Pathology of COPD

Pathology lecture for medical students. Pathologenesis of COPD,

1. “ Within the mind are all the resources required for successful living . Ideas are present in the consciousness, which when released and given scope to grow and take shape, lead to successful events ” - Wings of Fire : An Autobiography of Dr. APJ Abdul Kalam .

2. “ Whether you think you can or you can't, you are right…! ” – Henry Ford

3. CPC14: Mrs. PT . 64y Fem. SOB Mrs. P.T. 64 y female, to ED at TTH. Worsening SOB, years, worst today - At rest Previously SOB after exertion- COPD. Gradually worsening over the years, now O2 at night. Sputum chronic clear white, but light brown today. Cough - on and off for years , No wheeze, no hemoptysis , Chest pain worse with breathing today, fever , sweaty. Smoked 3 packs/day for 35 years ; quit 7y ago. Foreign travel: Norfolk Island 3wks. No health problem. RX: Pneumonia, COPD, Emphysema, CCF

4. CPC: 2011 – 58M Chronic cough. Trevor is 58 year old Caucasian man, years of coughing. pneumonia 3 years ago; bronchitis several times a year, Dyspnoea , Hoover’s & Campbell sign positive, leans forward for breathing. heavy smoker (30+/day); quit 3 years ago. Previous PFT: FEV1 = 1.3 FVC = 2.6 FEV1/FVC = 50% . (too sick to perform PFT today.) What is the significance of… Leaning forward – “arms on knees” Intercostal in-drawing Hoover's sign ? Tracheal tug ? Campbell's sign ? Pathogenesis of symptoms ? Further questions ? Differential diagnosis ? Learning issues ? PFT

5. Clinical Feature - ? Pathogenesis SOB, Dyspnoea Cough Wheezing, Stridor. Rhonchi, Crackles/ Rales . Dullness Hyper-resonance Hyperventilation Tachypnoea Pleural rub Pleurisy ( pleuritis ) Sleep apnoea central/obstructive. White sputum (frothy) Rusty, Yellow, green sputum Haemoptysis Night sweats Sleep apnoea Kussmaul’s breathing. Ataxic breathing Apneustic breathing. Cheyne -Stokes breathing . Paradoxical breathing Resp acidosis / alkalosis.

6. COPD: Questions What is Chronic Bronchitis & Emphysema ? Pathogenesis of COPD/CB/Emphysema ? Smoking – Disease, Pathogenesis ? Difference.. Obstructive / Restrictive disease ? What findings on PFT expected ? How is he maintaining normal pO2 & pCo2 ? why is he pink & puffing ? What Gross & Microscopic features in his lung ? What complications are expected ? Pneumoconiosis, TB, DPF,

7. COPD: Questions Bronchiectasis ? Atelectasis ? Lung abscess ? Honeycomb lung ? Pneumothorax ? Tension pneumothorax? Pleural effusion Emphysema types. Panacinar - α 1AT def. Paraseptal Irregular Bullous compensatory Text Book: Robbins Basic Pathology, 8th or 9th edition Tuberculosis Primary, secondary, anergic , milliary , caseous , fibrocaseous , fibrosing . Asthma – types. Atopic, non-atopic, drugs, occupational etc. Pathogenesis, gross, micro Curschmann spirals, Charcot-Leyden crystals. Pneumoconioses Silicosis, Anthracosis , Asbestosis IPF – Ideopathic pulm . fibrosis.

8. Core Learning Issues: Major: COPD Pathology – Restrictive / Obstructive. Emphysema & Bronchitis – types, pathology & clinical. Pathology of Tobacco related disorders. PFT - FEV1/FVC & its use and interpretation. Pneumonia – types & Pathology (Lobar, Broncho & Int.) Allergic bronchitis, Asthma , Tuberculosis * self study . Minor: Pneumoconiosis – Asbestosis, silicosis etc. Cor pulmonale , Pulmonary hypertension. Diffuse Pulmonary Fibrosis & honeycomb lung. Acute lung injury - ARDS, DAD, HMD of infants. Sarcoidosis ?

9. The cigarette does the smoking,..!

10. Normal Lung Diaphr. CP angle Tr.Air Sh Br. Mar. CP angle Gastric air Colon air

11. Normal Lung Tissue

12. Lung Histology Type 1-Pneumocyte Type 2 Alv . Macro. RBC-Cap Type 2 Bronchiole Alveoli

13. There is only one secret to staying young , being happy , and achieving success - You've got to “ enjoy what you do ”…! Including studying pathology….. 

14. Pathology of COPD, Chronic lung diseases & Pneumonia* Dr. Shashidhar Venkatesh Murthy. A/Prof. & Head of Pathology

15. 0.5 1.0 1.5 2.0 2.5 3.0 Proportion of 1965 Rate 1965 - 1998 1965 - 1998 1965 - 1998 1965 - 1998 1965 - 1998 –59% –64% –35% +163% –7% Coronary Heart Disease Stroke Other CVD COPD All Other Causes Percent Change in Age-Adjusted Death Rates, U.S., 1965-1998 4 th leading cause of death, women more , smoking >80%

16. Pathology of Smoking Research evidence: smoking  disease >4000 chemicals, 43 carcinogens. >90% of COPD is due to smoking. 15% of smokers develop COPD . Injury & inflammation central to damage. Smoking a single cigarette results in an acute increase in neutrophils at 1 hour . Increased neutrophils in smokers, which decrease following reduction/quitting. Patients with COPD have sputum neutrophilia that persists even after cessation of smoking.

17. Smoking effects: FEV 1 & Age

18. Smoking related diseases: Non-neoplastic: Bronchitis, pneumonia, bronchiectasis. Chronic bronchitis, emphysema ( COPD ) Atherosclerosis  IHD, Stroke, MI. Gastritis, Peptic Ulcer, Oesophagitis . Arteriosclerosis – Berger’s disease. Neoplastic: Lung Cancer (many types) Oral, laryngeal & oesophageal cancer. Carcinoma of bladder, Pancreas, cervix, larynx.

19. Ask, Aspire , Achieve..! …..Ask questions J . Robin Warren Australian 2005 Nobel price in Medicine - at RCPA conference 2006 Sydney .

20. Pathogenesis of COPD Dr. Shashidhar Venkatesh Murthy. A/Prof. & Head of Pathology

21. Pathogenesis of COPD Smoke, irritants, carcinogens. Tissue irritation & destruction Inflam  Mucous production. Airway damage  N arrowing. Alveolar damage  widening. Increase in Alveolar marcrophages CD8 Lymphocytes Neutrophils Proteases. Airway inflam  Bronchitis Alveoli damage  Emphysema. Both  COPD . α 1AT def.. Emphysema Bronchitis Emphysema

22. The mind is everything. What you think you become!   -- Buddha

23. Pathogenesis – Chronic Bronchitis 3p K-Ras C-myc p53 Irritation  COPD  Initiation  Promotion  Ca . Pathogenesis: Smoking – carcinogens 3p – tumor suppressor gene loss Mutations ( p53, KRAS, EGFR ..) Dysplasia Infiltration Spread Metastases. Chronic Bronchitis

24. COPD Pathogenesis: Emphysema

25. COPD: Overlap of Clinical syndromes COPD

26. Both affected  COPD (common)

27. Chronic Bronchitis - Emphysema: Predominant Bronchitis Predominant Emphysema Age ( yr ) 40-45 50-75 Dyspnea Mild; late Severe; early Cough Early; copious sputum Late; scanty sputum Infections Common Occasional Respiratory insufficiency Repeated Terminal Cor pulmonale Common Rare; terminal Airway resistance Increased Normal or slightly increased Elastic recoil Normal Low Chest radiograph Prominent vessels; large heart Hyperinflation; small heart Appearance Blue bloater Pink puffer Both affected  COPD (common)

28. “Know more today about the world than yesterday and lessen the suffering of others. You'd be surprised how far that gets you. ” ― Neil deGrasse Tyson

29. Lung Normal & in Smokers:

30. Smokers Lung: COPD - Emphysema Upper lobe – black spots of anthracotic (Co 2 ) pigmentation (centre of each lobule). Centrilobular alveolar destruction with carbon pigmentation. Other types: * Panacinar Paraseptal Bullous Interstitial Irregular. C

31. Normal - Emphysema

32. Normal Emphysema

33. Normal - COPD CB Emphysema

34. Centrilobular Emphysema: Pink Puffer: Lean/weight loss No cyanosis Forward stooping Barrel chest Flat diaphragm Hyperlucent Lung

35. Whether you think that you can or that you can't, you are right…! – Henry Ford

36. Chronic Bronchitis: Squamous Metaplasia. mucous gland. Hyperplasia Normal Chronic Bronchitis

37. Emphysema: Other types Panacinar Congenital, α 1AT def. Paraseptal , Bullous Old scar. Irregular Past diffuse scaring.

38. Complications of COPD: Pneumothorax, Infections, Bronchectasis . Polycythemia – hypoxia. End-stage lung disease . Acute Exacerbations. Cor Pulmonale – Right heart failure. syncope, hypoxia, pedal edema, passive hepatic congestion and death. Lung Cancer RV LV

39. Bronchiectasis: Permanent dilatation & Infection of bronchi. Cough, copious purulent sputum, mixed infections. Lower lobes common Secondary to COPD, Pneumonia or localised obstructions. Complications : Pneumonia, empyema, septicemia, meningitis. Types: Cylindrical, Saccular, Fusiform (no significance)

40. Bronchiectasis: Permanent dilatation with secondary infection Pus* filled, *visible bronchi till *periphery. Abundant, greenish, sputum, mix culture + ve .

41. COPD Summary: Definition : Progressive Irreversible Chronic airflow limitation due to inflammatory response to noxious substances . Progressive decrease in PF. Diagnosis : FEV1<80 %, FEV1/FVC <70% Etiology >90% smoking (15% of smokers COPD) Po llution, 1AT def. , genetic susceptibility, Asthma, idiopathic. Clinical Syndromes: CB, Emphysema , COPD, Asthma , & Bronchiectasis . Complications : Pulmonary failure, RS Cardiac failure, Endstage disease, Cancer.

42. Self Study - Restrictive Lung Disorders. - IPF, Diffuse fibrosis, - Honeycomb lung. - Pneumoconiosis - Silicosis, Asbestosis, Coal. - Tuberculosis. - Asthma - Good pasteur’s syndrome. - DAD: ARDS/HMD

43. Pneumonia : Clinical vignette 50y man, alcoholic, high fever, cough, copious foul smelling brown sputum, pleuritic rt sided chest pain. HPC: wife reports that he was brought home in a semi-conscious state a few days ago – drunk. Thin, distressed, pursed lip breathing, using accessory muscles of respiration, cannot speak in full sentences, leaning forwards…* 39°C, RR-22/min, peripheral cyanosis. Chest-rib in-drawing, diminished air entry, soft expiratory wheezes, bronchial breathing L lower post chest. PE : fever , consolidation right middle and lower lobes . sputum microscopy - abundant PMN and mixed oral flora. Pathogenesis, Differential diagnosis …..?

44. Pneumonia : Questions What is pneumonia ? Types ? pathogenesis ? Lobar, Broncho & Interstial pneumonia ? Community acquired / Nosocomial / hospital acquired pneumonia ? What is the difference ? Acute, Chronic & recurrent pneumonia ? Typical, Atypical pneumonia ? Common organisms causing pneumonia ? Microbiology – lab diagnosis, culture, tests. Gross and microscopy of pneumonia. Phases of pneumonia – Congestion, Red hepatization , Grey hepatization , Resolution ? Complications of pneumonia ? Lipoid pneumonia, Carcinomatous & Aspiration pneumonia ?

45. Goodpasture Synrome : Etiology Clinical Pathogenesis Diagnosis.

46. Diffuse Alveolar Damage (DAD): Etiology Clinical Pathogenesis Diagnosis. Diffuse bilateral consolidation with honeycombing in both lower lobes, focal in upper lobes . Microscopy: Hyaline membrane in ARDS.

47. Saddle Thomboemobulus : Etiology Clinical Pathogenesis Diagnosis.

48. The cigarette does the smoking,..!

49. Clinical Problem Solving - Course Free online course from UCSF https://class.coursera.org/clinprobsolv-001/class/index Future of Education …?

50. Restrictive lung disorders: Definition: Reduced expansion of lung. A. Intrinsic Lung Disorders: Sarcoidosis , diffuse fibrosis , pneumoconiosis . Tuberculosis, Interstitial Pneumonia B. Extrinsic Disorders (chest wall): Scoliosis, Kyphosis, Gross Obesity, Pleurisy, rib fracture etc. C. Neuromuscular Disorders: Paralysis of the diaphragm, Myasthenia Gravis, Poliomyelitis, Generalized Weakness – malnutrition .

51. Restrictive Disorders: Pathogenesis Interstitial inflammation & fibrosis. Lymph+Macrophages.

52. Idio . Pulm . Fibr .(IPF) >50y, ?viral, ?Imm ?Env "dry Velcro like inspiratory crackles. UIP (usual Int. Pneum) / Cryptogenic fibrosing alveolitis. Bilateral, lower and peripheral coarse reticulonodular shadowing and small lungs. CT – Peripheral honeycomb & scarring. Poor prognosis. (~3years )

53. Idiopathic Pulmonary Fibrosis: UIP/IFA Type 2 Pneum

54. Pneumoconioses: Disease due to inhaled dusts inorganic (mineral) or organic Reaction may be inert, fibrous, allergic or neoplastic. Morphologic Types: Inert - coal-worker's pneum. Fibrous - asbestosis, silicosis Allergic - extrinsic allergic alveolitis (Bird Neoplastic - mesothelioma, lung carcinoma.

55. Silicosis: Inorganic – sand & stone dust. Toxic to macrophages – destruction fibrosis. Scattered multiple small,fibrotic Nodules Surrounding Irregular emphysema. Restrictive pattern of PFT.

56. Asbestosis: Asbestos bodies in sputum. (Protein & Hemosiderin) “Inconsumable”, Beaded 5-100mm x 0.25mm. Within alveoli at lung bases. Dyspnoea, dry cough Clubbing is common. Diffuse fibrosis: Honey comb lung: Massive fibrosis: Coal-miners.

57. Coal Miner’s Lung: Athraco-Silicosis: Dense cardon pigmentation – Anthracosis and nodules of silicosis. Commonly seen in coal miners.

58. Sarcoidosis : Granulomatous, immune, multisystem, ??? Etiology. Multiple fine nodules. Like TB (no caseation). Smokers – Uncommon SOB, Erythema nodosum, lymphadenopathy, hypercalcemia, nephrocalcinosis, occular, skin & nerve damage.. Etc. Stage I asymptomatic to Stage IV – Pulm fibrosis.

59. Honeycomb lung: click for online link 

60. Tuberculosis: Mycobacterium tuberculosis (typical) Atypical mycobacteria – HIV Primary & Secondary, Pulm/non-pulm Chronic, Hypersensitivity, debilitating, weight loss. Upperlobe, nodular/cavity/fibrosing. Pleural effusion Caseating Granuloma lymph, marcrophages fibrosis Macrophages - LH giant cells. Systemic spread, miliary spread. Tuberculin Test – hypersensitivity.

61. Restrictive vs Obstructive Interstitial - (stiff lung) Increased tissue Relatively normal FEV1:FVC ratio Normal PEFR . Types: Acute – ARDS,Viral . Chronic - pneumoconioses & sarcoidosis , Int. fibrosis. Obstructive (soft lung) Destruction of tissue. Low FEV1:VC ratio Low PEFR . Types: Localised & Diffuse Reversible & progressive. COPD Asthma Bronchiectasis,

62. Pulmonary Function Testing: FVC - Forced Vital Capacity – Liters - diagnosis of obstructive and restrictive diseases. FEV1 - Forced Expiratory Volume in One Second – obstructive/restrictive diseases. FEV1/FVC - FEV1 Percent (FEV1%) - it indicates what percentage of the total FVC was expelled from the lungs during the first second of forced exhalation. critically important in differentiating obstructive from restrictive diseases. FEV3 - Forced Expiratory Volume in Three Seconds – equal to FVC in normal. FEV3/FVC - FEV3% - normal is 1 or 100% PEFR - Peak Expiratory Flow Rate - this is maximum flow rate achieved by the patient. For monitoring response to treatment. FEF - Forced Expiratory Flow - is a measure of how much air can be expired from the lungs (liters/second or liters/minute). The FVC expiratory curve is divided into quartiles and therefore there is a FEF that exists for each quartile. The quartiles are expressed as FEF25%, FEF50%, and FEF75% of FVC.

63. PFT: interpretation: Check FVC & FEV1 – normal  normal PFT If FVC and/or FEV1 are low - Pathology. Check FEV1/FVC ratio: FEV1/FVC% (<70%) - Obstructive. FEV1 /FEVC% (>80%)- Restrictive. An improvement in FEV1 of 200ml or more after bronchodilator suggests versibility  Asthma.

64. “A person with belief never grovels before anyone, whining and whimpering that it’s all too much, that he lacks support, that he is being treated unfairly. Instead, such a person tackles problems head on and then affirms, I am greater than anything that can happen to me.” - Wings of Fire : An Autobiography of Dr. APJ Abdul Kalam.

65. Asthma: Reversible & intermittent COPD Increased irritability of bronchi causes bronchospasm Paroxysmal attacks Hyper inflated lungs Mucus plugs in bronchi Enlarged bronchial mucous glands

66. Asthma Types: Atopic – Immune, hypersensitivity, IgE . Non-atopic – Non immune - infections Aspirin-induced – Genetic, excess cyclo-oxygenase inhibition. Occupational – Immune, hypersensitivity. Allergic bronchopulmonary aspergillosis : Hypersensitivity to inhalation of spores.

67. Asthma Pathogenetic Types: Extrinsic (Immune) Atopic - IgE Occupational - IgG A. Bronchopulomonary Aspergillosis - IgE Intrinsic (Non immune) Aspirin induced Infections induced Excercise

68. Asthma: Reversible & intermittent obstruction Hyperresponsive airways Increased irritability of bronchi causes bronchospasm Episodic attacks Inflammation Excessive and thick mucus plugs Hyperplasia of mucous glands and smooth muscle, minimal fibrosis

69. Asthma Types: Atopic – Immune, hypersensitivity. Non-atopic – Non immune - infections Aspirin-induced – Genetic hypersensitivity. Exercise induced Occupational – Immune, hypersensitivity. Allergic bronchopulmonary aspergillosis : Hypersensitivity to inhaled aspergillus Ag

70. Asthma Pathogenetic Types: Extrinsic (Immune) Atopic - IgE Occupational - IgG A. Bronchopulomonary Aspergillosis - IgE Intrinsic (Non immune) Aspirin induced Infections induced Excercise

71. INFLAMMATION Airflow Limitation SYMPTOMS Cough Wheeze Dyspnoea TRIGGERS Allergens, Exercise, Cold Air, SO2 Particulates Asthma Pathogenesis: Airway Hyper-responsiveness Genetic* INDUCERS Allergens,Chemical sensitisers, Air pollutants, Virus infections Hygiene hypothesis?

72. Asthma : Pathogenesis Early phase (immediate) and late phase reactions

73. Asthma Pathology: Barnes PJ Allergen Mucus hypersecretion Hyperplasia Vasodilatation New vessels Plasma leak Oedema Bronchoconstriction Hypertrophy/hyperplasia Cholinergic reflex Subepithelial fibrosis Sensory nerve activation Eosinophil Mast cell Th2 cell Neutrophil Macrophage/ dendritic cell Mucus plug Epithelial shedding Nerve activation Leukotrienes C4, D4 & E4 Leukotrienes Ach Histamine Prostaglandin D Platelet activating factor Interleukins

74. Asthma Morphology: Bronchial obstruction with overinflation Small areas of atelectasis (collapse) may be seen Inflammation & thickening of mucosa. Bronchial wall smooth muscle hypertrophy Thickening of bronchial basement membrane. Mucus plugging of bronchi Curschmann spirals: whorls of shed epithelium within mucus plugs Charcot-Leyden crystals: Within aggregates of eosinophils – crystalloids of galectin-10

75. Asthma Morphology: Asthma Microscopy Mucous Plugs +eosinophils Goblet cell hyperplasia Inflammation + Eosinophils Smooth muscle hyperplasia Mucous gl. Hyperplasia.

76. Asthma – Lung Gross features: Inflamed thick bronchi obstructed by mucous plugs.

77. Asthma : Microscopy Inflammed bronchi Obstruction by mucous plug Alveoli (normal)

78. Asthma : Microscopy Dilated BV Inflammatory cells Cartilage Mucous plug over the surface.

79. Asthma : Microscopy

80. Hyperinflation Status Asthmaticus:

81. Status Asthmaticus : Mucous plug

82. Status Asthmaticus : Mucous plug

83. Curschmann spirals:

84. Charcot-Leyden Crystals:

85. “ Whether you think you can or you can't, you are right …!” – Henry Ford

86. Lung volumes

87. Total Lung Capacity (TLC) - the total volume of the lung, the volume of air contained in the lung at the end of maximal inspiration Inspiratory Reserve Volume (IRV) - volume, which can be inspired beyond a restful inspiration Tidal Volume (TV) – volume of a single breath, usually at rest Functional Residual Capacity (FRC) - The amount of air left in the lungs after a tidal breath out, the amount of air that stays in the lungs during normal breathing Vital Capacity (VC) – maximum volume which can be ventilated in a single breath Inspiratory Capacity (IC) - the maximal volume that can be inspired following a normal expiration Expiratory Reserve Volume (ERV) – volume, which can be expired beyond a restful expiration Residual Volume (RV) – volume remaining in the lungs after a maximum expiration

88. Volumes Forced Vital Capacity (FVC) - the volume of air that can forcibly be blown out after full inspiration, measured in litres Forced Expiratory Volume in 1 Second (FEV1) - the maximum volume of air that can forcibly blow out in the first second during the FVC manoeuvre, measured in liters FEV1/FVC (FEV1%) - in healthy adults this should be approximately 75–80 %. Obstructive diseases (asthma, COPD) FEV1 is ↓ & FVC n/ ↑ so FEV1/FVC is decreased (<80%, often ~45%). In restrictive diseases (Lung fibrosis/silicosis) FEV1 and FVC are both reduced proportionally and the FEV1/FVC value may be normal or even increased as a result of decreased lung compliance

89. Obstructive lung diseases airway obstruction restricted expiration  FEV1,  FEV1/FVC  compliance, elasticity Chronic bronchitis Bronchiolitis Asthma Emphysema Bronchiectasia Cystic fibrosis N ormal Asthma COPD

90. Flow volume curves

91. Condition Major changes Causes Symptoms Chronic Hyperplasia Tobacco smoking Productive bronchitis and hypersecretion and air pollutants cough of mucus glands Bronchiectasis Dilation and scarring Persistent severe Cough, purulent of airways infections sputum and fever Asthma Smooth muscle Immunologic Episodic wheezing hyperplasia or idiopathic cough and dyspnea Excessive mucus Inflammation Emphysema Airspace enlargement Tobacco smoking Dyspnea Genetic and wall destruction

92. Bronchogenic Carcinoma:

93. Asthma pathogenesis:

94. Pathophysiology of Cor - Pulmonale :

95. 2013 feedback Did not go well - reorganize talk. No Asthma, restrictive disorders & pneumonia – next week. Check quiz – remove unwanted. Next year combine pneumonia + COPD.