Respiratory Tract Lung Pathology Chapter.pdf

See Targeted Therapy available online at studentconsult.com Lung C H A P T E R 13 CHAPTER OUTLINE Atelectasis (Collapse) 495 Acute Respiratory Distress Syndrome 496 Obstructive Versus Restrictive Pulmonary Diseases 498 Obstructive Lung (Airway) Diseases 498 Emphysema 498 Chronic Bronchitis 502 A...

See Targeted Therapy available online at studentconsult.com Lung C H A P T E R 13 CHAPTER OUTLINE Atelectasis (Collapse) 495 Acute Respiratory Distress Syndrome 496 Obstructive Versus Restrictive Pulmonary Diseases 498 Obstructive Lung (Airway) Diseases 498 Emphysema 498 Chronic Bronchitis 502 Asthma 503 Bronchiectasis 505 Chronic Interstitial (Restrictive, Infiltrative) Lung Diseases 506 Fibrosing Diseases 507 Granulomatous Diseases 512 Pulmonary Eosinophilia 515 Smoking-Related Interstitial Diseases 515 Pulmonary Diseases of Vascular Origin 515 Pulmonary Embolism, Hemorrhage, and Infarction 515 Pulmonary Hypertension 517 Diffuse Alveolar Hemorrhage Syndromes 519 Opportunistic Fungal Infections 535 Pulmonary Disease in Human Immunodeficiency Virus Infection 537 Lung Tumors 537 Carcinomas 537 Carcinoid Tumors 543 Pulmonary Infections 519 Pleural Lesions 544 Community-Acquired Bacterial Pneumonias 520 Community-Acquired Viral Pneumonias 523 Hospital-Acquired Pneumonias 524 Aspiration Pneumonia 525 Lung Abscess 525 Chronic Pneumonias 525 Tuberculosis 526 Histoplasmosis, Coccidioidomycosis, and Blastomycosis 532 Pneumonia in the Immunocompromised Host 533 Pleural Effusion and Pleuritis 544 Pneumothorax, Hemothorax, and Chylothorax 544 Malignant Mesothelioma 544 The major function of the lung is to replenish oxygen and remove carbon dioxide from blood. Developmentally, the respiratory system is an outgrowth from the ventral wall of the foregut. The midline trachea develops two lateral outpouchings, the lung buds. The right lung bud eventually divides into three main bronchi, and the left into two main bronchi, thus giving rise to three lobes on the right and two on the left. The main bronchi branch dichotomously, giving rise to progressively smaller airways, termed bronchioles, which are distinguished from bronchi by the lack of cartilage and submucosal glands within their walls. Additional branching of bronchioles leads to terminal bronchioles; the part of the lung distal to the terminal bronchiole is called an acinus. Pulmonary acini are composed of respiratory bronchioles (emanating from the terminal bronchiole) that proceed into alveolar ducts, which immediately branch into alveolar sacs, the blind ends of the respiratory passages, whose walls are formed entirely of alveoli, the ultimate site of gas exchange. The alveolar walls (or alveolar septa) consist of the following components, proceeding from blood to air (Fig. 13.1): • The capillary endothelium and basement membrane. • The pulmonary interstitium, composed of fine elastic fibers, small bundles of collagen, a few fibroblast-like cells, smooth muscle cells, mast cells, and rare mononuclear cells. Lesions of the Upper Respiratory Tract 545 Acute Infections 545 Nasopharyngeal Carcinoma 546 Laryngeal Tumors 546 • Alveolar epithelium, consisting of a continuous layer of two principal cell types: flattened, plate-like type I pneumocytes covering 95% of the alveolar surface; and rounded type II pneumocytes. The latter synthesize pulmonary surfactant and are the main cell type involved in repair of alveolar epithelium after damage to type I pneumocytes. I A few alveolar macrophages usually lie free within the alveolar space. In the city dwellers, these macrophages often contain phagocytosed carbon particles. Lung diseases can broadly be divided into those affecting (1) the airways, (2) the interstitium, and (3) the pulmonary vascular system. This division into discrete compartments is, of course, deceptively simple. In reality, disease in one compartment often causes secondary alterations of morphology and function in others. ATELECTASIS (COLLAPSE) S Atelectasis, also known as collapse, is loss of lung volume caused by inadequate expansion of air spaces. It results --in shunting of inadequately oxygenated blood from pulmonary arteries into veins, thus giving rise to a ventilationperfusion imbalance and hypoxia. On the basis of the - 495 http://ebooksmedicine.net 496 C H A P T E R 13 Lung ALVEOLAR SPACE Type II pneumocyte Type I pneumocyte Endothelium Interstitial cell CAPILLARY LUMEN Type I pneumocyte ALVEOLAR SPACE Endothelium 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. is now defined as respiratory failure occurring within 1 week of a known clinical insult with bilateral opacities on chest imaging, not fully explained by effusions, atelectasis, cardiac failure, or fluid overload. It is graded based on the severity of the changes in arterial blood oxygenation. Causes are diverse; the shared feature is that all lead to extensive bilateral injury to alveoli. Severe ARDS is characterized by rapid onset of lifethreatening respiratory insufficiency, cyanosis, and severe arterial hypoxemia that is refractory to oxygen therapy. The histologic manifestation of ARDS in the lungs is known as diffuse alveolar damage (DAD). ARDS may occur in a multitude of clinical settings and is associated with primary pulmonary diseases and severe systemic inflammatory disorders such as sepsis. The most frequent triggers of ARDS are pneumonia (35%–45%) and sepsis (30%–35%), followed by aspiration, trauma (including brain injury, abdominal surgery, and multiple fractures), pancreatitis, and transfusion reactions. ARDS should not be confused with respiratory distress syndrome of the newborn; the latter is caused by a deficiency of surfactant caused by prematurity. Pathogenesis underlying mechanism and the distribution of alveolar collapse, atelectasis is classified into three forms • Resorption atelectasis occurs when an obstruction prevents air from reaching distal airways. Any air present gradually becomes absorbed, and alveolar collapse follows. The most common cause of resorption collapse is obstruction of a bronchus. Resorption atelectasis most frequently occurs postoperatively due to intrabronchial mucous or mucopurulent plugs, but also may result from foreign body aspiration (particularly in children), bronchial asthma, bronchiectasis, chronic bronchitis, or intrabronchial tumor, in which it may be the first sign of malignancy. • Compression atelectasis is usually associated with accumulation of fluid, blood, or air within the pleural cavity. A frequent cause is pleural effusions occurring in the setting of congestive heart failure. Leakage of air into the pleural cavity (pneumothorax) also leads to compression atelectasis. Basal atelectasis resulting from a failure to breath deeply commonly occurs in bedridden patients, in patients with ascites, and during and after surgery. • Contraction atelectasis (or cicatrization atelectasis) occurs when local or diffuse fibrosis affecting the lung or the pleura hamper lung expansion. Atelectasis (except when caused by contraction) is potentially reversible and should be treated promptly to prevent hypoxemia and superimposed infection of the collapsed lung. ACUTE RESPIRATORY DISTRESS SYNDROME The epidemiology and definition of acute respiratory distress syndrome (ARDS) are evolving. Formerly considered to be the severe end of a spectrum of acute lung injury, it In ARDS, the integrity of the alveolar-capillary membrane is compromised by endothelial and epithelial injury. Most work suggests that ARDS stems from an inflammatory reaction initiated by a variety of pro-inflammatory mediators (Fig. 13.2). As early as 30 minutes after an acute insult, there is increased synthesis of interleukin 8 (IL-8), a potent neutrophil chemotactic and activating agent, by pulmonary macrophages. Release of IL-8 and other factors, such as IL-1 and tumor necrosis factor (TNF), leads to endothelial activation and sequestration and activation of neutrophils in pulmonary capillaries. Neutrophils are thought to have an important role in the pathogenesis of ARDS. Histologic examination of lungs early in the disease process shows increased numbers of neutrophils within the vascular space, the interstitium, and the alveoli. Activated neutrophils release a variety of products (e.g., reactive oxygen species, proteases) that damage the alveolar epithelium and endothelium. The assault on the endothelium and epithelium causes vascular leakiness and loss of surfactant that render the alveolar unit unable to expand. Of note, the destructive forces unleashed by neutrophils can be counteracted by an array of endogenous anti-proteases and anti-oxidants that are upregulated by proinflammatory cytokines. In the end, it is the balance between the destructive and protective factors that determines the degree of tissue injury and clinical severity of the ARDS. MORPHOLOGY In the acute phase of ARDS, the lungs are dark red, firm, airless, and heavy. Microscopic examination reveals capillary congestion, necrosis of alveolar epithelial cells, interstitial and intraalveolar edema and hemorrhage, and (particularly with sepsis) collections of neutrophils in capillaries. The most characteristic finding is the presence of hyaline membranes, particularly http://ebooksmedicine.net Acute Respiratory Distress Syndrome ACUTE LUNG INJURY NORMAL ALVEOLUS Bronchial epithelium Sloughed bronchial epithelium Inactivated surfactant Basement membrane Necrotic type I cell Edema fluid Leukotrienes PAF Proteases Alveolar macrophage Cellular debris Surfactant layer TNF IL-1 Alveolus Neutrophil sequestration and migration into alveolus Fibrin Type I cell TNF Chemokines Type II cell Hyaline membrane Fibroblast Interstitium Capillary Procollagen Edema Endothelial cell Injured, swollen endothelial cells Fig. 13.2 The normal alveolus (left) and the injured alveolus in the early phase of acute lung injury and the acute respiratory distress syndrome. Under the influence of proinflammatory cytokines such as interleukins IL-8 and IL-1 and tumor necrosis factor (TNF) (released by macrophages), neutrophils are sequestered in the pulmonary microvasculature and then egress into the alveolar space, where they undergo activation. Activated neutrophils release leukotrienes, oxidants, proteases, and platelet-activating factor (PAF), which contribute to local tissue damage, accumulation of edema fluid, surfactant inactivation, and hyaline membrane formation. Subsequently, the release of macrophage-derived fibrogenic cytokines such as transforming growth factor-β (TGF-β) and platelet-derived growth factor (PGDF) stimulate fibroblast growth and collagen deposition associated with the healing phase of injury. (Modified from Ware LB: Pathophysiology of acute lung injury and the acute respiratory distress syndrome, Semin Respir Crit Care Med 27:337, 2006.) lining the distended alveolar ducts (Fig. 13.3). Such membranes consist of fibrin-rich edema fluid admixed with remnants of necrotic epithelial cells. Overall, the picture is remarkably similar to that seen in respiratory distress syndrome of the newborn (Chapter 6). In the organizing stage, type II pneumocytes proliferate vigorously in an attempt to regenerate the alveolar lining. Resolution is unusual; more commonly, the fibrin-rich exudates organize into intraalveolar fibrosis. Marked thickening of the alveolar septa ensues due to proliferation of interstitial cells and deposition of collagen. Clinical Features The clinical syndrome of acute lung injury or ARDS affects approximately 190,000 patients per year in the United States. In 85% of cases, it develops within 72 hours of the initial insult. The overall hospital mortality rate is 38.5% (27%, 32%, and 45% for mild, moderate, and severe ARDS, respectively). Predictors of poor prognosis include advanced age, bacteremia (sepsis), and the development of multiorgan failure. Most patients who survive the acute insult recover normal respiratory function within 6 to 12 months, but the rest develop diffuse interstitial fibrosis leading to chronic respiratory insufficiency. SUMMARY ACUTE RESPIRATORY DISTRESS SYNDROME • ARDS is a clinical syndrome of progressive respiratory insufficiency caused by diffuse alveolar damage in the setting of sepsis, severe trauma, or diffuse pulmonary infection. • Neutrophils and their products have a crucial role in the pathogenesis of ARDS by causing endothelial and epithelial injury. • The characteristic histologic picture is that of alveolar edema, epithelial necrosis, accumulation of neutrophils, and presence of hyaline membranes lining the alveolar wall and ducts. http://ebooksmedicine.net 497 498 C H A P T E R 13 Lung By contrast, in diffuse restrictive diseases, FVC is reduced and the expiratory flow rate is normal or reduced proportionately. Hence, the ratio of FEV to FVC is near normal. Restrictive defects occur in two general conditions: (1) chest wall disorders in the presence of normal lungs (e.g., with severe obesity, diseases of the pleura, and neuromuscular disorders, such as the Guillain-Barré syndrome [Chapter 22], that affect the respiratory muscles) and (2) acute or chronic interstitial lung diseases. The classic acute restrictive disease is ARDS, discussed earlier. Chronic restrictive diseases (discussed later) include the pneumoconioses, interstitial fibrosis of unknown etiology, and infiltrative conditions such as sarcoidosis. OBSTRUCTIVE LUNG (AIRWAY) DISEASES A B Fig. 13.3 Acute lung injury and acute respiratory distress syndrome. (A) Diffuse alveolar damage in the acute phase. Some alveoli are collapsed, while others are distended; many are lined by bright pink hyaline membranes (arrow). (B) The healing stage is marked by resorption of hyaline membranes and thickening of alveolar septa by inflammatory cells, fibroblasts, and collagen. Numerous reactive type II pneumocytes also are seen at this stage (arrows), associated with regeneration and repair. OBSTRUCTIVE VERSUS RESTRICTIVE PULMONARY DISEASES Diffuse pulmonary diseases can be classified into two categories: (1) obstructive (airway) disease, characterized by an increase in resistance to air flow caused by partial or complete obstruction at any level; and (2) restrictive disease, characterized by reduced expansion of lung parenchyma and decreased total lung capacity. The major diffuse obstructive disorders are emphysema, chronic bronchitis, bronchiectasis, and asthma. In patients with these diseases, forced vital capacity (FVC) is either normal or slightly decreased, while the expiratory flow rate, usually measured as the forced expiratory volume at 1 second (FEV1), is significantly decreased. Thus, the ratio of FEV to FVC is characteristically decreased. Expiratory obstruction may result from anatomic airway narrowing, classically observed in asthma, or from loss of elastic recoil, characteristic of emphysema. In their prototypical forms, the four disorders in this group—emphysema, chronic bronchitis, asthma, and bronchiectasis—have distinct clinical and anatomic characteristics (Table 13.1), but overlaps between emphysema, chronic bronchitis, and asthma are common. It should be noted that emphysema is defined on the basis of morphologic and radiologic features, whereas chronic bronchitis is defined on the basis of clinical features (described later). The anatomic distribution of these disorders also is somewhat different, as chronic bronchitis initially involves the large airways, whereas emphysema affects the acinus. In severe or advanced cases of both, small airway disease (chronic bronchiolitis) is also present. Although emphysema may exist without chronic bronchitis (particularly in inherited α1-anti-trypsin deficiency, discussed later) and vice versa, the two diseases usually coexist. This is almost certainly because cigarette smoking is the major underlying cause of both. In view of their propensity to coexist, emphysema and chronic bronchitis often are grouped together under the rubric of chronic obstructive pulmonary disease (COPD). COPD affects more than 10% of the U.S. adult population and is the fourth leading cause of death in this country. The largely irreversible airflow obstruction of COPD distinguishes it from asthma, which, as discussed later, is characterized by reversible airflow obstruction (Fig. 13.4). Emphysema Emphysema is characterized by permanent enlargement of the air spaces distal to the terminal bronchioles, accompanied by destruction of their walls without significant fibrosis. It is classified according to its anatomic distribution. As discussed earlier, the acinus is the structure distal to terminal bronchioles, and a cluster of three to five acini is called a lobule (Fig. 13.5A). There are four major types of emphysema: (1) centriacinar, (2) panacinar, (3) distal acinar, and (4) irregular. Only the first two types cause significant airway obstruction, with centriacinar emphysema being about 20 times more common than panacinar disease. • Centriacinar (centrilobular) emphysema. The distinctive feature of centriacinar emphysema is that the central or proximal parts of the acini, formed by respiratory http://ebooksmedicine.net Obstructive Lung (Airway) Diseases Table 13.1 Disorders Associated With Airflow Obstruction: The Spectrum of Chronic Obstructive Pulmonary Disease Clinical Entity Anatomic Site Major Pathologic Changes Etiology Signs/Symptoms Chronic bronchitis Bronchus Mucous gland hypertrophy and hyperplasia, hypersecretion Tobacco smoke, air pollutants Cough, sputum production Bronchiectasis Bronchus Airway dilation and scarring Persistent or severe infections Cough, purulent sputum, fever Asthma Bronchus Smooth muscle hypertrophy and hyperplasia, excessive mucus, inflammation Immunologic or undefined causes Episodic wheezing, cough, dyspnea Emphysema Acinus Air space enlargement, wall destruction Tobacco smoke Dyspnea Small airway disease, bronchiolitis* Bronchiole Inflammatory scarring, partial obliteration of bronchioles Tobacco smoke, air pollutants Cough, dyspnea *Can be present in all forms of obstructive lung disease or by itself. bronchioles, are affected, while distal alveoli are spared. Thus, both emphysematous and normal air spaces exist within the same acinus and lobule (see Fig. 13.5B). The lesions are more common and severe in the upper lobes, particularly in the apical segments. In severe centriacinar emphysema, the distal acinus also becomes involved, and thus, the differentiation from panacinar emphysema becomes difficult. This type of emphysema is most common in cigarette smokers, often in association with chronic bronchitis. • Panacinar (panlobular) emphysema. In panacinar (panlobular) emphysema, the acini are uniformly enlarged, from the level of the respiratory bronchiole to the terminal blind alveoli (see Fig. 13.5C). In contrast to centriacinar emphysema, panacinar emphysema occurs more commonly in the lower lung zones and is associated with α1-anti-trypsin deficiency. • Distal acinar (paraseptal) emphysema. In this form of emphysema, the proximal portion of the acinus is normal but the distal part is primarily involved. The emphysema is more striking adjacent to the pleura, along the lobular connective tissue septa, and at the margins of the lobules. It occurs adjacent to areas of fibrosis, scarring, or atelectasis and is usually more severe in the upper half of the lungs. The characteristic finding is the presence of multiple, contiguous, enlarged air spaces ranging in diameter from less than 0.5 mm to more than 2.0 cm, sometimes forming cystic structures that, with progressive enlargement, give rise to bullae. The cause of this type of emphysema is unknown; it comes to attention most often in young adults who present with spontaneous pneumothorax. Alveolus NORMAL ACINUS Respiratory bronchiole Alveolar duct Chronic injury (e.g., smoking) Small airway disease A EMPHYSEMA Alveolar wall destruction Overinflation CHRONIC BRONCHITIS Productive cough Airway inflammation Alveolus Respiratory bronchiole Alveolar duct C ASTHMA Reversible obstruction Panacinar emphysema B Bronchial hyperresponsiveness triggered by allergens, infection, etc. Fig. 13.4 Schematic representation of overlap between chronic obstructive lung diseases. Centriacinar emphysema Fig. 13.5 Major patterns of emphysema. (A) Diagram of normal structure of the acinus, the fundamental unit of the lung. (B) Centriacinar emphysema with dilation that initially affects the respiratory bronchioles. (C) Panacinar emphysema with initial distention of all the peripheral structures (i.e., the alveolus and alveolar duct); the disease later extends to affect the respiratory bronchioles. http://ebooksmedicine.net 499 500 C H A P T E R 13 Lung Smoking or air pollutant + genetic predisposition Oxidative stress, increased apoptosis and senescence Inflammatory cells, release of inflammatory mediators Congenital !1-anti-trypsin deficiency Protease– anti-protease imbalance Alveolar wall destruction Fig. 13.6 Pathogenesis of emphysema. See text for details. • Irregular emphysema. Irregular emphysema, so named because the acinus is irregularly involved, is almost invariably associated with scarring, such as that resulting from healed inflammatory diseases. Although clinically asymptomatic, this may be the most common form of emphysema. to develop pulmonary emphysema, which is compounded by smoking. About 1% of all patients with emphysema have this defect. α1-anti-trypsin, normally present in serum, tissue fluids, and macrophages, is a major inhibitor of proteases (particularly elastase) secreted by neutrophils during inflammation. α1-anti-trypsin is encoded by a gene in the proteinase inhibitor (Pi) locus on chromosome 14. The Pi locus is polymorphic, and approximately 0.012% of the U.S. population is homozygous for the Z allele, a genotype that is associated with markedly decreased serum levels of α1-anti-trypsin. More than 80% of these individuals develop symptomatic panacinar emphysema, which occurs at an earlier age and is of greater severity if the individual smokes. Protease-mediated damage of extracellular matrix has a central role in the airway obstruction seen in emphysema. Small airways are normally held open by the elastic recoil of the lung parenchyma, and the loss of elastic tissue in the walls of alveoli that surround respiratory bronchioles reduces radial traction and thus causes the respiratory bronchioles to collapse during expiration. This leads to functional airflow obstruction despite the absence of mechanical obstruction. MORPHOLOGY Pathogenesis Inhaled cigarette smoke and other noxious particles cause lung damage and inflammation, which, particularly in patients with a genetic predisposition, result in parenchymal destruction (emphysema) and airway disease (bronchiolitis and chronic bronchitis). Factors that influence the development of emphysema include the following (Fig. 13.6): • Inflammatory cells and mediators: A wide variety of inflammatory mediators have been shown to be increased (including leukotriene B4, IL-8, TNF, and others) that attract more inflammatory cells from the circulation (chemotactic factors), amplify the inflammatory process (proinflammatory cytokines), and induce structural changes (growth factors). The inflammatory cells present in lesions include neutrophils, macrophages, and CD4+ and CD8+ T cells. It is not known if the T cells are specific for a particular antigen or are recruited as part of inflammation. • Protease–anti-protease imbalance: Several proteases are released from the inflammatory cells and epithelial cells that break down connective tissues. In patients who develop emphysema, there is a relative deficiency of protective anti-proteases (further discussed below). • Oxidative stress: Reactive oxygen species are generated by cigarette smoke and other inhaled particles and released from activated inflammatory cells such as macrophages and neutrophils. These cause additional tissue damage and inflammation (Chapter 3). • Airway infection: Although infection is not thought to play a role in the initiation of tissue destruction, bacterial and/or viral infections cause acute exacerbations. The idea that proteases are important is based in part on the observation that patients with a genetic deficiency of the anti-protease α1-anti-trypsin have a predisposition The diagnosis and classification of emphysema depend largely on the macroscopic appearance of the lung. Typical panacinar emphysema produces pale, voluminous lungs that often obscure the heart when the anterior chest wall is removed at autopsy. The macroscopic features of centriacinar emphysema are less impressive. Until late stages, the lungs are a deeper pink than in panacinar emphysema and less voluminous, and the upper two-thirds of the lungs are more severely affected than the lower lungs. Histologic examination reveals destruction of alveolar walls without fibrosis, leading to enlarged air spaces (Fig. 13.7). In addition to alveolar loss, the number of alveolar capillaries is diminished. Terminal and respiratory bronchioles may be deformed because of the loss of septa that help Fig. 13.7 Pulmonary emphysema. There is marked enlargement of the air spaces, with destruction of alveolar septa but without fibrosis. Note the presence of black anthracotic pigment. http://ebooksmedicine.net Obstructive Lung (Airway) Diseases tether these structures in the parenchyma. With the loss of elastic tissue in the surrounding alveolar septa, radial traction on the small airways is reduced. As a result, they tend to collapse during expiration—an important cause of chronic airflow obstruction in severe emphysema. Bronchiolar inflammation and submucosal fibrosis are consistently present in advanced disease. Clinical Features Dyspnea usually is the first symptom; it begins insidiously but is steadily progressive. In patients with underlying chronic bronchitis or chronic asthmatic bronchitis, cough and wheezing may be the initial complaints. Weight loss is common and may be severe enough to suggest an occult malignant tumor. Pulmonary function tests reveal reduced FEV1 with normal or near-normal FVC. Hence, the FEV1 to FVC ratio is reduced. The classic presentation of emphysema with no “bronchitic” component is one in which the patient is barrel-chested and dyspneic, with obviously prolonged expiration, sitting forward in a hunched-over position. In these patients, air space enlargement is severe and diffusing capacity is low. Dyspnea and hyperventilation are prominent, so that until very late in the disease, gas exchange is adequate and blood gas values are relatively normal. Because of prominent dyspnea and adequate oxygenation of hemoglobin, these patients sometimes are sometimes called “pink puffers.” At the other end of the clinical spectrum is a patient with emphysema who also has pronounced chronic bronchitis and a history of recurrent infections. Dyspnea usually is less prominent, and in the absence of increased respiratory drive the patient retains carbon dioxide, becoming hypoxic and often cyanotic. For unclear reasons, such patients tend to be obese—hence the designation “blue bloaters.” In most patients with COPD the symptoms fall in between these two extremes. Hypoxia-induced pulmonary vascular spasm and loss of pulmonary capillary surface area from alveolar destruction causes the gradual development of secondary pulmonary hypertension, which in 20% to 30% of patients leads to right-sided congestive heart failure (cor pulmonale, Chapter 11). Death from emphysema is related to either respiratory failure or right-sided heart failure. Conditions Related to Emphysema Several conditions involving abnormal airspaces or accumulations of air within the lungs or other tissues also are recognized: • Compensatory emphysema describes the dilation of residual alveoli in response to loss of lung substance elsewhere, such as occurs after surgical removal of a diseased lung or lobe. • Obstructive overinflation refers to expansion of the lung due to air trapping. A common cause is subtotal obstruction of an airway by a tumor or foreign object. Obstructive overinflation can be life-threatening if expansion of the affected portion produces compression of the remaining normal lung. • Bullous emphysema refers to any form of emphysema that produces large subpleural blebs or bullae (spaces >1 cm Fig. 13.8 Bullous emphysema with large apical and subpleural bullae. (From the Teaching Collection of the Department of Pathology, University of Texas Southwestern Medical School, Dallas, Texas.) in diameter in the distended state) (Fig. 13.8). Such blebs represent localized accentuations of one of the four forms of emphysema; most often the blebs are subpleural, and on occasion they may rupture, leading to pneumothorax. • Mediastinal (interstitial) emphysema is caused by entry of air into the interstitium of the lung, from where it may track to the mediastinum and sometimes the subcutaneous tissue. It may occur spontaneously if a sudden increase in intraalveolar pressure (as with vomiting or violent coughing) produces alveolar rupture, which allows air to dissect into the interstitium. Sometimes it develops in children with whooping cough. It may also occur in patients on respirators who have partial bronchiolar obstruction or in individuals with a perforating injury (e.g., a fractured rib). When the interstitial air gets into the subcutaneous tissue, the patient may literally blow up like a balloon, with marked swelling of the head and neck and crackling crepitation over the chest (subcutaneous emphysema). In most instances the air is resorbed spontaneously after the site of entry seals. SUMMARY EMPHYSEMA • Emphysema is a chronic obstructive airway disease characterized by enlargement of air spaces distal to terminal bronchioles. • Subtypes include centriacinar (most common: smokingrelated), panacinar (seen in α1-anti-trypsin deficiency), distal acinar, and irregular. • Smoking and inhaled pollutants cause ongoing accumulation of inflammatory cells, which are the source of proteases such as elastases that irreversibly damage alveolar walls. • Patients with uncomplicated emphysema present with increased chest volumes, dyspnea, and relatively normal blood oxygenation at rest (“pink puffers”). • Most patients with emphysema also have signs and symptoms of concurrent chronic bronchitis, since cigarette smoking is a risk factor for both. http://ebooksmedicine.net 501 502 C H A P T E R 13 Lung Chronic Bronchitis Chronic bronchitis is diagnosed on clinical grounds: it is defined by the presence of a persistent productive cough for at least 3 consecutive months in at least 2 consecutive years. It is common among cigarette smokers and urban dwellers in smog-ridden cities; some studies indicate that 20% to 25% of men in the 40- to 65-year-old age group have the disease. In early stages of the disease, the cough raises mucoid sputum, but airflow is not obstructed. Some patients with chronic bronchitis have evidence of hyperresponsive airways, with intermittent bronchospasm and wheezing (asthmatic bronchitis), while other bronchitic patients, especially heavy smokers, develop chronic outflow obstruction, usually with associated emphysema (COPD). Pathogenesis The distinctive feature of chronic bronchitis is hypersecretion of mucus, beginning in the large airways. Although the most important cause is cigarette smoking, other air pollutants, such as sulfur dioxide and nitrogen dioxide, may contribute. These environmental irritants induce hypertrophy of mucous glands in the trachea and bronchi as well as an increase in mucin-secreting goblet cells in the epithelial surfaces of smaller bronchi and bronchioles. These irritants also cause inflammation marked by the infiltration of macrophages, neutrophils, and lymphocytes. In contrast with asthma, eosinophils are not seen in chronic bronchitis. Whereas the defining mucus hypersecretion is primarily a reflection of involvement of large bronchi, the airflow obstruction in chronic bronchitis results from (1) small airway disease, induced by mucous plugging of the bronchiolar lumen, inflammation, and bronchiolar wall fibrosis, and (2) coexistent emphysema. In general, while small airway disease (chronic bronchiolitis) is an important component of early, mild airflow obstruction, chronic bronchitis with significant airflow obstruction almost always is complicated by emphysema. It is postulated that many of the effects of environmental irritants on respiratory epithelium are mediated by local release of cytokines such as IL-13 from T cells and innate lymphoid cells. The transcription of the mucin gene in bronchial epithelium and the production of neutrophil elastase are increased as a consequence of exposure to tobacco smoke. Microbial infection often is present but has a secondary role, chiefly by maintaining inflammation and exacerbating symptoms. Fig. 13.9 Chronic bronchitis. The lumen of the bronchus is above. Note the marked thickening of the mucous gland layer (approximately twice-normal) and squamous metaplasia of lung epithelium. (From the Teaching Collection of the Department of Pathology, University of Texas, Southwestern Medical School, Dallas, Texas.) lymphocytes and macrophages but sometimes also admixed neutrophils, are frequently seen in the bronchial mucosa. Chronic bronchiolitis (small airway disease), characterized by goblet cell metaplasia, mucous plugging, inflammation, and fibrosis, also is seen. In severe cases, there may be complete obliteration of the lumen as a consequence of fibrosis (bronchiolitis obliterans). It is the submucosal fibrosis that leads to luminal narrowing and airway obstruction. Emphysematous changes often coexist. Clinical Features The course of chronic bronchitis is quite variable. In some patients, cough and sputum production persist indefinitely without ventilatory dysfunction, while others develop COPD with significant outflow obstruction marked by hypercapnia, hypoxemia, and cyanosis. Patients with chronic bronchitis and COPD have frequent exacerbations, more rapid disease progression, and poorer outcomes than those with emphysema alone. Progressive disease is marked by the development of pulmonary hypertension, sometimes leading to cardiac failure (Chapter 11); recurrent infections; and ultimately respiratory failure. SUMMARY MORPHOLOGY CHRONIC BRONCHITIS As seen in gross specimens, the mucosal lining of the larger airways usually is hyperemic and swollen by edema fluid and is covered by a layer of mucinous or mucopurulent secretions. The smaller bronchi and bronchioles also may be filled with secretions. The diagnostic feature of chronic bronchitis in the trachea and larger bronchi is enlargement of the mucussecreting glands (Fig. 13.9). The magnitude of the increase in size is assessed by the ratio of the thickness of the submucosal gland layer to that of the bronchial wall (the Reid index— normally 0.4). Variable numbers of inflammatory cells, largely • Chronic bronchitis is defined as persistent productive cough for at least 3 consecutive months in at least 2 consecutive years. • Cigarette smoking is the most important underlying risk factor; air pollutants also contribute. • Chronic airway obstruction largely results from small airway disease (chronic bronchiolitis) and coexistent emphysema. • Histologic examination demonstrates enlargement of mucussecreting glands, goblet cell metaplasia, and bronchiolar wall fibrosis. http://ebooksmedicine.net Obstructive Lung (Airway) Diseases Asthma Asthma is a chronic inflammatory disorder of the airways that causes recurrent episodes of wheezing, breathlessness, chest tightness, and cough, particularly at night and/or early in the morning. The hallmarks of asthma are intermittent, reversible airway obstruction; chronic bronchial inflammation with eosinophils; bronchial smooth muscle cell hypertrophy and hyperreactivity; and increased mucus secretion. Sometimes trivial stimuli are sufficient to trigger attacks in patients, because of airway hyperreactivity. Many cells play a role in the inflammatory response, in particular eosinophils, mast cells, macrophages, lymphocytes, neutrophils, and epithelial cells. Of note, asthma has increased in incidence significantly in the Western world over the past 4 decades. One explanation for this troubling trend is the hygiene hypothesis, according to which a lack of exposure to infectious organisms (and possibly nonpathogenic microorganisms as well) in early childhood results in defects in immune tolerance and subsequent hyperreactivity to immune stimuli later in life. Pathogenesis Major factors contributing to the development of asthma include genetic predisposition to type I hypersensitivity (atopy), acute and chronic airway inflammation, and bronchial hyperresponsiveness to a variety of stimuli. Asthma may be subclassified as atopic (evidence of allergen sensitization) or nonatopic. In both types, episodes of bronchospasm may be triggered by diverse exposures, such as respiratory infections (especially viral), airborne irritants (e.g., smoke, fumes), cold air, stress, and exercise. There also are varying patterns of inflammation—eosinophilic (most common), neutrophilic, mixed inflammatory, and pauci-granulocytic—that are associated with differing etiologies, immunopathologies, and responses to treatment. The classic atopic form is associated with excessive type 2 helper T (TH2) cell activation. Cytokines produced by TH2 cells account for most of the features of atopic asthma— IL-4 and IL-13 stimulate IgE production, IL-5 activates eosinophils, and IL-13 also stimulates mucus production. IgE coats submucosal mast cells, which on exposure to allergen release their granule contents and secrete cytokines and other mediators. Mast cell–derived mediators produce two waves of reaction: an early (immediate) phase and a late phase (Fig. 13.10): • The early-phase reaction is dominated by bronchoconstriction, increased mucus production, and vasodilation. Bronchoconstriction is triggered by mediators released from mast cells, including histamine, prostaglandin D2, and leukotrienes LTC4, D4, and E4, and also by reflex neural pathways. • The late-phase reaction is inflammatory in nature. Inflammatory mediators stimulate epithelial cells to produce chemokines (including eotaxin, a potent chemoattractant and activator of eosinophils) that promote the recruitment of TH2 cells, eosinophils, and other leukocytes, thus amplifying an inflammatory reaction that is initiated by resident immune cells. • Repeated bouts of inflammation lead to structural changes in the bronchial wall that are collectively referred to as airway remodeling. These changes include hypertrophy of bronchial smooth muscle and mucus glands and increased vascularity and deposition of subepithelial collagen, which may occur as early as several years before initiation of symptoms. Asthma tends to “run” in families, but the role of genetics in asthma is complex. Genome-wide association studies have identified a number of genetic variants associated with asthma risk, some in genes enocding factors like the IL-4 receptor that are clearly involved in asthma pathogenesis. However, the precise contribution of asthma-associated genetic variants to the development of disease remains to be determined. Atopic Asthma This is the most common type of asthma and is a classic example of type I IgE–mediated hypersensitivity reaction (Chapter 5). It usually begins in childhood. A positive family history of atopy and/or asthma is common, and the onset of asthmatic attacks is often preceded by allergic rhinitis, urticaria, or eczema. Attacks may be triggered by allergens in dust, pollen, animal dander, or food, or by infections. A skin test with the offending antigen results in an immediate wheal-and-flare reaction. Atopic asthma also can be diagnosed based on serum radioallergosorbent tests (RASTs) that identify the presence of IgEs that recognize specific allergens. Non-Atopic Asthma Patients with nonatopic forms of asthma do not have evidence of allergen sensitization, and skin test results usually are negative. A positive family history of asthma is less common. Respiratory infections due to viruses (e.g., rhinovirus, parainfluenza virus) and inhaled air pollutants (e.g., sulfur dioxide, ozone, nitrogen dioxide) are common triggers. It is thought that virus-induced inflammation of the respiratory mucosa lowers the threshold of the subepithelial vagal receptors to irritants. Although the connections are not well understood, the ultimate humoral and cellular mediators of airway obstruction (e.g., eosinophils) are common to both atopic and nonatopic variants of asthma, so they are treated in a similar way. Drug-Induced Asthma Several pharmacologic agents provoke asthma, aspirin being the most striking example. Patients with aspirin sensitivity present with recurrent rhinitis, nasal polyps, urticaria, and bronchospasm. The precise pathogenesis is unknown but is likely to involve some abnormality in prostaglandin metabolism stemming from inhibition of cyclooxygenase by aspirin. Occupational Asthma Occupational asthma may be triggered by fumes (epoxy resins, plastics), organic and chemical dusts (wood, cotton, platinum), gases (toluene), and other chemicals. Asthma attacks usually develop after repeated exposure to the inciting antigen(s). http://ebooksmedicine.net 503 504 C H A P T E R 13 Lung A C NORMAL AIRWAY Mucus TRIGGERING OF ASTHMA Goblet cell Epithelium Basement membrane Lamina propria Smooth muscle Glands T cell receptor TH2 cell Pollen TH2 IgE B cell IL-4 Antigen (allergen) B Dendritic cell IL-5 Cartilage IgE antibody Eotaxin IL-5 IgE Fc receptor Mucosal lining Eosinophil recruitment Mast cell Goblet cell Activation Release of granules and mediators Antigen Mucosal lining B Mucus Mucus AIRWAY IN ASTHMA Mucus Goblet cell Eosinophil Basement membrane Vagal afferent nerve Macrophage Smooth muscle Mast cell Major basic protein Eosinophil cationic protein TH2 Glands TH2 Eosinophil Mast cell Eosinophil Neutrophil Lymphocyte Increased vascular permeability and edema Vagal efferent nerve D TH2 Basophil Smooth muscle IMMEDIATE PHASE (MINUTES) Eosinophil Neutrophil E LATE PHASE (HOURS) Fig. 13.10 (A and B) Comparison of a normal airway and an airway involved by asthma. The asthmatic airway is marked by accumulation of mucus in the bronchial lumen secondary to an increase in the number of mucus-secreting goblet cells in the mucosa and hypertrophy of submucosal glands; intense chronic inflammation due to recruitment of eosinophils, macrophages, and other inflammatory cells; thickened basement membrane; and hypertrophy and hyperplasia of smooth muscle cells. (C) Inhaled allergens (antigen) elicit a TH2-dominated response favoring IgE production and eosinophil recruitment. (D) On reexposure to antigen (Ag), the immediate reaction is triggered by Ag-induced cross-linking of IgE bound to Fc receptors on mast cells. These cells release preformed mediators that directly and via neuronal reflexes induce bronchospasm, increased vascular permeability, mucus production, and recruitment of leukocytes. (E) Leukocytes recruited to the site of reaction (neutrophils, eosinophils, and basophils; lymphocytes and monocytes) release additional mediators that initiate the late phase of asthma. Several factors released from eosinophils (e.g., major basic protein, eosinophil cationic protein) also cause damage to the epithelium. http://ebooksmedicine.net Obstructive Lung (Airway) Diseases MORPHOLOGY The morphologic changes in asthma have been described in individuals who die of prolonged severe attacks (status asthmaticus) and in mucosal biopsy specimens of individuals challenged with allergens. In fatal cases, the lungs are distended due to air trapping (overinflation), and there may be small areas of atelectasis. The most striking finding is occlusion of bronchi and bronchioles by thick, tenacious mucous plugs containing whorls of shed epithelium (Curschmann spirals). Numerous eosinophils and Charcot-Leyden crystals (crystalloids made up of the eosinophil protein galectin-10) also are present. Other characteristic morphologic changes in asthma (Fig. 13.10B), collectively called airway remodeling, include • Thickening of airway wall • Sub-basement membrane fibrosis (Fig. 13.11) • Increased submucosal vascularity • An increase in size of the submucosal glands and goblet cell metaplasia of the airway epithelium • Hypertrophy and/or hyperplasia of the bronchial muscle Clinical Features An attack of asthma is characterized by severe dyspnea and wheezing due to bronchoconstriction and mucus plugging, which leads to trapping of air in distal airspaces and progressive hyperinflation of the lungs. In the usual case, attacks last from 1 to several hours and subside either spontaneously or with therapy. Intervals between attacks are characteristically free from overt respiratory difficulties, but persistent, subtle deficits can be detected by pulmonary function tests. Occasionally a severe paroxysm occurs that does not respond to therapy and persists for days and even weeks (status asthmaticus). The associated hypercapnia, acidosis, and severe hypoxia may be fatal, although in most cases the condition is more disabling than lethal. Standard therapies include anti-inflammatory drugs, particularly glucocorticoids, Fig. 13.11 Bronchial biopsy specimen from an asthmatic patient showing sub–basement membrane fibrosis, eosinophilic inflammation, and smooth muscle hyperplasia. and bronchodilators such as beta-adrenergic drugs and leukotriene inhibitors (recall that leukotrienes are potent bronchoconstrictors). Agents that block specific immune mediators, such as IL-4 and IL-5, are of modest benefit in some patients but are not broadly efficacious, perhaps because of disease heterogeneity. Another approach called bronchial thermoplasty, which involves controlled delivery of thermal energy during bronchoscopy to reduce the mass of smooth muscle and airway responsiveness, is being evaluated in patients with severe, poorly controlled asthma. SUMMARY ASTHMA • Asthma is characterized by reversible bronchoconstriction caused by airway hyperresponsiveness to a variety of stimuli. • Atopic asthma most often is caused by a TH2 and IgE-mediated immunologic reaction to environmental allergens and is characterized by early-phase (immediate) and late-phase reactions. The TH2 cytokines IL-4, IL-5, and IL-13 are important mediators. Non-TH2 inflammation also has roles in atopic asthma that are being defined. • Triggers for nonatopic asthma are less clear but include viral infections and inhaled air pollutants, which also can trigger atopic asthma. • Eosinophils are key inflammatory cells found in almost all subtypes of asthma; eosinophil products (such as major basic protein) are responsible for airway damage. • Airway remodeling (sub-basement membrane thickening and hypertrophy of bronchial glands and smooth muscle) adds an irreversible component to the obstructive disease. Bronchiectasis Bronchiectasis is the permanent dilation of bronchi and bronchioles caused by destruction of smooth muscle and the supporting elastic tissue; it typically results from or is associated with chronic necrotizing infections. It is not a primary disorder, as it always occurs secondary to persistent infection or obstruction caused by a variety of conditions. Bronchiectasis gives rise to a characteristic symptom complex dominated by cough and expectoration of copious amounts of purulent sputum. Diagnosis depends on an appropriate history and radiographic demonstration of bronchial dilation. The conditions that most commonly predispose to bronchiectasis include: • Bronchial obstruction. Common causes are tumors, foreign bodies, and impaction of mucus. In these conditions, bronchiectasis is localized to the obstructed lung segment. Bronchiectasis also may complicate atopic asthma and chronic bronchitis. • Congenital or hereditary conditions—for example: • Cystic fibrosis, in which widespread severe bronchiectasis results from obstruction caused by abnormally viscid mucus and secondary infections (Chapter 7). • Immunodeficiency states, particularly immunoglobulin deficiencies, in which localized or diffuse bronchiectasis often develops because of recurrent bacterial infections. http://ebooksmedicine.net 505 506 C H A P T E R 13 Lung • Primary ciliary dyskinesia (also called the immotile cilia syndrome). This is a rare autosomal recessive disorder that is frequently associated with bronchiectasis and with sterility in males. It is caused by inherited abnormalities of cilia that impair mucociliary clearance of the airways, leading to persistent infections. • Necrotizing, or suppurative, pneumonia, particularly with virulent organisms such as Staphylococcus aureus or Klebsiella spp., predispose affected patients to development of bronchiectasis. Posttuberculosis bronchiectasis continues to be a significant cause of morbidity in endemic areas. Pathogenesis Two intertwined processes contribute to bronchiectasis: obstruction and chronic infection. Either may be the initiator. For example, obstruction caused by a foreign body impairs clearance of secretions, providing a favorable substrate for superimposed infection. The resultant inflammatory damage to the bronchial wall and the accumulating exudate further distend the airways, leading to irreversible dilation. Conversely, a persistent necrotizing infection in the bronchi or bronchioles may lead to poor clearance of secretions, obstruction, and inflammation with peribronchial fibrosis and traction on the bronchi, culminating again in full-blown bronchiectasis. Fig. 13.12 Bronchiectasis in a patient with cystic fibrosis who underwent lung resection for transplantation. Cut surface of lung shows markedly dilated bronchi filled with purulent mucus that extend to subpleural regions. MORPHOLOGY Bronchiectasis usually affects the lower lobes bilaterally, particularly those air passages that are most vertical. When caused by tumors or aspiration of foreign bodies, the involvement may be sharply localized to a single segment of the lungs. Usually, the most severe involvement is found in the more distal bronchi and bronchioles. The airways may be dilated to as much as four times their usual diameter and can be seen on gross examination almost out to the pleural surface (Fig. 13.12). By contrast, in normal lungs, the bronchioles cannot be followed by eye beyond a point 2 to 3 cm from the pleura. The histologic findings vary with the activity and chronicity of the disease. In full-blown active cases, an intense acute and chronic inflammatory exudate within the walls of the bronchi and bronchioles leads to desquamation of lining epithelium and extensive areas of ulceration. Typically, mixed flora are cultured from the sputum. The usual organisms include staphylococci, streptococci, pneumococci, enteric organisms, anaerobic and microaerophilic bacteria, and (particularly in children) Haemophilus influenzae and Pseudomonas aeruginosa. When healing occurs, the lining epithelium may regenerate completely; however, the injury usually cannot be repaired and abnormal dilation and scarring persist. Fibrosis of the bronchial and bronchiolar walls and peribronchiolar fibrosis develop in more chronic cases. In some instances the necrosis destroys the bronchial or bronchiolar walls, producing an abscess cavity. Clinical Features Bronchiectasis is characterized by severe, persistent cough associated with expectoration of mucopurulent, sometimes fetid, sputum. Other common symptoms include dyspnea, rhinosinusitis, and hemoptysis. Symptoms often are episodic and are precipitated by upperrespiratory tract infections or the introduction of new pathogenic agents. Severe, widespread bronchiectasis may lead to significant obstructive ventilatory defects, with hypoxemia, hypercapnia, pulmonary hypertension, and cor pulmonale. However, with current treatment outcomes have improved and severe complications of bronchiectasis, such as brain abscess, amyloidosis (Chapter 5), and cor pulmonale, occur less frequently now than in the past. CHRONIC INTERSTITIAL (RESTRICTIVE, INFILTRATIVE) LUNG DISEASES Chronic interstitial diseases are a heterogeneous group of disorders characterized by bilateral, often patchy, pulmonary fibrosis mainly affecting the walls of the alveoli (see Fig. 13.1). Many of the entities in this group are of unknown cause and pathogenesis; some have an intraalveolar and an interstitial component. Chronic interstitial lung diseases are categorized based on clinicopathologic features and characteristic histology (Table 13.2). However, it must be acknowledged that there is frequent overlap in histologic features among the different conditions. The shared histologic features and the similarity in clinical signs, symptoms, radiographic alterations, and pathophysiologic changes justify their consideration as a http://ebooksmedicine.net Chronic Interstitial (Restrictive, Infiltrative) Lung Diseases Table 13.2 Major Categories of Chronic Interstitial Lung Disease Fibrosing Usual interstitial pneumonia (idiopathic pulmonary fibrosis) Nonspecific interstitial pneumonia Cryptogenic organizing pneumonia Collagen vascular disease-associated Pneumoconiosis Therapy-associated (drugs, radiation) Granulomatous Sarcoidosis Hypersensitivity pneumonia Eosinophilic Loeffler syndrome Drug allergy–related Idiopathic chronic eosinophilic pneumonia Smoking-Related Desquamative interstitial pneumonia Respiratory bronchiolitis group. The hallmark of these disorders is reduced compliance (stiff lungs), which in turn necessitates increased effort to breathe (dyspnea). Furthermore, damage to the alveolar epithelium and interstitial vasculature produces abnormalities in the ventilation–perfusion ratio, leading to hypoxia. Chest radiographs show small nodules, irregular lines, or “ground-glass shadows.” With progression, patients may develop respiratory failure, pulmonary hypertension, and cor pulmonale (Chapter 11). When advanced, the etiology of the underlying diseases may be difficult to determine because they all result in diffuse scarring and gross destruction of the lung, referred to as end-stage or “honeycomb” lung. etiologic clues come from genetic studies. Germ line mutations leading to loss of telomerase are associated with increased risk, suggesting that cellular senescence contributes to a profibrotic phenotype. The link to cellular aging also is in line with the observation that IPF is a disorder of older adults, rarely occurring before the age of 55 years. Other genetic associations also point to the primary defect residing in epithelial cells. Specifically, approximately 35% of affected individuals have a genetic variant in the MUC5B gene that alters the production of mucin, while a smaller number of affected patients have germ line mutations in surfactant genes. These genes are only expressed in lung epithelial cells, indicating that epithelial cell abnormalities can be the primary initiators of IPF. It is hypothesized that abnormal epithelial repair at the sites of chronic injury and inflammation gives rise to exuberant fibroblastic or myofibroblastic proliferation, leading to the characteristic fibroblastic foci. Although the mechanisms of fibrosis are incompletely understood, recent data point to excessive activation of profibrotic factors such as TGF-β. MORPHOLOGY Grossly, the pleural surfaces of the lung are cobblestoned due to retraction of scars along the interlobular septa. The cut surface shows firm, rubbery white areas of fibrosis, which occurs preferentially within the lower lobe, the subpleural regions, and along the interlobular septa. Histologically, the hallmark is patchy interstitial fibrosis, which varies in intensity (Fig. 13.14) and Environmental factors: Smoking Occupational exposure Other irritants, toxins Viral infection Fibrosing Diseases Idiopathic Pulmonary Fibrosis Idiopathic pulmonary fibrosis (IPF) refers to a pulmonary disorder of unknown etiology that is characterized by patchy, progressive bilateral interstitial fibrosis. Because its etiology is unknown, it is also known as cryptogenic fibrosing alveolitis. Males are affected more often than females, and it is a disease of aging, virtually never occurring before 50 years of age. The radiologic and histologic pattern of fibrosis is referred to as usual interstitial pneumonia (UIP), which is required for the diagnosis of IPF. Of note, similar pathologic changes in the lung may be present in entities such as asbestosis, collagen vascular diseases, and other conditions. Therefore, IPF is a diagnosis of exclusion. At risk epithelium: Age Genetics: Telomerase mutations Surfactant mutations MUC5B variant Innate and adaptive immune response Pro-fibrogenic factors Pathogenesis The interstitial fibrosis that characterizes IPF is believed to result from repeated injury and defective repair of alveolar epithelium, often in a genetically predisposed individual (Fig. 13.13). The cause of the injury is obscure, and a variety of sources have been proposed, including chronic gastroesophageal reflux. However, only a small fraction of individuals suffering from reflux or exposed to other proposed environmental triggers develop IPF; thus, other factors must have a predominant role. The clearest Persistent epithelial injury/activation Abnormal intracellular signaling Proliferation, collagen production Fibrosis Fig. 13.13 Proposed pathogenic mechanisms in idiopathic pulmonary fibrosis. See text for details. http://ebooksmedicine.net 507 508 C H A P T E R 13 Lung findings (subpleural and basilar fibrosis, reticular abnormalities, and “honeycombing”) often are diagnostic. Antiinflammatory therapies have proven to be of little use, in line with the idea that inflammation is of secondary pathogenic importance. By contrast, anti-fibrotic therapies such as nintedanib, a tyrosine kinase inhibitor, and pirfenidone, an inhibitor of TGF-β, have produced positive outcomes in clinical trials and are now approved for use in patients with IPF. The overall prognosis remains poor, however; survival is only 3 to 5 years, and lung transplantation is the only definitive treatment. Other Fibrosing Diseases Fig. 13.14 Usual interstitial pneumonia. The fibrosis, which varies in intensity, is more pronounced in the subpleural region. worsens with time. The earliest lesions demonstrate exuberant fibroblastic proliferation (fibroblastic foci) (Fig. 13.15). Over time these areas become more collagenous and less cellular. Quite typical is the existence of both early and late lesions. The dense fibrosis causes collapse of alveolar walls and formation of cystic spaces lined by hyperplastic type II pneumocytes or bronchiolar epithelium (honeycomb fibrosis). The interstitial inflammation usually is patchy and consists of an alveolar septal infiltrate of mostly lymphocytes and occasional plasma cells, mast cells, and eosinophils. Secondary pulmonary hypertensive changes (intimal fibrosis and medial thickening of pulmonary arteries) are often present. Clinical Features IPF usually presents with the gradual onset of a nonproductive cough and progressive dyspnea. On physical examination, most patients have characteristic “dry” or “Velcrolike” crackles during inspiration. Cyanosis, cor pulmonale, and peripheral edema may develop in later stages of the disease. The characteristic clinical and radiologic Other rare pulmonary diseases associated