Pathgen 6.1 Lungs (PDF)

Objectives 1. Illustrate the normal respiratory system and its main functions. 2. Distinguish the types of atelectasis. 3. Analyze the causes, pathology and clinical consequences of Acute Respiratory Distress Syndrome. 4. Compare and contrast obstructive versus restrictive pulmonary...

Objectives 1. Illustrate the normal respiratory system and its main functions. 2. Distinguish the types of atelectasis. 3. Analyze the causes, pathology and clinical consequences of Acute Respiratory Distress Syndrome. 4. Compare and contrast obstructive versus restrictive pulmonary diseases and relate examples for each 5. Distinguish the symptoms and pathology of emphysema and bronchitis 6. Illustrate the features of asthma including pathogenesis and clinical findings 7. Illustrate the features of bronchiectasis. 8. Illustrate the features of fibrotic lung disease 9. Differentiate three examples of pneumoconioses. 10. Discuss Sarcoidosis, and Hypersensitivity pneumonitis. 11. Debate the causes, risk factors, and clinical features of pulmonary emboli. 12. Inventory the causes of pulmonary hypertension. 13. Relate the common causes and relate the pathogenesis and clinical features of pneumonia. 14. Distinguish the pathology and manifestations of tuberculosis 15. Distinguish the typical location, gross appearance, and histologic findings associated with various forms of lung cancer. 16. Apply the pathogenesis of pleurisy and the differential diagnosis of pleural effusions. 17. Cystic Fibrosis: Analyze the genetic principles, major phenotypic features, disease etiology and incidence, pathogenesis, phenotype and natural history, management, and risk inheritance. Normal Respiratory System IO: 1 Development of the lungs During embryogenesis, the respiratory system grows out from the ventral wall of the foregut Midline trachea develops into lung buds R lung bud divides into three main bronchi and the L into two  hence 3 Right lobes and 2 Left Main bronchi continue to bifurcate into smaller and smaller airways, eventually dubbed “bronchioles” which have lost their cartilage and submucosal glands These lead to “terminal bronchioles” The most distal part of these is called an “acinus” and these are composed of alveolar ducts and sacs Of course, it is in the capillaries surrounding alveoli that respiratory gasses are exchanged Alveolar spaces In between alveoli are “alveolar septa” (septum singular) Moving, then, from airspace to blood: Alveolar epithelium, consisting of continuous layer of two cell types Type I pneumocytes which cover 95% of the alveolar surface Type II pneumocytes that repair alveolar epithelium when it is damaged and create surfactant Pulmonary interstitium, made of elastic fibers, mast cells, and an assortment of miscellaneous cells and tissues The capillary basement membrane, This picture has a disease process at work, which is why there are capillary walls, endothelium, blood interleukins and neutrophils depicted, but many of the structures are permanent Atelectasis IO: 2 Atelectasis Definition Also known as “collapse,” this should not be confused with pneumothorax Atelectasis results in loss of lung volume caused by inadequate expansion of airspaces The basic principle is “use it or loose it” After the precipitating factor of atelectasis, physiologic “shunting” of blood occurs Blood moves from poorly perfused areas with inadequate gas exchange to elsewhere The alveoli, in turn, begin to close Atelectasis types Contraction atelectasis Fibrosis hampers lung expansion Resorption atelectasis Obstruction impairs air from reaching distal airways s/p thoracic surgery  mucopurulent plugs In children  FB aspiration Any air present (and now trapped) is absorbed over time Alveoli collapse Compression atelectasis Accumulation of fluid, blood, or air within pleural cavity Pleural effusion, pneumothorax Failure to breath deeply Pain, neuromuscular disease ARDS IO: 3 ARDS Definition “Respiratory failure occurring within 1 week of known clinical insult with bilateral opacities on chest imaging that is not fully explained by effusions, atelectasis, cardiac failure, fluid overload” * It will take place within hours, not days (85% percent of cases within 3 days, often within 30 minutes) Key Features of ARDS “Rapid onset of life-threatening respiratory insufficiency, severe arterial hypoxemia, +/- cyanosis” Airspace disease – occurring in the alveoli Integrity of alveolar-capillary membrane is compromised by endothelial and epithelial injury This leads to “diffuse alveolar damage” Finally, the issue becomes fluid build up in the airspace! How does this happen? Initial insult: Infxn, caustic substance, etc.  Inflammatory reaction initiated by variety of pro-inflammatory mediators  Synthesis of cytokines  neutrophil chemotaxis + interlukin 1 and TNF  sequestration and activation of neutrophils in pulmonary capillaries  PMNs now occupy vascular space, the interstitium, and alveoli  PMN release caustic products: ROSs, proteases  Vascular leaking occurs and there is a loss of surfactant  Fluid in the airspaces  Oxygen cannot diffuse readily through fluid: disease rapidly becomes refractory to 02 therapy ARDS Then what happens? If the patient lives, they will take 6 to 12 months to return to normal pulmonary function But often there is long-term damage (25% of cases) Type II pneumocytes proliferate to attempt to regenerate the alveolar lining  Proliferation of interstitial cells and deposition of collagen triggered by macrophages and placed down fibroblasts  Fibrin-rich exudates organize into interalveolar fibrosis  Thickening of alveolar septa  Chronic poor gas exchange  Less compliant and expansive lungs Chronic lung disease  ARDS Normal alveolus on the left and early ARDS on the right Cytokines lead to neutrophil sequestration and activation PMNs release their products Tissue damage Accumulation of edema fluid Surfactant inactivation Hyaline membrane formation Macrophage-derived fibrogenic cytokines ARDS Can occur in several different clinical settings Associated with primary pulmonary diseases and severe systemic inflammatory disorders: aka sepsis MC triggers PNA 35%-45% Sepsis 30%-35% Aspiration, trauma, pancreatitis, transfusion reactions Obstructive Disease IO: 4 Obstructive vs Restrictive Dz Obstructive: characterized by increase in resistance to air flow – measured by difficulty blowing out Restrictive: characterized by reduced expansion of lung and decreased total lung capacity Obstructive vs Restrictive Dz Obstructive forced vital capacity (FVC) is normal and expiratory flow rate (FEV1) is significantly decreased FVC: how much air you can blow out FEV1: how much air you blow out in the first second What does this look like? Very long expiratory phase... The ratio of FEV1/FVC is decreased Restrictive FVC is reduced and the expiratory flow rate is also reduced What does this look like? The person doesn’t fill their lungs, so they don’t blow out much... But what they do blow out comes out pretty easily In the FEV1/FVC ratio both numbers go down, but the ratio is roughly equal! Obstructive Disease The four main types are emphysema, chronic bronchitis, asthma and bronchiectasis Chronic bronchitis involves large airways Emphysema affects the acinus In COPD, these two diseases intermingle in the long-term smoker It is possible to have emphysema all by itself – genetic disease: alpha-1 antitrypsin disorder Stay tuned Asthma is a disease of bronchospasm Bronchiectasis involves scarring of the airways Emphysema and Bronchitis IO: 5 Emphysema Permanent enlargement of air spaces distal to terminal bronchioles – the acinus – with permanent destruction of their walls and significant fibrosis There are two clinically significant types Centriacinar and panacinar Emphysema In centriacinar emphysema the central or proximal parts of acini are affected, and distal alveoli are spared This is the one smokers get In panacinar emphysema the acini are uniformly enlarged This occurs with alpha-1 antitrypsin deficiency Emphysema Pathology How do you get COPD/emphysema type? Inhaled smoke causes lung damage and inflammation  Inflammatory mediators are initiated and inflammatory cells recruited  Inflammatory cells release protease  Protease breaks down connective tissues, in particular elastin  Acinar damage ensues, causing the bulging of the acinus  Alveoli are lost  Number of alveolar capillaries are diminished  Diffusing capacity and gas exchange are reduced Also, without elastic tissue, small airways collapse during expiration Don’t  Outward airflow obstruction smoke Emphysema Pathology How do you get emphysema from alpha-1 antitrypsin? Alpha-1 antitrypsin is usually present in serum, tissue fluids, macrophages: it inhibits elastase, which breaks down elastin  genetic disease affecting the lungs and liver  in the lung, alpha-1 antitrypsin is underproduced  it is therefore unable to inhibit elastase  elastase breaks down elastin in the lung  acinus is affected as in normal emphysema – (but panacinar)  obstructive disease * homozygous disease more severe Emphysema Patient Primary symptom is dyspnea Disease is compensated for with hyperventilation, which leads to increased energy demands and weight loss that is often profound Caloric intake is also sometimes reduced On physical exam, tachypnea, pursed-lip breathing, hunched posture, barrel chest Secondary effects Pulmonary hypertension Physiologic Shunting Obstructive overinflation Expansion of the lung due to air trapping Bullae Large, empty spaces in the lung where tissue is completely lost Chronic Bronchitis Pathology Defined as the presence of persistent productive cough for 3 consecutive months in at least 2 consecutive years How do you get COPD/bronchitis type? Cigarette smoke induces hypertrophy of mucous glands in trachea and bronchi Transcription of the mucin gene in bronchial epithelium occurs There is also an increase in mucin-secreting goblet cells in epithelial surfaces of small bronchi and bronchioles  mucous plugging of the bronchiolar lumen Smoke also induces inflammation via macrophages and neutrophils  Local tissue destruction  Fibrosis Of note: in chronic bronchitis we see PMNs and macrophages, but not eosinophils – the hallmark of asthma Also of note: They can also experience inflammation in the small bronchi–bronchioles. Sufferers of severe bronchiolitis can experience complete fibrotic obstruction, termed “bronchiolitis obliterans” Chronic Bronchitis Patient In early stages, cough raises mucoid sputum, but airflow is not yet obstructed – pts may have hyperreactive airways, though, that lead to intermittent bronchospasm and wheezing From there, the course is variable, but late-stage findings include Significant outflow obstruction Hypercapnia – can’t blow off the CO2 Hypoxemia – can’t intake 02 Cyanosis Pulmonary hypertension  you know where this leads... COPD pts. with bronchitis often have more rapid disease progression with poorer outcomes than the isolated emphysema type Pink or Blue? Long-term Smoking Effects Neutrophils are recruited Transcription of mucin  Elastase is produced gene  Acini are damaged  Mucus plugging of bronchial lumen  Inflammation and fibrosis There is almost always significant disease overlap in both types of COPD... Asthma IO: 6 Asthma Definition “Chronic inflammatory disorder marked by intermittent, reversible airway obstruction, chronic bronchial inflammation with eosinophils, bronchial smooth muscle hypertrophy and hyperreactivity” There are two types Atopic – hypersensitivity type I Non atopic  Asthma Pathology Atopic type Excessive helper T cell activation  Release cytokines: IL 5  Mast Cells IL 4  IgE production  IgE coats the mast cells IL 13  mucous production  cough Early phase: Coated mast cells encounter antigen and release histamine along with pro-inflammatory prostaglandin, and leukotrienes Histamine  bronchospasm  wheezing Leukotrienes  additional bronchoconstriction Late Phase Inflammation that has occurred thus far now prompts epithelial cells in the lung to attract further eosinophils  promote further involvement of leukocytes and amplify inflammation  when this inflammatory response is oft repeated, structural changes occur in the lung Structural changes Airway remodeling includes hypertrophy of bronchial smooth muscle Increased mucus glands Increased vasculature and deposition of epithelial collagen This gives asthma and irreversible component in the late stage only *Of note: atopic asthma demonstrates familial aggregation, which portends a genetic component Asthma Pathology Non-atopic type Do not have evidence of allergen sensitization and thus allergen skin tests for offending agent are usually negative Attacks may still be triggered by viral illness and air pollutants Many of the inflammatory mediators are the same and the treatment does not vary from atopic Less often any family history Asthma Patient These patients have recurrent episodes of wheezing, breathlessness, chest tightness and cough particularly at night Triggers of asthma attacks Most commonly viral illness, but often smoke, fumes, cold air, stress, exercise In the atopic type Triggers may also include pollen, dust, animal dander, food Onset of asthma attack may be preceded by rhinitis, urticaria, eczema The asthma attack Severe dyspnea Bronchoconstriction and mucus plugging  wheeze and cough  air trapping in distal airspaces  hyperinflation of the lungs X ray will be normal This lasts from 1 to several hours When these attacks do not respond to therapy, it is called status asthmaticus Hypercapnia  acidosis Hypoxia Fatality Physiology of asthma treatment Treatment involves direct response to the processes discussed Bronchodilators  beta-adrenergic drugs Anti-inflammatory  steroids Leukotriene inhibitors Bronchiectasis IO: 7 Bronchiectasis Pathology Permanent dilation of bronchi and bronchioles caused by destruction of SM and elastic tissue 1. Obstruction or chronic/necrotizing infection a) Foreign body / tumor  obstruction  superimposed infection b) CF  thick and viscous sputum  obstruction and recurrent infection c) Primary severe bacteria  obstructing purulent material 2. Inflammatory damage and fibrosis Bronchi and bronchioles enlarge greatly, and the walls thicken Bronchiectasis Patient Severe persistent cough Expectoration of copious sputum Sometimes fetid and mucopurulent Intermittent sx, correlate with new infections CF patient with 2nd bronchiectasis Fibrotic Lung Disease IO: 8 Idiopathic Pulmonary Fibrosis Disease of patchy, progressive bilateral interstitial fibrosis leading to restrictive disease Etiology unclear Genetic + environmental damage Disease of alveolar epithelial cells, linked to heritable mutations in MUC5B and germline mutations in surfactant genes – both of which only expressed in the lung Also linked to loss of telomerase and cell senescence  only in older individuals (at least 50+) Some connection to GERD  repeated cellular injury Only very small portion of reflux patients develop this Idiopathic Pulmonary Fibrosis Disease of patchy, progressive bilateral interstitial fibrosis leading to restrictive disease Etiology unclear Genetic + environmental damage Disease of alveolar epithelial cells, linked to heritable mutations in MUC5B and germline mutations in surfactant genes – both of which only expressed in the lung Also linked to loss of telomerase and cell senescence  only in older individuals (at least 50+) Some connection to GERD  repeated cellular injury Only very small portion of reflux patients develop this Idiopathic Pulmonary Fibrosis Disease of patchy, progressive bilateral interstitial fibrosis leading to restrictive disease Etiology unclear Genetic + environmental damage Disease of alveolar epithelial cells, linked to heritable mutations in MUC5B and germline mutations in surfactant genes – both of which only expressed in the lung Also linked to loss of telomerase and cell senescence  only in older individuals (at least 50+) Some connection to GERD  repeated cellular injury Only very small portion of reflux patients develop this Idiopathic Pulmonary Fibrosis Disease of patchy, progressive bilateral interstitial fibrosis leading to restrictive disease Etiology unclear Genetic + environmental damage Disease of alveolar epithelial cells, linked to heritable mutations in MUC5B and germline mutations in surfactant genes – both of which only expressed in the lung Also linked to loss of telomerase and cell senescence  only in older individuals (at least 50+) Some connection to GERD  repeated cellular injury Only very small portion of reflux patients develop this Idiopathic Pulmonary Fibrosis Patient Older Male Chronic, nonproductive cough “Dry” crackles on inspiration Late stage cor pulmonale “Honeycombing” on CT Other Rare Fibrosing Diseases Nonspecific interstitial pneumonia Less severe than IPF Cryptogenic organizing PNA Severe disease that sometimes resolves spontaneously! Pneumoconioses IO: 9 Pneumoconioses Accumulation of environmental particulate in the lung leading to disease Originally referred to “mineral dusts” Coal, silica, asbestos  3 Main causes Anthracosis (coal) Silicosis Asbestosis Particle size 10 micrometers are too big to get to distal airway and become lodged in the bifrucations – removed through ciliary motion 0.5 micrometers pass to alveoli and move out from them 1-5 micrometers cause issues Pneumoconioses General Pathology Trapped dust 1-5 micrometer particulate is trapped in distal lung in alveolar duct bifurcations  macrophages accumulate and engulf trapped particles  Inflammatory response initiated  fibroblasts proliferate  cells drain to lymphatics and amplify immune response through adaptive system Coal Worker’s Pneumoconiosis Called Anthracosis Depends upon the extent of damage – coal is inert and so can rest in the lung a long time, building up large amounts before having an effect Macrophages engulf carbon pigment and accumulate in connective tissue along pulmonary and pleural lymphatics “Simple CWP” Marked by “coal macules” and “coal nodules” Once lower lobes are heavily involved these pts develop emphysema Fibrotic element can progress to “progressive massive fibrosis” or “complicated CWP” “Complicated CWP” Simple CWP + multiple, dark black scars, between 2-10 cm in length Continues to worsen even after no more exposure Pulmonary HTN  cor pulmonale Silicosis Most prevalent chronic occupational disease in the world Sandblasting and hard-rock mining Quartz, crisobalite, tridymite Deposition in epithelial cells  fibrosis  “PMF” (progresisive massive fibrosis)  pulmonary HTN, cor pulmonale Asbestosis Fibers deposited in lung  eaten by macrophages  inflammation/ fibrosis  “diffuse pulmonary interstitial fibrosis with ‘asbestos bodies’”  mesothelioma *key feature from occupational medicine is that families of workers are also exposed Pt’s develop worsening dyspnea 10-20 years after exposure Parenchymal interstitial fibrosis Localized fibrous plaques Pleural effusions Lung carcinoma Malignant pleural and peritoneal mesothelioma Laryngeal carcinoma *Risk of cancer goes way up if they are also smoking Sarcoidosis and Hypersensitivity Pneumonitis IO: 10 Sarcoidosis Multisystemic disease Unknown etiology Defining feature is noncaseating granulomas in various tissues Lung involvement in 90% of cases with formation of granulomas and interstitial fibrosis Hypercalcemia Increased release 1,25-dihydroxy vitamin D PTH related peptide (PTHrp) secreted by granulomas Features: Dry cough Peri-hilar LAD node enlargement Eyes (sicca syndrome-dry eyes, iritis, iridocyclitis) Skin lesions ( erythema nodosum & sub q nodules) Visceral (liver)  Hypersensitivity Pneumonitis Immunologically mediated lung disease that primarily affects the alveoli (allergic alveolitis) Usually caused by occupational exposure and heightened sensitivity to inhaled antigens Pulmonary Emboli IO: 11  Pulmonary Embolus Almost all large pulmonary artery thrombi are embolic in origin, usually arising from the deep veins of the lower leg. Risk factors include prolonged bed rest, knee or hip surgery, severe trauma, use of oral contraceptives (especially those with high estrogen content), disseminated cancer, and genetic causes of hypercoagulability. Most emboli (60% to 80%) are clinically silent; a minority (5%, typically large “saddle emboli”) cause acute right-sided heart failure, shock, or sudden death; and the remainder cause pulmonary infarction. Risk for recurrence is high. Pulmonary HTN IO: 12  Pulmonary hypertension (defined as pressures of 25 mm Hg or more at rest) decrease in the cross-sectional area of the pulmonary vascular bed or, less commonly, by increased pulmonary vascular blood flow. Features Pulmonary Initial : dyspnea and fatigue Chronic : respiratory distress, cyanosis, and RVH HTN WHO classification Pulmonary arterial hypertension- affecting small pulmonary muscular arterioles; i.e. connective tissue diseases, HIV, and congenital heart disease (left to right shunts) Pulmonary hypertension due to left-sided heart disease, including systolic and diastolic dysfunction and valvular disease Pulmonary hypertension due to lung diseases and/or hypoxia, including COPD, interstitial lung disease, and sleep apnea Chronic thromboembolic pulmonary hypertension Pulmonary hypertension with unclear or multifactorial mechanisms  Pulmonary hypertension (defined as pressures of 25 mm Hg or more at rest) decrease in the cross-sectional area of the pulmonary vascular bed or, less commonly, by increased pulmonary vascular blood flow. Features Pulmonary Initial : dyspnea and fatigue Chronic : respiratory distress, cyanosis, and RVH HTN WHO classification Pulmonary arterial hypertension- affecting small pulmonary muscular arterioles; i.e. connective tissue diseases, HIV, and congenital heart disease (left to right shunts) Pulmonary hypertension due to left-sided heart disease, including systolic and diastolic dysfunction and valvular disease Pulmonary hypertension due to lung diseases and/or hypoxia, including COPD, interstitial lung disease, and sleep apnea Chronic thromboembolic pulmonary hypertension Pulmonary hypertension with unclear or multifactorial mechanisms Pneumonia IO: 13 Pneumoni a Pneumonia – any One-sixth of all infection in the deaths in the U.S. lung Pneumonia types Community Acquired Bacterial Pneumonia Community Acquired Viral Pneumonia Nosocomial Pneumonia (hospital acquired) Aspiration Pneumonia Chronic Pneumonia Necrotizing Pneumonia & Lung Abscess Pneumonia of the Immunocompromised patient Acute S. pneumoniae (the pneumococcus) is Pneumonia the most common cause of s community-acquired bacterial pneumonia and usually has a lobar pattern of involvement. Morphologically, lobar pneumonias involve an entire lobe and are bound by fissure lines. Congestion: Lung is heavy, boggy, and red. Red Hepatization: Massive confluent exudation as neutrophils, red cells and fibrin fill the alveolar spaces Resolution: exudate broken down by enzymatic activity  Other common causes of bacterial pneumonias in the community include: H. influenzae and M. catarrhalis (both associated with acute exacerbations of COPD), S. aureus (usually secondary to viral respiratory infections) K. pneumoniae (observed in chronic alcoholics), P. aeruginosa (seen in individuals with cystic fibrosis, in burn victims, and in patients with neutropenia), and L. pneumophila, seen particularly in organ transplant recipients. Viral pneumonias are characterized by respiratory distress out of proportion to the clinical and radiologic signs, and by inflammation that is predominantly Acute confined to alveolar septa – interstitial space, with Pneumoni generally clear alveoli. as Common causes of viral pneumonia include SARS Covid- 2, influenza A and B, respiratory syncytial virus Clinical Features of Acute Pneumonias Onset is usually abrupt Often follows an upper respiratory tract infection Systemic signs of infection – high fever, shaking chills, pleuritic chest pain Local signs of irritation – productive mucopurulent cough Airway obstruction – shortness of breath (dyspnea), rapid breathing (tachypnea) Occasional patients may have hemoptysis Complications of Acute Pneumonias Complications may occur in severe cases or in debilitated patients Pneumonia may extend to pleura, cause pleuritis, and heal as pleural fibrosis Empyema – pus in pleural space Abscess formation Bronchiectasis from chronic lung infection Interstitial fibrosis with cysts Tuberculosis IO: 14  Caused by World’s foremost Mycobacterium cause of death from tuberculosis a single infectious Rod-shaped bacterium agent with waxy capsule A communicable Tuberculosi Airborne chronic granulomatous s transmission disease Centers of tubercular granulomas undergo caseous necrosis Usually involves lungs, but may affect any organ  Caused by World’s foremost Mycobacterium cause of death from tuberculosis a single infectious Rod-shaped bacterium agent with waxy capsule A communicable Tuberculosi Airborne chronic granulomatous s transmission disease Centers of tubercular granulomas undergo caseous necrosis Usually involves lungs, but may affect any organ  Caused by World’s foremost Mycobacterium cause of death from tuberculosis a single infectious Rod-shaped bacterium agent with waxy capsule A communicable Tuberculosi Airborne chronic granulomatous s transmission disease Centers of tubercular granulomas undergo caseous necrosis Usually involves lungs, but may affect any organ  Caused by World’s foremost Mycobacterium cause of death from tuberculosis a single infectious Rod-shaped bacterium agent with waxy capsule A communicable Tuberculosi Airborne chronic granulomatous s transmission disease Centers of tubercular granulomas undergo caseous necrosis Usually involves lungs, but may affect any organ TB Pathology Lungs are sprayed with aerosolized TB TB  lands along the fissures and just under the exterior lung and the patient has “Primary TB” Macrophages address the invasion They will have trouble dealing with mycobacterium, and thus wall it off  caseating granuloma Ghon focus  lung Ghon focus + lymph node  Ghon Complex Our initial battle with TB leads to 1 of 3 possibilities for the bacteria 1. Death  TB dies 2. Dormancy  TB stops spreading 3. Division  TB replicates If option #2, the patient has “latent TB” and is without sx with normal CXR At this stage, your active immune system remembers TB and you will have antibodies  this is how the PPD test works If this patient with latent TB is either reinfected or enters an immunosuppressed state, the infxn can come back Now they have “secondary TB” For reasons not fully understood, secondary TP usually occurs in the lung apices  cavitary lesions From here, TB can sometimes spread to the rest of the body Primary Pulmonary Tuberculosis Primary infection in previously unexposed unsensitized patient Localized infection in lung and regional lymph nodes Ghon complex heals spontaneously by calcification and scarring Progressive primary TB rare, only 5% newly infected acquire significant disease (mainly children, immunosuppressed individuals) Pulmonary Tuberculosis  Secondary tuberculosis can result from reactivation of dormant primary infection or a re-infection by M. tuberculosis Bacteria typically spread to apex of lungs, causing granulomatous Secondary bronchopneumonia Confluent granulomas produce cavities Pulmonary Pulmonary cavities are sources of Tuberculosis hemoptysis Tissue destruction ensues, and occasional bacterial spread - Tuberculous pneumonia - Extrapulmonary tuberculosis - Miliary tuberculosis (system wide) Clinical Features of Tuberculosis Secondary tuberculosis-usually in the apices Nonproductive cough, low-grade fever, loss of appetite, malaise, night sweats, weight loss, hemoptysis Chest X-rays essential for diagnosis Definitively established by identifying bacilli in sputum by acid-fast stains Both progressive primary tuberculosis and secondary tuberculosis can result in systemic seeding, causing life-threatening forms of disease such as miliary tuberculosis and tuberculous meningitis. HIV-seropositive status is an important risk factor for the development or recrudescence of active tuberculosis. Lung Cancer IO: 15  Most important cause of cancer related deaths in industrialized countries Leading cancer killer in men and women in U.S. Carcinomas of the Lung Cancer) Smoking is the most important risk factor. At diagnosis, 50% of people have distant mets Five-year survival rate is 45% for cases Five-year survival rate is 16% detected when the disease is still localized (within the lungs)  Most important cause of cancer related deaths in industrialized countries Leading cancer killer in men and women in U.S. Carcinomas of the Lung Cancer) Smoking is the most important risk factor. At diagnosis, 50% of people have distant mets Five-year survival rate is 45% for cases Five-year survival rate is 16% detected when the disease is still localized (within the lungs)  Four major histologic subtypes of Carcinoma lung carcinoma: (95% of Adenocarcinoma (most primary common) lung Squamous cell carcinoma tumors) Small-cell carcinoma (sub-type of neuroendocrine tumor) Large-cell carcinoma Histologic Changes of Major Lung Cancer Types Carcinoma in the Lung Carcinoma Memory “S” stands for “Sentral” Squamous cell  scaley and obstructive Adeno  grow slow Small cell  small so it makes up for this with paraneoplastic disease Cushing’s and SAIDH Large cell, big deal because it grows fast Clinical Features Initial symptoms Subsequent Symptoms of of Lung Cough & expectoration symptoms (with poor prognosis) metastatic spread can be presenting complaint Cancer Hoarseness Brain- mental or neurologic Chest pain changes Superior vena cava syndrome Liver – hepatomegaly Pericardial or pleural effusions Bone-pain Lung Tumors HYPERCALCEMIA → PTH RELATED PEPTIDE CUSHING SYNDROME → ↑ PRODUCTION OF SYNDROME OF INAPPROPRIATE ANTI- as ACTH DIURETIC HORMONE (SIADH) Paraneoplasti c Syndromes NEUROMUSCULAR …AND OTHERS. SYNDROMES → MYASTHENIC SYNDROME  Rare CA of the mesothelial cells of visceral or parietal pleura Highly related to airborne asbestos (80-90%) Malignant Latent period from exposure to Mesothelio development is 25-40 years ma Secondary to causative driver mutations Once inhaled, asbestos fibers remain for live and do not diminish over time (as with cessation of smoking) Pleural Effusion IO: 16 Pleural Effusions Transudate → “hydrothorax” Most common cause: CHF Exudate → defined as protein >30 g/L Microbial invasion (direct extension of pulmonary infection or blood-borne seeding) Cancer: ie lung carcinoma, metastatic neoplasms, mesothelioma Pulmonary infarction Viral Pleuritis Cystic Fibrosis IO: 17 Cystic Fibrosis Disease Etiology and Incidence CF is an autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene The CFTR protein chloride channel located in the apical membrane of the epithelial cells affected by the disease (lung, pancreas, sweat gland, vas deferens) Cystic Fibrosis Disease Etiology and Incidence (cont.) The major features of classic cystic fibrosis are chronic pulmonary disease and malabsorption Although CF has been observed in all races, it is predominantly a disease of Northern Europeans, with an incidence of approximately 1 in 2500 Caucasian births Cystic Fibrosis Pathogenesis The CFTR protein maintains the hydration of secretions within the airways and ducts through the transport of chloride across the cell membrane and inhibition of sodium uptake In CF patients, the chloride channel is unable to open causing chloride ions to accumulate in the cell. To balance the chloride ions, the cells absorb excess sodium. In secretory glands, this leads to decreases in fluid production. Cystic Fibrosis Cystic Fibrosis Pathogenesis (cont.) Dehydrated and viscous secretions in the lungs interfere with mucociliary clearance, inhibit the function of naturally occurring antimicrobial peptides, provide a medium for growth of pathogenic organisms, and obstruct airflow  Mucus secretions and colonizing bacteria initiate an inflammatory reaction  Recurrent cycles of infection, inflammation, and tissue destruction eventually lead to respiratory failure Cystic Fibrosis Pathogenesis (cont.) Loss of CFTR chloride transport into the pancreatic duct impairs the hydration of secretions and leads to the retention of exocrine enzymes in the pancreas. Damage from these retained enzymes eventually causes fibrosis of the pancreas.  Without proper pancreatic enzyme action, malabsorption follows Cystic Fibrosis Pathogenesis (cont.) CFTR also regulates the uptake of sodium and chloride from sweat as it moves through the sweat duct In the absence of functional CFTR, the sweat has an increased sodium chloride content, and this is the basis of the historical "salty baby syndrome" and the diagnostic sweat chloride test Cystic Fibrosis Phenotype and Natural History CF classically manifests in early childhood, although approximately 4% of patients are diagnosed in adulthood At birth, most infants present with chronic respiratory complaints and 15-20% present with meconium ileus due to thickened meconium or failure to pass meconium CF patients have poor growth resulting from a combination of increased calorie expenditure because of chronic lung infections and malnutrition from pancreatic exocrine insufficiency Cystic Fibrosis Phenotype and Natural History (cont.) More than 95% of male patients with CF are azoospermic because of congenital bilateral absence of the vas deferens (CBAVD) The progression of lung disease is the chief determinant of morbidity and mortality The current average survival is 37 years of age in the United States Cystic Fibrosis Phenotype and Natural History (cont.) A correlation between particular CFTR mutant alleles and disease severity exists only for pancreatic insufficiency Environmental factors, such as exposure to cigarette smoke, markedly worsen the severity of lung disease among patients with CF Cystic Fibrosis Management Pulmonary physical therapy and use of bronchodilators, antibiotics, and mucolytic agents to manage pulmonary disease In those with pancreatic insufficiency, oral enzyme replacement is provided Cystic Fibrosis Inheritance Risk Two heterozygous carrier parents have a 25% risk of having a child with cystic fibrosis The heterozygous carrier frequency in the White population is approximately 1 in 50 Newborn screening for cystic fibrosis in all 50 states In many regions, carrier screening is provided based on detection of the most common CFTR mutations Thank you! Nussbaum, R. L., McInnes, R. R., Williard, H. F., Thompson, J. S., & Thompson, M. W. (2007). Genetics in medicine. Estados Unidos: Saunders. Robbins, S. L., Aster, J. C., Perkins, J. A., Abbas, A. K., & Kumar, V. (2018). Robbins basic pathology. Philadelphia: Elsevier.