Respiratory Pathology: Part II Restrictive Lung Disease PDF

Respiratory Pathology: Part II Restrictive Lung Disease Dr Sarah Knight Marvar Department of Pharmacology & Physiology Office: Med-Dent NE412 Email: [email protected] 1 Learning Outcomes Discuss differences between restrictive and obstructive lung disease Describe the pathogenesis and symptoms o...

Respiratory Pathology: Part II Restrictive Lung Disease Dr Sarah Knight Marvar Department of Pharmacology & Physiology Office: Med-Dent NE412 Email: [email protected] 1 Learning Outcomes Discuss differences between restrictive and obstructive lung disease Describe the pathogenesis and symptoms of idiopathic pulmonary fibrosis (IPF) Discuss the symptoms and pathogenesis of ARDS Describe the symptoms and pathogenesis of Sarcoidosis Understand the symptoms, pathogenesis and if possible treatments for lung diseases of vascular origin, such as embolism, edema & pulmonary hypertension Dynamic Lung Volumes Restrictive diseases result from a change in the elasticity of the lungs, chest wall disease & respiratory muscle weakness 3 Restrictive Lung Disease Reduced distensibility of the lungs Restrictions in lung expansion as a result of pleural, parenchymal or chest wall abnormalities Reduced compliance of lung tissue preventing inflation Reduced Total Lung Capacity (TLC) with a normal FEV1/FVC ratio (80%) Hypoxemia and V/Q mismatch Less common than obstructive lung disorders which account for 80% of lung disease Restrictive Lung Diseases 1. Chronic interstitial and infiltrative diseases – Intrinsic (pulmonary parenchyma) Chronic inflammation -> pulmonary fibrosis - Excessive fibrous connective tissue (scarring) in the lungs - Leads to stiffening of lung and decreased lung compliance Causes - Toxin exposure: airway irritants, drugs, radiation, etc. - Systemic disease Often accompanied by decreased diffusion capacity 2. Chest wall disorders – Extrinsic (extrapulmonary) - Neuromuscular - Guillain-Barre, myasthenia gravis, polio, muscular dystrophy - Non-muscular - Chest wall deformity, obesity, pain Pectus Excavatum Idiopathic Pulmonary Fibrosis (IPF) Rare, progressive disease associated with development of stiff non-compliant lung tissue with thickening and fibrosis of parenchyma with unknown origin Progressive and irreversible decline in lung function Symptoms include shortness of breath & nonproductive cough Smoking, GERD, viral infections and family history can increase risk of developing disease AKA: Usual Interstitial Pneumonia or cryptogenic fibrosing alveolitis (Europe) https://en.wikipedia.org/wiki/Idiopathic_pulmonary_fibrosis#/media/File:Ipf_NIH.jpg Idiopathic Pulmonary Fibrosis Within lungs overproduction and deposition of collagen = fibrosis in pulmonary interstitium Aberrant would healing of alveolar epithelial cells Destruction of alveolar architecture and the formation of cystic spaces lined by hyperplastic type II pneumocytes or epithelium Honeycomb fibrosis – fibrosis surrounding open cystic space Presence of both early stage and late stage lesions Healthy lung – top Lung with fibrocystic foci - bottom Idiopathic Pulmonary Fibrosis: Causes Environmental Exposure Smoking Air pollution Inhaling fumes, wood dust, farming Genetics Mutations in the TERT, TERC, PARN, and RTEL1 genes, involved in Telomere shortening (end of chromosomes) causing cell senescence Mutations resulting in type II pneumocytes becoming more sensitive to insult https://www.wired.com/story/john-deere-self-driving-tractor-stirs-debate-ai-farming/ Idiopathic Pulmonary Fibrosis Symptoms Progressive dyspnea Progress to hypoxia -> cyanosis, digital clubbing, cardiac complications Diagnosis Normal FEV1/FVC, reduced TLC in pulmonary function tests. Typical for restrictive disease Imaging showing interstitial markings & honeycombing Small volume lungs with bilateral increased interstitial markings Treatment Anti-inflammatory agents if caught early enough Lung transplant Tyrosine kinase inhibitor and a TGF-β antagonist slow progression Supportive care (vaccination, oxygen, pulmonary rehab) https://radiopaedia.org/cases/pulmonary-fibrosis-uip-pattern-1?lang=us Causes of Restrictive Disease: Exposure Exposure to toxic irritants, drugs causes chronic lung inflammation Genetic susceptibility, not everyone develops disease on exposure Type of particles, length of exposure, smoking/comorbidities important Coal miner’s pneumoconiosis Pneumoconiosis – lung reaction to inhalation of various caustic materials - Coal - mining with inhalation of other substances, “black lung” - 10% of patients develop fibrosis, most mild - Silica (silicosis) - ore processing, construction work, lung cancer risk - Asbestos (asbestosis) - farm workers, exposure in households, also linked to lung cancer Hypersensitivity Pneumonitis: Allergic Alveolitis Allergic inflammatory hypersensitivity response to a number of organic agents including dusts, grains, animal feces, molds, avian antigen etc. Farmer’s lung: molds/dust from coffee beans, tea plants, grapes, cheese, potatoes etc Pigeon breeders Diagnosis: History of exposure to substance ( > 10 yrs) Occupational history important Dyspnea, cough, fatigue, weight loss or asymptomatic Pulmonary Function Tests & imaging Treatment: Avoidance of exposure Disease generally not progressive if exposure is stopped Supportive care, corticosteroids https://www.netdoctor.co.uk/conditions/allergy-and-asthma/a6110/pet-allergies/ Systemic Disorders Disorders with pulmonary involvement: Sarcoidosis Connective tissue disease Vasculitis Rheumatoid arthritis Lupus Scleroderma Goodpasture syndrome Treatments usually targeted for specific disease Sarcoidosis Multi-system disease of unknown etiology Some genetic predisposition Characterized by noncaseating epithelioid cell granulomas in multiple organs, but morbidity and mortality are closely related to pulmonary manifestations present in 90% of patients Granulomas are small benign pockets of inflammation Occurs in patients under 40 yrs old, more prevalent in women & those of African descent. Impacts lungs, lymph nodes, bone marrow, skin & eyes Sarcoidosis Pathogenesis Immunological response to an unknown antigen Intra-alveolar and interstitial accumulation of CD4+ T cells Increased Th1 cytokines (IL-2 & Interferon –g) activating macrophages Increased cytokines IL-8, TNF & macrophage inflammatory protein 1a contributing to granulomas Impaired dendritic cell function Antigen response to PPD Sarcoidosis Patients have diverse symptoms On x-ray bilateral hilar adenopathy Unpredictable course, progressive or marked by periods of activity interspersed with remissions, Overall, 65% to 70% of patients recover with minimal or no residual manifestations. Progresses to Cor Pulmonale or progressive pulmonary fibrosis https://pmj.bmj.com/content/96/1132/113 Bronchus with characteristic noncaseating sarcoidal granulomas (asterisks) Acute Lung Injury (ALI) & Acute Respiratory Distress Syndrome (ARDS) Acute respiratory failure from acute lung injury and inflammation — Diffuse alveolar damage - injury of alveolar capillary membrane — Results in increased alveolar capillary permeability which leads to non-cardiogenic (not caused by heart failure) edema Edema: protein and fluid leak into alveoli — — — Prevents normal gas exchange -> hypoxemia Decreases compliance (acute restrictive lung disease) – fluid increases surface tension — Damage to type II pneumocytes – surfactant deficiency Increases pulmonary artery pressure – due to hypoxic vasoconstriction ARDS Pathogenesis ALI/ARDS is initiated by injury of pneumocytes and pulmonary endothelium & vicious cycle of increasing inflammation and pulmonary damage 1. Endothelial activation: by circulating cytokines or nearby macrophages secreting TNF 2. Adhesion and extravasation of neutrophils: Neutrophils adhere to the activated endothelium and migrate into interstitium & degranulate releasing proteases, reactive oxygen species, and cytokines 3. Accumulation of intra-alveolar fluid and formation of hyaline membranes: capillaries leaky, allowing interstitial and intra-alveolar edema fluid to form. Protein-rich edema fluid and debris from dead alveolar epithelial cells organize into hyaline membranes Acute Respiratory Distress (ARDS) ARDS Hyaline membranes Stages Exudative Diffuse alveolar damage (DAD) Edema, hyaline membrane (glassy) made from necrotic cell debris, protein Proliferative – edema resolves, cellular proliferation and collagen deposition Fibrotic – fibrotic changes and loss of lung architecture, variable Resolution – surviving patients regain lung function, weeks to months with possible lung impairment William Checkley Eur Respir J 2013;41:259-261 ©2013 by European Respiratory Society ARDS: Causes Most Common causes Sepsis - Systemic inflammatory response Aspiration pneumonia – aspiration of gastric content into lungs Pneumonia Multi-organ trauma (lung contusion) Burns Near drowning Inhalation of toxic irritants, smoke Drugs/alcohol overdose Pancreatitis Multiple blood transfusion, transfusion-related acute lung injury Emboli Chest X-ray of ARDS Patient https://www.aafp.org/afp/2012/0215/p352.html ARDS: Presentation https://pantherna-therapeutics.com/science-technology/ Profound dyspnea and tachypnea, followed by increasing respiratory failure, hypoxemia, cyanosis, and diffuse bilateral infiltrates on X-ray Hypoxemia may be refractory to oxygen therapy Lungs are heavy, firm, red, and boggy ARDS: Treatment Not easy Treat underlying cause if possible Support Sedation, fluid monitoring, prevention of deep vein thrombosis (DVT) Mechanical ventilation Complications common: Ventilator associated lung injury (VALI), hospital acquired infection Mortality: ~40% even with treatment Depends on cause, severity and co-morbidities Many patients die from primary illness, multi-organ failure, shock etc. rather than respiratory failure Improved outcomes: protective ventilation and fluid management https://www.fiercehealthcare.com/hospitals/white-house-left-states-their-own-to-buy-ventilators-inside-their-mad-scramble Ventilator Induced Lung Injury (VALI) Increases pressure (and O2) High tidal volumes - lung injury is exacerbated – release of proteases & immune cell cytokine release Low tidal volumes - limit further lung endothelial and epithelial injury Pulmonary Diseases of Vascular Origin Pulmonary Embolism (PE) Pulmonary hypertension (PH) Cor pulmonale Pulmonary edema - fluid in alveoli Cardiogenic – caused by elevation of capillary hydrostatic pressure from left heart dysfunction Non-cardiogenic – normal cardiac function, usually from lung injury and increased capillary permeability Pulmonary Edema Excessive fluid in alveoli Cardiogenic pulmonary edema - Caused by hemodynamic disturbances Increased hydrostatic pressure (blood pressure) Left-sided heart failure Pulmonary vein obstruction Non-cardiogenic pulmonary edema - increased capillary permeability by microvascular injury = Liquid aspiration Infection Trauma Pulmonary Edema Left heart dysfunction Valvular dysfunction Reduction in left ventricular contractility Dilated cardiomyopathy Fluid overload Renal failure http://www.columbia.edu/itc/hs/medical/pathophys/cardiology/2007/WR2.pdf Pulmonary Edema: Clinical Features Cardiogenic Non-Cardiogenic Symptoms: Dyspnea, tachypnea, hypoxemia, cough (with fluid) Exam: crackles and other abnormal sounds Similar presentation between different ideologies, history should focus on primary insult Treatment Different treatment for cardiogenic vs noncardiogenic edema Possibly helpful tests: ECG, X-ray X-ray showing pulmonary edema Chest x-ray - Enlarged cardiac size Definitive: Pulmonary artery catheterization https://en.wikipedia.org/wiki/Pulmonary_edema Pulmonary Hypertension Classified as mean pulmonary artery pressure greater than or equal to 25 mm Hg (normal is between 8-20mmHg) Pulmonary Hypertension: Pathophysiology Chronic stress on pulmonary vasculature Imbalance between vasodilation and vasoconstriction Hypertrophy of smooth muscle in pulmonary arteries Luminal narrowing and increased pressure Remodeling of arteries with fibrotic tissue Secondary right heart hypertrophy/dysfunction WHO classified Pulmonary Hypertension into 5 groups 1. Pulmonary arterial hypertension (PAH) Congenital heart defect, idiopathic, drugs, HIV 2. Pulmonary hypertension due to left heart failure mitral valve or aortic valve disease, left ventricle failure 3. Pulmonary hypertension due to lung diseases and/or hypoxia COPD, sleep apnea, pulmonary fibrosis 4. Chronic thromboembolic pulmonary hypertension and other obstructions pulmonary emboli, clotting disorders 5. Pulmonary hypertension with unclear and/or multifactorial mechanisms blood disorders, lung disorders, kidney disease, tumors Group 1: Pulmonary Artery Hypertension PH is progressive with eventual irreversible changes (vascular remodeling) Smooth muscle hypertrophy Fibrosis of intimal tissue Plexiform lesions – small capillary channels near arteries PAH as histological model Histologically defined as “onion skinning” Seen in severe PH Alice Huertas et al. Circulation. 2014;129:1332-1340 Group 2: Left Heart Dysfunction Most common form Increase in pressure in pulmonary vasculature needed to maintain forward driving force against dysfunctional left heart Reactive variant in chronic left heart disease explains increase in pulmonary vascular resistance Elevated pulmonary capillary wedge pressure Group 3: Lung Disease Lung disease/chronic hypoxemia Short term hypoxia leads to vasoconstriction to limit blood flow to poorly oxygenated lung (reversible) Chronic hypoxia: - Decreases endothelial nitric oxide synthase, NO is a vasodilator - Increase in arachidonic acid pathways and endothelin release - Increases smooth muscle calcium concentration COPD with Pulmonary Hypertension = poor prognosis - PH more common with chronic bronchitis - Late emphysema can lead to PH via alveolar/vascular bed destruction, hyperinflation and increased intra-alveolar pressure Group 4: Chronic Thromboembolic Pulmonary Hypertension Pulmonary vasculature occluded by clots Reduced vascular surface area increases vascular resistance Occurs after multiple recurring pulmonary embolisms If acute embolism, probably won’t develop Pulmonary Hypertension High pressure in remaining vasculature results in Pulmonary Hypertension Timescale: months - years https://err.ersjournals.com/content/26/143/160112 Pulmonary Hypertension: Symptoms Presentation Peripheral edema, heart murmurs Fatigue, chest pain, dyspnea, tachypnea, cough May be masked by primary disease Diagnosis Right heart catheterization to measure elevated pulmonary artery pressure Other findings: ECG indicates right ventricular hypertrophy, enlarged right heart border and pulmonary vasculature on x-ray, echo Pulmonary Hypertension: Treatment Treatment based on grouping classification Control of causative disorder Diuretics, anti-hypertensives for heart failure Anti-coagulants and endarterectomy for chronic thrombi PH directed therapy - limited Endothelin blockers, NO agonists, prostacyclin analogs COPD with Pulmonary Hypertension Long-term oxygen therapy shown most useful to stop PH progression and improve mortality rates Not all patients respond, especially if long term remodeling www.nejm.org/doi/full/10.1056/nejmra040291 Cor Pulmonale (Pulmonary Heart Disease) Right ventricular dysfunction (dilation, hypertrophy) due to Pulmonary Hypertension caused by lung disease (or disease of lung vasculature) Excludes left heart dysfunction, cardiac anomalies etc. Most common cause is COPD ~50% of Cor Pulmonale cases from COPD Cor pulmonale more likely in patients with more severe airway obstruction, disease progression Chronic back up of fluid/pressure into the right side of the heart, increased work of right ventricle Treatment: treat pulmonary hypertension, cardiovascular support Pulmonary Embolism (PE) Occlusion of pulmonary vasculature by embolism from origin outside of lung Most common is thrombus from deep venous thrombosis (blood clot in the deep veins - DVT) of lower limbs Can be blood (thrombus), fat, air, bone Acutely occurring or chronic (small PEs over time) Risk factors for DVT (hence PE) are known as Virchow’s Triad: 1. Venous stasis (prolonged immobility) 2. Hypercoagulation (cancer, pregnancy, estrogen contraceptives, congenital thrombophilia, systemic diseases (lupus, autoimmune), smoking) 3. Vascular endothelial injury (surgery, IV line, medication) https://www.venousforum.org/patients/what-is-vein-disease/what-is-pulmonary-embolism/ Pulmonary Embolism: Pathogenesis V/Q mismatch – dead space, hypoxemia Impaired gas exchange Embolus induces inflammatory response that furthers vasoconstriction and diminishes surfactant secretion leading to atelectasis (alveolar collapse) Increased pulmonary vascular resistance Reduced cardiac output, hypotension Pulmonary hypertension Right heart dysfunction, especially with severe vascular obstruction http://www.pathophys.org/vte/ Pulmonary Embolism: Symptoms Symptoms Dyspnea (acute onset), pleuritic chest pain, tachypnea, tachycardia, anxiety, can also present in shock or sudden death History of risk factors, presence of symptomatic DVT (swollen, erythematous, tender calf) but not always identifiable May be asymptomatic Saddle embolism Diagnosis Uniform ventilation patchy perfusion Chest x-ray (non-specific), ECG, elevated D-dimer (sign of clot degradation, only helpful if negative) Best test: CT-PA or pulmonary angiography, V/Q scan Treatment Anti-coagulation therapy (acute and out-patient) Thrombolytic therapy – severe PE Prevention of risk factors Inferior vena cava filter, embolism removal Anti-Coagulation Therapy International normalized ratio Tested thrombin time International sensitivity index PT (prothrombin time) measure blood clotting time when extrinsic clotting cascade is activated INR range of 2.5 for PE treatment Warfarin – possible adverse effects, bleeding risk, need for monitoring, many drug interactions etc. https://en.wikipedia.org/wiki/D-dimer 42 Pulmonary Embolism – Key Concepts Almost all large pulmonary artery thrombi are embolic in origin, usually arising from the deep veins of the lower leg. Risk factors include prolonged bed rest, leg surgery, severe trauma, congestive heart failure, use of oral contraceptives (especially those with high estrogen content), disseminated cancer, and inherited forms of hypercoagulability. The vast majority (60% to 80%) of emboli are clinically silent, a minority (5%) cause acute cor pulmonale, shock, or death (typically from large “saddle emboli”), and the remainder cause symptoms related to ventilation-perfusion mismatch and/or pulmonary infarction, particularly dyspnea and pleuritic chest pain. Risk of recurrence is high, and recurrent embolism may eventually lead to pulmonary hypertension and cor pulmonale.