Course Outline 1 2 3 Obstructive and Restrictive

Course Outline 1. สรรวทยาของระบบหายใจ 2. ความผดปกตของระบบหายใจ 3. Obstructive and Restrictive Defects 4. Obstructive Disorders 5. Restrictive Disorder 6. Pulmonary Infection

. 1สรรวทยาของระบบทางเดนหายใจ โครงสรางระบบหายใจ แบงเปน 2 สวน 1. The Upper Respiratory Tract - Nose - Pharynx - Larynx - Trachea 2. The Lower Respiratory Tract - Bronchioi - Alveoli

Anatomy of the respiratory tract. Histology of respiratory epithelium. With the exception of the pharynx, epiglottis and vocal cords, the respiratory tract is lined by specialised epithelium compring ciliated columnar epithelia cells with admixed mucus-secreting goblet cells and scattered neuroendocrine cells.

Figure 14. 2 Structure and nomenclature of the lower respiratory tract.

. 1สรรวทยาของระบบทางเดนหายใจ การหายใจ (Respiratory) แบงเปน • External Respiration O 2 g Lung g Blood g • Internal Respiration Intracellular metabolism Tissues

. 1สรรวทยาของระบบหายใจ ภาวะททำใหเกดการหายใจปกต • • Conducting airways Thoracic musculoskeletal system Neurochemical regulator control Normal lung tissue ภาวะททำใหการหายใจไมพอเพยง • • • Asthma Bronchitis Emphysema etc เชน

. 1สรรวทยาของระบบหายใจ fig 13 -1 Microscopic structure of the alveolar wall. Note that the basement membrane (yellow) is thin on one side and widened where it is continuous with the interstitial space. Portions of interstitial cells are shown.

. 1สรรวทยาของระบบหายใจ Table 1 Lung Volumes and Capacities Volume Symbol Measurement Tidal volume (about 500 m. L at rest) TV Amount of air that moves into and out of the lungs with each breath Inspiratory reserve volume (about 3000 m. L) IRV Maximum amount of air that can be inhaled from the point of maximal expiration Expiration reserve volume (about 1100 m. L) ERV Maximum volume of air that can be exhaled from the resting end expiratory level Residual volume (about 1200 m. L) RV Volume of air remaining in the lungs after maximal expiration. This volume cannot be measured with the spirometer; it is measured indirectly using methods such as the helium dilution method, the nitrogen washout technique, or body plethymography

. 1สรรวทยาของระบบหายใจ ปรมาตรของปอด (Lung Volumes) Table 1 Lung Volumes and Capacities (continue) Functional residual capacity (about 2300 m. L) FRV Volume of air remaining in the lungs at end -expiration (sum of RV and ERV) Inspiratory capacity (about 3500 m. L) IC Sum of IRV and TV Vital capacity (about 4600 m. L) VC Maximal amount of air that can be exhaled from the point of maximal inspiration Total lung capacity (about 5800 m. L) TLC Total amount of air that the lungs can hold; it is the sum of all the volume components after maximal inspiration. This value is about 20% less in females than in males.

. 1สรรวทยาของระบบหายใจ การควบคมการหายใจ (Regulation of Respiration) • ควบคมอตรา (rate) และจงหวะ (rhythm) โดยกลไก 3 อยาง : 1. Neural Control - Respiratory center in medulla, pons and brain stem - Phrenic nerve and intercostal nerve - Stimulate by impulse from cerebral cortex and Pco 2, H+ of blood and CSF 2. Chemical Control - Chemoreceptors sensitive to Po 2 , Pco 2 and p. H of blood - Peripheral chemoreceptors, aortic bodies and carotid bodies - Central chemoreceptors (medulla) sensitive to Pco 2 and H+ Co 2 + H 2 O D H 2 CO 2 D H+ + HCO 33. Mechanoreceptor - pulmonary stretch receptors - irritant receptors

. 1สรรวทยาการหายใจ Acid – Base Balance Depend on both alveola ventilation and perfusion and gas exchange • p. H of blood – 7. 35 – 7. 45 • ควบคมโดย p. H buffer system ในเลอดและของเหลวของรางกาย • Buffer system ทสำคญคอ bicarbonate/ carbondioxide (HCO 3 -/ Co 2) buffer system Co 2 + H 2 O D H 2 CO 3 D H+ + HCO 3 • Buffer system อนๆ ไดแก ฮโมโกลบน Hb. H D H- + H+ Oxy - Hb. H D Oxy. Hb- + H+ • Non – bicarbonate buffers อนๆ ไดแก plasma protien and inorganic phosphates/ organic phosphates H 2 PO 4 - D H+ + HPO 42 -

. 1สรรวทยาการหายใจ คาปกตจากการตรวจ arterial blood gas Pa. O 2 = 75 – 100 mm. Hg Pa. CO 2 = 35 -45 mm. Hg p. H = 7. 35 – 7. 45 HCO 3 = 22 – 26 m. Eg/ liter O 2 saturation = 97%

2. ความผดปกตของการหายใจ อตราการหายใจปกต ผใหญ 12 – 16 ครง เดก 35 ครง / นาท Table of Term for Varous Breathing Activities Hyperpnea Increased breathing movement Eupnea Normal breathing movements Hyporpnea Decreased breathing movements Apnea arrestd breathing Bradypnea Decreased rate of breathing Tachypnea Increased rate of breathing Dyspnea Labored breathing (subjective feeling) Asphyxia Inability to breathe Orthopnea Labored breathing, except in the sitting or upright position

Obstructive and restrictive defects • Two major patterns of abnormal pulmonary function test 1. Obstructive defects e. g. asthema 2. Restrictive defects e. g. pulmonary fibrosis – Obstructive airways disease, RV and TLC mildly increase, FEV 1, FVC + FEV 1 : VC ratio decreased – Results of pulmonary function test depend on clinical state of patient and useful for follow-up patients – Restrictive disease restrict lung movement, decrease RV and TLC, FEV 1 and VC may be reduced

Table 14 -3. Respiratory function tests and their diagnostic significance Test Diagnostic significance Peak expiratory flow Reduced with obstructed airways or muscle weakness rate (PEFR) Forced expiratory volume in 1 second (FEV 1) Reduced with obstructed airways, pulmonary fibrosis or oedema, or muscle weakness Vital capacity (VC) Reduced with reduction in effective lung volume (fibrosis or oedema), chest wall deformity (kyphoscoliosis), or muscle weakness Increased in emphysema Forced expiratory ratio (FEV 1: VC) Low in obstructive defects Normal or high in restrictive defects Carbon monoxide transfer (TCO) Reduced in pulmonary fibrosis, emphysema, oedema, embolism and anaemia Exhaled nitric oxide (NO) Increased in asthma, bronchiectasis and infections Decreased in pulmonary hypertension, cigarette smokers and after treatment with corticosteroids

Respiratory Failure เกดจาก • Ventilation defects – Nervous, e. g. nacrotic, encephalitis cerebral space occupuing lesion, poliomyelitis, motor neurones disease – Mechanical e. g. airway obstruction trauma, kypho scoliosis, muscle disease, pleural effusion, obesity (Pickwickian syndrome) 1. Restrictive defects e. g. pulmonary fibrosis – Perfusion defects e. g. cardiac failure or multiple pulmonary emboli – Gas exchange defects e. g. emphysema, diffuse pulmonary fibrosis

3. Obstructive Disorder 3. 1 Acute Obstruction Etiology - Foreign bodies aspiration - Swelling of trachea and pharynx - Spasm of larynx and bronchi - Tongue - Hypersecretion of muscus - Chemical irritation - Severe anaphylactic secretion - Infections

Figure 14. 17 Bronchial obstruction. The obstructing lesion causes a lipid or infective pneumonia in the distal lung and, if unrelieved, distal bronchiectasis.

Figure 14. 5 Laryngeal carcinoma. The tumour is protruding into the larynx and invading the underlying tissues

3. Obstructive Disorder 3. 1 Acute Obstructive Sign and Symptoms - Marked respiratory effort - Sternal, abdominal and intercostal retraction - Extreme anxiety - Cyanosis and coma Partial airway obstruction - h RR and h HR - Respiratory straidor - dyspnea

3. Obstructive Disorder 3. 1 Acute Obstructive Bronchiolitis - Viral infection : respiratory syncytial virus, adenovirus, parainluenza and rhinovirus - Inflamation of bronchiolar mucosa g obstruction of small bronchioles - Occur in infants less than 18 month old with fever, rhinorhea, prolonged expiratory phase, wheezing, nasal flaring and chest retraction

3. Obstructive Disorder 3. 1 Acute Obstructive Laryngotracheobronchitis - Viral infection : type I, III, parainluenza adenovirus and rhinovirus and respiratory syncytial virus - Extensive edema of subglotic area (larynx, trachea and bronchi with spiratory straidor)

3. Obstructive Disorder 3. 1 Acute Obstructive Acute epiglottitis - Emergency case - Sudden obstruction of URT - Inflammation of epiglottis, aryepiglottic folds and supraglottic area by hemophilus influenzae type B - Pt. 3 -7 yrs with high fever and swallow difficulty

3. Obstructive Disorder 3. 2 Chronic Obstruction - Chronic Obstructive pulmonary (lung) diseases (COPD, COLD) - Alveola hypoventilation, hypoxemia, h CO 2 and compensated respiratory acidosis - Four groups of diseases 1. Emphysema 2. Chronic bronchitis 3. Bronchial asthma 4. Bronchiectasis

3. Obstructive Disorder Table 15 -3 -- Disorders Associated with Airflow Obstruction: The Spectrum of Chronic Obstructive Pulmonary Disease Clinical Term Anato mic Site Major Pathologic Changes Etiology Signs/Symptoms Chronic bronchitis Bronc hus Mucous gland hyperplasia, hypersecretion Tobacco smoke, air pollutants Cough, sputum production Bronchiectasis Bronc hus Airway dilation and scarring Persistent or severe infections Cough, purulent sputum, fever Asthma Bronc hus Smooth muscle hyperplasia, excess mucus, inflammation Immunologic or undefined causes Episodic wheezing, cough, dyspnea Emphysema Acinus Airspace enlargement; wall destruction Tobacco smoke Dyspnea Small airway disease, * bronchiolitis Bronc hiole Inflammatory scarring/obliteration Tobacco smoke, air pollutants, miscellaneous Cough, dyspnea *A feature of chronic bronchitis (see text).

3. Obstructive Disorder 3. 2 Chronic Obstruction Emphysema - Enlarge of the airspace distal to the terminal bronchioles with destruction of the alveolar walls - Diseases affecting chronic cigarette smokers - In non smokers, genetic dificiency of α, - antitrypsin - Emphysema and chronic bronchitis usually coexist and clinically grouped together under COPD - Chronic bronchitis is defined clinically as productive cough 3 months per year for at least two years

3. Obstructive Disorder Figure 15 -5 A, Diagram of normal structures within the acinus, the fundamental unit of the lung. A terminal bronchiole (not shown) is immediately proximal to the respiratory bronchiole. B, Centriacinar emphysema with dilation that initially affects the respiratory bronchioles. C, Panacinar emphysema with initial distention of the peripheral structures (i. e. , the alveolus and alveolar duct); the disease later extends to affect the respiratory bronchioles.

3. Obstructive Disorder Table 15 -4 Emphysema and Chronic Bronchitis Predominant Bronchitis Predominant Emphysema Appearance Blue bloater Pink puffer Age (yr) 40– 45 50– 75 Dyspnea Mild; late Severe; early Cough Early; copious sputum Late; scanty sputum Infections Common Occasional Respiratory insufficiency Repeated Terminal Cor pulmonale Common Rare; terminal Airway resistance Increased Normal or slightly increased Normal Low Prominent vessels large heart Hyperinflation small heart Elastic recoil Chest radiograph

CLINICAL CORRELATE Respiratory Control in Chronic Obstructive Pulmonary Disease Chronic obstructive pulmonary disease (COPD) is most often associated with tobacco smoking and may be exacerbated by occupational exposure to certain pollutants. It is characterized by chronic bronchitis (coughing with sputum production) and emphysema (destruction of alveolar walls resulting in fewer, enlarged "alveoli" with reduction in total surface area for gas diffusion). As a result, patients with this disease become hypoxic and hypercapnic (Pa. O 2 is below normal and Pa. CO 2 is elevated); p. H is somewhat lower than normal, although significant compensation occurs by elevation of HCO 3 through renal mechanisms. In other words, the patients suffer from chronic respiratory acidosis, with metabolic compensation. In this state of chronic hypercapnea, normal CSF p. H is maintained by elevation of HCO 3 - in the CSF. The CNS is chronically exposed to high Pco 2, and the central chemoreceptors become unresponsive to CO 2. Thus, patients with COPD develop "hypoxic respiratory drive, " in which respiratory drive is mainly mediated by peripheral chemoreceptor responses to low Pa. O 2. When an acute exacerbation arises in such a patient, if supplemental O 2 is administered carelessly, results can be catastrophic and even fatal: Pa. O 2 will rise, but respiratory drive may fail as a result, causing a fall in minute ventilation and a further rise in Pa. CO 2. Ventilatory support with some supplemental oxygen may be beneficial, but suppression of ventilatory drive must be avoided.

3. Obstructive Disorder Figure 15 -6 A , Centriacinar emphysema. Central areas show marked emphysematous damage (E), surrounded by relatively spared alveolar spaces. B , Panacinar emphysema involving the entire pulmonary architecture.

3. Obstructive Disorder Figure 15 -7 Pathogenesis of emphysema. The protease-antiprotease imbalance and oxidant-antioxidant imbalance are additive in their effects and contribute to tissue damage. α 1 -antitrypsin (α 1 -AT) deficiency can be either congenital or "functional" as a result of oxidative inactivation. See text for details. IL-8, interleukin 8; LTB 4, leukotriene B 4; TNF, tumor necrosis factor.

3. Obstructive Disorder Figure 15 -8 Schematic representation of evolution of chronic bronchitis (left) and emphysema (right). Although both can culminate in chronic bronchitis and emphysema, the pathways are different, and either one may predominate. The dashed arrows on the left indicate that in the natural history of chronic bronchitis, it is not known whethere is a predictable progression from obstruction in small airways to chronic (obstructive) bronchitis. )Redrawn from Fishman AP: The spectrum of chronic obstructive disease of the airways. In Fishman AP (ed): Pulmonary Diseases and Disorders, 2 nd ed. New York, Mc. Graw-Hill, 1988, p. 1164. )

3. Obstructive Disorder • • This is severe emphysematous change characterised by large bullae at the pleural surface. Histology shows the presence of enlarged alveolar spaces characteristic of emphysema in comparison with that in a normal lung

3. Obstructive Disorder Chronic Bronchitis - Diagnosis based on clinical grounds : a persistent productive cough for at least 3 consecutive months in at least 2 consecutive years - Two forms of chronic bronchitis 1. Simple chronic bronchitis 2. Obstructive chronic bronchitis

3. Obstructive Disorder Pathology of chronic bronchitis FIGURE 12 -41. Chronic bronchitis. Morphological changes in chronic bronchitis.

3. Obstructive Disorder Figure 15 -8 Schematic representation of evolution of chronic bronchitis (left) and emphysema (right). Although both can culminate in chronic bronchitis and emphysema, the pathways are different, and either one may predominate. The dashed arrows on the left indicate that in the natural history of chronic bronchitis, it is not known whethere is a predictable progression from obstruction in small airways to chronic (obstructive) bronchitis. )Redrawn from Fishman AP: The spectrum of chronic obstructive disease of the airways. In Fishman AP (ed): Pulmonary Diseases and Disorders, 2 nd ed. New York, Mc. Graw-Hill, 1988, p. 1164. )

3. Obstructive Disorder fig - 3 พยาธกำเนดของโรคถงลมโปงพอง และหลอดลมอกเสบเรอรง Anatomic distribution of pure chronic bronchitis and pure emphysema. In chronic bronchitis the small-airway disease (chronic bronchiolitis) results in airflow obstruction, while the large-airway disease is primarily responsible for the mucus hypersecretion.

3. Obstructive Disorder Clinical Course - Productive cough for many years - Exertional dyspnea and cyanosis - Cyanosis and edema secondary to cor pulmonale led to the label “blue bloater”

3. Obstructive Disorder Bronchial Asthma - Bronchospasm causes severeairway obstruction - Paroxysms of wheezing, dyspnea and cough - Pts. have acute episodes of asthma alternate with asymptomatic periods or superimposed on chronic airway obstruction - Severe acute asthma unresponsive to theraphy is termed “Status asthmaticus”

3. Obstructive Disorder Bronchial Asthma - Two types of asthma : extrinsic (allergic) and intrinsic (idio syncratic) - or classified according to precipitating factors Table 3 Types of Asthma Precipating Factor* Mechanism Immunologic reaction Atopic Non reaginic Pharmacologic (e. g. aspirin-sensitive) Occupational Allergic Bronchopulmonary aspergilliosis Specific allergens Respiratory tract infection Aspirin Type I (Ig. E) immune reaction Unknown, hyperreactive airways Decreased prostaglands, increased leukotrines Type I immune reactions Type I and III immune reaction Chemical challenge Antigen (spore) challenge *All types may be precipated by cold, stress, excercise All have hyperreactive airways

3. Obstructive Disorder Pathogenesis of Athma fig 13 -11 A model for allergic asthma. A, Inhaled allergens (antigen) elicit a TH 2 -dominated response favoring Ig. E production and eosinophil recruitment (priming or sensitization). B, On re-exposure to antigen (Ag), the immediate reaction is triggered by Ag-induced cross-linking of Ig. E bound to Ig. E receptors on mast cells in the airways. These cells release preformed mediators that open tight junctions between epithelial cells. Antigen can then enter the mucosa to activate mucosal mast cells and eosinophils, which in turn release additional mediators. Collectively, either directly or via neuronal reflexes, the mediators induce bronchospasm, increased vascular permeability, and mucus production and recruit additional mediatorreleasing cells from the blood. C, The arrival of recruited leukocytes (neutrophils, eosinophils, and basophils; also lymphocytes and monocytes [not shown]) signals the initiation of the late phase of asthma and a fresh round of mediator release from leukocytes, endothelium, and epithelial cells. Factors, particularly from eosinophils (e. g. , major basic protein, eosinophil cationic protein), also cause damage to the epithelium.

3. Obstructive Disorder Figure 14. 20 Asthma. Tracheal mucous plug (arrowed) in death from status asthmaticus. Histological section of lung at autopsy showing occlusion of airways by oedema and mucous plugs (arrowed) accompanied by alveolar distension with entrapped gas.

3. Obstructive Disorder : Asthma Morphology - Grossy, lungs are overdistended due to over inflation and may be small area of atelectasis - Histologically, the mucus plugs contain whorls of shed epithelium (Curschmann spirals), numerous eosinophils and Charcot – Leyden crystals - Characteristic findings of asthma are called “airway remodeling”

3. Obstructive Disorder : Asthma Figure 13 -12 Comparison of a normal bronchiole with that in a patient with asthma. Note the accumulation of mucus in the bronchial lumen resulting from an increase in the number of mucussecreting goblet cells in the mucosa and hypertrophy of submucosal mucus glands. In addition, there is intense chronic inflammation due to recruitment of eosinophils, macrophages, and other inflammatory cells. Basement membrane underlying the mucosal epithelium is thickened, and there is hypertrophy and hyperplasia of smooth muscle cells.

3. Obstructive Disorder Clinical Course – Asthma attack is characterized by severe dyspnea and wheezing and difficult in expiration – Progressive hyperinflation of lung – Attack last for 1 to several hours and subside either spontaneous or with therapy – Occassionally, severe paroxysm occurs and persists for days or weeks (Status asthmaticus) – Associated hypercapnia, acidosis and severe hypoxia may be fatal

3. Obstructive Disorder Bronchiectasis - Permanent dilatation of bronchi and bronchioles caused by destruction of the muscle and elastic supporting tissue - Resulting from or associated with chronic necrotizing infections - Characteristic symptom complex dominated by cough and expectoration of copious amounts of purulent sputum.

3. Obstructive Disorder : Bronchiectasis Pathogenesis Obstruction Chronic persistent normal clearance mechanisms impaired secondary infection inflammatory damaged to bronchial wall accumulating exudate irreversible dilatation

3. Obstructive Disorder : Bronchiectasis Morphology Figure 14. 13 Bronchiectasis. Permanent dilatation of bronchi.

3. Obstructive Disorder : Bronchiectasis Morphology - Usually affect lower lobes - most severe in the more distal bronchi and bronchioles - Grossy, dilatation of bronchi and bronchioles with cystic pattern, emphysema and atlectasis may be seen - Histologically in full-blown and active case, acute and chronic inflammatory exudate within the wall of bronchi and bronchioles - Desquamation of lining epithelium and ulceration - Mixed flora can be cultured - Severe injury caused abnormal dilatation and scarring - In chronic case, fibrosis of bronchial and bronchiolar walls and peribronchiolar fibrosis, and sometimes lung absesses are formed

3. Obstructive Disorder : Bronchiectasis Clinical Course - Severe, persistent cough with expectorations of mucopurulent sputum - Sputum may contain flecks of blood - Frank hemoptysis can occur - Clubbing fingers may develop in severe and widespread bronchiectasis - Hypoxemia, hypercapnia, pulmonary hypertension and (rarely) corpulmonale

4. restrictive Disorders ความผดปกตของการขยายตวของชองอกและปอด “Restrictive disease” : reduced expansion of lung parenchyma accompanied by decreased total lung capacity สาเหต. 1 Musculoskeletal defects and neuromuscular impairment 2. Kyphoscoliosis 3. Muscular dystrophy e. g. Guillain – Barre Syndrome, myasthenia gravis 4. Drugs and toxins e. g. Curare, Succinylcholine 5. Obesity, e. g. pickwickian syndrome, sleep apnea, abdominal distension 6. Chest or abdominal pain 7. Pleura abnormalities, e. g. pleurisy or pleuritis, pleural effusion, pneumothorax, hemothorax

5. Surfactant Deficiency “Pulmonary Surfactant” : Complex lipoprotein containing phospholipid (dipalmitoyl phosphatidyl choline) produced by pneumocytes type II. Surfactant reduces surface tension of airways and alveoli and increase lung compliance, reducing the work of breathing

5. Surfactant Deficiency Hyaline membrane Diseases (Idiopathic Respiratory Distress syndrome) - Pulmonary surfactant deficiency in the newborn - Leading cause of morbidity and mortality among premature infants - The incidence varies inversely with gestational age and birth weight

5. Surfactant Deficiency : Hyaline Membrane Diseases Pathogenesis fig 7 -22 Pathophysiology of respiratory distress syndrome

5. Surfactant Deficiency : Hyaline Membrane Diseases Pathology fig 7 -23 Hyaline membrane disease (H&E stain). There is alternating atelectasis and dilation of the alveoli. Note the eosinophilic thick hyaline membranes lining the dilated alveoli.

5. Surfactant Deficiency : Hyaline Membrane Diseases Clinical Course - The first symptom appear within an hour of birth - Increase respiratory effort, forceful intercostal retraction - Die of asphyxia in severe cases - In mild cases, the symptoms peak within 3 days and gradual improvement

5. Surfactant Deficiency : Hyaline Membrane Diseases Complication - Patent ductus artereosus - Intraventricular hemorrhage - Necrotizing enterocolitis Prevention and treatment - Delaying labor g lung reach maturity - Asses fetal lung maturity by analysis of amniotic fluid phospholipids - Prophylactic administration of exogeneous surfactant

7. Alteration of Exchange Adult Respiratory Distress Syndrome (ARDS) or diffuse Alveolar Damage - Clinical syndrome caused by diffuse alveolar capillary and epithelial - Rapid onset of life – treatening respiratory insufficiency, cyanosis and severe hypoxemia and may progress to multisystem failure

7. Alteration of Exchange : ARDS Direct Lung Injury Indirect Lung Injury Common Causes Pneumonia Sepsis Aspiration of gastric contents Severe trauma with shock Uncommon Causes Pulmonary contusion Cardiopulmonary bypass Fat embolism Acute pancreatitis Near-drowning Drug overdose Inhalational injury Transfusion of blood products Reperfusion injury after lung transplantation Uremia Modified from Ware LB, Matthay MA: The acute respiratory distress syndrome. N Engl J Med 342: 1334, 2000. Table 13 -1. Clinical Disorders Associated with the Development of Acute Respiratory Distress Syndrome

7. Alteration of Exchange : ARDS Pathogenesis fig 13 -3 The normal alveolus (left) compared with the injured alveolus in the early phase of acute lung injury and the acute respiratory distress syndrome. Under the influence of proinflammatory cytokines such as IL-8, IL-1, and TNF (released by macrophages), neutrophils initially undergo sequestration in the pulmonary microvasculature, followed by margination and egress into the alveolar space, where they undergo activation. Activated neutrophils release a variety of factors such as leukotrienes, oxidants, proteases, and plateletactivating factor (PAF), which contribute to local tissue damage, accumulation of edema fluid in the airspaces, surfactant inactivation, and hyaline membrane formation. Subsequently, the release of macrophage-derived fibrogenic cytokines such as transforming growth factor β (TGF-β) and platelet-derived growth factor (PGDF) stimulate fibroblast growth and collagen deposition associated with the healing phase of injury. (Modified from Ware LB, Matthay MA: The acute respiratory distress syndrome. N Engl J Med 342: 1334, 2000. )

7. Alteration of Exchange : ARDS Pathogenesis ORGANIZING STAGE ACUTE STAGE Endothelial injury C 5 a PMN O-2 : OHPlatelets Vascular leakage { Epithelial injury } Edema Hyaline membranes Atelectasis Recovery Type II Cell Proliferation Interstitial Inflamation Interstitial fibrosis Organization Death Figure 12 Pathogenesis of acute respiratory distress syndrome – a consequence of diffuse alveolar damage. PMN : polymorphonulear leukocyte.

7. Alteration of Exchange : ARDS Morphology - Acute phase of ARDS : lungs are dark red, firm, airless and heavy - Histologically : - capillary congestion - necrosis of alveolar epithelium - Interstitial and intra – alveolar edema and hemorrhage - collection of neutrophils in capillaries - presence of Hyaline membrane

7. Alteration of Exchange : ARDS Pathogenesis fig 13 -4 A, Diffuse alveolar damage in acute lung injury and ARDS. Some alveoli are collapsed; others are distended. Many are lined by bright pink hyaline membranes (arrow). B, In the healing stage there is resorption of hyaline membranes with thickened alveolar septa containing inflammatory cells, fibroblasts, and collagen. Numerous atypical type II pneumocytes are seen at this stage (arrows), associated with regeneration and repair.

7. Alteration of Exchange : ARDS Clinical Course - Acute onset of tachypnea and dysnea - Dysnea worsen and patient become cyanosis - Radiologically, diffuse bilateral interstitial and alveolar infiltrates - O 2 theraphy hardly improved hypoxemia, and mechanical ventilation become neccessary - Fatal case, alveolar hypoventilation, progressive hypoxemia, Pa. CO 2 h - Patients who survive ARDS may recover normal lung; pulmonary function, but in severe cases left scarred lungs; respiratory dysfunction; and pulmonary hypertension

Pulmonary Infections

Pulmonary Infections Respiratory tract infections - upper respiratory tract infections (URI) caused by viruses (common cold, pharyngitis) - bacterial, viral, mycoplasmal, and fungal infections of the lung (pneumonia) - Pneumonia can result whenever these defense mechanisms are impaired or whenever the resistance of the host in general is lower

Pulmonary Infections Pneumonia • Factors that affect resistance in general • Chronic diseases, immunologic deficiency, and treatment with immunosuppressive agents, leukopenia, and unusually virulent infections • Loss or suppression of the cough reflex • As a result of coma anesthesia neuromuscular disorder drug or chest pain (this may lead to aspiration of gastric content) • Injury to the mucociliary apparatus • By either impairment of ciliary function or destruction of ciliated epithelium, owing to cigarette smoke, inhalation of hot or corrosive gases, viral diseases, or genetic disturbances (e. g. , the immotile cilia syndrome)

Pulmonary Infections • Interference with the phagocytic or bactericidal action of alveolar macrophage • by alcohol, tobacco smoke, anoxia, or oxygen intoxication • Pulmonary congestion and edema • Accumulation of secretions • in conditions such as cystic fibrosis and bronchial obstruction

Pulmonary Infections Table 15 -8 the Pneumonia syndromes Commuity-Acquired Acute Pneumonia Streptococus pneumoniae Haemophilus influenza Moraxella catarrhalis Staphylococcus aureus Legionella pneumophila Enterobacteriacae (Klebsiella pneumoniae) and Pseudomans spp. Coomunity-Acquired Atypical Pneumonia Mycoplasma pneumoniae Chlamydia spp. (C. Pneumoniae, C. psittaci, C. trachomatis) Viruses : respiratroy syncytical virus, parainfluenza virus (children); influenza A and B (adults); adenovirus (military recruits); SARS*_virus

Pulmonary Infections Nosocomal Pneumonia Gram-negative rods belonging to Enterobacteriaceae (Klebsiella spp. , Serratia marcescenes, Escherichia coli) and Pseudomonas spp. Staphylococcus aureus (usually penicilin-resistant) Aspiration Pneumonia Anaerobic oral flora (Bacteroides, prevotella, Fusobacterium, Peptostreptococcus), admixed with aerobic bacteria (Streptococcus pneumoniae, Staphylococcus aureus, Haemophilas influenzae, and Pseudomonas aeruginosea) Chronic Pneumonia Narcadia Actinomyces Granulomatous : Mycobacterium tuberculosis and atypical mycobacteria, Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis Necrotizing Pneumonia and lung Abscess Anaerobic bacteria (extremely common), with or without mixed aerobic infection Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pyogenes, and type 3 pneumococcus (uncommon)

Pulmonary Infections Pneumonia in the Immunocompromised Host Cytomegalovirus Pneumocytis carinii Microbacterium avium-intracellulare Invasive aspergillosis Invasivecandidiasis “Usual” bacterial, viral, and fungal organisms (listed above) *SARS, severe acute respiratory syndrome

Community-acquired acute pneumonias • Infection prior to admission in hospital • Often, the bacterial infection follows an upper respiratory tract viral infection • Bacterial invasion of the lung parenchyma causes the alveoli to be filled with an inflammatory exudate, thus causing “consolidation (solidification)” of the pulmonary tissue

Pneumonia Figure 13 -31 A, Acute pneumonia. The congested septal capillaries and extensive neutrophil exudation into alveoli corresponds to early red hepatization. Fibrin nets have not yet formed. B, Early organization of intraalveolar exudate, seen in areas to be streaming through the pores of Kohn (arrow). C, Advanced organizing pneumonia (corresponding to gray hepatization), featuring transformation of exudates to fibromyxoid masses richly infiltrated by macrophages and fibroblasts.

Pathogenesis of pneumococcal lobar pneumonia FIGURE 12 -13. Pathogenesis of pneumococcal lobar pneumonia. Pneumococci, characteristically in pairs (diplococci), multiply rapidly in the alveolar spaces and produce extensive edema. They incite an acute inflammatory response in which polymorphonuclear leukocytes and congestion are prominent (red hepatization). As the inflammatory process progresses, macrophages replace the polymorphonuclear leukocytes and ingest debris (grey hepatization). The process usually resolves, but complications may ensue. PMN =polymorphonuclearneutrophil; RBC = red blood cell.

Predisposing condition • include : • Extreme of age • Chronic disease (congestive heart failure, COPD, Diabetes Congenital or acquire immune deficiency) • Decrease or absent splenic function (sickle cell disease or post splenectomy, which put the patient at risk for infection with encapsulate bacteria such as pneumococcus)

Morphology of Pneumonia • Bronchopneumonia • bacterial infection of the intrapulmonary bronchi, bronchoiles, and adjacent alveoli. • The exudate in these structures consists of polymorphonuclear neutrophils (PMNs) , which accounts for the mucopurulent expectoration • Lobar pneumonia • Diffuse alveolar infection involving an entire lobe or lung • caused by Streptococcus pneumoniae in 90% of cases • often seen in debilitated or terminally ill patients (e. g. elderly patients, alcoholic patients, cancer patients)

Figure 13 -32 Bronchopneumonia. Gross section of lung showing patches of consolidation (arrows). Figure 13 -33 Comparison of bronchopneumonia and lobar pneumonia Figure 13 -34 Lobar pneumonia—gray hepatization, gross photograph. The lower lobe is uniformly consolidated.

Lobar Pneumonia Four stages of the inflammatory response • Congestion • lung is heavy, boggy and red • characterized by vascular engorgement, intraalveolar fluid with few neutrophils, and often the presence of numerous bacteria • Red hepatization • massive confluent exudate with red cells (congestion), neutrophils, and fibrin filling the alveolar spaces • gross appearance : red, firm and airless, with a liver-like consistency

Lobar Pneumonia Four stages of the inflammatory response (cont. ) • Gray hepatization • Progressive disintegration of red cells and the persistance of a fibrinosuppressive exudate • gross appearance : grasyish brown, dry surface • Resolution • Exudate within the alveolar spaces undergoes progressive enzymatic digestion to produce a granular, semifluid, debris • that is resorbed, ingested by macrophages, coughed up, or organized by fibroblasts growing into it • Resolving of pleural fibrinous reaction (pleuritis) undergoes organization, leaving fibrous thickening or permanent adhesions

Lobar Pneumonia Figure 13 -31 A, Acute pneumonia. The congested septal capillaries and extensive neutrophil exudation into alveoli corresponds to early red hepatization. Fibrin nets have not yet formed. B, Early organization of intraalveolar exudate, seen in areas to be streaming through the pores of Kohn (arrow). C, Advanced organizing pneumonia (corresponding to gray hepatization), featuring transformation of exudates to fibromyxoid masses richly infiltrated by macrophages and fibroblasts.

Complications of pneumonia 1. Tissue destruction and necrosis • causing absess formation (particularly common with type 3 pneumococci or Klebsiella infections) 2. spread of infection to the pleural cavity • causing the intrapleural fibrinosuppurative reaction known as empyema 3. organization of the exudate • which may convert a portion of the lung into solid tissue 4. Bacteremic dissemination • to the heart valves, pericardium, brain, kidneys, spleen, or joints causing metastatic abscesses, endocarditis, meningitis or supurative arthritis

Atypical (interstitial) pneumonia • caused by intracellular pathogens such as viruses : - adenovirus; paramyxovirus; cytomegalovirus (CMV), Mycoplasma pneumoniae and Chlamydia pneumoniae which infect alveolar cells • The alveolar septa are usually edematous and contain an inflammatory lymphocytic infiltrate. • PMN is not present

Lung abscess • Lung abscess is a localized area of liquerfactive necrosis in the pulmonary parenchyma • Staphylococcus aureus and Klebsiella pneumoniae are most often isolated Mechanisms of infection • aspiration of infective material • from the upper respiratory or gastrointestinal tracts • pulmonary infarction by septic emboli • bronchial obstruction by foreign bodies or tumors

Lung abscess Figure 13 -36 Pyemic lung abscess in the center of section with complete destruction of underlying parenchyma within the focus of involvement.

Tuberculosis • Mycobacterium tuberculosis • Primary infection : Ghon complex, which consists of - intraparenchymal granulomatous lesion - usually located subpleurally in the midsection of the lungs, and hilar lymphadenopathy - In most cases, this infection resolves spontaneously • Secondary infection - cavitary tuberculosis - Miliary tuberculosis

Tuberculosis Figure 13 -39 The natural history and spectrum of tuberculosis. (Adapted from a sketch provided by Dr. R. K. Kumar, The University of New South Wales, School of Pathology, Sydney, Australia. )

Tuberculosis Figure 13 -35 Primary pulmonary tuberculosis, Ghon complex. The gray -white parenchymal focus is under the pleura in the lower part of the upper lobe. Hilar lymph nodes with caseation are seen on the left.

Tuberculosis Figure 13 -37 Secondary pulmonary tuberculosis. The upper parts of both lungs are riddled with gray-white areas of caseation and multiple areas of softening and cavitation.

Tuberculosis Figure 13 -38 Miliary tuberculosis of the spleen. The cut surface shows numerous gray-white granulomas.

Fungal Infections • Most common in debilitated or immunocompromised patients • The typical lesions of pulmonary fungal infections are granulomas • Invasive candidiasis • Invasive aspergilliosis • Histoplasmosis • Blastomycosis • Coccidiodosis • Pneumocystis carinii pneumonia (PCP) • an intraalveolar infection, typically seen in patients with AIDS