Pulmonary Pathology PDF

 LUNG GENEREAL ➔ Three lobes on the right and two on the left. ➔ The main bronchi branch to bronchioles. ➔ *Bronchioles are distinguished from bronchi by the lack of cartilage and submucosal glands within their walls. ➔ Additional branching of bronchioles leads to terminal...

 LUNG GENEREAL ➔ Three lobes on the right and two on the left. ➔ The main bronchi branch to bronchioles. ➔ *Bronchioles 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: a) Respiratory bronchioles that proceed into b) Alveolar ducts, which immediately branch into c) Alveolar sacs the blind ends of the respiratory passages, whose walls are formed entirely of d) Alveoli (the ultimate site of gas exchange)  ALVEOLI MICROSCOPIC STRUCTURE The capillary endothelium and basement membrane. Alveolar epithelium contains a continuous layer of two principal cell types: flattened, platelike type I pneumocytes covering 95% of the alveolar surface and rounded type II pneumocytes. Type 2 pnmcyts: pulmonary surfactant and are the main cell type involved in repair of alveolar epithelium after damage to type I pneumocytes. The pulmonary interstitium is composed of fine elastic fibers, small bundles of collagen, a few fibroblast-like cells, smooth muscle cells, mast cells, and rare mononuclear cells. ➔ The alveolar walls are perforated by numerous pores of Kohn, which permit passage of air, bacteria, and exudates between adjacent alveoli. ➔ A few alveolar macrophages usually lie free within the alveolar space. ➔ In the adult, these macrophages often contain phagocytosed carbon particles. There are multiple primary lung diseases that can broadly be divided into those primarily affecting: (1) The airways, (2) The interstitium, and (3) The pulmonary vascular system  ATELECTASIS (ALVEOLAR COLLAPSE) ➔ 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 ventilation perfusion imbalance and hypoxia.  Contraction atelectasiss Resorption atelectasis 1- RESORPTION ATELECTASIS ➔ RA occurs when an obstruction prevents air from reaching distal airways ➔ The air already present, gradually becomes absorbed, and alveolar collapse follows. ➔ The most common cause is obstruction of a bronchus by a mucous or mucopurulent plug. (postoperatively, bronchial asthma, bronchiectasis, chronic bronchitis, tumor, or foreign body aspiration) 2- COMPRESSIONION ATELECTASIS ➔ CA is usually associated with accumulation of fluid, blood, or air within the pleural cavity. ➔ This is a frequent occurrence with pleural effusion, caused most commonly by congestive heart failure (CHF). ➔ Leakage of air into the pleural cavity (pneumothorax) also leads to compression atelectasis  3- CONTRACTION ATELECTASIS ➔ CA occurs when either local or generalized fibrotic changes in the lung or pleura hamper expansion and increase elastic recoil during expiration. ➔ **Atelectasis (except when caused by contraction) is potentially reversible and should be treated promptly to prevent hypoxemia and superimposed infection of the collapsed lung. ATELECTASIS  ACUTE LUNG INJURY ➔ The term acute lung injury encompasses a spectrum of bilateral pulmonary damage (both endothelial and epithelial), which can be initiated by numerous conditions. ➔ ***Clinically, acute lung injury manifests as: ➔ (1) acute onset of dyspnea, ➔ (2) decreased arterial oxygen pressure (hypoxemia), ➔ (3) development of bilateral pulmonary infiltrates on the chest radiograph. ➔ Acute lung injury can progress to the more severe acute respiratory distress syndrome (ARDS).  ACUTE RESPIRATORY DISTRESS SYNDROME Acute respiratory distress syndrome (ARDS) is a clinical syndrome caused by diffuse alveolar capillary and epithelial damage. The usual clinical course is characterized by rapid onset of: 1) Life-threatening respiratory insufficiency 2) Cyanosis 3) Severe arterial hypoxemia that is refractory to oxygen therapy and may progress to multisystem organ failure (MOF).  ARDS PATHOGENESIS ➔ In ARDS, the integrity of this barrier is compromised by either endothelial or epithelial injury, or, more commonly, both. ➔ Lung injury is caused by an imbalance of pro-inflammatory and anti- inflammatory mediators. ➔ Neutrophils are thought to have an important role in the pathogenesis of ARDS.  ARDS PATHOGENESIS **The acute consequences of damage to the alveolar capillary membrane include: 1) Increased vascular permeability 2) Alveolar flooding, 3) Loss of diffusion capacity, and 4) Widespread surfactant abnormalities caused by damage to type II pneumocytes Diffuse alveolar damage in acute lung injury and acute respiratory distress syndrome. ➔ A) Some alveoli are collapsed; others are distended. *** ➔ Many are lined by bright pink ***hyaline membranes (arrow). ➔ B) The healing stage is marked by resorption of hyaline membranes with thickening of alveolar septa containing inflammatory cells, fibroblasts, and collagen. ➔ Numerous reactive type II pneumocytes also are seen at this stage (arrows), associated with regeneration and repair  ARDS CLINICAL PICTURE ➔ Approximately 85% of patients develop the clinical syndrome of acute lung injury or ARDS within 72 hours of the initiating insult. ➔ With improvements in supportive therapy, the mortality rate has decreased from 60% to 40% in the last decade. OBSTRUCTIVE LUNG DISEASES vs. RESTICTIVE LUNG DISEASES ***OBSTRUCTIVE VERSUS RESTRICTIVE PULMONARY DISEASES Diffuse pulmonary diseases can be classified into two categories (1) Obstructive (airway) disease, characterized by limitation of airflow, usually resulting from an increase in resistance caused by partial or complete obstruction at any level. (2) Restrictive disease, characterized by reduced expansion of lung parenchyma accompanied by decreased total lung capacity.  OBSTRUCTIVE PULMONARY DISEASES ➔ In patients with obstructive (airway) diseases, forced vital capacity (FVC) is either normal or slightly decreased, ➔ The expiratory flow rate (Usually measured as the forced expiratory volume at 1st second) (FEV1), is significantly decreased. ➔ (Thus, the ratio of FEV1/FVC is characteristically decreased. ➔ Expiratory obstruction may result either from anatomic airway narrowing, classically observed in asthma, or from loss of alveolar elastic recoil, characteristic of emphysema. The major diffuse obstructive disorders are emphysema, chronic bronchitis, bronchiectasis, and asthma.  RESTRICTIVE PULMONARY DISEASES ➔ 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. ➔ The restrictive defect occurs 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, that affect the respiratory muscles). ➔ (2) Acute or chronic interstitial lung diseases. CHRONIC OBSTRUCTIVE PULMONARY DISEASES (COPD) OBSTRUCTIVE LUNG (AIRWAY) DISEASES 1- EMPHYSEMA ➔ Emphysema is characterized by abnormal permanent enlargement of the air spaces distal to the terminal bronchioles, accompanied by destruction of their walls without significant fibrosis. ➔ There are four major types of emphysema: ➔ (1) centriacinar, (2) panacinar, (3) distal acinar, and (4) irregular.  CENTRIACINAR (CENTRILOBULAR) EMPHYSEMA ➔ The distinctive feature is the pattern of involvement of the lobules: ➔ The central or proximal parts of the acini, are affected, while distal alveoli are spared. ➔ Thus, both emphysematous and normal air spaces exist within the same acinus and lobule. ➔ The lesions are more common and severe in the upper lobes, particularly in the apical segments. ➔ This type of emphysema is most commonly seen as a consequence of smokers.  PANACINAR EMPHYSEMA ➔ The acini are uniformly enlarged, from the level of the respiratory bronchiole to the terminal blind alveoli ➔ In contrast with centriacinar emphysema, panacinar emphysema tends to occur more commonly in the lower lung zones and is the type of emphysema that occurs in α1-antitrypsin deficiency.  DISTAL ACINAR EMPHYSEMA ➔ In distal acinar (paraseptal) emphysema, the proximal portion of the acinus is normal but the distal part is primarily involved. ➔ The emphysema is 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, enlarged air spaces ➔ (less than 0.5 mm to more than 2.0 cm), ➔ Sometimes forming cystic structures that, with progressive enlargement, are referred to as bullae. ➔ ***The cause of this type of emphysema is unknown; it is seen most often in cases of spontaneous pneumothorax in young adults  IRREGULAR EMPHYSEMA ➔ 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.  EMPHYSEMA- PATHOGENESIS ➔ Exposure to inhaled toxins (such as cigarette smoke) leads to epithelial cell death, inflammation, and extracellular matrix proteolysis. ➔ In susceptible persons, mesenchymal cell survival and reparative functions are impaired by direct effects of inhaled toxic substances and inflammatory mediators and by the loss of the peri and extracellular matrix. ➔ The result is loss of structural cells of the alveolar wall and the associated matrix components  EMPHYSEMA-CLINICAL FEATURES **Dyspnea usually is the first symptom. **Pulmonary function tests reveal reduced FEV1 with normal or near-normal FVC. Hence, the ratio of FEV1 to FVC is reduced. **In all cases, secondary pulmonary hypertension develops gradually.  CONDITIONS RELATED TO EMPHYSEMA Compensatory emphysema is a term used to designate the compensatory dilation of alveoli in response to loss of lung substance elsewhere, such as occurs in residual lung parenchyma after surgical removal of a diseased lung or lobe. Obstructive overinflation refers to the condition in which the lung expands because air is trapped within it. A common cause of emphysema is subtotal obstruction by a tumor or foreign object. Mediastinal (interstitial) emphysema is the condition resulting when air enters the connective tissue stroma of the lung, mediastinum, and subcutaneous tissue.  BULLOUS EMPHYSEMA ➔ Bullous emphysema refers to any form of emphysema that produces large subpleural blebs or bullae (spaces greater than 1 cm in diameter in the distended state). ➔ 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.  PNEUMOTHORAX Air pressing and collapsing the whole lung OBSTRUCTIVE LUNG (AIRWAY) DISEASES 2-CHRONIC BRONCHITIS ➔ Chronic bronchitis is common among cigarette smokers ➔ It is defined by the presence of a persistent productive cough for at least 3 consecutive months in at least 2 consecutive years.  CLINICAL FEATURES ➔ In patients with chronic bronchitis, a prominent cough and the production of sputum may persist indefinitely without ventilatory dysfunction. ➔ However, some patients develop significant COPD with outflow obstruction. ➔ This clinical syndrome is accompanied by hypercapnia, hypoxemia, and (in severe cases) cyanosis  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. ➔ The hallmarks of the disease are intermittent and reversible airway obstruction, chronic bronchial inflammation with eosinophils, bronchial smooth muscle cell hypertrophy and hyperreactivity, and increased mucus secretion. ➔ Many cells play a role in the inflammatory response, in particular eosinophils, mast cells, macrophages, lymphocytes, neutrophils, and epithelial cells.  ASTHMA- CLASSIFICATION Asthma may be categorized into: ➔ Atopic Asthma (evidence of allergen sensitization, often in a patient with a history of allergic rhinitis, eczema) and ➔ Nonatopic Asthma. ➔ In either type, episodes of bronchospasm can be triggered by diverse mechanisms, such as respiratory infections (especially viral), environmental exposure to irritants (e.g., smoke, fumes), cold air, stress, and exercise.  ASTHMA- ETIOLOGY  The major etiologic factors of asthma are genetic predisposition to type I hypersensitivity (atopy).  Acute and chronic airway inflammation,  Bronchial hyperresponsiveness to a variety of stimuli.  Type 2 helper T (TH2) cells are critical in the pathogenesis of asthma.  The classic atopic form of asthma is associated with an excessive TH2 reaction against environmental antigens.  PATHOLOGY OF ASTHMA s produced by TH2 cells account for most of the of asthma lates IgE production, ates eosinophils, ulates mucus production and also promotes IgE y B cells. submucosal mast cells, which, on exposure to ease granule contents. This induces two waves an early (immediate) phase and a late phase PATHOLOGY OF ASTHMA  ASTHMA GENETICS Asthma is a complex genetic disorder in which multiple susceptibility genes interact with environmental factors to initiate the pathologic reaction. One of the susceptibility loci is on the long arm of chromosome 5 (5q), where several genes involved in regulation of IgE synthesis and mast cell and eosinophil growth and differentiation. The genes at this locus include: IL13 (genetic polymorphisms linked with susceptibility to the development of atopic asthma), CD14 (single-nucleotide polymorphisms associated with occupational asthma), Class II HLA alleles (tendency to produce IgE antibodies), β2- adrenergic receptor gene, IL-4 receptor gene (atopy, total serum IgE level, and asthma).  ASTHMA GENETICS Another important locus is on 20q where ADAM-33 that regulates proliferation of bronchial smooth muscle and fibroblasts is located; this controls airway remodeling. Upregulation of various chitinase enzymes has been shown to be important in TH2 inflammation and severity of asthma; High serum YKL-40 levels (a chitinase family member) correlate with the severity of asthma A and B, Comparison of a normal bronchus with that in a patient with asthma. Note the accumulation of mucus in the bronchial lumen resulting from an increase in the number of mucus-secreting goblet cells in the mucosa and hypertrophy of submucosal 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 smooth muscle cells exhibit hypertrophy and hyperplasia. Inhaled allergens (antigens) elicit a TH2-dominated response favoring IgE production and eosinophil recruitment: (priming or sensitization). ➔ On reexposure to antigen (Ag), the immediate ➔ Recruited leukocytes reaction is triggered by signals the initiation of antigen-induced cross- the late phase of asthma linking of IgE bound to and a fresh round of IgE receptors on mast mediator release from cells in the airways. leukocytes, endothelium, and epithelial cells. ➔ These cells release preformed mediators. The mediators induce bronchospasm, increase vascular permeability and mucus production, and recruit additional ➔ Factors, particularly from eosinophils (e.g., major basic mediator-releasing cells protein, eosinophil cationic protein), also cause damage from the blood. to the epithelium.  ATOPIC ASTHMA ➔ This is the most common type of asthma, usually beginning in childhood, and is a classic example of type I IgE–mediated hypersensitivity reaction. ➔ A positive family history is common, and asthmatic attacks are often preceded by allergic rhinitis, urticaria, or eczema. ➔ The disease is triggered by environmental antigens, such as dusts, pollen, animal dander, and foods. ➔ Infections can also trigger atopic asthma. ➔ 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 IgE specific for a panel of 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 (rhinovirus, parainfluenza virus) and inhaled air pollutants (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.  DRUG INDUCED ASTHMA ➔ Several pharmacologic agents provoke asthma. ➔ Aspirin being the most striking example ➔ It is presumed that aspirin inhibits the cyclooxygenase pathway of arachidonic acid metabolism without affecting the lipoxygenase route, ➔ Shifting the balance of production toward leukotrienes that cause bronchospasm.  OCCUPATIONAL ASTHMA ➔ This form of asthma is stimulated 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).  Charcot Leyden crystals Crushmann spirals  CLINICAL FEATURES ➔ An attack of asthma is characterized by severe dyspnea with wheezing; the chief difficulty lies in expiration. ➔ The victim labors to get air into the lungs and then cannot get it out, so that there is progressive hyperinflation of the lungs with air trapped distal to the bronchi, which are constricted and filled with mucus and debris. ➔ In the usual case, attacks last from 1 to several hours and subside either spontaneously or with therapy, usually bronchodilators and corticosteroids. ➔ 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  OBSTRUCTIVE LUNG (AIRWAY) DISEASES BRONCHIECTASIS ➔ Bronchiectasis is the permanent dilation of bronchi and bronchioles caused by destruction of the muscle and the supporting elastic tissue, resulting from or associated with chronic necrotizing infections. ➔ Diagnosis depends on an appropriate history along with radiographic demonstration of bronchial dilation. Pathogenesis ➔ Two intertwined processes contribute to bronchiectasis: ➔ Obstruction and ➔ Chronic infection.  BRONCHIECTASIS ETIOLOGY Bronchial obstruction. Common causes are tumors, foreign bodies, and occasionally impaction of mucus. (atopic asthma and chronic bronchitis) Necrotizing, or suppurative, pneumonia, particularly with virulent organisms such as Staphylococcus aureus or Klebsiella spp.,  BRONCHIECTASIS ETIOLOGY Congenital or hereditary conditions: ➔ In cystic fibrosis, widespread severe bronchiectasis results from obstruction caused by the secretion of abnormally viscid mucus thus predisposing to infections of the bronchial tree. ➔ In immunodeficiency states ➔ Kartagener syndrome is a rare autosomal recessive disorder that is frequently associated with bronchiectasis and with sterility in males. ➔ In Kartagener’s, structural abnormalities of the cilia impair mucociliary clearance in the airways  BRONCHIECTASIS CLINICAL PICTURE ➔ The clinical manifestations consist of severe, persistent cough with expectoration of mucop sometimes fetid, sputum. ➔ The sputum may contain blood; frank hemoptysis can occur. ➔ Symptoms often are episodic and are precipitated by upper respiratory tract infections. ➔ Clubbing of the fingers may develop. ➔ In cases of severe, widespread bronchiectasis, significant obstructive ventilatory defects are hypoxemia, hypercapnia, pulmonary hypertension, and (rarely) cor pulmonale. ➔ Metastatic brain abscesses and reactive amyloidosis CHRONIC INTERSTITIAL LUNG DISEASES  CHRONIC INTERSTITIAL (RESTRICTIVE, INFILTRATIVE) LUNG DISEASES ➔ **Chronic interstitial diseases are a heterogeneous group of disorders characterized by bilateral, involvement of the pulmonary connective tissue (interstitium in the alveolar walls). ➔ **The hallmark feature of these disorders is reduced compliance (more pressure is required to expand the lungs because they are stiff), which in turn necessitates increased effort of breathing (dyspnea).  FIBROSING DISEASES: IDIOPATHIC PULMONARY FIBROSIS(IPF) ➔ 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, ➔ Virtually never occurring before 50 years of age.  FIBROSING DISEASES: 1-IDIOPATHIC PULMONARY FIBROSIS(IPF) ➔ 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.  IPF 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.  IPF CLINICAL PICTURE ➔ IPF usually presents with the gradual onset of a nonproductive cough and progressive dyspnea. ➔ On physical examination, most patients have characteristic dry crackles during inspiration. ➔ Cyanosis, cor pulmonale, and peripheral edema may develop in later stages of the disease. ➔ The characteristic clinical and radiologic findings (subpleural and basilar fibrosis, reticular abnormalities, and “honeycombing”) often are diagnostic.  IPF CLINICAL PICTURE ➔ 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.  FIBROSING DISEASES: 2-NON-SEPECIFIC INTERSTITIAL PNEUMONIA (NSIP) ➔ NSIP is a chronic bilateral interstitial lung disease of unknown etiology, which has distinct radiologic, histologic, and clinical features, including a frequent association with collagen vascular disorders such as rheumatoid arthritis. ➔ It is important to recognize NSIP because it has a much better prognosis than IPF. ➔ It is characterized by mild to moderate interstitial chronic inflammation and/or fibrosis that is patchy but uniform in the areas involved. (UIP is typically heterogeneous, patchy, and irregular in size).  FIBROSING DISEASES: 3-CRIPTOGENIC ORGANISING PNEUMONIA:BOOP ➔ It presents with cough and dyspnea, and chest radiographs demonstrate subpleural or peribronchial patchy areas of airspace consolidation which are due to intraalveolar plugs of loose organizing connective tissue. ➔ Some patients recover spontaneously while most require treatment, usually with oral steroids. CRIPTOGENIC ORGANISING PNEUMONIA ➔ Cryptogenic organizing pneumonia is synonymous with the previously popular designation bronchiolitis obliterans organizing pneumonia (“BOOP”) PULMONARY INVOLVEMENT IN COLLAGEN VASCULAR DISEASES ➔ Also in the differential diagnosis of fibrosing pulmonary disorders are several rheumatologic entities: ➔ Systemic sclerosis, ➔ Rheumatoid arthritis, ➔ Systemic lupus erythematosus, which may be complicated by diffuse pulmonary fibrosis.  PNEUMOCONIOSIS Pneumoconiosis is a term that describe the non-neoplastic lung reaction to inhalation of mineral dusts The mineral dust pneumoconiosis—the three most common of which result from exposure to coal dust, silica, and asbestos—nearly always result from exposure in the workplace.  COAL WORKER’S PNEUMOCNIOSIS The spectrum of lung findings in coal workers is wide: a) Asymptomatic anthracosis, in which pigment accumulates without a perceptible cellular reaction, to b) Simple coal worker’s pneumoconiosis (CWP), in which accumulations of macrophages occur with little to no pulmonary dysfunction c) Complicated CWP or progressive massive fibrosis (PMF), in which fibrosis is extensive and lung function is compromised COAL WORKER’S PNEUMOCNIOSIS ANTHRACOSIS COAL WORKER’S PNEUMOCNIOSIS  SILICOSIS ➔ **Silicosis is currently the most prevalent chronic occupational disease in the world. ➔ **It is caused by inhalation of crystalline silica, mostly in occupational settings. ➔ Workers in several occupations but especially those involved in sandblasting and hard-rock mining are at particular risk. **Silicosis is associated with an increased susceptibility to tuberculosis.  ASBESTOSIS AND ASBESTOS RELATED DISEASES Asbestos is a family of crystalline hydrated silicates with a fibrous geometry. **On the basis of epidemiologic studies, occupational exposure to asbestos is linked to (1) Parenchymal interstitial fibrosis (asbestosis); (2) Localized fibrous plaques or, rarely, diffuse fibrosis in the pleura; (3) Pleural effusions; (4) Lung carcinomas; (5) Malignant pleural and peritoneal mesotheliomas (6) Laryngeal carcinoma.  DRUG AND RADIATION INDUCED PULMONARY DISEASE ➔ Drugs can cause a variety of both acute and chronic alterations in respiratory structure and function. ➔ For example, bleomycin, an anticancer agent, causes pneumonitis and interstitial fibrosis, as a result of direct toxicity of the drug and by stimulating the influx of inflammatory cells into the alveoli. ➔ Similarly, amiodarone, an antiarrhythmic agent, also is associated with risk for pneumonitis and fibrosis.  DRUG AND RADIATION INDUCED PULMONARY DISEASE ➔ Radiation pneumonitis is a well-known complication of therapeutic irradiation of pulmonary and other thoracic tumors. ➔ Acute radiation pneumonitis, which typically occurs 1 to 6 months after therapy in as many as 20% of the patients, is manifested by fever, dyspnea, pleural effusion. and development of pulmonary infiltrates corresponding to the area of radiation. ➔ These signs and symptoms may resolve with corticosteroid therapy or progress to chronic radiation pneumonitis, associated with pulmonary fibrosis GRANULOMATOUS DISEASES  SARCOIDOSIS ➔ Sarcoidosis is a multisystem disease of unknown etiology characterized by noncaseating granulomas in many organs. ➔ **Other diseases, including mycobacterial or fungal infections and berylliosis, sometimes also produce noncaseating granulomas. ➔ ***Sarcoidosis can manifest in many clinical guises, ***bilateral hilar lymphadenopathy or lung involvement (or both), visible on chest radiographs, is the major presenting manifestation in most cases. ➔ Eye and skin involvement each occurs in about 25% of cases SARCOIDOSIS  SARCOIDOSIS ➔ Sarcoidosis occurs throughout the world, affecting both genders and all races and age groups. ➔ There are certain interesting epidemiologic trends, including: ➔ There is a consistent predilection for adults younger than 40 years of age. ➔ A high incidence has been noted in Danish and Swedish populations, and in the United States among African Americans (10 times greater than in whites). ➔ Sarcoidosis is one of the few pulmonary diseases with a higher prevalence among nonsmokers.  SARCOIDOSIS Non-necrotising (non-caseating granulomas are the hallmark of the disease. Multinucleated histiocytic giant cells (Schaumann bodies). Asteroid bodies: Asteroid bodies may be seen in the cytoplasm of epithelioid or giant cells in sarcoidosis as eosinophilic, stellate or spider-like inclusions.  SARCOIDOSIS- CLINICAL PICTURE ➔ In many affected persons the disease is entirely asymptomatic, discovered on routine chest films as bilateral hilar lymphadenopathy ➔ In others, peripheral lymphadenopathy, cutaneous lesions, eye involvement, splenomegaly, or hepatomegaly may be presenting manifestations. ➔ In about two thirds of symptomatic cases, there is gradual appearance of respiratory symptoms (shortness of breath, dry cough, or vague substernal discomfort) or constitutional signs and symptoms (fever, fatigue, weight loss, anorexia, night sweats). SARCOIDOSIS- CLINICAL PICTURE ➔ Because of the variable and non diagnostic clinical features, resort is frequently made to lung or lymph node biopsies. ➔ The presence of noncaseating granulomas is suggestive of sarcoidosis, but other identifiable causes of granulomatous inflammation must be excluded. ➔ Sarcoidosis follows an unpredictable course characterized by either progressive chronicity or periods of activity interspersed with remissions. ➔ The remissions may be spontaneous or initiated by steroid therapy and often are permanent. ➔ 65% to 70% of affected persons recover with minimal or no residual manifestations. ➔ 20% develop permanent lung dysfunction ➔ 10% to 15%, most succumb to progressive pulmonary fibrosis and cor pulmonale.  HYPERSENSITIVITY PNEUMONITIS ➔ Hypersensitivity pneumonitis is an immunologically mediated inflammatory lung disease that primarily affects the alveoli and is therefore often called allergic alveolitis. ➔ Most often, it is an occupational disease. ➔ Unlike bronchial asthma, in which bronchi are the focus of immunologically mediated injury, the damage in hypersensitivity pneumonitis occurs at the level of alveoli. ➔ Hence, it manifests as a predominantly restrictive lung disease with decreased diffusion capacity, lung compliance, and total lung volume  HYPERSENSITIVITY PNEUMONITIS- CLINICAL PICTURE ➔ Hypersensitivity pneumonitis may manifest either as an acute reaction, with fever, cough, dyspnea, and constitutional signs and symptoms arising 4 to 8 hours after exposure, or as a chronic disease characterized by insidious onset of cough, dyspnea, malaise, and weight loss. ➔ If antigenic exposure is terminated after acute attacks of the disease, complete resolution of pulmonary symptoms occurs within days  PULMONARY EOSINOPHILIA ➔ A number of clinical and pathologic pulmonary entities are characterized by an infiltration and activation of eosinophils, the latter by elevated levels of alveolar IL-5. ➔ These diverse diseases generally are of immunologic origin, but the etiology is not understood. ➔ Pulmonary eosinophilia is divided into the following categories  PULMONARY EOSINOPHILIA ➔ Acute eosinophilic pneumonia with respiratory failure, characterized by rapid onset of fever, dyspnea, hypoxia, and diffuse pulmonary infiltrates on chest radiographs. ➔ The bronchoalveolar lavage fluid typically contains more than 25% eosinophils. ➔ There is prompt response to corticosteroids. ➔ Simple pulmonary eosinophilia (Loeffler syndrome), characterized by transient pulmonary lesions, eosinophilia in the blood, and a benign clinical course. ➔ The alveolar septa are thickened by an infiltrate containing eosinophils and occasional giant cells.  PULMONARY EOSINOPHILIA ➔ Tropical eosinophilia, caused by infection with microfilariae and helminthic parasites ➔ Secondary eosinophilia, seen, for example, in association with asthma, drug allergies, and certain forms of vasculitis ➔ Idiopathic chronic eosinophilic pneumonia, characterized by aggregates of lymphocytes and eosinophils within the septal walls and the alveolar spaces, typically in the periphery of the lung fields, and accompanied by high fever, night sweats, and dyspnea. ➔ This disease is a diagnosis of exclusion, once other causes of pulmonary eosinophilia have been ruled out. SMOKING RELATED INTERSTITIAL DISEASE ➔ The role of cigarette smoking in causing obstructive pulmonary disease (emphysema and chronic bronchitis) has been discussed. ➔ Smoking also is associated with restrictive or interstitial lung diseases. ➔ ***Desquamative interstitial pneumonia (DIP) and respiratory bronchiolitis are the two related examples of smoking-associated interstitial lung disease.  DESQUAMATIVE INTERSTITIAL PNEUMONIA ➔ The most striking histologic feature is the accumulation of macrophages with cytoplasm containing dusty-brown pigment (smoker’s macrophages) in the air spaces. ➔ The alveolar septa are thickened by a sparse inflammatory infiltrate (usually lymphocytes), and interstitial fibrosis. ➔ Pulmonary functions usually show a mild restrictive abnormality, and patients have a good prognosis with excellent response to steroid therapy and smoking cessation  TUBERCULOSIS  Tuberculosis is a chronic granulomatous disease caused by Mycobacterium tuberculosis.  It usually involves the lungs but may affect any organ or tissue in the body.  Typically, the centers of tubercular granulomas undergo caseous necrosis.  TBC EPIDEMIOLOGY  It is estimated that 1.7 billion people are infected worldwide, with 8 to 10 million new cases and 3 million deaths per year.  Tuberculosis flourishes under conditions of poverty, crowding, and chronic debilitating illness.  Similarly, elderly persons, (weakened defenses) are vulnerable.  In areas of the world where HIV infection is prevalent, it has become the single most important risk factor for the development of tuberculosis  TUBERCULOSIS  It is important that infection be differentiated from disease.  Infection implies seeding of a focus with organisms, which may or may not cause clinically significant tissue damage (i.e., disease)  Most infections are acquired by direct person-to person transmission of airborne droplets  In most persons, an asymptomatic focus of pulmonary infection is self-limited.  Uncommonly, primary tuberculosis may result in the development of fever and pleural effusions.  TUBERCULOSIS  Generally, the only evidence of infection, if any remains, is a fibrocalcific nodule at the site of the infection.  Viable organisms may remain dormant in such loci for decades, and possibly for the life of the host.  Such persons are infected but do not have active disease and therefore cannot transmit organisms to others.  When their immune defenses are lowered, the infection may reactivate to produce communicable and potentially life-threatening disease.  TUBERCULOSIS  Infection with M. tuberculosis typically leads to the development of delayed hypersensitivity, which can be detected by  The tuberculin (Mantoux) test about 2 to 4 weeks after the infection has begun.  Intracutaneous injection of 0.1 mL of PPD induces a visible and palpable induration (at least 5 mm in diameter) that peaks in 48 to 72 hours.  TUBERCULOSIS  A positive tuberculin skin test result signifies cell-mediated hypersensitivity to tubercular antigens.  It does not differentiate between infection and disease.  A well-recognized limitation of this test is that false-negative reactions (or skin test anergy) may be produced by certain viral infections, sarcoidosis, malnutrition, Hodgkin lymphoma, immunosuppression and active disease.  False positive reactions may result from infection by atypical mycobacteria.  About 80% of the population in certain Asian and African countries is tuberculin-positive  TUBERCULOSIS  Mycobacteria are rods that are acid-fast (Ziehl-Neelsen] stain.  M. tuberculosis hominis is responsible for most cases of tuberculosis.  The reservoir of infection typically is found in persons with active pulmonary disease.  Transmission usually is direct, by inhalation of airborne organisms in aerosols generated by expectoration or by exposure to contaminated secretions of infected persons.  TUBERCULOSIS  Oropharyngeal and intestinal tuberculosis contracted by drinking milk contaminated with Mycobacterium bovis infection is now rare in developed nations, but it is still seen in countries with tuberculous cows and sales of unpasteurized milk.  Other mycobacteria, particularly Mycobacterium avium complex, are much less virulent than M. tuberculosis and rarely cause disease in immunocompetent persons.  However, they cause disease in 10% to 30% of patients with AIDS. Pathogenesis  PRIMARY TUBERCULOSIS  Primary tuberculosis is the form of disease that develops in a previously unexposed and therefore unsensitized patient.  Elderly persons and profoundly immunosuppressed patients may lose their sensitivity to the tubercle bacillus, so they may develop primary tuberculosis more than once.  It is asymptomatic.  PRIMARY TUBERCULOSIS The major consequences of primary tuberculosis are that (1) It induces hypersensitivity and increased resistance. (2) The foci of scarring may harbor viable bacilli for years, perhaps for life, and thus be the nidus for reactivation at a later time when host defenses are compromised. (3) Uncommonly, it may lead to progressive primary tuberculosis.  RANKE COMPLEX Healed (fibrosis, calcification) Ghon complex is called Ranke complex  SECONDARY TUBERCULOSIS Secondary tuberculosis is the pattern of disease that arises in a previously sensitized host. It may follow shortly after primary tuberculosis, but more commonly it arises from reactivation of dormant primary lesions many decades after initial infection, particularly when host resistance is weakened. It also may result from exogenous reinfection Whatever the source of the organism, only a few patients (less than 5%) with primary disease subsequently develop secondary tuberculosis.  SECONDARY TUBERCULOSIS Secondary pulmonary tuberculosis is classically localized to the apex of one or both upper lobes. The reason is obscure but may relate to high oxygen tension in the apices. Cavitation occurs readily in the secondary form, leading to erosion into and dissemination along airways. Such changes become an important source of infectivity, because the patient now produces sputum containing bacilli.  TBC CLINICAL FEATURES Localized secondary tuberculosis may be asymptomatic. When manifestations appear, they are usually insidious in onset, with gradual development of both systemic and localizing symptoms and signs. Systemic manifestations, related to the release of cytokines by activated macrophages (e.g., TNF and IL-1), often appear early in the disease course and include malaise, anorexia, weight loss, and fever. Commonly, the fever is low grade and remittent (appearing late each afternoon and then subsiding), and night sweats occur  TBC CLINICAL FEATURES When cavitation is present, the sputum contains tubercle bacilli. Some degree of hemoptysis is present in about half of all cases Pleuritic pain may result from extension of the infection to the pleural surfaces The diagnosis of pulmonary disease is based in part on the history and on physical and radiographic findings of consolidation or cavitation in the apices of the lungs. Ultimately, however, tubercle bacilli must be identified  TBC CLINICAL FEATURES The most common methodology for diagnosis of tuberculosis remains demonstration of acid-fast organisms in sputum by acid-fast stains Conventional cultures for mycobacteria require up to 10 weeks, but liquid media–based radiometric assays that detect mycobacterial metabolism are able to provide a result within 2 weeks. PCR amplification can be performed on positive liquid media, as well as on tissue sections, to identify the mycobacterium. However, culture remains the standard diagnostic modality because it can identify the occasional PCR-negative case and also allows testing of drug susceptibility.  NON-TUBERCULOUS MYCOBACTERIAL DISEASES Nontuberculous mycobacteria most commonly cause chronic but clinically localized pulmonary disease in immunocompetent persons Most frequently include Mycobacterium avium intracellulare (also called M. avium complex), Mycobacterium kansasii, and Mycobacterium abscessus In immunosuppressed persons (primarily HIV-seropositive patients), M. avium complex infection manifests as disseminated disease  HISTOPLASMOSIS, COCCIDIOIDOMYCOSIS, and BLASTOMYCOSIS Infections caused by the dimorphic fungi, which include Histoplasma capsulatum, Coccidioides immitis, and Blastomyces dermatitidis, manifest either with isolated pulmonary involvement, as commonly seen in infected immunocompetent persons, or with disseminated disease in immunocompromised persons. T cell–mediated immune responses are critical for containing the infection, persons with HIV are more prone to systemic disease Clinical manifestations may take the form of (1) acute (primary) pulmonary infection, (2) chronic (granulomatous) pulmonary disease, or (3) disseminated miliary disease  PLEURAL EFFUSION AND PLEURITIS In pleural effusion the fluid can be either a transudate or an exudate When the pleural fluid is a transudate, the condition is termed hydrothorax The four principal causes of pleural exudate formation are (1) microbial invasion through either direct extension of a pulmonary infection or blood-borne seeding (suppurative pleuritis or empyema); (2) cancer (lung carcinoma, metastatic neoplasms to the lung or pleural surface, mesothelioma); (3) pulmonary infarction (4) viral pleuritis.  PNEUMOTHORAX, HEMOTHORAX AND CHYLOTHORAX Refer to presence of air or other gas in the pleural sac. It may occur in young, apparently healthy adults, usually men without any known pulmonary disease (simple or spontaneous pneumothorax), or As a result of some thoracic or lung disorder (secondary pneumothorax), such as a fractured rib, emphysema, lung abscess, tuberculosis, carcinoma, Mechanical ventilatory support with high pressure also may trigger secondary pneumothorax.  PNEUMOTHORAX, HEMOTHORAX AND CHYLOTHORAX Hemothorax, the collection of whole blood (in contrast with bloody effusion) in the pleural cavity, is a complication of a ruptured intrathoracic aortic aneurysm that is almost always fatal. With hemothorax, in contrast with bloody pleural effusions, the blood clots within the pleural cavity. Chylothorax is a pleural collection of a milky lymphatic fluid containing microglobules of lipid. HEMOTHORAX PULMONARY VASCULAR DISEASES PULMONARY EMBOLISM  PULMONARY EMBOLISM Blood clots that occlude the large pulmonary arteries are almost always embolic in origin. More than 95% of all pulmonary emboli arise from thrombi within the large deep veins of the lower legs, typically originating in the popliteal vein and larger veins above it. Autopsy data on the incidence of pulmonary embolism vary widely, ranging from 1% in the general hospitalized population, to 30% in persons dying after severe burns, trauma, or fractures.  PULMONARY EMBOLISM The influences that predispose the patient to venous thrombosis in the legs are (1) prolonged bedrest (particularly with immobilization of the legs) (2) surgery, especially orthopedic surgery, of knee and hip (3) severe trauma (including burns or multiple fractures) (4) congestive heart failure (5) in women, the period around parturition or oral contraception using birth control pills with high estrogen content (6) disseminated cancer and (7) primary disorders of hypercoagulability (e.g., factor V Leiden, etc)  PULMONARY EMBOLISM The pathophysiologic consequences of thromboembolism in the lung depend largely on the size of the embolus: There are two important consequences of embolic pulmonary arterial occlusion: (1) An increase in pulmonary artery pressure from blockage of flow and, possibly, vasospasm caused by neurogenic mechanisms and/or release of mediators (e.g., thromboxane A2, serotonin); (2) Ischemia of the downstream pulmonary parenchyma  PULMONARY EMBOLISM Occlusion of a major vessel results in: A sudden increase in pulmonary artery pressure Diminished cardiac output Right-sided heart failure (acute cor pulmonale) even Death.  PULMONARY EMBOLISM Usually hypoxemia also develops, as a result of multiple mechanisms: Perfusion of lung zones that have become atelectatic. The alveolar collapse occurs in the ischemic areas because of a reduction in surfactant production, Pain associated with embolism leads to reduced movement of the chest wall, some of the pulmonary blood flow is redirected through areas of the lung that normally are hypoventilated. The decrease in cardiac output causes a widening of the difference in arterial-venous oxygen saturation.  PULMONARY EMBOLISM Right-to-left shunting of blood may occur through a patent foramen ovale, present in 30% of normal persons. If smaller vessels are occluded, the result is less catastrophic, and the event may even be clinically silent. (Recall that the lungs are oxygenated not only by the pulmonary arteries but also by bronchial arteries and directly from air in the alveoli). Thus, ischemic necrosis (infarction) is the exception rather than the rule, occurring in as few as 10% of patients with thromboemboli. It occurs only if there is compromise in cardiac function or bronchial circulation, or if the region of the lung at risk is underventilated as a result of underlying pulmonary disease  PULMONARY EMBOLISM- CLINICAL FEATURES Most pulmonary emboli (60% to 80%) are clinically silent because they are small; the embolic mass is rapidly removed by fibrinolytic activity, and the bronchial circulation sustains the viability of the affected lung parenchyma until this is accomplished. In 5% of cases, sudden death, acute right-sided heart failure (acute cor pulmonale), or cardiovascular collapse (shock) may occur typically when more than 60% of the total pulmonary vasculature is obstructed by a large embolus or multiple simultaneous small emboli.  PULMONARY EMBOLISM- CLINICAL FEATURES Pulmonary embolism is one of the few causes of literally instantaneous death, even before the person experiences chest pain or dyspnea. Obstruction of relatively small to medium pulmonary branches (10% to 15% of cases) that behave as end arteries causes pulmonary infarction when some element of circulatory insufficiency is present. Typically, persons who sustain such infarction manifest dyspnea. In a small but significant subset of patients (accounting for less than 3% of cases), recurrent multiple emboli lead to pulmonary hypertension, chronic right-sided heart strain (chronic cor pulmonale), and, in time, pulmonary vascular sclerosis with progressively worsening dyspnea  PULMONARY EMBOLISM- CLINICAL FEATURES Emboli usually resolve after the initial acute event. They contract, and endogenous fibrinolytic activity may cause total lysis of the thrombus. However, in the presence of an underlying predisposing factor, a small, innocuous embolus may presage a larger one, and patients who have experienced one pulmonary embolism have a 30% chance of developing a second. PULMONARY EMBOLISM- TREATMENT Prophylactic therapy may include anticoagulation, early ambulation for postoperative and postparturient patients, application of elastic stockings, intermittent pneumatic calf compression, and isometric leg exercises for bedridden patients. Patients with massive pulmonary embolism are candidates for thrombolytic therapy. Nonthrombotic forms of pulmonary embolism include several uncommon but potentially lethal forms, such as air, fat, and amniotic fluid embolism Intravenous drug abuse often is associated with foreign body embolism in the pulmonary microvasculature; the presence of magnesium trisilicate (talc). in the intravenous mixture elicits a granulomatous response within the interstitium or pulmonary arteries. Involvement of the interstitium may  PULMONARY HYPERTENSION The pulmonary circulation normally is one of low resistance; pulmonary blood pressures are only about one eighth of systemic pressures. Pulmonary hypertension is most often secondary to a decrease in the cross- sectional area of the pulmonary vascular bed or to increased pulmonary vascular blood flow.  PULMONARY HYPERTENSION The causes of secondary pulmonary hypertension include: 1-Chronic obstructive or 2-interstitial lung disease, which is accompanied by destruction of lung parenchyma and consequent reduction in alveolar capillaries. This causes increased pulmonary arterial resistance and secondarily, elevated arterial pressure. 3-Recurrent pulmonary emboli. Presence of these emboli leads to a reduction in the functional cross-sectional area of the pulmonary vascular bed, leading in turn to increased vascular resistance. Antecedent heart disease, for example, 4-mitral stenosis, which increases left atrial pressure, leading to higher pulmonary venous pressures, and ultimately pulmonary arterial hypertension. 5-Congenital left-to-right shunts (PDA, etc) are another cause of secondary pulmonary hypertension  PRIMARY PULMONARY HYPERTENSION Uncommonly, Primary idiopathic pulmonary hypertension exists even though all known causes of increased pulmonary pressure have been excluded. Of these, the vast majority of cases are sporadic, and only 6% are familial with an autosomal dominant mode of inheritance. According to current thinking, pulmonary endothelial cell and/or vascular smooth muscle dysfunction is the probable underlying basis for most forms of pulmonary hypertension  PRIMARY PULMONARY HYPERTENSION In primary pulmonary hypertension, especially in the uncommon familial form the TGF-β signaling pathway has emerged as a key mediator of endothelial and smooth muscle dysfunction. Specifically, germline mutations of bone morphogenetic protein receptor type 2 (BMPR-2), a cell surface molecule that binds to a variety of TGF-β pathway ligands, have been demonstrated in 50% of familial cases. The BMPR2 gene product is inhibitory in its effects on proliferation; hence, loss-offunction mutations of this gene result in abnormal vascular endothelial and pulmonary smooth muscle proliferation. However, not all persons with germline mutations of BMPR2 develop primary pulmonary hypertension, suggesting the existence of modifier genes that probably affect penetrance of this particular phenotype  PRIMARY PULMONARY HYPERTENSION Studies on sporadic forms of primary pulmonary hypertension point to a possible role for the serotonin transporter gene (5HTT). Specifically, pulmonary smooth muscle cells from some patients with primary pulmonary hypertension demonstrate increased proliferation on exposure to serotonin or serum. Genetic polymorphisms of 5HTT that lead to enhanced expression of the transporter protein on vascular smooth muscle are postulated to cause their proliferation.  SECONDARY PULMONARY HYPERTENSION In states of secondary pulmonary hypertension, endothelial cell dysfunction arises as a consequence of the underlying disorder (e.g., shear and mechanical injury due to increased blood flow in left-to-right shunts, or biochemical injury produced by fibrin in recurrent thromboembolism). Endothelial cell dysfunction reduces production of vasodilatory agents (e.g., nitric oxide, prostacyclin) while increasing synthesis of vasoconstrictive mediators like endothelin. In addition, there is production of growth factors and cytokines that induce the migration and replication of vascular smooth muscle and elaboration of extracellular matrix.  1° and 2 °PULMONARY HYPERTENSION- CLINICS Clinical Features Secondary pulmonary hypertension may develop at any age. The clinical features reflect the underlying disease, usually pulmonary or cardiac, with accentuation of respiratory insufficiency and right-sided heart strain. Primary pulmonary hypertension, on the other hand, is almost always encountered in young adults, more commonly women, and is marked by fatigue, syncope (particularly on exercise), dyspnea on exertion, and sometimes chest pain. Eventually severe respiratory insufficiency and cyanosis develop, and death usually results from right-sided heart failure (decompensated cor pulmonale) within 2 to 5 years of diagnosis. Without lung transplantation the prognosis is grim.  GOODPASTURE SYNDROME Goodpasture syndrome, the prototype disorder of this group, is an uncommon condition characterized by a proliferative, usually rapidly progressive, glomerulonephritis And hemorrhagic interstitial pneumonitis. Both the renal and the pulmonary lesions are caused by antibodies targeted against the noncollagenous domain of the α3 chain of collagen IV. These antibodies can be detected in the serum of more than 90% of persons with Goodpasture syndrome.  GOODPASTURE SYNDROME Plasmapheresis and immunosuppressive therapy have markedly improved the once-dismal prognosis for this disease. Plasma exchange removes offending antibodies, and immunosuppressive drugs inhibit antibody production. With severe renal disease, renal transplantation is eventually required.  DIFFUSE ALVEOLAR HEMORRHAGE SYNDROME Diffuse Alveolar Hemorrhage Syndromes While there may be several “secondary” causes of pulmonary hemorrhage (necrotizing bacterial pneumonia, passive venous congestion, bleeding diathesis), the diffuse alveolar hemorrhage syndromes constitute a group of “primary” immune- mediated diseases that manifest as the triad of hemoptysis, anemia, and diffuse pulmonary infiltrates. DIFFUSE ALVEOLAR HEMORRHAGE SYNDROME  IDIOPATHIC PULMONARY HEMOSIDEROSIS Idiopathic pulmonary hemosiderosis is a rare disease of uncertain etiology that has pulmonary manifestations and histologic features similar to those of Goodpasture syndrome, But there is no associated renal disease or circulating anti-basement membrane antibody. Most cases occur in children, although the disease is reported in adults as well, who have a better prognosis. With steroid and immunosuppressive therapy, survival has markedly improved from the historical 2.5 years; thus, an immune-mediated etiology is postulated.  WEGENER GRANULOMATOSIS LUNG MENIFESTATIONS Pulmonary Angiitis and Granulomatosis (Wegener Granulomatosis) More than 80% of patients with Wegener granulomatosis (WG) develop upper respiratory or pulmonary manifestations at some time in the course of their disease. The lung lesions are characterized by a combination of necrotizing vasculitis (“angiitis”) and parenchymal necrotizing granulomatous inflammation. The manifestations of WG can include both upper respiratory symptoms (chronic sinusitis, epistaxis, nasal perforation) and pulmonary signs and symptoms (cough, hemoptysis, chest pain). PR3-ANCAs are present in close to 95% of cases. LESIONS OF THE UPPER RESPIRATORY TRACT  RESPIRATORY SYSTEM Respiratory system: Carrying out the 02-C02 gas exchange of the organism, Maintains the body's acid-base balance, Creating sound and speech, Providing the sense of smell It is the system that ensures blood and lymph flow (through breathing).  RESPIRATORY SYSTEM The respiratory system is divided into two basic regions. 1- Conductive part: Nasal cavity, nasopharynx, trachea, bronchi, bronchioles and terminal bronchioles. 2- Respiratory section: It consists of respiratory bronchioles, alveolar ducts and alveoli. A large part of the respiratory tract is lined with pseudostratified columnar ciliated epithelium rich in goblet cells. RESPIRATORY TYPE EPITHELIUM NASAL PATHOLOGY  NASAL POLYP The inflammatory type is the most common. It develops due to recurrent allergic or inflammatory rhinitis. Seen in people aged 30 and above. Relapse often occurs after surgery. Asthma, Chronic rhinitis, Cystic fibrosis, Kartagener syndrome and Aspirin intolerance (allergy).  NASAL POLYP GROSS Usually multiple, Bilaterally located Do not cause destruction in the mucosa Translucent, moist, edematous Polypoid structures  NASAL POLYP MICROSCOPY lined with respiratory epithelium It usually contains squamous metaplasia. Loose, edematous stroma. Lymphocyte, plasmacyte, eosinophil, mast hc, neutrophils The mucosa may ulcerate. It may contain hyperplastic glands. SINONASAL PAPILLOMA (SCHNEIDERIAN PAPILLOMA) HPV is the causative agent. Inverted and exophytic forms. 3th-6th decades. INVERTED PAPILLOMA INVERTED PAPILLOMA EXOPHYTIC PAPILLOMA  INVERTED EXOPHYTIC PAPILLOMA PAPILLOMA Frequency Most common form 2nd most common form Localization Lateral nose/paranasal Nasal septum sinuses M/F 2-3/1 10/1 HPV High and low risk HPV Low risk HPV Architectural pattern Endophytic Exophytic Molecular changes EGFR activating mutations - Risk of malignant %5-15 0 transformation  NASOPHARYNX AND PHARYNX PATHOLOGY  NASOPHARYNX It is lined with respiratory epithelium. The movement of cilia are towards the oropharynx. Lymphoid follicles in the lamina propria arecalled pharyngeal tonsils (ADENOID). Enlargement of follicles due to various infections: Adenoid hyperplasia. ADENOİD VEJETASYON ADENOID FACE  NASOPHARYNGEAL CARCINOMA Nasopharyngeal carcinoma is a rare neoplasm that merits comment There is a strong epidemiologic links to EBV The high frequency of this form of cancer among the Chinese which raises the possibility of viral oncogenesis on a background of genetic susceptibility. It is thought that EBV infects the host by first replicating in the nasopharyngeal epithelium Infecting nearby tonsillar B lymphocytes.  EBV and NASOPHARYNGEAL CANCER In some persons this leads to transformation of the epithelial cells. Unlike the case with Burkitt lymphoma another EBV-associated tumor: The EBV genome is found in virtually all nasopharyngeal carcinomas, including those that occur outside the endemic areas in Asia  NASOPHARYNGEAL CARCINOMA There are three histologic variants: Keratinizing squamous cell carcinoma, Non-keratinizing squamous cell carcinoma, and Undifferentiated carcinoma; the last-mentioned is the most common and the one most closely linked with EBV. SINUSES  SINUSES They are located in four skull bones Frontal sinus They are lined with Sphenoid sinus Ethmoid sinus respiratory epithelium They reduce bone Maxillary sinus weight They warm and humidify the air They add resonance to the sound SINUS DISEASES  SINUSITIS Inflammation of the sinuses Acute or chronic inflammation.  SINUSITIS Rhinogenic: The infection spreads from the nasal cavity to the sinuses. This is the most common way the infection spreads. It occurs as a complication of flu and cold (URTI). Odontogenic: Infection occurs as upper tooth and gum infections spread to the sinuses. Maxillary sinusitis most commonly presents in this way. Traumatic Hematogenic Allergic. SINUSITIS PATHOGENESIS 1-Blocked sinus opening (edematous mucosa) 2-Anatomical sinus anomalies. Sinus mucosa is damaged by bacteria and viruses (cilia become immobile…) When the oxygen concentration decreases, the bacterial population  SINUSITIS SINUSITIS PATHOGENESIS Ek faktörler: Immün yetmezlik Sinüslerden normal akışı zorlaştıran/engelleyen patolojik burun/nazofarinks değişiklikleri: - Septum deviasyonu - Tonsil/adenoid hipertrofileri MAJOR AND MINOR CRITERIA IN THE DIAGNOSIS OF ACUTE RHINOSINUSITIS Major criteria Minor criteria Pressure/pain on face Pressure/pain on ears Congestion Weakness Nasal obstruction Halitosis Postnasal dripping Gingival (purulent:yellow/greenish) pain/tenderness Hiposmia/anosmia Cough Fever RADIOLOGY- (RIGHT MAXILLARY SINUSITIS UNILATERAL SPHENOIDITIS TREATMENT: NASAL IRRIGATION, MEDICAL AND SURGICAL Sterile saline solution Irrigation with ocean water! Antibiotherapy Decongestants  SURGICAL INDICATIONS 1. In chronic sinusitis that does not respond to medical treatment 2. In cases of orbital complications (orbital abscess, phlegmon) 3. In the presence of intracranial complications 4. In the presence of polyps. 5. In fungal sinusitis. LARYNGEAL PATHOLOGY ANATOMY  ANATOMY The larynx is located in the anterior part of the neck, inferior-anterior to the pharynx and superior to the trachea. It has three anatomical regions: supraglottis, glottis and subglottis. SUPRAGLOTTIC LARYNX: epiglottis, pseudovocal cords, ventricles, aryepiglottic folds arytenoids; GLOTTIS: true vocal cords anterior and posterior Contains commissures.  HISTOLOGY Epiglot ve Gerçek vokal kordlar: Çok katlı skuamöz epitel. Geri kalan bölümler solunum tipi epitel. BENIGN LESIONS OF LARYNX LARINGEAL POLYP: LARINGEAL NODULE (SINGER'S NODULE) It is a non-inflammatory response to damage. In heavy smokers And it is the most important cause of hoarseness in singers. There is no malignant transformation. LARINGEAL POLYP: LARINGEAL NODULE (SINGER'S NODULE) LARİNGEAL PAPİLLOMA LARİNGEAL PAPİLLOM  LARINGEAL PAPILLOMA Associated with HPV 6 and 11 Proliferating, well-differentiated squamous epithelium containing fibrovascular cores It may include mild, moderate and severe dysplasia. DYSPLASIA: Increased cellularity Loss of polarization with basal layer hyperchromatic nucleus Increased mitotic activity It may develop into invasive SCC. LARYNX MALIGNANT LESIONS  LARYNX CARCINOMA ETHIOLOGY Cigarette consumption is the most important risk factor for laryngeal carcinoma. Mortality rate from laryngeal carcinoma in heavy smokers: X20. Heavy and chronic alcohol consumption is also an identified risk factor. When combined, these two factors have a synergistic effect.  LARYNX CARCINOMA ETHIOLOGY Low socioeconomic status, male gender and being over 55 years of age. Gastroesophageal reflux disease. The risk is increased in people exposed to the exhaust fumes of diesel vehicles. In some studies, HPV types 16 and 18 infections It has been shown to constitute 10% of laryngeal squamous intraepithelial lesions  PATHOGENESIS The formation and development of malignant tumors of the larynx occur at the molecular and histological levels. Carcinogenesis is triggered by abnormal methylation of genes associated with laryngeal cancer. Molecular steps that play a role in tumorigenesis: Loss of RB1 expression, MYC and EGFR amplification. Tp53 mutations and CCND1 amplifications are seen in advanced stage patients.  HISTOPATHOLOGICAL FEATURES Transformation from normal laryngeal mucosa dysplastic mucosa carcinoma in situ  invasive carcinoma.  LOCALIZATION Most laryngeal carcinomas are located in the glottic region. Supraglottic region cancers are less common. The subglottic region is most rarely affected.  MACROSCOPY The macroscopic appearance of invasive squamous cell carcinoma is highly variable. It has an ulcerated, exophytic, verrucoid or papillary growth pattern. MUCOSAAL CHANGES CLINICSPATHOLOGY Clinically, precancerous lesions of mucosal surfaces: It is observed as leukoplakia, erythroplakia and variegated leukoplakia. Although these terms are clinical terms, they often have specific histopathological equivalents. Lesions that appear as erythroplakia are often diagnosed histopathologically as severe dysplasia, carcinoma in situ or invasive carcinoma. Lesions that look like leukoplakia may not always reflect a premalignant lesion. ERYTHROPLAKIA  MUCOSAAL CHANGES CLINICSPATHOLOGY Lesions resembling leukoplakia, increased surface keratinization without dysplasia Keratinizing invasive squamous cell carcinoma may represent a broad histopathological spectrum between  WHAT IS DYSPLASIA? Although dysplasia is used and perceived synonymously with atypia by clinicians, Histopathologically, dysplasia is the term used to describe epithelial architectural changes, and atypia is the term used to describe cellular morphological changes. In order to diagnose laryngeal intraepithelial neoplasia (LIN), which is used synonymously with laryngeal dysplasia, the lesion must contain the features of both terms.  LIN (LARYNGEAL INTRAEPITHELIAL NEOPLASIA) Mild Moderate Severe Normal Mild dysplasia Moderate dysplasia Ağır derecede displazi İN SİTU/ İNVAZİV KARSİNOM  LARYNX CARCINOMA PROGNOSTIC FACTORS The most important prognostic factor of laryngeal cancers is the increase in T and N stages. Other poor prognostic factors: Subglottic region Male gender Increasing age decrease in the patient's performance status, High tumor grade, High ki-67 proliferation index, Surgical margin positivity, Presence of lymphovascular and perineural invasion Extracapsular spread in lymph node metastasis  The three histologic variants are keratinizing squamous cell carcinoma, nonkeratinizing squamous cell carcinoma, and undifferentiated carcinoma; the last-mentioned is the most common and the one most closely linked with EBV. The undifferentiated neoplasm is characterized by large epithelial cells with indistinct cell borders (reflecting “syncytial” growth) and prominent eosinophilic nucleoli. As described in Chapter 11, in infectious mononucleosis, EBV directly infects B lymphocytes, after which a marked proliferation of reactive T lymphocytes causes atypical lymphocytosis, seen in the peripheral blood, and enlarged lymph nodes. Similarly, in nasopharyngeal carcinomas, a striking influx of mature lymphocytes often can be seen. These neoplasms are therefore referred to as  transmission from an infected mother during delivery. Therefore, the recent availability of an HPV vaccine that can protect women of reproductive age against infection with types 6 and 11 provides an opportunity for prevention of RRP in children. Carcinoma of the Larynx Carcinoma of the larynx represents only 2% of all cancers. It most commonly occurs after age 40 years and is more common in men than in women (with a gender ratio of 7 :1). Environmental influences are very important in its causation; nearly all cases occur in smokers, and alcohol and asbestos exposure may also play roles. Human papillomavirus sequences have been detected in about 15% of tumors, which tend to have a better prognosis than other carcinomas. About 95% of laryngeal cancers are typical squamous cell carcinomas.