the proximal portion of the pulmonary artery and are frequently called a saddle embolus • (2) Small emboli occlude medium-sized and small pulmonary arteries (PAs). Saddle embolus of the pulmonary artery 8/29/2024 87 • Potential consequences of PA occlusion include: • (1) increase in PA pressure. • (2) decrease in blood flow to the pulmonary parenchyma with the potential for developing a hemorrhagic infarction • Approximately 8% to 10% of patients die within the first hour. • Pulmonary infarction is a red-blue, raised, wedge-shaped area that usually extends to the pleural surface 8/29/2024 88 Clinical findings • If the patient has a saddle embolus, the sudden increase in PA pressure produces acute right ventricular (RV) strain and sudden death. • Pulmonary infarction results in: • (1) sudden onset of dyspnea (difficulty with breathing) and tachypnea (rapid breathing); fever. • (2) pleuritic chest pain (pain on inspiration), friction rub, and percussion signs of an effusion. • (3)Expiratory wheezing caused by release of thromboxane A2 (bronchoconstrictor) from platelets in the thromboembolus. 8/29/2024 89 Chest radiographic features of pulmonary thromboembolism and infarction 8/29/2024 90 Fat Embolism • Often occurs after a long bone facture • Fat may cross lungs--------small artery infarctions • Fat embolism syndrome:pulmonary,neuro, skin 8/29/2024 91 Fat Embolism • Lung • Dyspnea, hypoxemia • Diffuse capillary leak (ARDS) • Often requires mechanical ventilation • Neurological • Usually confusion • May develop focal deficits • Petechiae 8/29/2024 92 Amniotic Fluid Embolism • During labor or shortly after delivery • Amniotic fluid, fetal cells,fetal debris enter maternal circulation • Inflammatory reaction • Often fatal 8/29/2024 93 Amniotic Fluid Embolism • Phase I • Pulmonary artery vasospasm ----- pulmonary hypertension • Right heart failure • Hypoxia • Myocardial capillary damage ------ left heart failure • Pulmonary capillary damage --------ARDS /Acute respiratory distress syndrome/ • Key features: respiratory distress, ↓O2, hypotension 8/29/2024 94 Amniotic Fluid Embolism • Phase II (hemorrhagic phase) • Massive hemorrhage • DIC • Key feature: bleeding • Seizures also often occur 8/29/2024 95 Pulmonary arterial hypertension (PAH) • AHigh pressure in the pulmonary circuit (mean arterial pressure > 25 mm Hg; normal is 10 mm Hg) • Characterized by atherosclerosis of the pulmonary trunk, smooth muscle hypertrophy of pulmonary arteries, and intimal fibrosis; plexiform lesions are seen with severe, long-standing disease. • Leads to right ventricular hypertrophy with eventual cor pulmonale • Presents with exertional dyspnea or right-sided heart failure • Subclassified as primary or secondary based on etiology 8/29/2024 96 Primary PAH • Etiology is unknown • Generally occurs in younger patients (20–40 years old) • Some familial forms are related to inactivating mutations of BA1PR2, leading to vascular hyper reactivity with proliferation of vascular smooth muscle. 8/29/2024 97 Secondary PAH • Hypoxemia and respiratory acidosis stimulate vasoconstriction (VC) of PAs; causes SMC hyperplasia and hypertrophy • Causes include Chronic hypoxemia. Examples: chronic lung disease, living at high altitude Chronic respiratory acidosis. Examples: chronic bronchitis (CB), OSA Loss of pulmonary vasculature, which increases the workload for remaining vessels. Examples: emphysema, recurrent pulmonary emboli Left-to-right cardiac shunts, which produces volume overloading of the pulmonary vasculature. Examples: ventricular septal defect (VSD), atrial septal defect (ASD), PDA. Left-sided valvular disease in which there is a backup of blood into the pulmonary veins, causing pulmonary venous hypertension (PVH). Example: mitral valve stenosis 8/29/2024 98 Diffuse Pulmonary Hemorrhage Syndromes Goodpasture syndrome • Antibodies are directed against basement membrane (BM) in pulmonary capillaries and glomerular capillaries • Type II hypersensitivity reaction [HSR]) • Pulmonary hemorrhage with hemoptysis often precedes renal failure 8/29/2024 99 PULMONARY INFECTIONS Pneumonia Lung Abscess Pneumocystis pneumonia Tuberculosis 8/29/2024 100 Pneumonia /infection of the lung / • Acute Inflammation of the pulmonary parenchyma that is usually caused by bacterial ,virus or fungal infection. • May involve the alveoli and/or interstitial in one or both lungs. • Pneumonia may be acquired in the community or within a hospital or health care facility (sometimes called nosocomial). • Classically divided by gross and mic morphology into • Bronchopneumonia, • Lobar pneumonia • Interstitial/atypical/ pneumonia 8/29/2024 101 Lobar pneumonia • Classic form of pneumonia (S.pneumoniae) • Bacteria acquired in nasopharynx • Aerosolized to alveolus • Enter alveolar type II cells • Pneumococci multiply in alveolus • Invade alveolar epithelium • Pass from one alveolus to next(pores of kohn) • Inflammation/consolidation of lobes • Can involve entire lung 8/29/2024 102 Pathophysiology • Bacteria can reach the lungs in several ways • Airborne droplet spread • Microaspiration of pathogens that have colonized the oropharynx is a common mechanism in bronchopneumonia • Spread to the lungs via the pulmonary or systemic blood supply 8/29/2024 103 4 Stages of bacterial pneumonia • #1: Congestion (1st 24hours) • Alveolar capillaries dilate • Exudate of bacteria develops • #2: Red hepatization (2-3days) • Exudate of RBCs, neutrophils, fibrin • “Fresh" exudate: RBCs/WBCs intact • Pneumococci alive • Lobes look red 8/29/2024 104 • #3: Gray hepatization (4-6days) • Gray, firm lobe • Exudate with neutrophils/fibrin • RBCs disintegrate • Dying pneumococci • #4: Resolution • Return to normal (little scarring) • Enzymes digests exudate • Type II pneumocyte key for regeneration 8/29/2024 105 Stages of bacterial pneumonia . (A) Acute pneumonia. The congested septal capillaries and numerous intra-alveolar neutrophils are characteristic of early red hepatization. Fibrin nets have not yet formed. (B) Early organization of intra-alveolar exudate, seen focally to be streaming through the pores of Kohn (arrow). (C) Advanced organizing pneumonia. The exudates have been converted to fibromyxoid masses rich in macrophages and fibroblasts. 8/29/2024 106 Bronchopneumonia • Type of pneumonia that begins as an acute bronchitis with subsequent extension of the infection into surrounding alveoli • Lower lobes or right middle lobe are most often involved. • Lung has patchy areas of consolidation (firm, dense mass involving the alveoli. • Staphylococcus aureus • Microabscesses containing neutrophils phagocytosing bacteria are present in the areas of consolidation 8/29/2024 107 8/29/2024 108 8/29/2024 109 Atypical pneumonia /Interstitial type pneumonia / • Type of pneumonia in which inflammatory cells are present in the interstitium or alveolar wall rather than the alveoli • Most indolent course • Most commonly caused by Mycoplasma pneumoniae • Other pathogens include: Chlamydophila pneumonia • Viruses such as respiratory syncytial virus (RSV), influenzavirus, and adenovirus • Chlamydia trachomatis is the most common cause in newborns 8/29/2024 110 8/29/2024 111 Causes of pneumonia 8/29/2024 112 Causes of pneumonia Adults • S. pneumoniae – most common • Haemophilus influenzae • Mycoplasma pneumoniae • C. pneumoniae • Legionella • Gram-negative rods • Klebsiella, E. Coli, Pseudomonas Uncommon unless severe PNA Often isolated in hospitalized patients • S. Aureus (postinfluenzapneumonia) • Anaerobes (aspiration PNA; lungabscess) • Viruses • Influenza • RSV (children) 8/29/2024 113 Signs/Symptoms • High Fever • Cough • Sputum production • Elevated WBC • Pleuritic chest pain 8/29/2024 114 Diagnosis • Usually: • History • Physical exam • X-ray (sometimes CT scan) • Rarely • Sputum culture • Bronchoalveolar lavage 8/29/2024 115 1) Community-acquired pneumonia • Lung infection in otherwise healthy individuals acquired from normal environment(in contrast to hospital acquired pneumonia) • May be bacterial or viral • Streptococcus pneumoniae is the most common bacteria causing community acquired pneumonia followed by H.Influenza,S.Aureas • Sometimes Mycoplasma,Chlamydia,legionella 8/29/2024 116 2) Nosocomial Pneumonia 1. Hospital acquired pneumonia (HAP) • Pneumonia not incubating at the time of hospital admission and occurring > 48 hours after admission • They are common in patients with severe underlying disease, immunosuppression, prolonged antibiotic therapy • Gram-positive cocci (mainly S. aureus) and gram-negative rods (Enterobacteriaceae and Pseudomonas species) are the most common isolates 2. Ventilator associated pneumonia (VAP) Pneumonia occurring > 48 hours after endotracheal intubation 8/29/2024 117 3) Aspiration Pneumonia • Aspiration of microorganisms • Microorganisms from oral cavity and nasopharynx to lungs • Risk factors: • Reduced consciousness/stroke/ • Seizures • Alcoholics • Classic patients: • Debilitated patient • Alcoholic 8/29/2024 118 • The resultant pneumonia is partly chemical due to the irritating effects of gastric acid and partly bacterial (from the oral flora) • Typically, more than one organism is recovered on culture, aerobes/klebsiella, S.Areus being more common than anaerobes. • This type of pneumonia is often necrotizing, pursues a fulminant clinical course, and is a frequent cause of death • Classically results in a right lower lobe abscess • Anatomically* the right main stem bronchus branches at a less acute angle than the left. 8/29/2024 119 Complications of Pneumonia • Sepsis • Respiratory failure • Lung abscesses • Pleural effusion • ARDS 8/29/2024 120 Lung Abscess • The term pulmonary abscess describes a local suppurative process that produces necrosis of lung tissue and contained,fluid filled space in lungs • Air fluid level on imaging • Abscesses vary in diameter from a few millimeters to large cavities of 5 to 6 cm . • They may affect any part of the lung and may be single or multiple. • Predominantly anaerobes ( Peptostreptococcus , Prevotella ,Bacteroides ,Fusobacterium ) • Sometimes S. Aureus,Klebsiella 8/29/2024 121 Cut surface of lung showing two abscesses 8/29/2024 122 Pneumocystis pneumonia (PCP) • Serious infection caused by the fungus Pneumocystis jirovecii in immunocompromised patients • Diffuse interstitial pneumonia • Requires immunocompromise • Classically HIV • AIDS-defining illness • Yeast -- inhaled • Usually no symptoms if immune system intact 8/29/2024 123 • Diagnosed by microscopy • Sputum sample or BAL • Staining required--------- cannot be cultured • Special stains used • Silver stains often used 8/29/2024 124 Tuberculosis • Infectious disease caused by Mycobacterium tuberculosis • Disease can be manifested as primary, secondary and miliary tuberculosis • Patients with active TB who release mycobacterium in sputum via person to person transmission of airborne organisms. • –Unpasteurized milk which contains M.BOVIS 8/29/2024 125 Mycobacterium tuberculosis • Obligate aerobes • Prefer lungs • Reactivation disease prefers upper lobes • Facultative intracellular pathogens • Infect macrophages 8/29/2024 126 Culture of TB • Difficult to culture • Special media used • Lowenstein-Jensen agar • Slow growing /1 -8 weeks/ • Does not stain well with Gramstain • This is due to mycolic acids in cellwall • Also fatty acids and complex lipids 8/29/2024 127 Acid Fast • Cell walls impermeable to many dyes • Stain with very concentrated dyes plus heat • Lipid soluble; contain phenols • Once stained, plate rinsed with acid decolorizer • “Acid fast stain” • TB resists decolorization with acid solvents 8/29/2024 128 Spread of TB • Spreads through the air • Active TB patient’s cough, sneeze, etc. • Inhaled by uninfected person • Can spread rapidly in crowded areas 8/29/2024 129 Exposure to TB • Most patients will not develop active disease • Infection can clear or remain “latent” • Small proportion patients develop active disease 8/29/2024 130 8/29/2024 131 Primary TB Clinical Picture • Mainly a disease of childhood or chemo patients • Ineffective immune response • Gradual onset: weeks • Fever • Cough • Pleuritic chest pain • Fatigue, arthralgias 8/29/2024 132 Primary TB Pathophysiology • First week • TB infects macrophages • Phagocytosed • Intracellular bacterial proliferation • Two to four weeks • Cell-mediated immune system controls TB • TH1 response • Activation of CD4+ T cells • Interferon-γ secreted • Activated macrophages and cytotoxic T lymphocytes 8/29/2024 133 Granulomas • Granulomatous inflammation • Caseating necrosis /gross appearance/ • Macrophages transform to: • Epithelioid cells • Langhans giant cells • Fibroblasts activated -----collagen • T-cell mediated delayed type hypersensitivity reaction • Type IV hypersensitivity reaction 8/29/2024 134 Hilar Lymphadenopathy • CXR often normal • Classic finding is hilar lymphadenopathy • Occur as early as 1 week after infection • Resolve slowly over months to years 8/29/2024 135 Ghon Foci • Ghon fociform • Granulomas • Subpleural • Mid to lower lungs • Ghon foci plus lymph node is Ghon complex • Calcified Ghon complex is a Ranke complex 8/29/2024 136 Primary TB Resolution • Most (90%) patients control infection • Disease heals leaving fibrosis • Sometimes completely clears • Usually enters latent phase (“walled off”) • Immunity develops • PPD positive • Rare (10%) patients have expanded illness • Miliary dissemination • More common with HIV, CKD, DM (impaired immunity) 8/29/2024 137 Miliary TB • Hematogenous spread ofTB • Progressive primary infectionor reactivation • Nearly any organ system can be involved • Bones • Liver • CNS (meningitis) • Heart (pericarditis) • Skin • Pott’s disease • Spine infection (osteomyelitis) • Back pain, fever, night sweats, weight loss • Constrictive pericarditis 8/29/2024 138 Innumerable tiny nodules in both lungs 8/29/2024 139 Reactivation TB • Reactivation of dormant TB • Cough, weight loss,fatigue • Fever • Night sweats • Chest pain • Often cavitation (caseous and liquefactive necrosis) • Hemoptysis (erode pulmonary vasculature) • CXR classically shows upper lobelesions 8/29/2024 140 Reactivation TB • Can occur when immune compromised • HIV infection • TNF-α inhibitors • Used in autoimmune diseases • Etanercept, Infliximab • Diabetes 8/29/2024 141 Aspergilloma • Fungus ball • Caused by Aspergillus fumigatus • Grows in pre-formed cavities • Pulmonary TB is most common association • Often asymptomatic • Can cause hemoptysis • Diagnosis: Imaging plus sputum culture 8/29/2024 142 Diagnosis of Active TB • Usual method: 3 sputum samples • Usually about 8hrs apart • Spontaneous or induced Acid-fast smear and culture 8/29/2024 143 Diagnosis of Latent TB • Identification of latent TB crucial to infection control • Diagnosis: Tuberculin skin testing(TST) • SC injection purified protein derivative(PPD) • 5 tuberculin units (0.1 mL) • Wait 48 hours • Measure diameter of induration (not erythema) • + >15mm are taken as positive 8/29/2024 144 BCG Vaccine • Bacille Calmette-Guérin • Live strain of Mycobacterium bovis • More effective in patients with no TB exposure • About 80% effective in children • Less effective in adults • Used in children in areas with high prevalence of TB • Creates false positive PPD 8/29/2024 145 Lung Cancer Small cell leng ca Non Small cell ca – Squamous cell carcinoma Adenocarcinoma Large cell carcinoma 8/29/2024 146 Risk Factors • Cigarette/tobacco/ smoking • Radiation Therapy • Hodgkin's and breast cancer survivors • Environmental toxins • Asbestos • Radon 8/29/2024 147 Symptoms • Usually advanced at presentation • Cough, dyspnea, rarely hemoptysis • Usually leads to chest imaging 8/29/2024 148 Diagnosis • Pulmonary nodule • “Coin lesion” • Compare with prior • Biopsy for definitive diagnosis 8/29/2024 149 Lung Cancer classification • Small cell lung ca (15%) • Fast growing; Early metastasis • Non amenable to surgical resection • Smokers • Treated with chemotherapy • Poor prognosis • Non-small cell lung ca (Most Common:85%) • Can sometimes be resected • Better prognosis • Smokers and non-smokers 8/29/2024 150 Small Cell Cancer • Poorly differentiated small cells • Classic in male smokers • Neuroendocrine tumor • Central tumor • Paraneoplastic Syndromes • ACTH • • • Cushing syndrome Progressive obesity Hyperglycemia • ADH • SIADH • Hyponatremia (confusion) • Antibodies • • • • 8/29/2024 Antibodies against pre-synaptic Ca channels in neurons Block release of acetylcholine Lambert-Eaton syndrome Main symptom is weakness 151 Non-Small Cell Cancers • Squamous Cell Carcinoma • Adenocarcinoma • Large cell carcinoma • Carcinoid tumor 8/29/2024 152 Squamous Cell Carcinoma • Hilar mass arising from bronchus • Key pathology features • Keratin production (“pearls”) by tumor cells • Intercellular desmosomes ("intercellular bridges") • Male smokers • Can produce PTHrP • Hypercalcemia central 8/29/2024 153 Adenocarcinoma • Glandular tumor • Most common lung cancer:nonsmokers/females • Peripheral location 8/29/2024 154 Large cell carcinoma • Poorly differentiated • Lacks glandular or squamous differentiation • Lacks small cells • Smokers cancer • Central or peripheral • Poor prognosis 8/29/2024 155 Carcinoid tumor • Neuroendocrine • Well-differentiated cells • Chromogranin positive • Non-smokers • Rarely causes carcinoid syndrome • Secretion of serotonin • Flushing, diarrhea 8/29/2024 156 Complications • Pleural effusions • Tap fluid, send for cytology • Phrenic nerve compression • Diaphragm paralysis • Dyspnea • laryngeal nerve compression • Hoarseness • Superior vena cava syndrome 8/29/2024 157 Metastasis from Lung Cancer • Adrenals • Usually found on imaging without symptoms • Brain • Headache, neuro deficits, seizures • Bone • Pathologic fractures • Liver • Hepatomegaly, jaundice 8/29/2024 158 Metastasis to Lung • More common than primary lung tumors • Most commonly from breast or colon cancer • Usually multiple lesions on imaging 8/29/2024 159 Pleural Disease Pneumothorax Pleural effusion Mesothelioma 8/29/2024 160 What are the pleura? • Two layers of tissue surrounding lungs • Visceral pleura – attached to lung • Parietal pleura – attached to chest wall • Pleural space/cavity – between layers • Pleural lined by mesothelial cells • Secrete small amount pleural fluid for lubrication 8/29/2024 161 Pneumothorax • Air in pleural space • Two types to know about • Spontaneous • Tension 8/29/2024 162 Spontaneous PTX • Primary • Rupture of subpleural bleb • Common in tall, thin young males • Secondary • Older patients with underlying pulmonary disease • COPD 8/29/2024 163 Spontaneous PTX • Sudden onset dyspnea • Sometimes pleuritic chest pain • CXR for diagnosis 8/29/2024 164 Tension PTX • Usually from trauma • Air enters pleural space but cannot leave • Medical emergency • Emergent thoracentesis/chest tube placement • Trachea deviates AWAY from affected side 8/29/2024 165 Pleural Effusion • Accumulation of fluid in pleural space • Three general etiologies • Transudative • Exudative • Lymphatic 8/29/2024 166 Transudative Effusion • Something driving fluid into pleural space • Most commonly due to CHF (High pressure) • Other causes: • Nephrotic syndrome (low protein) • Cirrhosis (low albumin) • Mostly fluid in effusion • Very little protein in effusion • Usually treat for underlying cause (no drainage) 8/29/2024 167 Exudative Effusion • Fluid leaking into pleural space • High vascular permeability • Many causes • Malignancy • Pneumonia • More protein in pleural fluid vs.transudative • Usually requires drainage 8/29/2024 168 Transudate vs. Exudate • Thoracentesis to obtain fluid sample • Test for protein, LDH • Light’s Criteria – Exudate if: • Pleural protein/serum protein greater than 0.5 • Pleural LDH/serum LDH greater than 0.6 • Pleural LDH greater than 2/3 upper limits normal LDH 8/29/2024 169 Lymphatic Effusions “Chylothorax” • Lymphatic fluid effusion • From thoracic duct obstruction/injury • Malignancy most common cause • Trauma (usually surgical) • Milky-appearing fluid • Very high triglycerides • TG usually > 110 mg/dL 8/29/2024 170 Other Effusions • Hemothorax • Hct in fluid • Empyema • Infected pleural fluid • Pus, putrid odor, positive culture • Malignant effusion • Positive cytology 8/29/2024 171 Mesothelioma • Pleural tumor • Asbestos is only known risk factor • Decades after exposure • Imaging: Pleural thickening and pleural effusion • Slow onset symptoms (dyspnea, cough, chest pain) • Poor prognosis 8/29/2024 172 8/29/2024 173
