Quiz Yourself - Respiratory

Quiz Yourself - Respiratory

The FEV1 is reduced when:
airway obstruction is present as with these diseases: Asthma Emphysema FEV1/FVC ratio is reduced when airway obstruction is present. The normal ratio is: 70-75 The FVC is reduced with restrictive lung disease Pulmonary fibrosis

If there is a scooped part of expiration, there is a noted obstruction (ex – emphysema)
If there is fibrosis, there is fine expiration

Lung Volumes in Disease States
TLC is largely about lung elasticity Obese patients have a decreased FRC and increased RV because of the increased chest wall pressures (due to all that extra weight) What does each of these represent?

What is the alveolar gas equation?
PAO2 = FIO2 x (PB – PH2O) – PaCO2/RQ What is the standard version (room air/temp)? PAO2 = 150 – PaCO2/RQ RQ = 0.8 – 1.0

What are the 2 ways to alter V/Q ratio?
Dead space Regions of the lung that are ventilated but not perfused Anatomic? Normal. Like the trachea. About 30% of tidal volume. Physiologic? Includes anatomic, but in theory, when there are unperfused regions, as with a pulmonary embolism Shunt Regions of the lung that are perfused but not ventilated! V/Q mismatch = incomplete shunt. Responsive to O2 therapy Shunt is refractory to O2 therapy Key pt: regions with a high V/Q ratio cannot compensate for regions with a low V/Q ratio b/c the high V/Q is normal!

What are the causes of hypoxemia and how do we distinguish them?
We distinguish between them using blood gas and A-a gradient Hypoventilation indicated by hypoxemia with a high pCO2, normal A-a. Increasing frequency of breathing while lowering tidal volume increased the proportion of dead space ventilation to alveolar ventilation V/Q mismatch Shunt indicated by hypoxemia with a HUGE A-a difference Common causes include intracardiac lesions, structural abnormalities of the pulmonary vasculature, filling of alveolar spaces w/ fluid or complete alveolar collapse Low inspired O2 (Low altitude)

What is the diffusing capacity?
Measured by DLCO Impacted by diffusion barrier and aggregate surface area of alveoli Measured with CO (but possible errors if the hemoglobin levels are low) What does emphysema do? reduces the area  reduced DLCO What does fibrosis do? increases the thickness  reduced DLCO

What are the volume patterns for the following diseases?
Obstructive diseases? larger TLCs Chronic bronchitis? increased RV, increased FRC Emphysema? increased RV, VERY increased TLC Restrictive diseases? smaller TLCs Fibrosis? all lung volumes decreased Obesity? FRC reduced Inspiratory muscle weakness? TLC reduced Expiratory muscle weakness? RV is elevated

Mechanisms of Hypoxemia
Hypoventilation V/Q Mismatch Shunt Low Inspired pO2 How do we measure lung volumes? Helium dilution Used to measure absolute FRC Doesn’t work if there’s lots of obstructed airways where a Plethysmography The small sealed box Makes measurements using Boyle’s law - We can distinguish between these w/ equations of blood gases, A-A gradient/difference

What patterns of impairment are associated with:
Obstructive lung disease? Diminished rates of expiratory flow (increased FEV1, decreased FEV1/FVC) Restrictive lung disease? Diminished lung volumes Preserved expiratory flow What gives a characteristic scooped appearance in the expiratory phase of flow-volume loops? Airway obstruction like emphysema When is obstruction increased during inspiration? When it’s an extra-thoracic variable obstruction When is obstruction increased during expiration? When it’s an intra-thoracic variable obstruction

What’s this? Normal Alveoli!

Muco-Purulent Debris in Dilated Bronchi
- Empty bronchi Bronchiectasis

Bronchiectasis What is it? Pre-disposing syndromes? Radiology?
A chronic dilation of bronchi or bronchioles secondary to inflammation or obstruction Pre-disposing syndromes? Cystic fibrosis (CF) Primary ciliary dyskinesia syndrome (Kartagener’s s.) Radiology? Airway dilation which extends to the periphery Pathology? Permanent dilation of bronchi peri-bronchial inflammation and organization (fibrosis) Can sometimes see mucopurulent debris in bronchioles According to Steadman’s - Bronchiectasis: chronic dilation of bronchi or bronchioles as a sequel of inflammatory disease or obstruction. - organization: fibrosis tissue

Curschmann Spirals – mucus casts
Eosinophil What disease is this? Charcot-Leyden crystals – eosinophil granule contents Circle highlighting an eosinophil This is ASTHMA!!!! Asthma Curschmann Spirals – mucus casts

Asthma Clinical: Radiology: Pathology: Airway hyperresponsiveness
Triggers: antigens, exercise, drugs, infections, stress Acute, usually reversible diffuse bronchial narrowing Sxs: Wheezing, dyspnea Radiology: Alternating atelectasis and overexpansion Pathology: Edema smooth muscle thickening BM thickening mucous cell hyperplasia increased submucosal eosinophils thickened intralumenal mucus Curschmann spirals – mucus casts Charcot-Leyden crystals – eosinophil granule contents According to Steadmans: an inflammatory disease of the lungs characterized by reversible (in most cases) airway obstruction. Originally, a term used to mean “difficult breathing”; now used to denote bronchial asthma. Lots of different triggers Infxns like aspergillius  asthma Unlike bronchiestasis, asthma is acute and reversible! d

Increased numbers of mucinous glands in submucosa
Chronic Bronchitis Increased numbers of mucinous glands in submucosa A Clinical Diagnosis! Definitional: Productive cough > 3months/year x > 2 years Radiology is non-specific Pathology: Mucous cellular and glandular hyperplasia May have submucosal chronic inflammation May have respiratory bronchiolitis Might look like this: This is a clinical diagnosis, NOT pathologic We will not see a tissue specimen asking us if this is a chronic bronchitis Commonly presents in SMOKERS! COPD may present with either chronic bronchitis or emphesyma predominance

Centrilobular Emphysema in COPD

Emphysema Clinical: Radiology: Pathology:
Associated with cigarette smoking (component of COPD) 1-antitrypsin deficiency, esp PIZZ mutation Radiology: Increased lucency (dark region) Upper>lower lobe suggests centrilobular type Lower>upper lobe suggests panlobular type Possible increased AP diameter Possible flattened diaphragm Pathology: Dilation of distal airspaces with septal destruction Locations: Centrilobular: Cigarette smoke Panlobular: A1AT deficiency or cigarette smoke Increased elastase activity There are 2 flavors of emphysema Cigarette smoking related alpha-1 – antitrypsin deficiency. KNOW BOTH! - If you see panlobular type emphysema in a young, non-smoking patient, you should think A1AT

Bronchiolitis Obliterans/Organizing Pneumonia (BOOP)
Clinical: Acute onset cough, dyspnea, fever, and malaise Multiple associations, e.g. collagen-vascular dz Most patients respond to corticosteroids Radiology: Multiple patchy airspace infiltrates Pathology: Patchy fibromyxoid plugs in distal bronchioles – the BO Fibromyxoid plugs in alveoli, +/- endogenous lipid pneumonia – the OP Think bronchiolar and alveolar airspace fibroblasts Defnition made by pathologists via wedge biopsies In the lung, patchy means focal

Classification of Asthma
Intrinsic Asthma- No allergic or (personal family) history Usually adult onset Often follows severe respiratory illness Symptoms usually perennial More refractory to treatment, become other diseases, progress to vasculitis Eosinophils still impt Extrinsic Asthma- Strong family history of allergies Usually onset at a young age Other allergic manifestations in patients History of specific allergic association triggers (e.g. pollen, animal dander) Correlation with skin and inhalation responses to specific antigens Type I hypersensitivity rxn IgE mast cell and eosinophils

ALLERGIC SHINER: Edema/ Discoloration Around the Eye
What does this demonstrate? What is it? ALLERGIC SHINER: Edema/ Discoloration Around the Eye

What are the important cells in asthma?
Eosinophils (in sputum) B lymphocytes in mediating the asthma – more impt What’s the point of the methacholine challenge? It demonstrates that there’s something different in the architecture of the asthmatic’s airways that makes them non-specifically hyperreactive What is a key feature of the pathophysiology of asthma that contributes to death? Mucous plugs occluding airways What are Creola bodies? Agglomerated bronchial epithelial cells, seen in asthma What happens when you administer a beta-agonist? You initially decrease the O2 saturation via V/Q mismatch. What is AM dipping? When peak flow is decreased in the morning; associated w/ more severe asthma What is the late phase reaction? Delayed reduction in FEV1 due to IgE and influx of inflammatory cells What is the cornerstone of asthma therapy? Corticosteroids (effective in reducing late phase reaction)

Findings/Diagnosing Asthma?
Spirometry Increase lung volumes (TLC, FRC, RV) Decreased peak flow, FVC, FEV1, FEV1/FVC Auto peak end expiratory pressure (auto-PEEP)-with rate respiratory rate. DLCO Increased - useful in establishing dx Methacholine challenge Hyper-responsive b-agonist Reversible airflow obstruction when treated; albuterol Eosinophils Increased in blood and found in sputum ABG Low PO2, low PCO2

Treatment of Asthma Avoid asthmatic triggers Use bronchodilators
Sympathomimetics – usually B2-AR specific to increase cAMP. albuterol Salmeterol is a long acting B2 Methylxanthines – inhibits PDE  increased cAMP Anticholinergics – reserved for COPD Use anti-inflammatory drugs Corticosteroids – the cornerstone of therapy Cromolyn and nedocromil – inhaled prophylactics Zileuton, Zafirlukast – decreases leukotrienes Omalizumab – anti IgE antibody

General Strategy for Management of Asthma
Infrequent attacks? Inhaled sympathomimetics (B2) More frequent? Add an anti-inflammatory as maintenance, usually a corticosteroid Still not good enough? Regular use of inhaled B2 agonists Add methylxanthines (theophylline) Significant attack? Systemic steroids Status asthmaticus? IV corticosteroids Aggressive bronchodilators

Classification of asthma?
Mild intermittent Mild persistent – more than 2X/week, but <1QD Moderate persistent – daily symptoms Severe persistent – continual symptoms

Common precipitating stimuli of asthma?
Allergen exposure – involves histamines, leukotrienes Leukotrienes = why NSAIDS can precipitate asthma! Inhaled irritants Respiratory tract infections Exercise (cool air) When is airflow most compromised in asthmatics? Expiration Why is FRC chronically increased in asthma? Dynamic hyperinflation – can’t fully exhale all air Persistent activity of inspiratory muscles What are the common symptoms of asthma? Cough Dyspnea Wheezing – airflow through narrowed airways Chest tightness What is the mechanism of low PO2, low PCO2 in asthmatics? V/Q mismatch

What are the 2 disorders under COPD? Basic defs?
Chronic bronchitis – diagnosis based on chronic cough and sputum production Emphysema – diagnosis based on destruction of lung parenchyma and enlargement of air spaces distal to the terminal bronchiole What’s the pathogenesis of alveolar destruction? Protease and protease inhibitors are in balance in lung Smoking inhibits protease inhibitors Neutrophils and macrophages in inflammation release damaging proteases What are the risk factors for COPD? Cigarette Smoking (also 2nd hand) Hyperresponsive Airways Occupational Factors (firemen) Alpha1-antitrypsin Deficiency – PIZZ is BAD! Normally keeps elastase in check to maintain lung elastin

Mechanisms of Airflow limitation in COPD?
loss of alveolar attachments obstruction of the airway due to inflammation airway-wall fibrosis airway smooth muscle constriction luminal obstruction with mucus. Loss of elastic recoil in emphysema results in: Decreased expiratory flow rates Lower driving pressure for expiratory airflow Loss of radial traction from supporting alveolar walls Functional abnormalities in COPD? Decreased FVC, FEV1, FEV1/FVC Increased RV, FRC, TLC Decreased DLCO in emphysema Increased Reid index in chronic bronchitis Hypoxia Hypercapnia in chronic bronchitis

Major secondary problem with COPD? Causes?
Pulmonary HTN  cor pulmonale (more common in chronic bronchitis patients) Major Cause: Hypoxia  vasoconstriction Hypercapnia Polycythemia Destruction of the pulmonary vascular bed What is the protease-antiprotease hypothesis? Alveolar integrity is maintained via a balancing act Smoke increases the # of PMNs in the lung PMNs produce elastase  degrades elastin Smoke oxidants, oxidants from inflammatory cells impair A1AT anti-elastase activity Neutrophil elastase stimulate mucus release PMNs and macrophages make matrix metalloproteinases  shift balance towards degradation

Clinical Distinctions Between Blue Bloater and Pink Puffer COPD Pathophysiology
Feature Pink Puffer Blue Bloater Pathophys. Type A Type B Disease Association Emphysema Chronic Bronchitis Major Sxs Dyspnea Cough & sputum Appearance Thin, wasted Cyantoic, obese PO2 Decreased PCO2 Normal or decreased Normal or increased Elastic recoil Normal DLCO Hematocrit Increased Cor pulmonale Infrequent Common

Treatment of COPD Bronchodilators Antibiotics Corticosteroids
Supplemental O2 Exercise rehab Chest PT, postural drainage Surgery (last resort) Lung transplant Lung volume reduction Vaccines: pneumovax, flu Plasma A1AT if the patient is A1AT deficient Mechanical ventialtion

Major Points from Smoking Cessation Lecture
Tobacco dependence is chronic and requires repeated intervention If at first you don’t succeed, try, try again! ALL pts who smoke should be offered at least ONE tobacco dependence treatment. Pharmacotherapy CAN be helpful Nicotine withdrawal can be fairly severe Clinicians, hospitals, etc must institute consistent ID, documentation, and tx of tobacco users Brief tobacco dependence tx is VERY effective – all pts should be offered at least brief tx Strong dose-response relation between tobacco dependence tx and it’s effectiveness

Major Points from Smoking Cessation Lecture
The 3 types of counseling/behavioral therapy found to be very effective and should be used: Social Support within treatment Social Support outside treatment Skills training/problem solving Unless contraindicated, use of effective pharmacotherapies for smoking cessation in all pts trying to quit should be used Tobacco dependence treatments are both clinically effective and cost-effective relative to other medical and disease prevention interventions Setting a quit date is IMPT! Set up follow-up dates after quit date to see your pt. People tend to gain weight upon quitting…

5 first line pharmacotherapies for smoking abstinence that WORK
Bupropion SR Nicotine gum Nicotine inhaler Nicotine nasal spray Nicotine patch 2 second line pharamcotherapies for smoking: - clonidine - nortiptyline

What is the most successful self-help format to quit smoking?
Hotline “quitlines” Person-to-Person contact – how much helps? Even <3min is (moderately) better than none! 10min or more is best Asking your pt to quit smoking helps/doesn’t help? It DOES! What are 3 things associated with unsuccessful attempts at quitting? Not practicing total abstinence Drinking alcohol Other smokers in da’ house

Sarcoidosis What disease? Peribronchovascular space Is dilated
Giant cell Sarcoidosis What disease?

Sarcoidosis Clinical: Radiology: Pathology:
Multi-system granulomatous disease Adults, B>W, F>M Dyspnea Radiology: Interstitial infiltrates in bronchovascular distribution (= lympagenic distribution) Usually have hilar adenopathy (picked up on routine CXR) Pathology: Tight, well-formed non-caseating granulomata Def of granulomata: Focal accumulations of epithelioid histiocytes

Hypersensitivity Pneumonia
Loose Granulomas Interstitial expansion Peri-Bronchiolar Expansion

Hypersensitivity Pneumonitis (Extrinsic Allergic Alveolitis)
Clinical: Organic dusts Doesn’t mean carbon based Means related to organic products Occupational or environmental exposure Acute and chronic: dyspnea, cough, fatigue Radiology: Bilateral interstitial linear or nodular pattern Pathology: Patchy peri-bronchiolar and interstitial chronic inflammation with loosely formed granulomata - Know both names

Coal dust macules Coal-worker’s Pneumoconiosis

Patchy Sub-Pleural Fibrosis
Ferruginous Body Asbestosis

Fibrotic Nodules Late Silicosis
The fibroblasts are responding to silicatic dust Know that quarry work and sandblasting work expose workers to silicon Late Silicosis

UIP: Sub-pleural fibrosis adjacent to normal lung

Usual Interstitial Pneumonia (UIP)
Clinical: Syn. with “Idiopathic pulmonary fibrosis (IPF)” Adults, mean 51 yo; poor response to steroids, 66% mortality Radiology: Patchy subpleural infiltrates, DDx asbestos, rheum Pathology: Patchy interstitial inflammation; fibrosis alternating with normal parenchyma Temporally heterogeneous = ongoing injury to lung Morph overlap with rheum dzs, e.g. scleroderma This disease occurs in patients older than 40 The only tx is transplantation (otherwise they die) Asbestos also presents with patchy, subpleural infiltrates and have similar CXR features. Also rheumatoid lung diseases (RA, SLE, etc) Patchy = focal

Proliferative phase DAD
Fibroblasts in the interstitium Alveolus Proliferative phase DAD

Proliferative (Organizing) Phase Diffuse Alveolar Damage (DAD)
Clinical: > 1-2 wks after identifiable acute lung injury (ex: MVA, septic shock, kidney stone, inhalation of noxious chemical) Decreased pulm compliance -> mechanical ventilation 50% mortality Radiology: Diffuse, interstitial>alveolar pattern Pathology: Interstitial + intra-alveolar fibroblastic proliferation Temporally uniform If it’s temporally heterogeneous = UIP You HAVE to see interstitial fibroblastic proliferation If it’s purely intra-alveolar = BOOP Also called ARDS = adult respiratory distress syndrome Fibrinization in the 1st week  There is a characteristic step wise progression 50% will die, but we can’t predict which half, so we tx all pts aggressively Pure intra-alverolar fibroblastic proliferation = BOOP Temporally heterogenous = UIP

What characterizes Pulmonary function in Restrictive Lung Disease?
Characterized by reduced FVC, normal or high FEV1/FVC ratio Identify which is interstitial lung disease, obesity, and inspiratory & expiratory muscle weakness. Muscle Weakness Normal ILD Obesity TLC TLC TLC TLC Lung volumes are very useful in distinguishing between the 3 categories of restrictive lung diseases Muscle weakness: you see weakness of expiratory and inspiratory muscles  decreased TLC and EV (increased RV)! FRC FRC FRC RV FRC RV RV RV

What are unknown etiological diffuse parenchymal lung diseases?
What’s the differential diagnosis for bilateral diffuse infiltrates that mimic diffuse parenchymal disease? Congestive heart failure Pulmonary infection Lymphangitic carcinomatosis What are known causes of diffuse parenchymal lung disease? Inhaled organic dusts (asbestosis, silicosis, coal workers, berylliosis Inhaled organic antigens  hypersensitivity pneumonitis Iatrogenic (drugs – amniodirone, radiation) What are unknown etiological diffuse parenchymal lung diseases? IPF/UIP Sarcoidosis BOOP Goodpasture’s Wegener’s And many more… (Connective tissue disease associated, Chronic eosinophilic pneumonia, Lymphangioleiomyomatosis, Pulmonary Langerhan’s cell histiocytosis, Alveolar proteinosis, Pulmonary vasculitides)

Pathophysiology of Parenchymal Lung Diseases
Decreased lung compliance (increased stiffness) Reduced FVC, reduced FEV1, normal ratio Reduced lung volumes TLC, FRC, RV Diffusion impairment Destruction of alveolar-capillary interface by inflammation and fibrosis, reducing the surface area for gas exchange (there is a reduced DLCO on testing) Pulmonary Hypertension Hypoxemia Obliteration of small pulmonary vessels by fibrosis As a result of inflammation and fibrosis, the following are seen Although thickening of the alveolar-capillary interface form interstitial inflammation and fibrosis might be expected to be responsible for the diffusion impairment seen in DPLDs, in fact it is really due to

Clinical Features of Parenchymal Lung Diseases
Symptoms Dyspnea Cough (non-productive) Signs Dry crackles or rales (sound like velcro) Clubbing Cor pulmonale JVD Loud P2, TR murmer edema Dyspnea at first only with exertion, then at rest Non-productive cough Velcro crackles 1st heard at mid-axillary line

What is thought to be the pathogenesis of sarcoidosis?
What’s the major benefits of high resolution CT in diffuse parenchymal lung diseases? Detects sub-radiographic disease Distinguishes inflammation from fibrosis Ground glass appearance suggests inflammation What is thought to be the pathogenesis of sarcoidosis? A chronic systemic granulomatous idiopathic disease where there’s an immune response to an exogenous agent in a genetically predisposed individual What key cells are thought to be involved in sarcoidosis? Macrophages Results in increased release of TNF T cells (specifically CD4) BAL will reveal CD4>CD8 There may be lymphopenia on peripheral blood smears MHC II is more impt than MHC I Results in increased IL-2, INF-gamma, and other cytokines

What are the presentations/associated diseases of sarcoidosis?
Lofgrens Acute onset Bilateral hilar lymphadenopathy Eythema nodosum Fever Arthralgias Associated with a good prognosis Eye manifestations Acute or chronic uvetitis Sjorgens – destruction of exocrine glands, specifically partoid and lacrimal Heerfordts – uvetis + uveoparotid fever, facial palsies, parotid swelling Keratoconjunctivitis sicca – decreased tear production  conjuctival and corneal inflammation Papilledema Lupus pernio Associated with chronic sarcoidosis Usually on face, sometime butt and extremities

What are common abnormalities/diagnostic test results in sarcoidosis?
Hypergammaglobulinemia – T cells non-specifically activate B-cells  lots of Igs Hypercalcemia, hypercalciuria – increased Ca2+ absorption from GI tract due to increased vitamin D formation Lymphopenia – lymphocytes involved in granuloma formation CD4 > CD8 in BAL – CD4 plays a greater role in granuloma formation ACE elevated – due to vascular epithelial cells of granulomas CXR or HRCT – parenchymal infiltrates, hilar adenopathy, sublpleural micronodules, upper lobe predominant, honeycombing, ground glass appearance Gallium-67 scan – panda sign Diagnosis is one of exclusion and heavily reliant on biopsy

How do we treat sarcoidosis?
Systemic corticosteroids anti-TNF may be best tx (infliximab) hydroxychloroquine What is the staging of sarcoidosis? Stage I – adenopathy Stage II – parenchymal infiltrates & adenopathy Stage III – just parenchymal infiltrates Stave IV – fibrosis, hilar retractionm, cysts, bullae, honeycombing changes

UIP/IPF Pathogenesis? Commonly presents in? Signs and Symptoms?
Inflammatory process of the walls  fibrosis due to dyregulated response to damage of alveolar epithelial cells Factors that are dysregulated  fibrosis? Cytokines Chemokines Matrix metallic proteases and balance with inhibitors Decreased fibrinolysis Eicosanoid imbalance: increased luekotrienes, decreased prostaglandins Commonly presents in? Older adults, M>F Signs and Symptoms? Exertional dyspnea that increases over time Non-productive cough Possible clubbing

What are common abnormalities/diagnostic test results in UIP?
Velcro-like dry crackles Peripheral edema or cor pulmonale in advanced stages Hypoxemia, cyanosis, clubbing CXR Honeycombing Diffuse reticulations NO hilar enlargement HRCT Patchy, peripheral subpleural densities associated with small cystic spaces Pathology of UIP? Fibrosis Temporal heterogeneity

What Occupational Exposure Materials can cause inflammatory reactions in the Airways?
Secretory Inflammation Formaldehyde – upper airways Ammonia – upper airways Particulates (coal, dust, cotton) – bronchitis Nitrogen dioxide – bronchiolitis Hyperreactive Airways Ozone, cotton dust – non-specific reactivity TDI – occupational asthma

What Occupational Exposure Materials can cause Parenchymal responses Acutely? Chronically?
Pulmonary Edema due to toxic reactions Chlorine, phosgene Acute silicosis Hypersensitivty Pneumonia Organic materials – farmer’s lung (mold spores in hay) Inorganic materials Chronically Nodular fibrosis Coal – macules Silica – collagenous lamellated nodules Beryllium – Granulomata Diffuse Fibrosis Asbestosis Cancer Asbestos Chloromethyl Ether, Coke oven emissions

What are the causes/common types of pneumonoconiosis?
Nodular or diffuse fibrosis… Silicosis Asbestosis Berylliosis Coal Worker’s Important things to do to make a diagnosis in occupational exposure related respiratory diseases? Take a detailed history CXR to document pneumonoconoiosis Blood studies to document specific exposures Lung tissue analysis Measure peak flow throughout week Specific inhalational challenges Investigation of workplace by industrial hygienist

Respiratory Diseases due to Asbestos
Non-Malignant A. Pleural Disease 1. Pleural Effusion 2. Diffuse Pleural Thickening 3. Localized Pleural Thickening (Plaques) B. Diffuse Pulmonary Fibrosis (asbestosis) Malignant A. Malignant Mesothelioma - bad stuff - cigarette smoking is NOT related - latency is years B. Bronchogenic Carcinoma C. Possibly Laryngeal Carcinoma

Asbestosis – a restrictive Lung Dz
Latency period? 20-30days Pathologic features? Ferruginous bodies! Peri-bronchiolar inflammation and fibrosis May eventually honeycomb Tendency towards the lower lobes of the lungs Clinical Symptoms and CXR? Dyspnea on exertion Dry cough Late inspiratory crackles in bases Opacification in bases Pleural thickening

Occupational Asthma Definition? Risk factors? Types of presentations:
Clinically significant variable airflow obstruction due to specific workplace agent in lower [ ]s than should cause non-specific irritant response in normals or asthmatics who are not sensitized Risk factors? Potency of sensitizing material Level of exposure Accidental high exposures Individual patient – atopy and smoking Types of presentations: Typical immediate onset – w/in 30 minutes; clears hrs after leaving work. AM cough & sputum. Responds to bronchodilators Typical late onset – may not have wheezing; 4-8hrs afterwards with longer duration. Refractory to bronchodilators Dual Response Recurrent Attacks Post Exposure – at night after exposure Standard Treatment: Inhaled steroids and bronchodilators

Reactive Airways Dysfunction Syndrome (RADS)
Characteristics: No preceding respiratory symptoms. Onset of symptoms after single high level exposure to an irritant. Onset of symptoms is abrupt (without 24 hours) and symptoms persist for at least 3 months. Symptoms of variable airway obstruction and/or hyperresponsiveness. Non-specific airway hyperresponsiveness present (methacholine challenge). Persistent airway inflammation but lack of eosinophils

Pleural Diseases What is pleuritic pain?
Caused by inflammatory processes that intensify upon breathing What’s going on with a tension pneumothorax? Air escapes into pleural space  positive pressure Air can’t escape on exhalation How can a tension pneumothorax cause shock? By compromise of venous return How can ANY pneumothorax be caused? Trauma  sucking wound Iatrogenic - Overzealous use of positive pressure ventilation, central lines, lung biopsies Abnormal lungs  air trapping (think asthma) Spontaneous in very tall people

What kind of pneumothorax?
21 y o center for BB team Has sudden onset of R sided chest pain & mild dyspnea Patient is uncomfortable but vital signs are WNL Not Sean May hopefully! Pneumothorax disease b/c it’s a popped lung, the pneumothorax is limited and should spontaneously resolve 20 y o severe asthmatic Intubated & on mechanical ventilation Suddenly becomes hypotensive & cyanotic This is a tension pneumothorax – must decompress the patient emergently! What will the CXR look like on a pneumothorax? On side of pneumothorax Absent vascular markings Appearance of a little nub near hilum (atelectic lung) Diaphragm depressed downwards On side opposite of pneumothorax Mediastinum, trachea, other structures shifted over

It’s a dark and stormy night… And a patient is brought into your ER with:
Pleuritic chest pain Dyspnea Dullness of lungs to percussion Egophony at upper level Pleural friction rub After you’re told he’s NOT possessed and isn’t just freaked out after watching that scary movie, you get a CXR. That CXR shows: Blunting of the right costaphrenic angle Elevation or flattening of right hemi diaphragm And the mediastinum shifted to the left side Then the scary, menacing attending asks you what does he have. You, being the superstar that you are, reply:

“Why A Pleural Effusion, DUH!”
How is normal pleural fluid made? Generated by Starling forces across a capillary bed Radiographic signs of pleural effusion include: Blunting of costophrenic angle on upright film Elevation or flattening of hemi diaphragm on upright film Diffuse haziness of hemi thorax on supine film If large, will cause shift of mediastinum to contra-lateral side How do you relieve a massive pleural effusion? Thoracentesis Helpful diagnostically Helps relieve symptoms Remove 1500cc or less! Otherwise, you might suddenly inflate the lung. Too little surfactant  pulmonary edema

How do you relieve a massive pleural effusion?
Thoracentesis Helpful diagnostically Helps relieve symptoms Remove 1500cc or less! Otherwise, you might suddenly inflate the lung. Too little surfactant  pulmonary edema How do you safely do a thoracentesis? Make sure the fluid is freely flowing and not loculated Use a lateral decubitus film Use ultrasound to locate effusion Be sure to draw close to the upper part of the rib directly below the needle you’re using, or you might hit an intercostal artery, vein, nerve

What are Lyte’s Criteria? Why do we use them in the first place?
Helps us distinguish between an exudate and a transudate pleural effusion Ratio of pleural-fluid protein to serum protein > 0.5 Ratio of pleural-fluid LDH > 0.6 Pleural fluid LDH level > 2/3 upper limits of normal for serum Any one of these characteristics means the fluid is an exudate What other studies might you do on fluid from a pleural effusion cell count & differential, glucose, cytology, Gram stain, AFB stain & culture, amylase, cholesterol, triglyceride level, pH, adenosine deaminase What if the effusion is borderline according to Lyte? Look at albumin gradient - If difference btw albumin in serum minus pleural fluid is > 1.2 than more likely a true transudate

What are the potential causes of a Transudate?
CHF – due to increased pulmonary venous pressures, usually bilateral, usually resolves in 48 hours after diuresis Nephrosis – low oncotic pressures Cirrhosis Atelectasis – increased negative pleural pressure Ascites – can preferentially form in pleural space, hepatic-hydrothorax What are the potential causes of a massive exudate? Malignancy Trauma - hemothorax Empyema – bacterial infections Chylothorax – disruption of thoracic duct Rarely, TB

How do you define a hemothorax?
Causes of bloody exudates? Cancer Pulmonary infarction Penetrating & nonpenetrating trauma Central line malplacement Chondrosarcoma S/P CABG Causes of turbid exudates? Chylothorax Empyema How do you define a hemothorax? Defined as pleural fluid hematocrit of 50% of blood hematocrit Will coagulate & may lead to loculation with complications of fibrothorax & possible empyema If small, may defibrinate & remain free flowing

So the good doctor said there’s a good exam question in here…
What kind of cell count in an exudate would make you suspect cancer or Tb? >50% lymphocytes! Now what additional information on this exudate could help you decide that it’s probably NOT Tb? >5% mesothelial cells Remember, mesothelial cells are normally found in pleural fluid to some degree since they are the cells that comprise the pleura!

Empyemas Why should you distinguish between an empyema and a parapneumonic effusion? b/c empyemas need to be drained STAT! What the hell IS a parapneumonic effusion? Effusion secondary to a pneumonia Resolves with antibiotics. Course is usually very benign Great, so what about an empyema and why do I care? Implies active bacterial infection in the pleural space. Failure to recognize & drain can lead to unresolved sepsis & fibro thorax So how do I tell the difference between the two? Well if it’s an empyema, there should be: Gross pus pH < 7.1 glucose < 40 positive Gram stain or cultures And if it’s all borderline you need to retap that…um…lung…

Ack! It’s an Empyema! What Do I do?
Well a tube thoracostomy for one Antibiotics to get those microbes Thrombolytics if loculated or stops draining despite fluid present on X-ray Helps combat if the thing is trying to wall itself off Don’t let it hide – go and get it! Decortication if unable to achieve drainage & lung is trapped in fibrinous peel Yeah – RIP off that clot and scar tissue that I wish you saw… So what if I don’t and say I did? Untreated you might get empyema necessitans (where it attempts to drain through the chest wall b/c you were too lazy to drain it) Or you might get a bronchopleural fistula causing overwhelming sepsis

Hamartoma! STOP! Cartilage in excess and disarray Solitary Pulmonary
Nodule - A very bad, old x-ray STOP! Hamartoma!

Hamartoma It’s BENIGN!!!! Clin: Rad: Path: Adolescence  adulthood
None in newborns - not congenital Rad: Solitary nodule +/- popcorn calcification Peripheral > central Path: Gross: solitary, lobulated, cartilagenous Micro: normal tissues in excess/disarray If it’s calcified, it’s comforting b/c it tends to be non-malignant! It is an acquired neoplasm, never congenital Solitary, pulmonary nodules in adults are scary b/c you think of new lung CA When it’s calcified, it’s comforting, b/c they tend to be non-malignant If it’s non-calcified they will remove it, guranteed

What are the Malignant epithelial neoplasms (Carcinomas)?
Squamous cell carcinoma Adenocarcinoma Large cell undifferentiated carcinoma Small cell undifferentiated carcinoma One of these things is not like the others. One of these things just doesn’t belong… Small cell is treated differently and has a much more severe progression! This is a very common disease b/c of smokers We need to know about these 4 types of cancer The line represents that the top 3 are non-small cell lung carcinoma (NSCLC) Small cell is treated differently (chemo and radiotherapy) and has a much more severe progression. It’s faster and more lethal.

Squamous Cell Carcinoma
Desmosomes Keratin Squamous Cell Carcinoma NORMAL Normal

Squamous cell carcinoma
Clin: Smokers association? YES Prevalence? 20-30% of common carcinomas May secrete PTH-like compound Radiology: central > > peripheral Path: Bronchi > Larynx > Trachea KEY CHARACTERISTICS? +/- Desmosomes (intercellular bridges) /- Keratin production, e.g. keratin pearls This PTH like cmpd will cause the pt to present to an endocrinology clinic!

Adenocarcinoma Primary Gland formation Pleural effusion
Mucin production (red on PASd stain) Pleural effusion Increased shadow due to a mass lesion Also, the right sided costophrenic angle is blunted due to fluid or a tumor You see that this is gravity dependent, therefore a fluid This fluid is likely a malignant pleural exudate Adenocarcinoma

Adenocarcinoma Clin: Rad: Path: +/- glands +/- mucin
30-40% of common carcinomas Smoking association? Most common carcinoma in non-smokers, but 80% of adenoCAs occur in smokers Rad: peripheral > central Path: +/- glands +/- mucin Bronchiolo-alveolar carcinoma subset - These are the most common carcinomas to find in non-smokers

Bronchiolo-alveolar carcinoma
- These little nodules might be metastases, but in BAC, they aren’t! Bronchiolo-alveolar carcinoma - Note the mucin in the alveoli. Gas exchange is gonna suck in this patient!

Bronchioloalveolar carcinoma (BAC)
Subset of? Adenocarcinoma Incidence? Rising incidence (presently 20-25%) Associated w/ smoking? Not associated with cigarette smoking Rad: Peripheral, can be multifocal and bilateral Path: Lepidic (butterfly-like) growth pattern Mucinous or non-mucinous Unifocal or multifocal

Large cell undifferentiated carcinoma
There is a big water dense mass lesion There’s also a malignant pleural effusion here

Large cell undifferentiated carcinoma
Clin: 10% of common carcinomas Rad: non-specific Path: H&E: Undifferentiated cDNA microarrays: distinct disease Basically, it’s a carcinoma with no distinguishing features

Small Cell Carcinoma Necrotic carcinoma Viable carcinoma
Normal lymphocytes Response to therapy At diagnosis Small Cell Carcinoma

Small cell carcinoma Clin: Rad: Path: Think small round blue cells!
Smokers? YES 20 % of common carcinomas Paraneoplastic Syndromes: Ectopic ACTH, ADH, Eaton-Lambert, carcinoid s. Commonly high stage at presentation Responsive to chemo/RT, but low 5 yr survival Rad: Central in >90% Frequent metastases to LNs and distant sites Path: Malignant cytology; high N:C ratio No nucleoli; punctate salt and pepper nucleoli High mitotic activity and tumor cell necrosis Think small round blue cells! This is a VERY bad CA Squamous and SCC are pretty much ltd to smokers Bone, skin, lung, breast, liver, kidney, etc – it can metastasize anywhere NONE of them will survive beyond 5 years

Thin delicate microvilli
Visible C-P Angle Associated w/ ferruginous bodies Thickened pleura Normal thickness pleura Mesothelioma Loss of C-P Angle = Pleural effusion or mass

Most Common Metastatic carcinomas in the Lung?
Breast adenoCA GI adenoCA Renal adenoCA Head/neck squamous cell CA

Lung Cancer - Basics What are the 2 most impt risk factors for lung cancer? Genetics Smoking (15% smokers will get lung cancer; 85% CA in smokers) What types of molecules are the predominant carcinogens in cigarettes? Polycyclic hydrocarbons What sex is more susceptible to lung CA? Theories why? WOMEN Differences in metabolism, CYP450 Hormonal effects in lungs What are some mutations that have been implicated? 3p – NSCLC Ras – adenocarcinoma Myc – small cell NSCLC – p53 Rb – small cell Random breaks in 1, 3, 5, 7, 15, 17

More Lung Cancer Basics
Most common sites of metastases: Liver Bone Brain Adrenals What are the paraneoplastic syndromes associated w/ NSCLC? Clubbing, Hypertrophic orthropathy (adeno), Hypercalcemia (squamous) What are the paraneoplastic syndromes associated w/ SCLC? SIADH (hyponatremia), Cushings, Lambert-Eatons, peripheral neuropathy, cerebellar degeneration

Diagnostic Tools for Lung CA
The Basics Detailed hx and physical (esp lungs and supraclavicular nodes) CXR Chest CT Lab tests: CBC, liver fxn, alkaline phosphatase, serum Ca2+ The Good, Special Stuff For central, endobronchial lesions Sputum cytology (3+ specimens for 90% yield) Bronchoscopy Can also do transtracheal needle aspirate of nodes near trachea and bronchi For peripheral lesions Transthoracic needle biopsy (CT guided) Thoracentesis (effusions) Malignant (w/ CA cells in exudate) or paramalignant

Staging Lung CA SCLC What’s Useful? What’s not so useful?
Limited stage disease vs. extensive stage disease Limited stage - confined to hemithorax; within a radiation port Extensive - Tumor beyond a radiation port, includes malignant pleural effusion; what most pts present with What’s not so useful? TNM system (which is used in NSCLC) T – location, size N – nodes M – metastases Stage I – no nodes involved Stage II – nodes on the same side/hilum of CA Stage III – nodes/mediastinum Stage IV – another organ involved or a second lesion in the lung IIIA, IIIB = locally advanced IIIB, IV = advanced, effusion EARLY

Tricks to help us stage NSCLC?
Intrathoracic Chest CT FDG PET Scan Mediastinoscopy Extrathoracic Bone scan CT/MRI of brain Abdominal CT (liver, adrenals) Biopsies of extrathoracic lesions Treating NSCLC Early – surgical resection + chemo Locally Advanced – chemo + surgery or radiation Advanced – chemo Can help improve sxs, cost effective, increases 1yr survival Treating SCLC Limited – chemo + radio Extensive – chemo, w/ palliative radio as needed

Bronchioloalveolar carcinoma
Adenocarcinoma Most common NSCLC in US Smokers and non-smokers Peripheral (in the lung parenchyma) May arise in area of previous scarring More likely to spread to lymph nodes and outside of the chest Hypotrophic orthopathy or clubbing alone may be present Bronchioloalveolar carcinoma Subtype of adenocarcinoma More common in women More common in non-smokers than smokers for poorly defined reasons Cough and bronchorrhea (frothy sputum production) Variable radiographic presentation: solitary nodule, multiple nodules, infiltrate/consolidation with air-bronchograms Squamous cell lung CA used to be more prevalent. But over time, perhaps with the filtered cigarettes, adenocarcinomas have become more common Squamous are more central airway, but with filtered cigarettes, you’re sucking down finer particles further into the lung parenchyma HPO – hypertrophic othropothy (painful joints) Clubbing = NSCLC (either adeno or squamous)

Squamous cell carcinoma
Exclusively in smokers Generally arise in proximal airways May cause obstruction of the airway with distal atelectasis, post obstructive pneumonia May cavitate Hypercalcemia due to PTH like substance (weakness, dehydration, mental status changes), clubbing Small Cell Lung Cancer 15-20% of all lung CAs (decreasing) The least common lung CA Generally originate within bronchial wall Bulky central tumor with extensive mediastinal lymph node involvement Rapid grown and early distant metastases Paraneoplastic syndromes especially SIADH (low sodium or hyponatremia associated with mental status changes)

Time to Take a Study Break!!!
Got Your Sound On? Time to Take a Study Break!!! Is it close to midnight? And that exam is lurking in the morn

Types of inflammatory responses/cells in infections and likely disease process
Neutrophils Acute pneumonia (usually bacterial) Usually in alveoli Lymphocytes Usually viral or atypical pneumonia Usually in interstitium Granulomatous inflammation (epitheloid histiocytes, lymphocytes, giant cells) Usually mycobacterial or fungal pneumonia In bacterial pneumonia, you’ll see neutrophils as your most prevalent inflammatory cell Viral pneumonias are longer processes, so you see more lymphocytes. These cells normally exist in the interstitum rather than the alveolar spaces Giant cells are multinucleoid epitheloid cells

Neutrophils filling alveolar space in acute pneumonia

Interstitial lymphocytes in viral pneumonia

in mycobacterial pneumonia
- All the other pale pink cells with foot shaped nuclei are macrophages Giant Celll Histiocytes and multinucleated giant cells (granulomatous inflammation) in mycobacterial pneumonia

Common bacterial pneumonia microbes
Community acquired normal flora, common agents Pneumococcal (streptococcus pneumoniae) Klebsiella Hemophilus, Staph aureus, other strep Nosocomial (hospital acquired) Pseudomonas aeruginosa especially in cystic fibrosis patients Methicillin resistant staphylococcus aureus (MRSA) Types of pneumonia patterns on CXR Lobar (entire lobe Bronchopneumonia (patchy in more than one lobe surrounding a bronchus

What is the agent of Pneumococcal pneumonia. How do you get it. Sxs
What is the agent of Pneumococcal pneumonia? How do you get it? Sxs? Pathology? Streptococcus pneumoniae is the prototype of bacterial pneumonia Encapsulated gram + cocci (diplococcus) Normal resident of the nasopharynx Often preceded by a viral infection  sets you up for bacterial pneumonia Clinical: fever, chills, chest pain, purulent or bloody sputum, opacified chest X ray Pathology Early: pulmonary edema and proliferation of bacteria, intra-alveolar accumulation of neutrophils and erythrocytes (“red hepatization”) Later: serum and fibrinous exudates, intra-alveolar organization, macrophages (“gray hepatization”) This is our gold standard pneumonia Early pneumonia: the lung looks like a slab of meat, is really firm. Lots of gooey red stuff in the alveoli Later pneumonia: by then the red cells are gone, and the fibrin looks gray white

What are the sxs of Legionella pneumonia?
“Legionnaires’ disease” Acute onset of malaise, fever, pneumonia, myalgias, abdominal pain, diarrhea Type of bact? Gram stain? How do you see it? Small gram negative bacillus Need special stains to visualize What does CXR look like? Pathology: bronchopneumonia with multiple lobes involved, alveoli filled with fibrin and inflammation X ray is frequently more worrisome than clinical symptoms would suggest

What are characteristics of anaerobic pneumonias?
What patients are susceptible to pneumonias caused by anaerobic bacteria? Anesthetized patients Alcoholics Seizure disorder What are characteristics of anaerobic pneumonias? Normal inhabitants of oral cavity Streptococci, fusobacteria, bacteroides Often cause necrosis Foul smelling sputum May develop abscess formation

What are common complications of bacterial pneumonias?
Lung abscesses Walled off area of infection with destruction of pulmonary parenchyma  destruction of all normal architecture Clinical: fever, cough, foul smelling sputum, mortality 5-10% Pyothorax/empyema Infection of pleural fluid with purulent material within the pleural space. May become loculated (fibrous walls around the inflammation), which requires drainage as well as antibiotics to treat. A clinical problem b/c it doesn’t have normal blood flow for tx with antibiotics AND it doesn’t drain normally w/ a chest tube Bacteremia Bacteria within the bloodstream May seed distant sites Endocarditis, meningitis, pericarditis

Alcoholics on the right lung b/c that’s where aspiration goes!
What does this demonstrate? Center of pulmonary abscess showing acute inflammation with destruction of Normal pulmonary architecture (no alveolar walls) Can be suspected on CXR b/c there is an air/fluid level You can positionally change the patient and see the stuff change Alcoholics on the right lung b/c that’s where aspiration goes! An abscess. Who’s likely to get it and where?

Initial tuberculous infection: Ghon complex
necrotizing granulomatous inflammation Peripheral focus of granulomatous Inflammation (Ghon focus) Granulomatous inflammation In hilar lymph node Beaded look to the bact Positive AFB Initial tuberculous infection: Ghon complex (Ghon focus + involved hilar nodes)

Tuberculosis Primary tuberculosis Secondary tuberculosis
Inhalation of aerosolized droplets  settle in periphery of lower lobes Ghon complex: Peripheral focus of infection (granuloma, Ghon focus, often in a lower lobe) and the infected hilar/ mediastinal lymph node Pathology: caseous (cheese like) necrotizing granulomatous inflammation 90% of primary infections are asymptomatic; 10% progressive primary Tb (enlarged lesion >6cm, spread to other parts of the lung, children or immunosuppressed patients) Secondary tuberculosis Reactivation of primary Tb OR a new infection in previously sensitized pt Clinical: fever, fatigue, weight loss, sweats, cough, hemoptysis Numerous caseating granulomas most common in the apical and posterior segments of upper lobes (highest aeration) These may heal and calcify, but some may erode into a bronchus, leading to tuberculosis cavity Usually 3-10 cm, often in apex of lung Communication with bronchus allows dissemination of organisms throughout lung

Complications of tuberculosis
Miliary Tb Multiple small (millet seed size) granulomas in many organs Results from hematogenous dissemination Kidneys, adrenals, bone marrow, spleen, liver lymph nodes are common sites Hemoptysis Erosion of inflammatory response/Tb granuloma into a pulmonary artery Bronchopleural fistula Erosion of inflammatory response/granuloma into the pleural space, resulting in Tb empyema Unusual complications – you cough up Tb and swallow it, and it’s happy to colonize somewhere else Tuberculous laryngitis Intestinal tuberculosis

Other mycobacterial diseases
Mycobacterium avium-intracellulare Found in soil, water, food Causes disease in immunocompromised patients, particularly HIV+ (HIV Tb) Mycobacterium kansasii Associated with Hairy cell leukemia Mycobacterium bovis Infection from ingested milk (the bow Tb)

Histoplasmosis Found in: Appearance: Common location:
in infected dust, bird droppings Appearance: dimorphic fungus with tiny yeast forms Common location: Endemic in midwest and southeast US, particularly Mississippi and Ohio valleys Clinical and pathologic findings Similar to Tb Yeast phagocytosed by macrophages and PMNs result in focal infections with parenchyma and hilar lymph nodes granulomas and caseating necrosis Old granulomas frequently calcify Immunosuppressed patients may have disseminated disease involving lungs, liver, adrenals, intestines

Coccidioidomysis Appearance: Geography/location:
dimorphic fungi with large thick walled sporangia microns filled with endospores 1-5 microns Geography/location: Endemic in southwestern US, particularly San Joaquin valley. Clinical and pathologic findings Similar to Tb and histoplasmosis, Immunocompromised patients may have release of endospores into lung causing with fulminant disease with purulent response Meningeal and MSK involvement possible A big problem for lab workers A mold form in the environment Very immunogenic Inhaled Similar presentation to histo and Tb

Cryptococcosis Appearance? yeast 4-9 microns with mucinous capsule
Found in? pigeon droppings Clinical and pathological presentation? Clinical disease almost exclusively in immunocompromised patients Lung is the portal of entry CNS is the most common symptomatic site (especially cryptococcal meningitis) Organism may be demonstrated in CSF, lung washings/BAL and biopsy with special stains (India Ink, mucin stains). Cryptococcus is one of the few fungi with mucicarmine positive capsule. Can resemble a neoplasm Cryptococcus: mucicarmine positive capsule Cryptococcus on GMS stain showing narrow based budding

Blastomycosis Appearance: Geography/location: Pathology:
a large dimorphic fungus with broad based budding. Geography/location: In US in Mississipi and Ohio River valleys and Great Lakes regions Pathology: Disease usually confined to lungs, causes mixed granulomatous and suppurative inflammation Always in DDx of a pt with a lung mass Blastomycosis: Large yeast with broad based budding

Aspergillosis Grows with preexisting cavity, often Tb cavity
Appearance: septate hyphae with acute angle branching, found in soil and decaying plant material Diseases/Presentation Aspergilloma (Mycetoma, “fungus ball”) Grows with preexisting cavity, often Tb cavity Tangled mat of hyphae within cavity, X-ray may show mass and air within cavity Allergic-Bronchopulmonary aspergillosis (ABPA) Asthmatics develop immunological reaction to Aspergillus, w/ infiltrates on CXR, eosinophilia of blood/sputum, wheezing, cough and sputum production Treatment with steroids to control immune response It’s not the fungus that hurts you, it’s your body’s response Invasive aspergillosis – usually fatal Almost exclusively in immunocompromised hosts Invasion of pulmonary blood vessels with organismcausing infaction, thrombosis, exsanguination Really 3 different diseases from one organism One of these is apergilloma Very common in older bldgs Will grow in a cavity with a slightly lower temperature Usually not very problematic May cause sputum production

Aspergilloma showing non-invasive fungus within granulation tissue lined
cavity Aspergilloma (fungus ball) within pre-existing cavity

Aspergillus: septate hyphae with 45 degree branching

Aspergillus within blood vessel wall Invasive aspergillus

Mucormycosis (Zygomycosis)
Caused by inhalation of spores of several fungi (Mucor, Rhizopus, Absidia) ubiquitous in soil, food, decaying vegetable material Appearance? grow as non-septate hyphae Common patients? patients with underlying illness, particularly diabetics Common presentation? rhinocerebral (nasal sinuses and brain) and pulmonary. Causes vascular invasion, septic infaction, hemorrhage Mainly a problem for diabetics Need big surgery; try to cut it out with surgery like a cancer

Mucomycosis

Bronchoalveolar lavage useful for diagnosis
Pneumocystis carinii What is it? A common pulmonary pathogen causing pneumonia in immunosuppressed patients, especially HIV What do you see? Trophozoites and cysts, latter identifiable with GMS stain, fills alveolar spaces with organisms and proteinaceous fluid, preventing gas exchange Bronchoalveolar lavage useful for diagnosis Causes dyspnea and CXR with infiltrates Dx by cytology

Pneumocystis on GMS stain: cup shaped organisms within alveolar spaces

Viral pneumonias Cytomegalovirus – most common viral infxn Interstitial pneumonia in infants and immunocompromised patients, especially organ transplant patients, now we screen (donor & recipient) Large cell, big nucleus w/ large, single basophilic intranuclear inclusion Measles Multinucleated giant cells with nuclear inclusions Varicella (chicken pox and herpes zoster) are usually asymptomatic Interstitial mononuclear cell pneumonia, may produce focal necrosis Nuclear eosinophilic viral inclusions, may be mutlinucleated Herpes simplex necrotizing tracheobronchitis and diffuse alveolar damage Other viruses (especially in children) Adenovirus Respiratory syncytial virus

Measles pneumonia: multinucleated giant cells with viral inclusions

Cytomegalovirus pneumonia

Viral inclusion Herpes virus on cytology specimen

Mycoplasm pneumonia: sparse lymphocytic interstitial inflammation

Mycoplasma Small free-living prokaryote, common cause of acute self-limited pneumonia and tracheobronchitis, milder than usual bacterial pneumonia (“walking pneumonia”) Highly transmissible through airborne droplets Cause of 15-20% of pneumonias in developed countries Pathology: patchy consolidation, mononuclear infiltrate, usually of a lower lobe Very common but not very bad You’ll see something on CXR but not lots of sxs Really common at college/in dorms

What are common host defenses to respiratory infection?
ANATOMIC Upper Airway (nose) Epiglottis/Larynx Epithelial Tight Junctions MECHANICAL (“INNATE”) Mucociliary and Cough Clearance IMMUNE “Innate” (lysozyme; lactoferrin; “defensins”) Immune Response Secretory IgA (nasal/bronchial) Humoral Antibody Cellular GENERAL Alveolar Macrophages (AM) Inflammatory Response (PMNs, etc.) Anti-Proteases

What defenses are protecting the proximal airways and nose?
Primary Components: cilia, liquid/mucus, submucosal gland secretions Mucociliary clearance – respond to neurohormonal and mechanical stimuli Secretions of the submucosal glands – what’s in this? Lysozymes IgA – neutralizing; secreted as a dimer IgG – opsonizing What are the defenses in the alveoli/distal airways? No cilia or mucus Macrophages – they can seek and phagocytose pathogens, as well as coordinated the cellular response via chemotactic factors and cytokines IgG Secondary defense mechanisms thoughout the lung? Neutrophils and other inflammatory cells

Lung Defense Failures Common: Severe failures of lung defense include:
viral infection - after influenza, other infxns can occur cigarette smoking COPD patients w/ underlying lung disease Severe failures of lung defense include: AIDS Medications (corticosteroids like prednisone, other immunosuppressives, chemotherapy Malignancies (leukemia, lymphoma) – can lower cell and antibody mediated immunity Endotracheal tubes – HAP

Routes of Infection of Lung
Aspiration Microaspiration of pathogens colonizing the oropharynx (your upper away) Gross aspiration of mouth/GI tract contents into lungs Inhalation Ambient droplets/particles entrained (e.g. TB, fungi) Hematogenous e.g. Staph. aureus with IVDA, endocarditis, or a catherter The route by which a potential pathogen reaches the lower airways is typically one of three: 1 Aspiration of bacterial pathogens from the oropharynx is most common, both in CAP and HAP. This is usually an extremely low volume aspiration event, which occurs in all of us, but the establishment of a pathogen as colonizer of the OP is key initial event. Alternatively, aspiration of a large volume of mouth or GI tract secretions may occur with vomiting or when a normal swallowing mechanism is impaired e.g. after stroke, with LOC, alcoholics etc.. this is not talking about aspiration pneumonia. Aspiration pneumonia is aspiration of a LARGE volume of stuff 2. Some pathogens exist as aerosol droplets in the environment and are directly inhaled without first colonizing the upper airway/OP – especially TB and fungi - INHALATION 3. Finally, bacteria may get to the lung via the blood stream – so called hematogenous spread – as is the case with Staph aureus in the setting of IVDA and endocarditis

Typical vs Atypical Pneumonia
Rapid onset Ill appearing High fever, rigors (shaking chills), chest pain, purulent sputum Consolidation, rales on exam Leukocytosis (15-20K) Airspace filling/lobar infiltrate on CXR with air bronchograms Meant to describe: S. pneumo, S. aureus, GN bacilli like Klebsiella Atypical Pneumonia Indolent onset (7-10days) Less ill appearing Low-grade fever, malaise, headache, dry cough Rales without consolidation Mild/no leukocytosis; negative cultures Patchy/interstitial infiltrates on CXR Meant to describe: Mycoplasma, or Chlamydia So, to suspect pneumonia you really must have an understanding of the spectrum with which this disease presents. Classically, we’ve discussed typical and atypical pneumonia as a description of the presentation for specific etiologic agents, and thus guided the choice of antibiotics. Today, we understand that these clinical presentations are not predictive of specific pathogens, and therefore should not guide the choice of therapy, but are still useful as demonstration of the fairly wide range with which pneumonia presents. Typical pneumonia: Atypical pneumonia Key Pt: Don’t use the presentation to determine the therapy NOT HIGHLY PREDICTIVE OF SPECIFIC PATHOGENS!!!

CXR will ESTABLIGH THAT YOU HAVE PNEUMONIA…
This is the most important test that needs to be done in diagnosing pneumonia? Chest Radiography May distinguish pneumonia from other problems (bronchitis, CHF, TB, PE, cancer) Assesses severity/distribution (multilobar) of disease and identifies complications (pleural effusion, abscess, empyema) Many patterns observed Airspace filling processes (lobar; patchy “bronchopneumonia”) Interstitial patterns Location, cavitation, adenopathy… CXR will ESTABLIGH THAT YOU HAVE PNEUMONIA… But CXR won’t tell you what the responsible pathogen is When the clinical picture suggests that a patient may have pneumonia, the most important test that needs to be done is the CXR. The CXR not only is a key for establishing that pneumonia is present – e.g. by differentiating from other diseases that may present similarly; but is useful for the assessment of disease severity, distribution, and to look for disease complications. Various patterns may be discribed, as Dr. Wilcox will talk about later….including…. But suffice it to say that this test is poorly predictive of the pathogen causing pneumonia

Since CXR and clinical presentation only tells you the patient has pneumonia, do you even care what the causative microbe is? YES The pathogen determines how you treat it (and in my case, how much I freak out) Great, so how do I figure out WHAT the pathogen is then? Sputum Gram’s stain and culture: used but utility debated due to high false+ and false- rates Blood cultures: for hospitalized patients (specific, but not sensitive); much better. Strep pneumoniae causes the most + blood cultures Ancillary testing for specific organisms Legionella: Urinary antigen immunoassay (serotype 1) DFA, selective media Chlamydia, Mycoplasma: serologies, but these are relatively unhelpful in the acute setting TB: AFB smear/culture Fungus: KOH/culture Let me preface this section by saying that the firm identification of the causal pathogen is very helpful, in that the therapy may be appropriately tailored toward that agent. However, even when aggressively sought after in a research setting using invasive methods, the precise diagnosis is not found in about 50% of cases. With that in mind, let’s consider the tests that we have available. Most commonly ordered are sputum gm stains and cultures, which are controversial and problematic, as we’ll discuss in a moment. Blood cultures are helpful when positive (20% of S. pneumo; much less with other pathogens), and are generally reserved for hospitalized patients. Other useful tests include Legionella urinary antigen – but only detects serotype 1; DFA and culture -chlamydia and mycoplasma have serologic tests, but are not typically useful in the acute setting.

Yeeeeeeeearrrrrrhhhhh!!!
So when is this sputum Gram stain & Culture going to be worth me missing sleep? When you’ve got… Large numbers of bacteria with a single morphology observed in setting of many PMN’s and few/no squamous epithelial cells (i.e. lower airway specimen) Obtained before antibiotics Detection of a non-colonizer (mycobacteria, endemic fungi, Legionella, PCP) That’s when I go: Yeeeeeeeearrrrrrhhhhh!!! (yes I know I’m a dork, but you’re laughing – admit it. And I have to entertain myself SOMEHOW!) Squamous epithelial cells are from the mouth. If you see a lot of these, then the specimen is likely contaminated by cells from the mouth

This is a sputum sample and it tells us?
As an example – Poor specimen, lots of squamous epithelial cells, few inflammatory cells, and mixed GP/GN flora That it was probably an incompetent med student who this specimen, b/c it SUCKS. Look at all the squamous epithelial cells and where are the inflammatory cells?!?!?

Besides thinking “damn, I’m good” you should be thinking STREP!!!
So after you fix that previous person’s mistake, you see this. What are you thinking? -good specimen with inflammatory cells, no epithelial cells, and only gram + diplococci Circle around diplococci Likely dx: strep! Besides thinking “damn, I’m good” you should be thinking STREP!!!

When Do I give up on the whole idea of a bacterial pneumonia and consider TB/fungal agents?
CXR: Upper lobe cavitary infiltrate: TB!! Clinical course: Indolent course x weeks/months Non-resolving on treatment Exposure history: Outdoorsman (Blastomycosis) Desert southwest (Coccidioidomycosis) TB contacts or from endemic area

The patient asks you to predict how bad the infxn is
The patient asks you to predict how bad the infxn is. You’ll assess the severity looking at what? And what’ll make you panic? Demographics: Age >60 years, comorbidities (cancer, “organ failures”, immunosuppressed conditions, CHF) Clinical findings: altered mental status severe vital sign abnormalities (RR>30; SBP < 90; T>40 or <35; HR >125) Lab data: WBC >30k or <4k; hypoxemia; acidosis CXR: multilobar involvement, fulminant progression or you could just use a magic eight ball… Predictors include: Clinical findings – both severe hyper or hypothermia! Labs CXR One or more of these predictors of severity should definitely be considered when deciding whether you will treat the patient at home, versus admitting them to the hospital or even ICU. As you’ll see, this decision will in turn determine which empiric therapy you choose for the patient.

Pathogens ~ Modifying Risk Factors
Aerobic GN bacilli Alcoholism, nursing home, cariopulmonary disease like Klebsiella Anaerobes Loss of consciousness (alcohol, seizure), swallowing dysfunction, poor dental hygiene, airway obstruction H. influenzae COPD, smoker S. aureus Nursing home, post-influenza, IVDA, bronchiectasis P. aeruginosa Structural lung disease (bronchiectasis, CF), recent broad spectrum antibiotics therapy, malnutrition, chronic steroids DRSP Age > 65; b-lactam therapy within 3 months; exposure drug resistant S. pneumoniae to child in daycare; underlying medical co-morbidities Before I talk about the 4 treatment categories, let’s talk briefly about clinical cues that increase the likelihood of a particular pathogen. Aerobic GN bacilli: EtOH, nurisng home, underlying disease Anaerobes: LOC, swallowing dysfunction, poor dental hygeine, airwy obstruction H. influenze: COPD, smokers S. aureus: nursing home, post-influenza, IVDA, bronchiectasis P. aeruginosa: structural lung disease, malnutrition, chronic steroids, recent broad spectrum anaerobics (nosocomial) DRSP: comorbidity, recent B-lactam therapy, increased age, exposure to child in daycare IVDA = IV drug abusers

What are your basic Treatment Groups for Pneumonia?
Outpatient No underlying. disease or modifying factors Underlying comorbidities or modifying factors (COPD, CHF, alcoholism,…) Inpatient Inpatients not needing ICU care No comorbidities Underlying comorbidities Severe pneumonia requiring ICU care Low risk for pseudomonas Risk for pseudomonas Therapeutic Groups: First divide into outpatient or inpatient Then divide the outpatient into healthy, young and those with nothing looking majorly bad on CXR, lab tests, etc but have a comorbid risk factor

How do you treat each group?
Outpatient: No cardiopulmonary disease or modifying factors Advanced generation macrolide (azithromycin, clarithromycin) OR Antipneumococcal fluoroquinolone (levofloxacin, moxifloxacin) Outpatient: With Cardiopulmonary Disease/Modifying Risk Factors Antipneumococcal fluoroquinolone 2nd/3rd generation cephalosporin + macrolide Inpatient: Not needing ICU IV 3rd generation cephalosporin + macrolide IV antipneumococcal fluoroquinolone Inpatients: ICU requiring Consider Vancomycin (MRSA and PRSP) If there is a Pseudomonas risk, add these: Anti-pseudomonal B-lactam + cipro

HAP Pathogens and Treatment
Treatment based upon the local hospital flora Commonly available along w/ the drug resistances! Common pathogens: P. aeruginosa, Enterobacter, E. coli, Klebsiella, Proteus, Serratia, S. aureus, Acinetobacter, anaerobes HAP more likely to be polymicrobial Resistant GN’s and S. aureus (MRSA) more common, and may spread rapidly to at risk patients Treatment – based on culture results; empiric based upon epidemiology locally

Risk for pathogens reflect specific immune deficit
So in the Immunocompromised Host, what is reflective of the specific immune deficit? Risk for pathogens reflect specific immune deficit Neutropenia: bacteria, aspergillus, candida Splenectomy: encapsulated organisms T-cell number (HIV) or function (immunosuppressives): fungi, mycobacteria, viruses (CMV, EBV), bacteria Pneumonia in this population is a large topic in and of itself – but we’ll focus on HIV primarily. However, I do want you to understand that the underlying immune deficit determines the risk for individual pathogens – e.g. neutropenia post chemo allows bacteria, aspergillus and candida to prosper; encapsulated organisms are most important after splenectomy; and when T-cell number or function is compromised, other fungi, mycobacteria, and viruses play a large role.

HIV lung infections reflect what?
Risk for infection proportional to CD4 count: >500: lower risk (M. tuberculosis, bacterial pneumonia) <200: Pneumocystis carinii <50: disseminated M. avium complex Higher frequency of bacterial pneumonia, esp. S. pneumoniae and H. influenzae, and tuberculosis at all CD4 counts How do you avoid PCP in HIV+ patients? Prophylactic therapy in compliant patients quite effective trimethoprim/sulfa – also used to treat Dapsone inhaled pentamidine – also used to treat

AIDS and Pneumocystis carinii
Clinical Presentation Dyspnea, dry cough, fever – insidious onset Diffuse infiltrates typical (normal in 5%; atypical with inhaled pentamidine) Hypoxemia prominent feature Diagnosis Visualization (DFA, silver stain) of organisms in lower resp. secretions (induced sputum; bronchoalveolar lavage 85-95% sensitive in HIV) Treatment: Trimethoprim-Sulfamethoxazole (Bactrim) IV pentamidine Corticosteroids: for pO2 < 70 mmHg or A-a grad >35 mmHg (reduces risk of resp. failure and death) Treatment: TMP/SMX or pentamidine. Steroids help when significant hypoxemia is present Risk of death/respiratory failure higher with pO2 < 70mmHg of A-a >35mmHg

AIDS and Non-TB mycobacteria
Primary species are within M. avium complex Risk when CD4 count < 50 (prophylaxis with clarithromycin) Primarily cause disseminated disease, rather than pulmonary disease Fever, weight loss, anemia/leukopenia, diarrhea, hepatitis, adenopathy MAC cultured from blood, bone marrow, stool Treated with Clarithromycin + ethambutol NTM – especially MAC, are seen at low CD4 counts. Typically, they cause disseminated disease involving bone marrow, liver, spleen, etc… rather than pulmonary disease. SKIPPED

AIDS and Fungal Pneumonia
Cryptococcus neoformans: Common cause of meningitis, usually without pneumonia May cause local or diffuse pulmonary disease; disseminate Histoplasmosis, Coccidiodomycosis: Usually disseminated disease in HIV Invasive Aspergillosis: End-stage (CD4 < 50) disease, concomitant neutropenia (e.g. meds…) are risk factors Fungal pathogens: more to come next hour on clinical features. -Crypto: is ubiquitous; usually causes meningitis without lung disease, but can cause local or diffuse (esp with advanced disease) pneumonia -Histo and cocci; both endemic; usually cause disseminated disease in HIV and may be the result of reactivation of dormant disease or progressive primary infection -Invasive aspergillosis – seen in end stage disease, especially in the setting of neutropenia; marajuana smokers more at risk. SKIPPED

AIDS and Non-infectious Lung Diseases
Kaposi’s sarcoma: infiltrates, nodules, pleural effusions, adenopathy, and airway lesions all possible (Gallium scan negative) human herpesvirus-8 Lymphocytic interstitial pneumonitis (LIP) especially children with HIV Non-specific interstitial pneumonitis (NSIP) Pulmonary Hypertension Pathology identical to primary pulmonary hypertension Finally, although we’re always thinking about infectious causes of infiltrates in HIV, a number of non-infectious problems are encountered as well. This includes neoplasms, such as Kaposi’s sarcoma. Kaposi’s commonly causes skin and mucous membrane lesions, but may involve the lung in a variety of fashions; LIP is a diffuse interstitial pneumonitis, especially prevalent in children with HIV; and finally for unclear reasons, patients may present with pulmonary htn which presents identically to PPH (dyspnea, fatigue, signs of right heart failure; prom PA;s with clear lungs) SKIPPED

What is bronchiectasis? 2 modes of pathogenesis? Its vicious cycle?
“Irreversible dilation of airways caused by inflammatory destruction of airway walls” Pathogenesis Infection/Inflammation bacterial pneumonia, tuberculosis, measles, pertussis Airway obstruction Cystic Fibrosis (CF) Primary Ciliary Dyskinesia (PCD; Kartagener’s Syndrome) Hypogammaglobulinemia (total; IgG2/IgG4; IgA) Airway obstruction/Infection Airway wall damage/dilation Impairment of mucus clearance Promotion of Airway Infection

Other Etiologies of Bronchiectasis
“Traction bronchiectasis” - ILD Airway obstruction (e.g. foreign body) ABPA (Allergic bronchopulmonary aspergillosis) 1-antitrypsin deficiency COPD Rheumatologic diseases (Sjogren’s syndrome, RA) Young’s syndrome (bronchiectasis, obstructive azoospermia, sinusitis; normal sweat Cl- and CFTR genotype) What happens to the bronchial arteries in bronchiectasis and why? Marked hypertrophy of bronchial arteries due to chronic inflammatory stimuli - Traction bronchiectasis -

Clinical features of bronchiectasis
Chronic cough copious purulent sputum production ~10% with “dry bronchiectasis” Periodic hemoptysis May be massive, as source is hypertrophied bronchial arteries, which are at system blood pressure Abnormal lung sounds and clubbing variably present What is suggestive history of bronchiectasis? How do we diagnose bronchiectasis? HRCT – procedure of choice to demonstrate presence, location, and extent of disease

So you have a pt and the HRCT shows bronchiectasis. Now what?
Figure out what the cause is! CF: Sweat chloride or CFTR genotyping Immunoglobulin deficiency: IgG/subclasses, IgA PCD: nasal scrape for cilia structure; exhaled NO level 1-antitrypsin ABPA: immediate aspergillus skin test; IgE Treatment? Antibiotics aimed at airway flora Airway clearance Chest percussion (manual, devices), exercise -agonists Reduces reversible airway obstruction and promotes mucociliary clearance Surgery For refractory symptoms/hemoptysis from localized disease

Cystic Fibrosis What are the major defects?
Production of thick, tenacious secretions from exocrine glands Elevated concentrations of Na2+, K+, and Cl- in sweat What are the major clinical problems from CF? Pancreatic insufficiency Recurrent episodes of tracheobronchial infections Bronchiectasis What is the genetic basis of CF? Most common lethal genetic disease in Caucasian population Affects 1 : 3,300 Caucasian births Monogenetic, autosomal recessive Affected gene is called “Cystic Fibrosis Transmembrane Conductance Regulator”, or CFTR. >1000 individual CFTR mutations identified, but DF508 mutation accounts for 2/3 of CF alleles worldwide

What is the Cascade to Lung Disease in CF?
CFTR Gene Mutation Altered Ion Transport Abnormal airway surface liquid (volume depletion) Impaired airway defenses (reduced mucociliary clearance) Chronic airway infection/inflammation Progressive bronchiectasis Sodium is reabsorbed WAY too much from the airways. Water follow inwards. This leads to the collapse of mucociliary clearance.

How do you diagnose CF? 1+ typical phenotypic features and evidence of CFTR malfunction CFTR malfxn: Sweat Chloride Test – gold standard; > 60 mmol/L CFTR Mutation Analysis – genotyping; 2 mutations required Nasal Potential Difference (PD) testing – demonstrates ion transport abnormalities Phenotypic features: Chronic Sinopulmonary Disease: Persistent infection with P. aeruginosa, S. aureus Chronic cough/sputum PFTs (obstruction) Radiographs: bronchiectasis (upper lobe) Nasal Polyps, sinusitis Digital Clubbing GI: Meconium ileus, rectal prolapse, Distal Intestinal Obstruction Syndrome (DIOS) Pancreatic insufficiency Malnutrition Fat soluble vitamin deficiency Focal biliary cirrhosis Others: Salt loss syndromes: acute salt depletion, chronic metabolic alkalosis Obstructive azoospermia (CBAVD)

How do you get pseudomonas in CF?
Impaired mucociliary clearance Static, hypoxic mucus layer Pseudomonas growth in biofilms by altering metabolism from aerobic  anaerobic Intense inflammation with resolution of infection What are serious complications of CF? Pneumothorax Massive hemoptysis due to dilation of bronchial arteries Respiratory insufficiency Cor pulmonale

What is the standard maintenance therapy for CF?
Airway obstruction from thick secretions Airway clearance DNase, mucolytics Hypertonic saline – speeds up clearance of mucus Bronchodilators Infection Inhaled and oral antibiotics Inflammation Ibuprofen Corticosteroids Azithromycin – also an antibiotic! Shown to slow disease Nutritional Support High fat/calorie diet Pancreatic enzyme supplementation Fat soluble vitamin supplementation (A,D,E,K) Screening for other complications CF-related diabetes Liver disease Bone disease

Occluded artery Parenchymal infarct with hemorrhage Pulmonary Thromboembolism

Pulmonary Thromboemboli (pulmonary embolism, PE)
Clinical: Dyspnea, hemoptysis Commonly due to lower extremity thrombi Radiology: Decreased flow, V/Q mismatch  abnormal V/Q scan Pathology: Pulmonary arterial thromboemboli Survivors may have peripheral wedge-shaped infarction May cause death Lots of different things can cause an emboli: amniotic fluid, fat, blood thrombus

Medial and intimal hypertrophy
Plexiform lesion This is a cross-section of a small artery The endothelium is “bloomin out”

Pulmonary Artery Hypertension
Clinical: Sporadic Primary PH: Idiopathic; young adults; 5% Familial Primary PH: Autosomal dominant; 5% Secondary PH: Identifiable cause of increased pulmonary blood flow and/or increased resistance; 90% Radiology: Non-specific Pathology: Medial hypertrophy intimal proliferation intimal fibrosis plexiform vascular lesions

Elastica disruption = vascular injury
Necrotizing Granulomatous Vasculitis Elastica disruption = vascular injury Hemosiderin-laden macrophages = prior hemorrhage These pts tend to bleed repeatedly  hemosiderin-laden macs Wegener’s Granulomatosis

What are the 2 Mechanisms That are Used when there’s increased blood flow through the lungs?
2 impt mechanisms to prevent increased pulmonary vascular resistance At rest, there are some blood vessels that are NOT perfused. But during increased CO (as w/ exercise), these vessels can be recruited and perfused Distension is possible due the very elastic nature of the pulmonary vessels

How do you define pulmonary hypertension?
What’s going on with the pulmonary vasculature resistance as you inhale? Total pulmonary vasculature resistance increases as you inhale/increase lung volumes Alveolar components increase with inspiration Extra-alveolar components decrease w/ inspiration How do you define pulmonary hypertension? Defined as mean pulmonary artery pressure >25 mm Hg at rest or 30 mm Hg during exercise What is the general progression of disease w/ increased pulmonary vasculature resistance? Pulmonary vascular obstruction  increased pulmonary vascular resistance  pulmonary HTN  increased RV work  cor pulmonale

What is the vicious cycle of pulmonary HTN?
Decreased Cross- Sectional Area Vascular Changes Intimal proliferation Medial hypertrophy Angiomatoid transformation Fibrinoid necrosis

What are the Mechanisms of Pulmonary Hypertension
Passive: increased left atrial pressure, e.g. mitral stenosis, mitral regurgitation, LV failure Hyperkinetic: high flow states: VSD, ASD Occlusive: Chronic PE Obliterative: emphysema, interstitial lung disease, vasculitis, sarcoidosis Vasoconstrictive: hypoxia, scleroderma

What is the basis of Primary Pulmonary Hypertension
Potential etiologies  PGIS, endothelin, Kv-channels, eNOS, mutant BMPR2, ANP Mean age at diagnosis is 36 More common in females than males No racial predilection Familial Disease accounts for ~10% of cases Disease progresses to cor pulmonale and premature death if not treated with median survival of years PGIS = prostaglandin synthase Endothelin – potent vasoconstrictor

Symptoms of PPH Patient may faint upon exercise Physical Exam Findings
Progressive exertional dyspnea—virtually 100% Patient may faint upon exercise Fatigue Chest pain—due to right ventricular Ischemia Exercise syncope or near syncope Hemoptysis Hoarseness Peripheral edema Physical Exam Findings Jugular venous distention Accentuated second heart sound (P2) Right ventricular left sternal border Right sided gallops (S3, sternal border Tricuspid regurgitation murmur (systolic) or pulmonic (diastolic) murmur Peripheral edema due to RHF

Therapy of Pulmonary Hypertension
Anticoagulation– improves survival Oxygen – in hypoxemic patients Ca2+ channel blockers – may improve exercise tolerance and hemodynamics in patients (~25%) with mild-moderate disease Prostacyclin—intravenous/subcutaneous administration improves hemodynamics, exercise tolerance, and prolongs survival in severe PPH Bosentan—endothelin receptor antagonist that improves exercise tolerance. Transplantation – the last resort - Pulmonary HTN used to be fatal, but not anymore thanks to these treatments

What are the Pathophysiological Consequences of Pulmonary Embolism
Pulmonary consequences Increased alveolar deadspace Pneumoconstriction—described in animals Hypoxemia—shunt, V/Q mismatch Hyperventilation Depletion of alveolar surfactant—takes ~24 hr Pulmonary infarction Hemodynamic consequences Decrease in x-section area of pulmonary vascular bed: 50-60% reduction  significant pulmonary HTN, RHF, hypotension Humoral reflex mechanisms—hypoxic vasoconstriction, mediator release (like 5HT)

Diagnostic Tests for DVT
Venography Impedance Plethysmography Duplex Scanning Dopper flow velocity MRI scans

Diagnosis of Acute Pulmonary Embolism
Symptoms Dyspnea Pleuritic pain Apprehension Cough Hemoptysis Syncope Signs Tachycardia Increased P2 Thrombophlebitis – in lower extremeties S3,S4 gallop Diaphoresis Edema Murmur Cyanosis Laboratory Studies ECG- non-specific, sign of Right heart strain S1Q3 pattern in precordial leads CXR Blood Gases D-Dimers – more useful to r/o Ventilation Perfusion Scanning – w/ good sxs, it’s fairly reliable Spiral or helical CT scanning Pulmonary Angiography

Contraindications to Heparin Therapy
Absolute: Recent (w/in two weeks) hemorrhagic CVA. Recent neurosurgery, ocular or spinal surgery Relative: Recent major surgery Major trauma Intracranial neoplasm Recent gastrointestinal bleeding Concurrent guaiac positive stool Mild to moderate hemostatic defects Severe uncontrolled hypertension >200mm Hg Systolic or >110mm Hg diastolic Hematuria In these situations, you would use an IVC!

TYPE II pneumocytes (main cell)
So you’ve got edema in the distal airways and alveolar epithelium. What cell helps you deal? TYPE II pneumocytes (main cell) By increasing Na-K ATPase on basolateral surface, you can increase influx of Na+ from the airspaces via ENaC Water follow Na+ Na-K ATPase is inhibited by oubain ENaC is inhibited by amiloride This process is accelerated by beta-agonists Can upregulate in at risk infants w/ corticosteroids to mom and infant  more type II cells  more surfactant and more efflux Dexamethasone also helps increase expression of ENaC How can you measure the efficacy of alveolar fluid clearance in the lung? Inject a mix of regular and radioactive albumin

Fibrin-rich “hyaline membranes”
Alveolar filling pattern with air bronchograms - Note that this is alveolar process in that there are empty bronchograms and the shadow is unaffected by the patient standing upright/gravity

Exudative (Acute) Phase Diffuse Alveolar Damage (DAD)
Clinical: Adult respiratory distress syndrome (ARDS) Identifiable lung injury 0-2 wks before Acute dyspnea, hypoxemia, decreased compliance Radiology: Diffuse alveolar filling pattern Pathology: Endo- or epithelial injury, Type II cell hyperplasia First 2 wks after injury: edema  fibrin

Respiratory distress syndrome of newborns
Clinical: Prematurity Tachypnea, intercostal muscle retraction, hypoxemia Radiology: Diffuse alveolar filling pattern with air bronchograms Pathology: Insufficient surfactant production by type II cells Atelectasis  hypoxia/acidosis  epith necrosis Diffuse intra-alveolar hyaline membrane formation (exudative DAD) - They get fibrin formation

RBCs filling alveolar spaces Alveolar Hemorrhage Syndrome

Causes of Alveolar Hemorrhage Syndrome
Goodpasture’s syndrome Acute lupus pneumonitis Wegener’s granulomatosis

Goodpasture’s syndrome
Clinical: Young adults, M>F Radiology: Diffuse alveolar pattern Pathology: Anti-basement membrane IgG antibodies damage pulmonary and renal basement membranes Linear IgG and C’ deposition by ImmunoFluorescence and Electron microscopy Anti-GBM IgG is detectable in serum

Acute lupus pneumonitis
Clinical: Component of systemic lupus erythematosus (SLE) Children & adults, F>M Radiology: Diffuse alveolar pattern Pathology: Necrotizing capillaritis due to immune complexes Granular IgG/C’ deposition by IF and EM ANA or anti-dsDNA Ab detectable in serum

Lipid Aspiration of cooked fat

Aspiration Clinical: Radiology: Pathology: Children - foreign bodies
Adults - gastric acid, food Lipids, e.g. mineral oil laxatives or nasal drops (“exogenous lipid pneumonia”) Radiology: Focal alveolar pattern typically RLL Pathology: Gastric acid  DAD Foreign material  foreign body giant cell reaction with exogenous material - Where you aspirate determines on what lobe things go to

Endogenous lipoid pneumonia (“post-obstructive”, “golden” pneumonia)
Clinical: Central major airway obstruction Radiology: Peripheral infiltrates +/- central mass Pathology: Increased numbers of foamy alveolar macrophages distal to an airway obstruction, +/- cholesterol clefts, without foreign material

Foamy Macrophages Endogenous (Post-Obstructive) Lipid Pneumonia

Transudate in interstitium and alveolar airspaces
Capillary congestion Severe Pulmonary Edema

Pulmonary Edema Clinical: Radiology: Pathology:
Cardiogenic: LV pump failure, mitral valve stenosis Radiology: Incr. vascular markings, reticular +/- nodular Think Kerley B lines Pathology: Venous and capillary congestion Incr. free water in the interstitium +/- alveoli - Cardiogenic edema  increased water markings

Define ARDS Common Causes? Most Common Cause?
Acute Respiratory Distress Syndrome A clinical definition Acute onset Bilateral infiltrates on CXR Pulmonary Artery wedge pressure <18 or no evidence of left atrial hypertension PaO2/FIO2 < 300: Acute Lung Injury PaO2/FIO2 < 200: ARDS Common Causes? Most Common Cause? Indirect Lung Injury Sepsis Multiple Trauma Other Shock Acute Pancreatitis Multiple Transfusions Drug Toxicity Direct Lung Injury Pneumonia Aspiration Pulmonary Contusion Fat Emboli Inhalational Injury Near Drowning

Septic Shock Inflammatory Cytokines
Nitric Oxide from Vasc. Endothelium Low Systemic Vascular Resistance High Cardiac Output Hypotension To sum it up The chest is hyperdynamic as the heart is going crazy trying to supply the body Wide pulse pressure ex: (90/30) Brisk capillary refill Hyperdynamic Decreased urine output Decreased mental status Lactic Acidosis – b/c all these tissues are underperfused

Continuum and Definitions of Septic Shock
Infection Inflammatory response to microorganisms, or Invasion of normally sterile tissues Systemic Inflammatory Response Syndrome (SIRS) Systemic response to a variety of processes Fever, tachypnea, tachycardia, Leukocytosis Be careful; there are some infections that resemble sepsis but AREN’T despite the overlap with SIRS It all comes down to is it multiorgan?!?! Sepsis Infection plus 2 SIRS criteria Severe Sepsis Organ dysfunction (ex: hypotension, hypoxemia) Septic shock Hypotension despite fluid resuscitation Multiple Organ Dysfunction Syndrome (MODS) Altered organ function in an acutely ill patient Homeostasis cannot be maintained without intervention

Acute or Exudative Phase of ARDS
Exposure to a Risk Factor Alveolar Capillary Injury Epithelial Cell Injury Leak of Protein Rich Fluid into Interstitium and Alveolus Arterial hypoxemia refractory to oxygen = SHUNT! Bilateral patchy infiltrates VERY Decreased lung compliance (need PEEP) Rapid onset respiratory failure

Macs are like “what’s all this crap in my house”
Macs secretes stuff and calls over the neutrophils = the bad asses There’s hyaline membrane formation And the type II cells are hyperplastic to replace the necrotic type I cells _______________________________ If you overdo the heroin, you start the process from the vascular system If you overdo the crack pipe, you start the process inside the alveoli

So you either recover or you don’t
Type II cells are really impt in the recovery phase. They will move ions out of the alveoli and fluid will flow out. They are also responsible for regeneration of type I cells that were destroyed in ARDS

Proliferative or Fibrotic Phase of ARDS
Fibrosing Alveolitis Procollagen III peptide present day 1 or 2 Histologic changes day 5-7 Clinical Evidence Day 5-10 Persistent hypoxemia Increased alveolar dead space Further decrease in compliance Pulmonary hypertension - Obliteration of pulmonary capillary bed Steroids are helpful in this stage (but not in the acute/exudative phase) When ventilating a patient, make sure you don’t overdo it You don’t want to injure the healthy parts of the lung Use a low tidal volume at a higher frequency (despite the inability to get rid of CO2) Initially the capillaries were well perfused and the problem was with the alveoli But later on, the fibrosis obliterates the capillaries The PCO2 increases as a consequence of the increased alveolar dead space

2 General Classes of Respiratory Failure
Hypoxemic - inadequate O2 delivery Hypercapnic - respiratory acidosis (high PCO2) secondary to failure to adequately ventilate - Think about consciousness, syncope, thinking, cardiac arrhythmias from hypoxemia

Hypoxemic respiratory failure is usually due to lung failure
Hypercapnic respiratory failure is usually due to cardiac pump failure

Hypoxemic Failure Physiological Causes
Decreased PIO2 Decreased VA C. Ventilation/Perfusion [V/Q] Mismatch D. RL Shunt E. Diffusion Limitation only problematic during exercise Decreased VA is hypoxemia and hypercapnia Diffusion limitation is only problematic when there is exercise stress V/Q mismatch is the most common

Physiologic Causes of Hypoxemic Failure
Decreased PIO2 As with high altitude Decreased VA Hypoxia (PAO2) secondary from hypercapnia (PACO2) V/Q Mismatch Can be corrected by supplemental O2 RL Shunt Refractory to O2 treatment Diffusion Limitation Only a problem under exercise stress due to increased CO (common in pulmonary fibrosis)

Physiologic Causes of Hypercapnic Failure
Increased VE 2o  VCO2 fever, trauma Increased VE 2o  VD/VT pulmonary embolism, emphysema Decreased VA Many, many causes Causes of Decreased Minute Ventilation 1. Respiratory drive (e.g., narcotic overdose) 2. Nerve conduction (e.g., cervical cord trauma, Guillain-Barre syndrome) 3. Neuromuscular (e.g., myasthenia gravis, muscle atrophy) 4. Chest wall (e.g., flail chest, kyphoscoliosis) 5. Lung disease (e.g., asthma, COPD) 6. Upper airway obstruction

Arterial blood gases and diagnosis
pH pCO2 HCO3- Normal Acute Failure Compensated Failure Acute and Chronic Failure

respiratory muscle weakness
Clinical signs of respiratory muscle weakness 1. Tachypnea 2. Decreasing Vital Capacity 3. Decreasing Maximum Inspiratory Force 4. Ineffective cough Note: Hypercapnea is a late sign of respiratory failure due to neuromuscular limitations. Support ventilation prior to Resp. Failure

How do you TREAT Hypercapnic Failure?
A. Diagnose and treat underlying cause Consider respiratory stimulants 1. Naloxone (opioid antagonist) 2. Controlled hypoxemia (in proper clinical settings) 3. Chemicals (rarely effective; xanthines, progesterone) Assist devices 1. Negative pressure - Iron lung, Cuirass ventilator 2. Nasal/Face Mask CPAP - Continuous Positive Airway Pressure 3. Cycled CPAP (BiPAP) - Bilevel Positive Airway Pressure D. Threshold for tracheal intubation and positive pressure ventilation - usually low pH. Mechanical ventilation techniques 1. Breath initiation/Respiratory Rate 2. Tidal volume 3. Patient regulation of VE -Spontaneous breaths - Tidal volume 4. PEEP = Positive End Expiratory Pressure

Damage to these parts of the brain are associated with what types of breathing patterns?
Forebrain Post hyperventilation apnea Cheyne Stokes Respiraton: crescendo-decrescendo Due to problems w/ CNS or HF Hypothalamus Central reflex hypernea Pons Apneustic breathing – pause btw inspiration and expiration Cluster breathing Ataxic breathing Medullary Ondine’s Curse – no involuntary control of breathing

What is Sleep Apnea? Repetitive episodes of diminished air flow associated with oxygen desaturation or arousal Patients may have hundreds of events per night Two types: Obstructive You try to breath, but the airway is closed Relaxation of upper airway muscles Central There is no stimulus to breath Relaxation of lower airway muscles Associated w/: Snoring Obesity (can still occur in normal body habitus) Mixed w/ Cheyne-Stokes or hypoventilation HTN Tachycardia Narrow airway, edema, large neck Risk factors: smoking, alcohol, GERD, brain disease, heart disease, ADHD (any kid who snores, evaluate!) IS a risk factor for: HTN, MI, Stroke, RHF, pulmonary HTN, Diabetes, Motor vehicle accidents, HA, Depression, Shorter life span by 7-10yrs

Who needs evaluated for OSA ?
Snoring associated with HTN, obesity, DM, or any vascular disease. Snoring in individuals with unrefreshing sleep, excessive sleepiness or insomnia. All children who snore (American Academy Pediatric).

OSA Treatment Continuous Positive Airway Pressure (CPAP, BiPAP)
Surgery – chance of success Dental Device Weight Loss Medication Avoidance of alcohol Sleep on side

Respiratory Failure Lung Failure Ventilation Failure
Gas Exchange Failure Hypoxemia Hypercapnia Low Inspired O2 Diffusion Limit CNS Depression Shunt Muscular Fatigue Poor VA Mechanical Failure VQ Mismatch

Causes of Hypercapnic Failure
Normal Ventilation Increased Production of CO2 (fever, tramua) Normal Ventilation with Increased Deadspace (VQ Mismatch) Pulmonary Embolus Emphysema Decreased Ventilation (lots of causes) Breath Holding Obesity Drugs

What’s the Poor Mans Rule of Thumb for Acute versus Chronic Respiratory Acidosis?
Acute Respiratory Acidosis -HCO3 rise by 1 mEq/L for each 10 mmHg PCO2 Chronic Respiratory Acidosis -HCO3 rise by 4 mEq/L for each 10 mmHg PCO2 The body has had time to renally/metabolically compensate for the respiratory acidosis by increasing HCO3- amts to counteract the drop in pH.

What are the causes of dyspnea?
Abnormal gas exchange or acidosis Hypercapnia – sensed in medulla, carotid bodies Hypoxemia – sensed in carotid bodies Low pH - sensed in medulla, carotid bodies Increased neuromuscular stimuli Chest wall muscle receptors Parenchymal and airway receptors Abnormal perception/psychogenic

If given these Sxs in the history, what diseases
should you be thinking about?

If given these findings in the physical exam,
what diseases should you be thinking about?

If given these findings in the physical exam,
what diseases should you be thinking about? - Hepatomegaly could interfere w/ nml diaphragmatic fxn  dyspnea

If given these diagnostic results,
what diseases should you be thinking about?

What are these diagnostic tests useful for
in making diagnoses?

Congrats! You’re Done! Good luck on the exam &

Quiz Yourself - Respiratory

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