Pathology Outline: Test 3 RESTRICTIVE LUNG DISEASES 1 Restrict ...
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  • 1. Pathology Outline: Test 3<br />RESTRICTIVE LUNG DISEASES 1<br />
    • Restrict lung expansion >> decreased lung volume, increased work of breathing, inadequate ventilation and/or oxygenation.
    • 2. Intrinsic diseases - interstitial lung disease - involve alveolar tissues >> pulmonary fibrosis, restrictive lung physiology
    • 3. Extrinsic diseases - extraparenchymal diseases - affect chest wall, pleura, and respiratory muscles.
    Physiologic Changes in Restrictive Lung Disease <br />
    • Characterized by reduced lung volume >> reduced total lung capacity (TLC)
    • 4. Decreased measures of forced vital capacity (FVC) and forced expiratory volume (FEV1). Ratio of FEV1/FVC remains normal
    • 5. Consequence of reduced pulmonary compliance >> attributed to accumulation of parenchymal scar tissue
    • 6. Impaired gas exchange --- Resting arterial blood gas is normal >> Exercise-induced hypoxemia
    Idiopathic Pulmonary Fibrosis<br />
    • Chronic, progressive and lethal --- characterized by fibrosis of pulmonary interstitium of unknown etiology.
    Epidemiology: Affects elderly persons with mean age of 66 years --- more frequent in men.<br />Clinical Manifestations<br />
    • Latency period
    • 7. May last one decade --- asymptomatic but have histologically-proven IPF >> progresses toward symptomatic IPF.
    • 8. Early stage
    • 9. Insidious onset of exertional dyspnea with a dry, nonproductive cough
    • 10. Auscultation of lungs reveals early inspiratory crackles located in lower posterior lung zones.
    • 11. Rales have a fine acoustic character reminiscent of sound made by Velcro.
    • 12. Digital clubbing
    • 13. Late complications
    • 14. Respiratory failure with cyanosis, pulmonary hypertension and cor pulmonale
    • 15. Loud P2 component of 2nd heart sound, fixed split S2, holosystolic tricuspid regurgitation murmur, and pedal edema.
    Imaging <br />
    • Plain chest radiograph: Bilateral reticular markings (curvilinear opacities) at periphery and bases.
    • 16. High-resolution computed tomography (HRCT): More accurate
    • 17. Patchy reticular opacities, predominantly subpleural and bibasilar
    • 18. Traction bronchiectasis, i.e. secondary involvement of medium-sized airways
    • 19. Subpleural honeycombing, i.e. small, round translucencies and distortion with basal and peripheral distribution
    Morphology<br />
    • Gross --- changes primarily in lower lobes
    • 20. Pleural surfaces are cobblestoned as a result of the retraction of scars along interlobular septa.
    • 21. Microcysts with intervening dense fibrosis.
    • 22. Honeycomb --- cystic, dilated bronchioles (mucous and leukocytes) in scarred, fibrotic lung tissue.
    • 23. Histopathology
    • 24. Chronic fibrosing interstitial pneumonia associated with a histological pattern of usual interstitial pneumonia (UIP).
    • 25. Patchy interstitial fibrosis, often in subpleural and/or paraseptal distribution, alternating with areas of normal lung.
    • 26. Fibrosis is heterogeneous (different ages) with architectural destruction, and dense scarring with honeycombing
    Disease Course<br />
    • Survival is poor --- mean survival ranging from 2 to 4 years after diagnosis.
    • 27. Suppressing inflammation prevents progression to pulmonary fibrosis --- However, response to steroids is usually poor
    Pathogenesis<br />
    • Original hypothesis --- unknown stimuli injure lung resulting in chronic inflammation, fibrogenesis and end-stage fibrotic scar.
    • 28. Recent studies challenged the concept that inflammation is driving force in development of IPF.
    • 29. Evident from disappointing effects of anti-inflammatory treatment
    • 30. Increasing evidence that changes present in IPF result from sequential alveolar epithelial injury and abnormal wound repair.
    • 31. Injuries induce alveolar epithelial damage resulting in necrosis, fibrin deposition (hyaline membranes) and hemostasis
    • 32. Secrete growth factors and induce proliferation and differentiation to myofibroblasts that secrete proteins (collagens)
    • 33. Myofibroblasts --- expression of alpha-smooth muscle actin
    • 34. Responsible for wound contraction, which takes place during development of pulmonary fibrosis.
    • 35. Production and secretion of collagen and a variety of cytokines, including profibrotic TGF-beta.
    • 36. Imbalance of pro- and antifibrotic factors >> deposition of extracellular matrix within alveoli >> pulmonary fibrosis.
    • 37. TGF-beta1 is known to be fibrogenic and is released from injured type I alveolar epithelial cells.
    • 38. Favors transformation of fibroblasts into myofibroblasts and deposition of collagen
    • 39. Down-regulates caveolin-1 (inhibitor of pulmonary fibrosis -- restoring alveolar epithelial repair processes)
    Pneumoconioses<br />
    • Caused by inhalation of mineral dust, nearly always in occupational settings.
    • 40. Develop after many years of cumulative exposure; often diagnosed in older individuals, long after onset of exposure.
    Coal Worker’s Pneumocoiosis<br />
    • Accumulation of coal dust in lungs and tissue's reaction to its presence.
    • 41. Spectrum of lung findings
    • 42. Anthracosis
    • 43. Asymptomatic --- innocuous coal-induced pulmonary lesion
    • 44. Inhaled carbon particles are engulfed by alveolar macrophages which then accumulate in connective tissue
    • 45. Accumulation of carbon particles causes no cellular reaction.
    • 46. Grossly: focal black pigmentation scattered in upper zones of upper and lower lobes.
    • 47. Simple CWP
    • 48. Accumulation of carbon-laden macrophages occurs with little or no pulmonary dysfunction.
    • 49. Characterized by coal macules (1 to 2 mm in diameter) and somewhat larger coal nodules.
    • 50. Upper lobes and upper zones of lower lobes are heavily involved --- adjacent to respiratory bronchioles
    • 51. Complicated CWP (progressive massive fibrosis)
    • 52. Occurs on a background of simple CWP and generally requires many years to develop.
    • 53. Characterized by intensely blackened scars larger than 2 cm
    • 54. Center of the lesion is often necrotic, most likely due to local ischemia.
    • 55. Clinical presentation.
    • 56. Benign disease that causes little decrement in lung function.
    • 57. Rarely, progressive massive fibrosis (PMF) develops
    • 58. Leading to pulmonary dysfunction, respiratory insufficiency, pulmonary hypertension, and cor pulmonale
    Silicosis <br />
    • Potentially fatal, irreversible, fibrotic pulmonary disease --- develop subsequent to inhalation of large amounts of silica dust.
    • 59. Decades of exposure >> slowly-progressing, nodular, fibrosing pneumoconiosis.
    • 60. Pathogenesis.
    • 61. Crystalline and amorphous forms --- crystalline forms are more fibrogenic (quartz is most commonly implicated)
    • 62. After inhalation, silica particles are cleared from lung by alveolar macrophages
    • 63. Generates silicon-based radicals >> production of hydroxyl, hydrogen peroxide, and other oxygen radicals
    • 64. Become damaged and release mediators -- IL-1, TNF, fibronectin, lipid mediators, and fibrogenic cytokines.
    • 65. Morphology
    • 66. Acute silicosis
    • 67. Follows massive exposure to dust >> stimulates hypersecretion of alveolar surfactant
    • 68. Alveoli are filled with a lipoproteinaceous material that is eosinophilic, PAS-positive and diastase resistant.
    • 69. Chronic silicosis
    • 70. Simple silicosis
    • 71. Characterized by tiny, hard, palpable, discrete pale to blackened nodules in upper zones of lungs.
    • 72. Nodule composed of silica surrounded by whorled collagen, macrophages, lymphocytes, fibroblasts
    • 73. Examination of the nodules by polarized microscopy reveals birefringent silica particles.
    • 74. Complicated silicosis (progressive massive fibrosis)
    • 75. Develops when the above described silicotic nodules coalesce forming pulmonary scars >2 cm.
    • 76. Central softening and cavitation --- due to superimposed tuberculosis or to ischemia.
    • 77. Fibrotic lesions may also occur in the hilar lymph nodes and pleura.
    • 78. Thin sheets of calcification occur in lymph nodes --- seen radiographically as eggshell calcification
    • 79. Clinical manifestations.
    • 80. Acute silicosis
    • 81. Causes symptoms weeks to a few years after exposure.
    • 82. Severe dyspnea, cough, fever, weight loss, pleuritic pain
    • 83. Chest radiograph suggest a ground-glass appearance, similar to pneumonia or pulmonary edema.
    • 84. Chronic silicosis
    • 85. Simple silicosis: may be asymptomatic
    • 86. Abnormalities detected by x-ray --- Small, rounded opacities in upper lung zones
    • 87. Chronic cough and exertional dyspnea develop later.
    • 88. Simple silicosis progresses toward complicated silicosis because of development of severe scarring where
    • 89. Nodules become confluent, reaching a size of 1.0 cm or greater >> more severe symptoms
    • 90. Imaging
    • 91. Chest radiography reveals nodular opacities scattered diffusely throughout lungs more prominent in upper lung fields.
    • 92. Complicated silicosis manifests as bilateral upper lobe masses, which are formed by the coalescence of nodules.
    • 93. Pulmonary physiologic changes
    • 94. Disease progression >> restrictive or mixed pattern of obstruction and restriction
    • 95. Progressive massive fibrosis causes severe restriction, decreased compliance, and hypoxemia.
    Asbestos-Related Diseases <br />
    • Caused by inhalation and retention of asbestos fibers.
    • 96. Occur after high intensity and/or long-term exposure to asbestos.
    • 97. Types of asbestos fibers.
    • 98. Chrysotile (serpentine)
    • 99. Fibers are curly, longer and more flexible
    • 100. Fibers settle in large airways and are eliminated by ciliary action
    • 101. Amphiboles
    • 102. Fibers are characteristically straight, rigid, and needlelike.
    • 103. Fibers reach small bronchi and alveoli and are most dangerous
    • 104. Spectrum of asbestos-related diseases.
    • 105. Benign pleural effusion, pleural plaques, diffuse pleural thickening, asbestosis, mesothelioma, and lung carcinoma.
    • 106. Asbestosis -- diffuse lung fibrosis due to inhalation of asbestos fibers >> major cause of occupational lung damage
    • 107. Mesothelioma -- malignant pleural tumor arising from mesothelium lining lungs
    • 108. Morphology.
    • 109. Asbestosis
    • 110. Diffuse pulmonary interstitial fibrosis
    • 111. Asbestos bodies: golden brown, fusiform or beaded rods with a translucent
    • 112. Consist of asbestos fibers coated with an iron-containing proteinaceous material.
    • 113. Arise when macrophages attempt to phagocytose asbestos fibers >> phagocyte ferritin.
    • 114. ‘Ferruginous bodies’ -- similar to asbestos bodies - mineral filament coated with protein-iron
    • 115. Fibrous tissue distorts lung architecture, creating enlarged airspaces enclosed within thick fibrous walls.
    • 116. Affected regions become honeycombed.
    • 117. Assessing severity of asbestosis
    • 118. Grade 1 is fibrosis in the wall of a respiratory bronchiole without extension to distant alveoli.
    • 119. Grades 2 and 3 define more extensive disease
    • 120. Grade 4 corresponds to honeycombing, i.e. pulmonary fibrosis with spaces larger than alveoli
    • 121. Begins in lower lobes >> progresses to middle and upper lobes of lungs
    • 122. Scarring may trap and narrow pulmonary arteries, causing pulmonary hypertension and cor pulmonale.
    • 123. Pleural plaques
    • 124. Most common manifestation of asbestos exposure -- asymptomatic and detected on radiographs
    • 125. Well-circumscribed plaques of dense collagen, often containing calcium.
    • 126. Develop frequently on anterior and posterolateral aspects of parietal pleura and over domes of diaphragm.
    • 127. Do not contain asbestos bodies.
    • 128. Lung carcinomas and mesothelioma: Develop in workers exposed to asbestos.
    • 129. Clinical manifestations.
    • 130. Dyspnea is usually first manifestation; at first, it is provoked by exertion, but later it is present even at rest.
    • 131. Accompanied by a cough associated with production of sputum.
    • 132. Chest x-rays reveal irregular linear densities, particularly in both lower lobes.
    • 133. With advancement of pneumoconiosis, a honeycomb pattern develops.
    • 134. May remain static or progress to respiratory failure, cor pulmonale, and death.
    Granulomatous Diseases<br />Sarcoidosis <br />
    • Systemic disease of unknown cause characterized by noncaseating granulomas in many tissues and organs.
    • 135. Etiology and pathogenesis.
    • 136. Unknown --- evidence suggest that it is a disease of disordered immune regulation.
    • 137. Immunological abnormalities --- development of a cell-mediated response driven by CD4+ helper T cells.
    • 138. Systemic immunological abnormalities --- anergy to common skin test antigens such as Candida or PPD.
    • 139. Evidence of genetic influences --- association with certain HLA genotypes.
    • 140. Several putative organisms (e.g., mycobacteria, Propionibacterium acnes, and Rickettsia species).
    • 141. Morphology.
    • 142. Non-caseating granulomas composed of epithelioid cells, often with Langhans or foreign body-type giant cells.
    • 143. Enclosed within fibrous rims or may eventually be replaced by hyaline fibrous scars.
    • 144. Composed of calcium and proteins known as Schaumann bodies and stellate inclusions known as asteroid bodies
    • 145. May be encountered in other granulomatous diseases (e.g., tuberculosis).
    • 146. Sites of involvement.
    • 147. Lungs are common sites of involvement.
    • 148. Lesions are distributed along lymphatics, around bronchi and blood vessels – also alveolar lesions
    • 149. Tendency for lesions to heal in lungs, so varying stages of fibrosis and hyalinization are often found.
    • 150. Lymph nodes: particularly tonsils, hilar and mediastinal nodes >> Enlarged, discrete, and sometimes calcified.
    • 151. Spleen (granulomas and splenomegaly),
    • 152. Liver (one third of patients have liver granulomas and hepatomegaly),
    • 153. Bone marrow, skin (erythema nodosum, macules, papules, and plaques),
    • 154. Eye (iritis and iridocyclitis)
    • 155. Muscle (weakness, aches, tenderness, and fatigue).
    • 156. Hypercalcemia: Epitheloid cells in sarcoidosis granulomas can produce calcitriol (1,25 vitamin D) and cause hypercalcemia,
    • 157. Hypercalciuria: 3 times more common than hypercalcemia --- result in nephrocalcinosis and renal failure.
    • 158. Clinical manifestations.
    • 159. Bilateral hilar lymphadenopathy or lung involvement is visible on chest radiographs is most common.
    • 160. Eye and skin lesions occur next in frequency.
    • 161. Peripheral lymphadenopathy, cutaneous lesions, eye involvement, splenomegaly, or hepatomegaly.
    • 162. Onset of respiratory abnormalities (shortness of breath, cough, chest pain, hemoptysis)
    • 163. Onset of constitutional signs and symptoms (fever, fatigue, weight loss, anorexia, night sweats).
    • 164. Disease course.
    • 165. Unpredictable course characterized by either progressive chronicity or periods of activity interspersed with remissions
    • 166. Usually recover with minimal or no residual manifestations.
    Hypersensitivity pneumonitis <br />
    • Immunologically mediated lung disorders caused by intense, prolonged exposure to inhaled organic antigens.
    • 167. Farmer's lung results from exposure to dusts generated from harvested humid, warm hay
    • 168. Permits rapid proliferation of the spores of thermophilic actinomycetes.
    • 169. Pigeon breeder's lung (bird fancier's disease) is provoked by proteins from serum, excreta, or feathers of birds.
    • 170. Humidifier or air-conditioner lung is caused by thermophilic bacteria in heated water reservoirs.
    • 171. Categorized as acute, subacute, and chronic progressive -- based on length and intensity of exposure
    • 172. Epidemiology: Prevalence varies by region, climate, and farming practices --- mean age is 53 years. 
    • 173. Pathogenesis.
    • 174. Initially thought to be an immunocomplex-mediated process (type III hypersensitivity)
    • 175. Complement and immunoglobulins have been demonstrated within vessel walls
    • 176. Subsequent studies showed that cell-mediated immunity (type IV hypersensitivity) --- noncaseating granulomas
    • 177. Morphology.
    • 178. Early stage
    • 179. Alveolitis with fibrinous exudates and neutrophils within alveolar lumina.
    • 180. Leads to organization of alveolar exudate by granulation tissue growing and filling alveoli and bronchioles.
    • 181. Later stage
    • 182. Non-necrotizing granulomas in lungs >> thickening of alveolar walls by a diffuse lymphocytic infiltrate. 
    • 183. Hilar lymph nodes are unaffected.
    • 184. Resolution within 6 months unless is further exposure >> inflammation may progress to an irreversible scarring.
    • 185. In fatal cases lungs show “honeycombing” with dense fibrosis.
    • 186. Clinical manifestations.
    • 187. Acute attacks consist of recurring episodes of fever, dyspnea, cough, and leukocytosis >> 4 to 6 hours after exposure
    • 188. Infiltrates appear in chest radiograph, and pulmonary function tests show acute restrictive disorder.
    • 189. If exposure is continuous and protracted >> chronic disease >> respiratory failure, dyspnea, and cyanosis
    • 190. Laboratory studies.
    • 191. Leukocytosis and neutrophilia, elevated ESR, and C-reactive protein, and hypergammaglobulinemia
    • 192. Precipitating antibodies to offending antigen are commonly present --- marker or exposure
    Pulmonary alveolar proteinosis (PAP) <br />
    • Characterized radiologically by bilateral patchy asymmetric pulmonary opacifications
    • 193. Characterized histologically by accumulation of acellular surfactant in the intra-alveolar and bronchiolar spaces.
    Classification: Primary (or acquired), secondary and congenital PAP --- different pathogenesis but similar histologic changes <br />Epidemiology: Rare --- M:F = 4:1. Age of onset varies from 20-50 years old <br />Morphology<br />
    • Characterized by a peculiar granular precipitate within alveoli, causing focal-to-confluent consolidation of large areas of lungs
    • 194. On section, turbid fluid exudes from these areas >> increase in size and weight of lung.
    • 195. Alveolar precipitate is periodic acid-Schiff positive and also contains cholesterol clefts.
    • 196. Immunohistochemical staining reveals abundant accumulation of surfactant protein.
    Pathogenesis<br />
    • Congenital PAP.
    • 197. Autosomal Recessive --- Caused by mutations in genes that encode for:
    • 198. Surfactant proteins B or C (SP-B and SP-C)
    • 199. Beta chain of receptor for granulocyte–macrophage colony-stimulating factor (GM-CSF).
    • 200. GM-CSF -- hematologic growth factor which stimulates production of myeloid cells from hematopoietic precursors.
    • 201. Disruption of gene causes accumulation of abundant surfactant in alveoli
    • 202. Defect in the catabolism of surfactant by alveolar macrophages.
    • 203. Pulmonary GM-CSF stimulates production of high levels of PU.1 in alveolar macrophages.
    • 204. Promotes growth and differentiation of myeloid progenitors required for production of macrophages.
    • 205. Primary PAP.
    • 206. Autoimmune disease - Circulating antibodies inhibit GM-CSF activity >> accumulation of proteinaceous fluid in alveoli
    • 207. Secondary PAP.
    • 208. Develops with conditions involving functional impairment or reduced numbers of alveolar macrophages.
    • 209. Hematologic malignancies, particularly chronic myeloid leukemia and lymphomas
    • 210. Occupational exposures, particularly mineral dusts (silica) and fumes
    • 211. Infections, including those caused by Nocardia, Mycobacterium tuberculosis, and fungal infections
    Clinical Manifestations<br />
    • Nonspecific respiratory difficulty of insidious onset, cough, and abundant sputum containing chunks of gelatinous material.
    • 212. Progressive dyspnea, cyanosis, and respiratory insufficiency may occur, but some patients tend to have a benign course.
    • 213. Congenital PAP: fatal respiratory disorder that is usually immediately apparent in the newborn.
    • 214. Develops progressive respiratory distress shortly after birth
    Prognosis<br />
    • Very good, with achievement of complete remissions in many patients with whole-lung lavage, but relapses may occur.
    • 215. GM-CSF therapy is effective in 50% of patients
    • 216. Congenital PAP responds favorably to lung transplantation.
    RESTRICTIVE LUNG DISEASES 2<br />Pulmonary Surfactant<br />
    • Dipalmitoyl phosphatidylcholine (DPPC), or lecithin, is functionally the primary phospholipid.
    • 217. Four surfactant proteins (SPs) expressed by respiratory epithelial cells, designated as SP-A, SP-B, SP-C and SP-D.
    • 218. Surfactant components are synthesized, secreted and recycled by type II pneumocytes in alveolus.
    Lung Immaturity in Premature Infants <br />
    • Immaturity of the lungs poses one of most common and immediate threats to viability of low-birth-weight infant.
    • 219. Lining cells of fetal alveoli do not differentiate into type I and type II pneumocytes until late pregnancy.
    • 220. Composition of lung surfactant changes as fetus matures:
    • 221. Concentration of lecithin increases rapidly at beginning of 3rd trimester and rises rapidly to reach a peak near term
    • 222. Most of lecithin in mature lung is dipalmitate -- in immature lung it is less-surface-active alpha-palmitate species
    • 223. Phosphatidylglycerol starts to increase only at 35 weeks and is found to be predictive of fetal lung maturity
    • 224. Before 35th week, immature surfactant contains a higher proportion of sphingomyelin than adult surfactant.
    • 225. Pulmonary surfactant is released into amniotic fluid, which can be sampled by amniocentesis to assess maturity of fetal lung.
    • 226. Lecithin-to-sphingomyelin ratio (L/S ratio) above 2:1 >> fetus will survive without respiratory distress syndrome.
    • 227. After 35th week, appearance of phosphatidylglycerol in amniotic fluid is best proof of the maturity of fetal lungs.
    Hyaline Membrane Disease (HMD) <br />
    • Acute lung disease of premature newborns caused by surfactant deficiency.
    Epidemiology<br />
    • Associated with prematurity --- related to a relative lack of mature type II epithelial cells of alveolus (type II pneumocytes).
    • 228. Twice as common in boys as in girls at every gestational age.
    Pathogenesis<br />
    • Result of anatomic pulmonary immaturity and a deficiency of surfactant.
    • 229. Absence of surfactant results in poor pulmonary compliance, atelectasis (failure of pulmonary alveoli to expand).
    • 230. Atelectasis results in perfused but not ventilated alveoli >> decreased gas exchange, severe hypoxia and acidosis.
    Pathology<br />
    • Gross appearance.
    • 231. Lungs are heavy, dark and airless
    • 232. Hepatization --- texture of cut sections of firm, homogeneous, atelectatic tissue is reminiscent of liver.
    • 233. Microscopic appearance.
    • 234. Microscopy confirms atelectasis, with air limited to bronchioles.
    • 235. Interstitial edema --- result of transudation of fluid into the interstitium from capillary leak.
    • 236. Hyaline membranes are found at boundary of air-filled bronchioles and collapsed alveoli.
    • 237. Separate from bronchial wall at 36–48 hours and are cleared by alveolar macrophages.
    • 238. Airways containing hyaline membranes are surrounded by collapsed acini of surfactant-deficient lungs.
    • 239. Consequence of injury to bronchiolar and alveolar lining.
    • 240. Physical: shear forces on epithelium at the air-liquid interface >> alveoli collapse.
    Clinical Presentation<br />
    • First symptom within an hour of birth: increased respiratory effort -- forceful intercostal retraction and use of neck muscles.
    • 241. Respiratory rate > 100 breaths/min, expiratory grunting (due to partial closure of glottis), nasal flaring and cyanosis.
    • 242. In severe cases, infant becomes progressively obtunded and flaccid.
    • 243. Long periods of apnea ensue, and the infant eventually dies of asphyxia.
    Laboratory Studies<br />
    • Arterial blood gas studies show hypoxemia, hypercapnia, and mixed respiratory and metabolic acidosis.
    • 244. Respiratory acidosis due alveolar atelectasis (decreased gas exchange >> increased blood carbon dioxide and decreased pH)
    • 245. Metabolic acidosis results from poor tissue perfusion and anaerobic metabolism (hypoxemia >> production of lactic acid).
    Imaging<br />
    • Mild to moderate cases of HMD.
    • 246. Generalized acinar collapse that results from surfactant deficiency.
    • 247. Chest radiography demonstrates
    • 248. Decreased lung expansion
    • 249. Symmetric generalized consolidation of variable severity
    • 250. Effacement of normal pulmonary vessels
    • 251. Air bronchograms (air-filled bronchi seen as radiolucent, branching bands within pulmonary densities).
    • 252. ‘Reticulogranular’ texture of lung opacities
    • 253. Represents collapsed alveoli, fluid into interstitium from capillary leak, and distention by air of bronchioles
    • 254. Severe cases of HMD.
    • 255. Dense bilateral symmetric lung consolidations (white out) completely efface cardiac and diaphragm contours.
    • 256. Chest radiographs demonstrate granularity that evolved to generalized hazy opacities to clearing
    Evaluation of Lung Maturity by Amniotic Fluid Analysis <br />
    • Tests of fetal lung maturity -- which measure surfactant obtained by amniocentesis or collected from vagina.
    • 257. Risk of HMD is low when lecithin/sphingomyelin ratio is > 2, and phosphatidylglycerol is present.
    Prevention: Giving mother betamethasone or dexamethasone at least 48h before premature delivery induces fetal surfactant production<br />Complications<br />
    • Major complications related to anoxia and acidosis:
    • 258. Intraventricular cerebral hemorrhage.
    • 259. Anoxic injury to the periventricular capillaries, venous sludging and thrombosis, and impaired vascular autoregulation.
    • 260. Persistence of patent ductus arteriosus.
    • 261. With recovery, pulmonary pressure declines, and high aortic pressure reverses direction of blood flow in ductus
    • 262. Creating a persistent left-to-right shunt >> Congestive heart failure
    • 263. Necrotizing enterocolitis.
    • 264. Ischemia of intestinal mucosa >> bacterial colonization with C. difficile >> lesions, gangrene and perforation of bowel.
    • 265. Bronchopulmonary dysplasia.
    • 266. Results from oxygen toxicity --- infants maintained on a positive-pressure respirator with high oxygen tensions
    • 267. Respiratory distress reflected in hypoxia, acidosis, oxygen dependency, and onset of right-sided heart failure.
    • 268. Radiographs: change from complete opacification >> spongelike appearance (lucent areas with denser foci).
    • 269. Microscopic examination: hyperplasia of bronchiolar epithelium and squamous metaplasia in bronchi and bronchioles.
    • 270. Atelectasis, interstitial edema, and thickening of alveolar basement membranes
    Evolving Nomenclature <br />
    • ‘Hyaline membrane disease’ is now less commonly used in clinical practice
    • 271. ‘Respiratory distress syndrome’ is used to denote surfactant, but ‘surfactant deficiency disorder’ has been proposed.
    Risk Factors for Hyaline Membrane Disease <br />
    • Cesarean section
    • 272. Iatrogenic respiratory distress syndrome (RDS)
    • 273. Result of: (1) cesarean section as a mode of delivery and (2) birth prior to the onset of labor.
    • 274. Cesarean section as a mode of delivery
    • 275. Vaginal birth
    • 276. Higher catecholamine concentration enhances cardiac performance and mobilized glucose
    • 277. Stimulates absorption of lung liquid and enhances release of surfactants.
    • 278. Cesarean section: Larger residual volume of lung fluid, secrete less surfactant >> higher risk for HMD
    • 279. Maternal diabetes mellitus
    • 280. Poor glycemic control leads to preterm delivery
    • 281. Hyperglycemia induces endothelial dysfunction and nitric oxide-depended vasodilatation.
    • 282. NO is a uterine relaxant -- decreased synthesis of NO in uterus is associated with initiation of labor.
    Acute Respiratory Distress Syndrome (Synonym: adult respiratory distress syndrome)<br />
    • Initiated by damage to alveolar epithelium and pulmonary capillary endothelium (diffuse alveolar damage)
    • 283. Followed by increased permeability into lung interstitium and alveolar spaces (noncardiogenic pulmonary edema).
    • 284. High mortality rate, survivors appear to recover completely but tests of lung function show mild restrictive or diffusion defect.
    • 285. Hypoxemia from intrapulmonary shunting manifests clinically as cyanosis refractory to oxygen therapy.
    Pathogenesis of Diffuse Alveolar Damage <br />
    • Type I alveolar pneumocyte and capillary endothelial cell are exceptionally thin >> vulnerable to non-specific damage.
    • 286. Necrosis of type I alveolar pneumocyte and capillary endothelial cell.
    • 287. Type I alveolar epithelial cells show cytoplasmic blebbing >> necrosis resulting in denudation of basement membrane
    • 288. Similar blebbing seen in alveolar capillary endothelium but denudation of basement membrane is seldom observed
    • 289. Increase in alveolar and pulmonary capillary permeability.
    • 290. Escape of protein-rich exudates into interstitial and alveoli, loss of alveolar lining film and pulmonary collapse.
    • 291. Inflammatory cascade.
    • 292. Activated neutrophils and macrophages follow exudate, and an inflammatory cascade is initiated.
    • 293. Release of interleukins, tumor necrosis factor, and other inflammatory mediators.
    • 294. Neutrophils release oxidants, leukotrienes, and various proteases.
    • 295. Massive cell damage, alveolar denudation, and sloughing of cell debris into lumen of alveolus >> Surfactant depletion
    • 296. Alveolar collapse.
    • 297. Surfactant depletion leads to alveolar collapse because of increased surface tension.
    • 298. As alveoli collapse, closing lung volume decreases and reduced compliance further increasing work of breathing.
    • 299. Small vessel thrombosis.
    • 300. In pulmonary capillary, injury to endothelial cells induces platelets to aggregate >> procoagulant cascade
    • 301. Impairment of oxygen-diffusing capacity.
    • 302. Widened interstitial space between alveolus and vascular endothelium decreases oxygen-diffusing capacity.  
    • 303. Respiratory muscle fatigue.
    • 304. Decrease in lung compliance increases work of breathing and leads to respiratory muscle fatigue.
    Clinical Presentation<br />
    • Characterized by acute dyspnea and hypoxemia after event (trauma, sepsis, drug overdose, transfusion, or aspiration)
    • 305. Onset of lung injury >> dyspnea with exertion >> progresses to severe dyspnea at rest, tachypnea, anxiety, agitation
    • 306. Associated hypotension, peripheral vasoconstriction with cold extremities, cyanosis of lips and nailbeds may occur.
    Diffuse Alveolar Damage <br />
    • Exudation.
    • 307. Lasts about 1 week -- lungs are wet, heavy, dark and airless -- cut surface exudes heavily bloodstained watery fluid.
    • 308. Collapse of alveoli, intense congestion of capillaries, interstitial edema and distension of lymphatics.
    • 309. At air/tissue interface respiratory movements deposit a fibrin-rich exudate mixed with necrotic epithelial debris
    • 310. Compact into a thin layer that covers an epithelial basement membrane >> formation of hyaline membranes.
    • 311. Regeneration.
    • 312. Healing may be by
    • 313. Resolution, which involves fibrinolysis and permits the lungs to return to normal
    • 314. Repair, which involves fibrosis and leaves the lungs permanently scarred.
    • 315. Stem cell concerned in epithelial regeneration is type II alveolar epithelial cell.
    • 316. First proliferate and then differentiate into type I cells >> re-epithelializing denuded basement membranes.
    • 317. Type II cells form simple cuboidal epithelium beneath exudates >> casting hyaline membranes into air space
    • 318. Atelectatic induration: Regenerating epithelial cells bridge collapsed alveoli so air spaces never re-expand
    • 319. Repair.
    • 320. Honeycombing suggests extensive lung fibrosis with alveolar destruction >> Presence of thick-walled, air-filled cysts.
    • 321. Myofibroblasts contracture -- results in harmful distortion of bronchioloalveolar architecture and shrinkage of lungs.
    • 322. Fibroblasts proliferate and lay down collagen, leading to development of interstitial fibrosis.
    • 323. Fibrosis by accretion: incorporation of alveolar collagen into interstitium as basement membrane is formed.
    • 324. Increase in lung collagen can be detected --- Survivors of ARDS may suffer from debilitating fibrotic lung disease.
    Etiology of Adult Respiratory Distress Syndrome <br />
    • Entrance to lungs directly via airways, e.g. high oxygen, poisonous gases and metallic fumes.
    • 325. Penetrate chest wall to damage lungs (e.g. ionizing radiation) or reach lungs via bloodstream, (ingested or injected).
    • 326. Shock.
    • 327. State of prolonged hypotension, generally attributable to trauma, hypovolemia, cardiac failure, sepsis or anaphylaxis.
    • 328. Hypotension leads to inadequate tissue perfusion and multiorgan failure.
    • 329. Congestive atelectasis or hemorrhagic edema, as described above.
    • 330. Accumulation of neutrophils in alveolar walls >> damage by production of oxygen radicals and releasing enzymes
    • 331. Blood transfusion.
    • 332. Leukocyte antibodies - cause of lung injury > initiate alveolar capillary damage by stimulating granulocyte aggregation
    • 333. Fat embolism.
    • 334. Pulmonary fat embolism accompanies bony injury >> progressive hypoxemia, confusion and petechial hemorrhages.
    • 335. Chemical vasculitis caused by toxic effects of free fatty acids released by action of pulmonary lipase on neutral fats.
    • 336. Causes necrosis of endothelial and type I cells >> proliferation of type II cells >> progressive fibrosis
    • 337. Cardiopulmonary bypass.
    • 338. Entails oxygenation and circulation of blood by extracorporeal devices, permitting major heart surgery.
    • 339. "Postperfusion lung": showes alveolar damage with degranulation of neutrophils in pulmonary capillaries.
    • 340. Complement cascade >> Aggregation of neutrophils in lungs >> damage from lysosomal enzymes and radicals.
    • 341. Oxygen toxicity.
    • 342. Due to high partial pressure of oxygen for hypoxemia treatment >> intracellular production of active oxygen radicals.
    • 343. Earliest ultrastructural change is swelling of endothelial cells; cytoplasm becomes grossly edematous and vacuolated.
    • 344. Swelling and fragmentation of type I epithelial cells follows --- become separated from their basement membrane
    Prognosis<br />
    • Survivors frequently have significant functional impairment even 1 year after discharge.
    • 345. Spirometry and lung volumes normalize within 6 months, but diffusing capacity remains diminished at 1 year.
    • 346. Health-related quality of life is below normal, however, no patient remains oxygen-dependent at 12 months
    NON INFECTIOUS UPPER RESPIRATORY TRACT DISORDERS<br />  <br />Vocal Cord Nodules and Vocal Cord Polyps<br />
    • Tissue growths that develop on vocal cords --- most often in heavy smokers or those who impose great strain on vocal cords
    Vocal Cord Nodules (synonym: singer’s nodule)<br />
    • Localized, benign growths on medial surface of true vocal folds that are commonly believed result of phonotrauma.
    • 347. Smooth, rounded, and sessile --- Bilateral with location at junction of anterior and middle third of vocal cord.
    • 348. Most often observed in women aged 20-50 years, but are also found commonly in children (Boys>Girls) prone to shouting
    Vocal Cord Polyps<br />
    • Unilateral with broad spectrum of appearances -- hemorrhagic to edematous, pedunculated to sessile, gelatinous to hyalinized
    • 349. Pedunculated -- involve free edge of anterior third of vocal cord mucosa.
    • 350. Result from phonotrauma; however, event that triggers formation is vocal cord bleeding.
    Histopathology<br />
    • Both covered by squamous epithelium
    • 351. Core is a loose myxoid connective tissue -- fibrotic or punctuated by numerous vascular channels.
    • 352. Characteristically change character of voice with progressive hoarseness >> never give rise to cancers.
    DIagnosis<br />
    • Videostrobolaryngoscopy (or stroboscopy) is most sensitive for detecting laryngeal lesions
    • 353. Demonstrate subtle differences in appearance, pliability, and mucosal wave characteristics.  
    • 354. Remains clinical gold standard for assessing properties of glottal phonatory function.
    Squamous Papilloma of Larynx<br />
    • Most common benign laryngeal tumor -- located on true vocal cords -- form soft, raspberry-like excrescences
    • 355. Histologically -- slender, finger-like projections supported by fibrovascular cores and covered by stratified squamous epithelium
    • 356. Arise as multiple tumors, usually in children -- tendency to recur frequently and to spread downward >> trachea, and bronchi.
    • 357. Known as ‘recurrent respiratory papillomatosis’.
    Epidemiology<br />
    • Bimodal distribution -- initial peak in childhood (juvenile-onset SP) and a second peak in adulthood (adult-onset SP).
    • 358. Children: diagnosed at 2–3 years of age, male-to-female ratio is approximately equal
    • 359. Adult: manifests in age range of 20-40 years. Male-to-female ratio is estimated to be 4:1
    Clinical Presentation<br />
    • Larynx is most frequently affected site and hoarseness is most common presenting symptom.
    • 360. Other symptoms include: voice change, foreign body sensation, cough, choking episodes, inspiratory wheezing
    • 361. Stridor: whistling sound with inspiration resulting from turbulent air flow; indicates obstruction of larynx
    Etiology: Caused by low-risk human papillomavirus (HPV) types 6 and 11. <br />Pathogenesis<br />
    • Juvenile-onset SP results from peripartum transmission of virus from an infected mother.
    • 362. Condylomas during pregnancy and vaginal delivery appear to be at greatest risk of infecting their newborn.
    • 363. Mode of transmission of virus in adults is unknown, but sexual transmission is probable.
    Laryngeal Carcinoma<br />
    • Malignant tumor of epithelial origin that arises from laryngeal mucosa -- Most common cancer of upper aerodigestive tract.
    Epidemiology: Most commonly affects men (African Americans > Caucasians) 50 - 60 years old who are smokers and use alcohol<br />Etiology<br />
    • Smoking and alcohol.
    • 364. Most widely accepted risk factors
    • 365. Hyperplastic morphological changes of laryngeal mucosa often regress after cessation of smoking.
    • 366. Other risk factors: Gastroesophageal reflux disease (GERD), HPV infection, nutritional factors, and irradiation.
    Clinical Presentation<br />
    • Sites of origin.
    • 367. True vocal cords are most common site, followed by supraglottis, and subglottis.
    • 368. Anterior portion of true vocal cord is the most common location -- most lesions occurring along free margin
    • 369. Clinical presentation.
    • 370. Glottic cancer: Hoarseness is most common symptom, since small irregularities in vocal fold result in voice changes.
    • 371. Supraglottic cancer: Arises from laryngeal or lingual surface of epiglottis.
    • 372. Asymptomatic until it manifests as a mass lesion
    • 373. Odynophagia (painful swallowing), dysphagia (difficulty swallowing), and neck mass >> Hoarseness
    • 374. Subglottic cancer: Manifest as mass lesion >> airway compromise (inspiratory stridor) or dysphagia >> Hoarseness
    • 375. Physical findings.
    • 376. Palpation of neck looking for enlarged lymph nodes is paramount in patient's evaluation.
    • 377. Patients presenting with hoarseness should undergo a flexible laryngoscope evaluation.
    • 378. Malignant lesions appear as friable, fungating, ulcerative masses or as subtle changes in mucosal color.
    • 379. Extremely vulnerable to secondary infection of ulcerating lesion.
    • 380. With surgery, irradiation, or combination therapy, many patients can be cured, but ~1/3 die of disease.
    • 381. Usual causes of death are infection of distal respiratory passages or widespread metastases and cachexia.
    Sequence of Hyperplasia-Dysplasia-Carcinoma <br />
    • The concept of preinvasive stages 
    • 382. Encompassed within laryngeal squamous epithelium -- not breach basement membrane to reach lamina propria.
    • 383. Transition from a normal epithelium to squamous cell carcinoma of larynx is a lengthy, multistage process
    • 384. Progressive accumulation of genetic changes >> selection of a clonal population of transformed epithelial cells.
    • 385. Histological changes ranges from simple squamous hyperplasia to atypical hyperplasia to carcinoma in situ.
    • 386. Morphology of preinvasive stages.
    • 387. Simple squamous hyperplasia: Characterized by a thickening of epithelium. No atypia - mitoses are rare
    • 388. Atypical hyperplasia: Characteristics of former and, in addition, atypia (enlarged, irregular, hyperchromatic nuclei)
    • 389. Carcinoma in situ: Atypical changes -- entire thickness of epithelium -- no extension beyond the basement membrane
    • 390. Potential for malignant transformation.
    • 391. Likelihood of development of an overt carcinoma is directly proportional to level of atypia.
    • 392. Simple squamous hyperplasias have almost no potential for malignant transformation.
    Morphology – Gross Appearance <br />
    • Exophytic lesions.
    • 393. Mass-forming lesions -- may be nodular, fungating, papillary or verrucous in appearance.
    • 394. Color varies from red to white, depending on amount of keratinization of epithelial surface.
    • 395. Feel hard (indurated) due to fibrosis of underlying stroma in response to tumor invasion.
    • 396. Endophytic lesions: Diffuse enlargement and hardening of mucosa -- infiltrate deeply rather than forming an external mass.  
    • 397. Ulcerated lesions: Appear as a depressed, irregularly shaped, ulcerated central zone.
    Morphology – Microscopic Appearance <br />
    • Squamous cell carcinoma.
    • 398. Form irregular nests and strands of tumor cells separated by varying amounts of fibrous stroma.
    • 399. Flattened polyhedral, round, or ovoid epithelial cells -- large irregular nuclei, clumped chromatin, varying nucleoli
    • 400. Keratinization:
    • 401. Individually, keratinized cells are rounded and have slightly refractile eosinophilic cytoplasm
    • 402. Easier to recognize when it forms concentrically laminated squamous ‘pearls’.
    • 403. Intercellular bridging
    • 404. Represent desmosomal cell junctions -- cell shrinkage results in stretching across intercellular spaces
    • 405. Histopathologically graded as follows:  
    • 406. Well-differentiated (grade 1): prominent keratinization throughout
    • 407. Moderately differentiated (grade 2)
    • 408. Poorly differentiated (grade 3): require careful scrutiny to identify keratinization or intercellular bridging.
    • 409. Immunohistochemically
    • 410. Cytokeratins (densely packed filaments attached to desmosomes) and epithelial membrane antigen
    • 411. Verrucous carcinoma.
    • 412. Uncommon, locally aggressive, slow-growing, and well-differentiated SCC which never metastasizes.
    • 413. Most often in oral cavity, but also involvement in larynx.
    • 414. Grossly, large, tan or white, exophytic, and warty mass attached by a broad base
    • 415. Tends to produce prominent surface keratin.
    • 416. Histologic pattern
    • 417. Undulating outer densely keratinized layer covering large papillary fronds
    • 418. Sharply circumscribed deep margin composed of rows of bulbous extremely well-oriented downgrowths.
    • 419. Stroma is infiltrated by abundance of chronic inflammatory cells.
    • 420. Well circumscribed and clearly demarcated from adjacent mucosa.
    • 421. Metastasis is rare, but growth is inexorable if untreated and the tumor can result in the patient's death.
    • 422. Etiology and clinical presentation is same as laryngeal squamous cell carcinoma. 
    Metastases<br />
    • Cervical lymph nodes: Single most important prognostic factor in squamous cell carcinoma of head and neck.
    • 423. Distant metastases.
    • 424. Distant metastases from laryngeal SCC are significantly less frequent than from other human malignancies
    • 425. Lung metastases are the most commonly found, followed by metastases to bone and liver.
    Imaging: Neck instrumental investigation is mandatory -- CT scanning and MRI -- accurate in clinical staging <br />Nasopharyngeal Carcinoma<br />
    • Carcinoma arising in nasopharyngeal mucosa that shows microscopic evidence of squamous differentiation
    Epidemiology<br />
    • Uncommon in U.S., but common among Southeast Asians
    • 426. Bimodal age distribution: peak in late childhood (10-20 years of age), and a second peak occurs in people aged 50-60 years.
    • 427. Occurs more frequently in men, with a 2:1 male-to-female ratio.
    Morphology<br />
    • Gross appearance: Discrete raised nodule or a frankly infiltrative fungating mass.
    • 428. Common site of origin is lateral wall of nasopharynx (fossa of Rossenmüller - behind opening of Eustachian tube)
    • 429. Microscopic appearance.
    • 430. Squamous cell carcinoma
    • 431. Well-differentiated type -- squamous differentiation, with intercellular bridges and/or keratinization
    • 432. Nonkeratinizing carcinoma
    • 433. Poorly differentiated type
    • 434. Characterized by large tumor cells with indistinct cell borders, round-oval nuclei, large central nucleoli
    • 435. No intercellular bridges or single keratinized cells can be seen, but tumor cells are of squamous origin. 
    • 436. Basaloid squamous cell carcinoma
    • 437. Aggressive variant of SCC -- Composed of both basaloid and SC components
    • 438. Basaloid component – predominant
    • 439. Solid tumor nests surrounded by fibrous stroma -- round to ovoid basaloid cells with scanty cytoplasm.
    • 440. Non-neoplastic lymphoid component
    • 441. Prototype of lymphoepithelial carcinomas: benign reactive lymphocytes and plasma cells infiltrate tissue
    Etiology<br />
    • Epstein-Barr virus.
    • 442. Elevated levels of antibodies (IgA) against Epstein-Barr virus
    • 443. Presence of Epstein-Barr DNA or RNA in practically all tumor cells
    • 444. Presence of Epstein-Barr virus in a clonal episomal form >> virus has entered tumor cell before clonal expansion;
    • 445. Keratinizing SCCs tend to carry lower copy numbers of Epstein-Barr virus compared with nonkeratinizing carcinomas.
    • 446. Environmental factors.
    • 447. Ingestion of Cantonese-style salted foods (fish, vegetables) is an important factor among Chinese, and North Africans
    • 448. Large amounts of nitrites, converted to carcinogenic nitrosamine >> carcinoma of nasal and paranasal sinus cavities
    • 449. Genetic factors.
    • 450. HLA locus A and B antigen association in Chinese with nasopharyngeal carcinoma is well established.
    • 451. HLA B17 and HLA Bw46 are associated with increased risk.
    Clinical Presentation<br />
    • Painless neck mass representing unilateral or bilateral enlargement of upper cervical lymph nodes (lymph node metastases)
    • 452. Ear pain, serous otitis media, and ipsilateral hearing loss may occur (due to Eustachian tube obstruction)
    • 453. Nasal obstruction with rhinorrhea and epistaxis (due to presence of tumor mass in the nasopharynx).
    • 454. Features of more advanced disease associated with superior extension of tumor
    • 455. Headaches indicate invasion of the base of skull.
    • 456. Ophthalmoplegia (paralysis of motor nerves of eye) indicates cavernous sinus invasion with damage of cranial nerves
    • 457. Palsy of 5th and 6th CNs causes diplopia, facial pain and numbness; palsy of 3rd CN causes ptosis
    Laboratory Studies<br />
    • Positive serology against Epstein-Barr virus is found in close to 100% of nonkeratinizing squamous cell carcinoma types
    • 458. IgA against viral capsid antigen and IgG/IgA against early antigens -- most extensively used diagnostic tool
    • 459. Test for elevated levels of circulating Epstein-Barr virus DNA or RNA by quantitative PCR in the plasma or serum 
    Pathogenesis<br />
    • Epstein-Barr virus infection -- early event in multistep carcinogenesis of nasopharyngeal carcinoma
    • 460. Leads to increased expression of EBNA1, LMP1, LMP2, and EBERs in epithelial cells.
    • 461. EBNA1 is important in replication and maintenance of viral genome during cell division.
    • 462. LMP1 acts as an oncogenic factor: it upregulates several cellular proteins that inhibit apoptosis
    • 463. Activation of transcription factors, cellular adhesion molecules, and cytokines.
    • 464. LMP2 prevents reactivation of the virus by blocking phosphorylation by tyrosine kinases.
    • 465. EBERs do not encode proteins, but they may be important for oncogenesis and resistance to apoptosis.
    • 466. Inactivation of the p16 tumor suppressor gene by homozygous deletion -- most common molecular alteration
    • 467. Cyclin-dependent kinase (CDK) inhibitor - inactivates CKD4 enzyme that phosphorylates and activates Rb protein
    • 468. Rendering retinoblastoma protein inactive >> removes inhibition provided by Rb protein (cell cycle)
    Tumor Spread<br />
    • Highly malignant behavior, with extensive loco-regional infiltration, early lymphatic spread, and hematogenous dissemination.
    • 469. Most common sites of hematogenous deposits are, in descending order of frequency, bone, liver, and lung.
    • 470. Natural history of disease is short, with most metastases diagnosed within 18 months after appearance of first symptoms
    Imaging<br />
    • CT scanning and MRI of head and neck used to determine tumor extent, base of skull erosion, and cervical lymphadenopathy.
    Prognosis<br />
    • Nasopharyngeal carcinomas with no distant metastasis are typically treated with nonsurgical means
    • 471. Surgery is usually reserved for tumors that fail to regress after irradiation.
    • 472. Because of the high doses of radiotherapy used in this disease, these late toxicities can be significant.
    ASTHMA 1<br />  <br />
    • Chronic lung disease caused by increased responsiveness of airways > bronchiolar smooth muscle contraction/bronchospasm
    • 473. Obstruction to air flow – maximal in expiration – and a high pitched wheeze
    • 474. Paroxysms of wheezing, dyspnea, and cough.
    • 475. Status asthmaticus: episodes severe, prolonged and unresponsive to therapy >> acute ventilator failure and even death.
    Etiology<br />
    • Atopic asthma.
    • 476. Commonest form of asthma
    • 477. Atopy: genetic -- immediate hypersensitivity reactions (IgE) in response to common environmental proteins.
    • 478. Allergens -- have protease activity
    • 479. Usually begins in childhood and is paroxysmal (attack starting suddenly and lasting a few hours or days).
    • 480. Tends to become less severe as child grows older and often ceases during adolescence.
    • 481. Patients commonly suffer from other atopic diseases, particularly allergic rhinitis and atopic dermatitis.
    • 482. Intrinsic (non-allergic) asthma.
    • 483. Negative skin test to common inhalant allergens and normal serum concentrations of IgE.
    • 484. Onset in adult life (> 40yo), chronic with exacerbations and remissions less evident and tends to worsen with age
    • 485. Hyperreactive airways that constrict in response to a variety of nonspecific stimuli.
    • 486. Aspirin, cold air, exercise, perfumes, cleaning agents, fumes, smoke, and upper respiratory infections
    • 487. Possible virus-induced inflammation of respiratory mucosa lowers threshold of receptors to irritants.
    • 488. Tends to be less responsive to treatment than atopic asthma.
    • 489. Increased incidence of nasal polyps.
    Genetic Considerations<br />
    • Polygenic disease.
    • 490. Multifactorial disorder of airways brought about by complex interaction between genetic and environmental factors.
    • 491. Association of asthma and atopy with polymorphisms of genes on chromosome 5q (contains IL genes)
    • 492. IL influence T cell development and recruitment of eosinophils, mast cells, neutrophils to site
    • 493. Novel genes that have been associated with asthma
    • 494. ADAM33 encodes disintegrin matrix metalloproteinase 33 and is associated with airway remodeling events.
    • 495. DPP-10 is associated with brochial hyperresponsiveness and IgE.
    • 496. SPINK5 is another gene that is associated with airway remodeling.
    • 497. Role of CD14 polymorphisms
    • 498. Receptor for endotoxin -- maps on chromosome 5q -- expressed by monocytes, macrophages and neutrophils
    • 499. Play a role in the polarisation of T lymphocytes into Th1 and Th2 subsets
    • 500. Influence cytokines >> IgE production
    • 501. Polymorphism in promotor for CD14 (TT genotype)
    • 502. Associated with reduced levels of IgE and risk for asthma/atopy with low (household) endotoxin exposure
    • 503. Associated with increased levels of IgE and risk for asthma/atopy with high endotoxin exposure (>> Th2)
    • 504. Differences may relate to influence of endotoxin levels on regulation of Th1 versus Th2 responses.
    • 505. Hygiene hypothesis
    • 506. Lack of early childhood exposure to infectious agents and parasites increases susceptibility to allergic disease
    • 507. Global microbial burden in early life could deviate immune responses away from allergic responses.
    • 508. Suspect polymorphisms in CD14 could be protective against allergies in people with high levels of exposure
    Morphology<br />
    • Sputum: Viscous and yellow (due to myeloperoxidase within eosinophils)
    • 509. Charcot-Leyden crystals.
    • 510. Slender, dipyramidal crystals -- hallmark of eosinophilic leukocyte infiltration
    • 511. Composed of lysolecithin acylhydrolase -- eosinophil proteins involved in antiparasitic and immune functions
    • 512. Damage respiratory epithelium and increase vascular permeability.
    • 513. Curschmann spiral: Corkscrew-shaped twist of condensed mucus -- represent casts of small bronchioles
    • 514. Creola bodies: Compact clumps of columnar epithelial cells shed from bronchial mucosa
    • 515. Lungs - Gross appearance.
    • 516. Lungs are greatly distended (overinflation); fail to retract as normal lungs do when opening pleural cavities.
    • 517. Small areas of atelectasis seen as dark, airless, firm areas, depressed below level of surrounding lung.
    • 518. Occlusion of bronchi and bronchioles by thick, tenacious mucus plugs.
    • 519. Air can pass the plugs only on inspiration.
    • 520. Lungs – Microscopic appearance.
    • 521. Bronchial plugging by mucus from increased amounts of mucus
    • 522. Bronchial lumen is compromised by accumulation of mucus
    • 523. Numerous eosinophils are present admixed with desquamated epithelial cells.
    • 524. Excessive mucus is produced by hyperplastic goblet cells and enlarged submucosal mucinous glands
    • 525. Airway mucus is abnormal, reflecting interactions between
    • 526. Inflammatory cells infiltrating bronchial wall
    • 527. Hyperplasia of mucosal goblet cells and submucosal mucinous glands in bronchial wall
    • 528. Pathologic changes in blood vessels in the bronchial wall.
    • 529. Albumin and DNA are increased, reflecting increased vascular permeability and inflammatory cells.
    • 530. Increases in plasma-derived proteins, cytokines, and chemokines, reflecting complex inflammation
    • 531. Bronchial eosinophilic infiltration and inflammatory edema
    • 532. In status asthmaticus, infiltration by eosinophils, T lymphocytes and mast cells.
    • 533. Inflammatory infiltration accompanied by marked congestion and edema of bronchial wall.
    • 534. Loss of ciliated cells contributes to impaired bronchial clearance.
    • 535. Shedding of epithelial cells
    • 536. Separation of mucosal cells leaving an intact basal cell layer resting on basement membrane
    • 537. May be due to eosinophil granules, release of TNF by macrophages, proteases or oxygen radicals.
    • 538. Remaining epithelium has "fragile" appearance, ciliated cells are swollen, vacuolized and show loss of cilia.
    • 539. Moderately severe to severe asthmatic patients.
    • 540. Consequences -- denudation of nerves and bronchial hyperreactivity >> smooth muscle contraction
    • 541. Thickening of epithelial basement membrane
    • 542. Thickening is confined to deepest layer, produced by myofibroblasts rather than epithelium.
    • 543. Bronchial muscle hypertrophy
    • 544. Increase in amount of bronchial muscle -- reflects sustained muscular contraction
    • 545. Most apparent in small bronchi
    • 546. Attributable to smooth muscle cell hyperplasia as well as hypertrophy
    Clinical Manifestations<br />
    • Typical asthma attack.
    • 547. Begins with a feeling of tightness in chest and nonproductive cough.
    • 548. Both inspiratory and expiratory wheezes appear, respiratory rate increases, and patient becomes dyspneic.
    • 549. Ends with severe coughing and expectoration of thick mucus
    • 550. Physical examination findings.
    • 551. Hyperexpansion of thorax (especially in children)
    • 552. Use of accessory muscles
    • 553. Hyperresonance to percussion
    • 554. Diminished breath sounds
    • 555. Sounds of wheezing during normal breathing or a prolonged phase of forced exhalation (typical of airflow obstruction)
    • 556. Increased nasal secretion, mucosal swelling and nasal polyps.
    • 557. Clinical classification of severity.
    • 558. Mild episode
    • 559. Characterized by an increased respiratory rate; HR is less than 100/min.
    • 560. Accessory muscles of respiration are not used. Pulsus paradoxus is not present.
    • 561. Moderate wheezing, often end expiratory. Oxygen saturation of hemoglobin with room air is > 95%.
    • 562. Moderately severe episode
    • 563. Respiratory rate is increased; HR is 100-120/min.
    • 564. Accessory muscles of respiration are used, and suprasternal retractions are present.
    • 565. Loud expiratory wheezing can be heard. Oxygen saturation of hemoglobin with room air is 91-95%.
    • 566. Severe episode
    • 567. Respiratory rate is often greater than 30/min; HR is more than 120/min.  
    • 568. Accessory muscles of respiration are usually used, and suprasternal retractions are commonly present.
    • 569. Loud biphasic (expiratory and inspiratory) wheezing can be heard.
    • 570. Pulsus paradoxus is often present (pulse becomes weaker with inhalation and stronger with exhalation)
    • 571. Inspiratory diminution in arterial pressure exceeds 10 mm Hg
    • 572. Oxygen saturation of hemoglobin with room air is less than 91%.
    • 573. Status asthmaticus.
    • 574. Severe bronchoconstriction that does not respond to drugs that usually abort acute attack.
    • 575. Begins with mild symptoms of dyspnea >> as airway obstruction worsens, respiratory distress may all be observed. 
    • 576. Abnormally prolonged expiratory phase with audible wheezing. Vital signs show tachycardia and hypertension.
    • 577. Airflow obstruction might be so extreme as to cause severe cyanosis and even death.
    • 578. Hypoxemia and hypercapnia develop >> seizures and coma (late signs of respiratory compromise). 
    Imaging: Chest radiography findings are normal or may indicate hyperinflation. <br />Laboratory Studies – non-specific<br />
    • Blood eosinophilia supports diagnosis
    • 579. Elevated total serum IgE levels observed in allergic patients
    Arterial Blood Gases<br />
    • Important to determine severity of asthma attack. 4 stages of blood gas progression in status asthmaticus are as follows:
    • 580. First stage: characterized by hyperventilation with a normal partial pressure of oxygen (PO2).
    • 581. Second stage: characterized by hyperventilation accompanied by hypoxemia (low PO2) and normal PCO2.
    • 582. Third stage: hypoxemic (low PO2) but not hyperventilating because of respiratory muscle fatigue. Normal PCO2
    • 583. Last stage: characterized by a low PO2 and a high PCO2, which occurs with respiratory muscle insufficiency.
    Pulmonary Function Testing (Spirometry) <br />
    • Primary test to establish asthma diagnosis -- include measurements before and after inhalation of a short-acting bronchodilator
    • 584. Measures forced vital capacity (FVC), maximal amount of air expired from point of maximal inhalation, and FEV1.
    • 585. Reduced ratio of FEV1 to FVC, when compared with predicted values, demonstrates the presence of airway obstruction.
    • 586. Reversibility is demonstrated by increase of 12% and 200 mL after administration of a short-acting bronchodilator.
    Allergy Skin Test<br />
    • Useful adjunct in individuals with atopy -- Results help guide indoor allergen mitigation.
    • 587. Two methods: allergy skin tests and blood radioallergosorbent tests (RAST).
    Loading, Please Wait ... <br />ASTHMA 2<br /> <br />Asthma and Chronic Obstructive Pulmonary Disease <br />
    • Adults with asthma may have an increased risk of developing COPD
    • 588. Coexisting signs of asthma (reversibility, atopy), chronic bronchitis (sputum) and emphysema (hyperinflation).
    • 589. Factors such as smoking and repeated episodes of acute bronchitis may facilitate evolution of asthma into COPD.
    • 590. Coexisting asthma and COPD >> most severe disease based on degree of airflow limitation.
    Pathogenesis<br />
    • Atopic asthma -- genetic predisposition to type I hypersensitivity (atopy) and exposure to environmental triggers.
    • 591. Th2 reactions -- bronchial inflammation in which type 2 helper T (Th2) cells (type of CD4 helper T cell) are prominent.
    • 592. Preceded by IgE-mediated sensitization to common aeroallergens.
    • 593. Formation of IgE Abs -- inhaled aeroallergens are engulfed by dendritic cells lining airway.
    • 594. Dendritic cells migrate to lymph nodes >> present antigen to T-cells
    • 595. Stimulated T-cells (Th2) secrete cytokines >> promote inflammation and stimulate B cells to produce IgE
    • 596. Early allergic response
    • 597. IgE antibodies bind to receptors on surface of mast cells, basophils, dendritic cells, and lymphocytes
    • 598. Activation >> release of proinflammatory cytokines and mediators >> Leukocyte recruitment
    • 599. Bronchoconstriction, increased mucus production, and vasodilation with increased vascular permeability.
    • 600. Late allergic response
    • 601. Activated mast cells and T cells >> Cytokines >> Infiltration of inflammatory cells
    • 602. Epithelial cells >> cytokines
    • 603. Eotaxin -- produced by airway epithelial cells, potent chemoattractant and activator of eosinophils.
    • 604. Protein of eosinophils causes epithelial damage and more airway constriction.
    • 605. "Suspects" -- subclassified by clinical efficacy of pharmacologic intervention with antagonists of mediators.
    • 606. Mediators with role in bronchospasm clearly supported by efficacy of pharmacologic intervention:
    • 607. Leukotrienes C4, D4, and E4: also cause increased vascular permeability and mucus secretion
    • 608. Acetylcholine: causse airway smooth muscle constriction by directly stimulating muscarinic receptor
    • 609. Agents present with potent asthma-like effects -- lack of efficacy of potent antagonists or synthesis inhibitors:
    • 610. Histamine:potent bronchoconstrictor
    • 611. Prostaglandin D2: elicits bronchoconstriction and vasodilatation
    • 612. Platelet-activating factor: aggregation and release of histamine and serotonin from granules
    • 613. Suspects for whom specific antagonists or inhibitors are not available:
    • 614. Cytokines (IL-1, TNF, IL-6), chemokines (eotaxin), neuropeptides, NO, bradykinin, and endothelins
    • 615. Repeated allergen exposure and immune reactions >> structural changes in bronchial wall ("airway remodeling")
    • 616. Hypertrophy and hyperplasia of bronchial smooth muscle, epithelial injury, increased airway vascularity,
    • 617. Increased subepithelial mucus gland hypertrophy/hyperplasia, and deposition of subepithelial collagen.
    • 618. Infections with respiratory pathogens can exacerbate chronic changes >> serious worsening of clinical manifestations
    Phenotypes<br />
    • Allergic asthma
    • 619. Most common form -- usually seen in children – usually substantial or complete remission of symptoms by age 20
    • 620. Strongly correlated with skin-test reactivity.
    • 621. Infectious asthma
    • 622. Precipitating factor is a viral respiratory tract infection
    • 623. In children under 2 years, respiratory syncytial virus is the usual agent;
    • 624. In older children, rhinovirus, influenza, and parainfluenza are common inciting organisms.
    • 625. Inflammatory response to viral infection >> trigger episode of bronchoconstriction and bronchial hyperreactivity
    • 626. Exercise-induced asthma
    • 627. Exercise >> bronchospasm -- related to magnitude of heat or water loss from airway epithelium.
    • 628. More rapid ventilation and colder and drier air breathed, more likely an attack of asthma.
    • 629. Consequence of mediator release or vascular congestion secondary to rewarming of airways after exertion.
    • 630. Occupational asthma
    • 631. 3 distinct sub-phenotypes, defined by underlying mechanism.
    • 632. Non-immunologically mediated: response to irritant chemicals >> reactive airways dysfunction syndrome
    • 633. Immunologically mediated: inflammatory response is IgE-mediated
    • 634. Response to low molecular-weight triggers >> immunologically-mediated, but IgE involvement is variable.
    • 635. Therapy: avoidance of asthma trigger
    • 636. Aspirin-induced asthma
    • 637. Classic triad of aspirin intolerance, sinusitis with nasal polyps, and asthma.
    • 638. Ingestion of aspirin/NSAIDs will result in an acute asthma attack accompanied by rhinitis and conjunctival injection
    • 639. Severe and poorly responsive to corticosteroids
    • 640. Mechanism: shunt of AA metabolism from prostanoid production >> leukotriene production and bronchoconstriction
    • 641. Mutations in leukotriene pathway identified
    • 642. Air pollution
    • 643. Usually in episodes associated with temperature inversions -- associated with bronchospasm
    • 644. SO2, oxides of nitrogen, and ozone are commonly implicated environmental pollutants.
    • 645. Emotional factors: Psychological stress >> bronchospasm due to vagal efferent stimulation.
    Bronchiectasis <br />
    • Abnormal and permanent dilatation of conducting bronchi or airways, most often secondary to an infectious process.
    • 646. Involved bronchi are dilated, inflamed, and easily collapsible >> airflow obstruction and impaired clearance of secretions. 
    Epidemiology: Uncommon in U.S. - more common in females and most commonly presents in their 60s and 70s.<br />Pathogenesis<br />
    • Bronchial obstruction leads to impaired normal clearing mechanisms >> pooling of secretions distal to obstruction
    • 647. Infection and inflammation of the airway >> necrosis and destruction of surrounding tissue.
    • 648. Fibrosis causes bronchi to dilate, leading to dilatation of affected bronchi >> vicious cycle of recurrent infections
    Etiology<br />
    • Categorized as idiopathic, postinfectious, or due to an underlying anatomic or systemic disease
    • 649. Most patients have no history of lung injury prior to the onset (idiopathic bronchiectasis).
    • 650. Patients with known history of lung diseases (postinfecitous bronchiectasis) >> pneumonia, childhood infections, TB. 
    • 651. Minimal or silent infections caused by nontuberculous mycobacteria, Mycobacterium avium complex (MAC).
    • 652. Congenital causes: associated with defects of mucociliary clearance >> first-line defense against pathogenic microorganisms
    • 653. Cystic fibrosis
    • 654. Autosomal recessive defects in gene for cystic fibrosis transmembrane conductance regulator (CFTR),
    • 655. CFTR encodes for a protein that functions as a chloride channel.
    • 656. Mutations result in decreased secretion of chloride and increased reabsorption of sodium and water
    • 657. Electrolytic abnormalities result in viscid secretions in respiratory tract, pancreas, GI, sweat glands.
    • 658. Secretions difficult to clear >> Lung disease results from clogging of airways
    • 659. Resulting chronic bronchial infection, especially with Pseudomonas aeruginosa.
    • 660. Primary ciliary dyskinesia
    • 661. Autosomal recessive -- characterized by abnormal ciliary motion and impaired mucociliary clearance.
    • 662. Gene mutations in DNAI1 and DNAH5, which encode for components of outer dynein arm complex.
    • 663. Leads to recurrent or persistent respiratory infections, sinusitis, otitis media, and male infertility.
    • 664. Kartagener syndrome: bronchiectasis, sinusitis and situs inversus.
    • 665. Young syndrome: bronchiectasis, rhinosinusitis and congenital epididymis obstruction (reduced fertility)
    • 666. Alpha1-antitrypsin deficiency
    • 667. Autosomal recessive disorder caused by defective production of AAT >> decreased serum AAT levels.
    • 668. Causes panacinar emphysema and bronchiectasis (with chronic cough and sputum expectoration)
    • 669. Infectious factors.
    • 670. Lung injury prior to onset of bronchiectasis
    • 671. Lung damage occurring after pneumonia, pertussis, measles, or tuberculosis as a cause of bronchiectasis
    • 672. Microbiological profile in bronchiectasis
    • 673. Main pathogen isolated is Haemophilus influenzae followed by Pseudomonas aeruginosa.
    • 674. Others: Moxarella catarrhalis, Streptococcus pneumoniae, Aspergillus and Mycobacterium avium complex
    • 675. Pseudomonas aeruginosa
    • 676. Not a primary cause of bronchiectasis, but is associated with increased clinical severity of disease.
    • 677. MAC
    • 678. Seen in thin elderly women (>60 yo), have never smoked and have no underlying pulmonary disease.
    • 679. Bronchiectasis caused by MAC is most often located in right middle lobe and lingula.
    • 680. Also known as Lady Windermere syndrome
    • 681. Staphylococsu aureus: relatively uncommon -- repeated isolation should lead to consideration of undiagnosed CF.
    • 682. Immunodeficiency states.
    • 683. Congenital immunodeficiency conditions involve B-lymphocyte functions, specifically hypogammaglobulinemia.
    • 684. IgG subclass deficiency; X-linked agammaglobulinemia; or selective IgA, IgM, or IgE deficiency.
    • 685. Present in childhood with repeated sinus or pulmonary infections
    • 686. Acquired immunodeficiency, ie. HIV disease, with resultant AIDS
    • 687. Bronchiectasis secondary to bronchial damage from repeated infections in immunosuppressed patients
    • 688. Bronchial obstruction.
    • 689. Right-middle lobe syndrome results from tuberculous lymphadenitis of middle lobe bronchopulmonary lymph nodes.
    • 690. Proximal stenosis of right middle lobe bronchus leads to bronchiextasis of more distal segments or divisions.
    • 691. Foreign Body Aspiration: Altered mental state and unchewed food >> postobstructive pneumonia >> focal bronchiectasis.
    • 692. Allergic bronchopulmonary aspergillosis.
    • 693. Not an infection but represents an immune reaction to Aspergillus that results in airway damage and bronchiectasis.
    • 694. Characterized by bronchospasm, bronchiectasis, and immunologic evidence
    • 695. Viscid secretions containing hyphae of Aspergillus species
    • 696. Rheumatologic/autoimmune diseases.
    • 697. Particularly rheumatoid arthritis, SLE and inflammatory bowel disease
    • 698. May be due to increased susceptibility to infections in these patients.
    Clinical Presentation<br />
    • Dominant symptom is a chronic cough with sputum production.
    • 699. Paroxysms of cough frequent when patient rises in morning (changes in position >> drainage secretions into bronchi)
    • 700. Sputum described as mucoid, mucopurulent, thick, tenacious, or viscous (viscid).
    • 701. Dyspnea and wheezing, Pleuritic chest pain, Hemoptysis (erosive airway damage caused by an acute infection).
    • 702. Auscultatory findings are nonspecific. Most commonly, crackles, rhonchi, and wheezing may be heard upon auscultation.
    • 703. Rhinosinusitis with visible abnormalities on CT scanning of their nose and sinuses.
    • 704. Chronic fatigue and clubbing
    Complication<br />
    • Recurrent pneumonia, abscess, empyema, abscess, obstructive respiratory insufficiency and pulmonary hypertension.
    • 705. Sinusitis and life-threatening hemoptysis are frequent complications as well.
    • 706. Obstructive respiratory insufficiency can lead to marked hypoxia, manifested by dyspnea and cyanosis.
    • 707. Cor pulmonale, brain abscesses, and amyloidosis are less frequent complications
    Classification<br />
    • Cylindrical bronchiectasis
    • 708. Bronchi have uniform, thick straight walls and are mildly increased in diameter
    • 709. Bronchi do not taper and the number of bronchial subdivisions is reduced.
    • 710. Have a tram track appearance when viewed in a sagittal section or a signet ring appearance in a coronal section.
    • 711. Varicose bronchiectasis
    • 712. Bronchi are irregular in shape and size; with alternating areas of constriction and dilatation
    • 713. Do not taper as they extend peripherally.
    • 714. Terminations are irregular and bulbous -- give beaded appearance of saphenous varicosities or a string of pearls.
    • 715. Saccular (cystic) bronchiectasis
    • 716. Most severe form
    • 717. Bronchi are dilated and balloon into cysts or “saccules,” -- honeycomb or “cluster of grapes” appearance.
    • 718. Saccules formed when diseased bronchi are destroyed/fibrosed; inflammation extends and pull bronchi
    Gross Morphology<br />
    • Involves bronchi of medium size (>2 mm diameter).  
    • 719. Bronchiectasis caused by childhood infections and aspirations affects lower lobes bilaterally (air passages that are vertical)
    • 720. Upper lobes are more frequently affected in patients with cystic fibrosis and tuberculosis.
    • 721. Middle lobes are more frequently affected in patients with MAC, cystic fibrosis and allergic bronchopulmonary aspergillosis.
    • 722. Bronchiectasis is more diffuse in patients with cystic fibrosis and those with immunodeficiency states.
    • 723. When tumors or aspiration of foreign bodies lead to bronchiectasis, involvement may be sharply localized to a single segment
    • 724. Airways are dilated – appear as cysts filled with mucopurulent secretions.
    • 725. Focal destruction of bronchial wall, increased mucus secretion and retention, and peribronchial fibrosis occur
    • 726. Surrounding lung shows volume loss, fibrosis, emphysema, and nodular inflammatory foci.
    • 727. Generalized bronchiectasis: widespread dilation of bronchi and may be congenital or result from bacterial infection.
    • 728. Inherited conditions: cystic fibrosis, primary ciliary dyskinesia, hypogammaglobulinemia, and IgG deficiencies
    Histopathology<br />
    • Intense acute and chronic inflammatory exudation within walls of bronchi and bronchioles
    • 729. Associated with desquamation of lining epithelium and extensive areas of necrotizing ulceration.
    • 730. May be squamous metaplasia of remaining epithelium.
    • 731. Mixed flora cultured from ectatic bronchi, including staph, strep, pneumococci, enteric, anaerobic and microaerophilic bacteria,
    • 732. Particularly in children: Haemophilus influenzae and Pseudomonas aeruginosa.
     Diagnosis of Bronchiectasis <br />
    • High-resolution CT scanning (HCRT) is able to detect airway abnormalities
    • 733. Criteria are internal diameter of bronchus wider than its adjacent artery and failure of the bronchi to taper.
    • 734. Bronchial wall thickening appears to indicate airway inflammation and may have prognostic implications.
    Pulmonary Function<br />
    • Spirometry often shows a limitation of airflow, with:
    • 735. Reduced ratio of forced expiratory volume in one second (FEV1) to forced vital capacity (FVC)
    • 736. Normal or slightly reduced FVC - may indicate that airways are blocked by mucus, collapse with forced exhalation
    • 737. Reduced FEV1.
    • 738. Airway hyperresponsiveness demonstrated
    • 739. Improvement in FEV1 after the administration of a beta-adrenergic
    • 740. Markedly reduced FEV1 after histamine or methacholine challenge.
    Loading, Please Wait ... <br />OBSTRUCTIVE PULMONARY DISEASE<br /> <br />Chronic Obstructive Pulmonary Disease <br />
    • Chronic bronchitis, emphysema, asthma, and bronchiectasis
    • 741. Obstruction to air flow in the lungs.
    • 742. Forced expiratory volume is decreased.
    • 743. FEV1 (in 1 sec): maximum volume that can forcibly blow out in first second after full inspiration, measured in liters.
    • 744. Air flow can be reduced by increasing resistance to air flow or reducing outflow pressure.
    • 745. Narrowed airways produce increased resistance, whereas loss of elastic recoil results in diminished pressure.
    Epidemiology: Men are more likely to have COPD than women -- predominantly in individuals older than 40 years. <br />Chronic bronchitis<br />
    • Affects majority of patients with COPD
    • 746. Presence of a chronic productive cough for 3 months during each of 2 consecutive years
    • 747. Airflow limitation in chronic bronchitis is due to narrowing of airway caliber and increase in airway resistance.
    Differential with Acute Bronchitis <br />
    • Most frequently in children younger than 5 years in association with viral respiratory tract infection
    • 748. Caused by infections with influenza, parainfluenza, adenovirus, rhinovirus, and respiratory syncytial virus.
    • 749. Mucosa is acutely inflamed, with acute inflammatory cells and copious secretion of mucus.
    • 750. Symptoms include cough that produces phlegm that last for no more than 3 weeks.
    • 751. Repeated viral infections may damage airway lining and lead to bacterial infections of the lower respiratory tract
    • 752. Most common bacterial pathogen that causes lower respiratory tract infections is Streptococcus pneumoniae.
    • 753. Also, infections with Mycoplasma, Chlamydia pneumoniae, Moraxella catarrhalis, and H. influenzae
    Epidemiology: More prevalent in people older than 50 years, and affects males more than females<br />Pathogenesis<br />
    • Smoking
    • 754. Impairs ciliary movement, inhibits alveolar macrophages, hypertrophy and hyperplasia of mucus-secreting glands.
    • 755. Retained secretions predispose for infection -- increased risk for bacterial infections H. influenzae and S. pneumoniae
    • 756. Increase airway resistance via vagally mediated smooth muscle constriction.
    • 757. Air pollution: In particular traffic-related air pollution in urban areas
    • 758. Occupational exposures.
    • 759. Agents includes coal, manufactured vitreous fibers, oil mist, cement, silica, silicates, osmium, vanadium, welding fumes, organic dusts, engine exhausts, fire smoke, and secondhand cigarette smoke.
    Clinical Presentation<br />
    • Symptoms.
    • 760. Cardinal symptom -- persistent cough productive of sputum
    • 761. Dyspnea on exertion develops.
    • 762. Hypercapnia, hypoxemia, and mild cyanosis ("blue bloaters").
    • 763. Long-standing severe chronic bronchitis commonly leads to cor pulmonale with cardiac failure.
    • 764. Physical examination findings.
    • 765. Sputum is mucoid and white >> may become purulent
    • 766. Accumulates in bronchi during sleep and causes severe obstruction of airways until it is coughed up in morning.
    • 767. Bacteriological examination of sputum -- Haemophilus influenzae, and Streptococcus pneumoniae are most frequent
    Morphology<br />
    • Gross appearance.
    • 768. Bronchi, especially in lower lobes, are found to be filled with a mixture of mucus and pus.
    • 769. Underlying mucous membrane is seen to be a dusky red.
    • 770. Microscopic structure of normal bronchus.
    • 771. Intrapulmonary bronchi are lined by pseudostratified columnar ciliated bronchial epithelium
    • 772. Supported by a thin layer of lamina propria composed of fine connective tissue and a few lymphocytes.
    • 773. A thin layer of smooth muscle surrounds lamina propria and separates it from submucosa.
    • 774. Submucosa contains numerous seromucous bronchial glands.
    • 775. Bronchial epithelium displays three types of epithelial cells: (a) ciliated columnar, (b) goblet, and (c) basal cells.
    • 776. Chronic bronchitis – Microscopic appearance.
    • 777. Increase in size of bronchial mucus-secreting apparatus.
    • 778. Two types of cells line the mucous glands: pale mucous cells (which are more common) and serous cells.
    • 779. Hyperplasia and hypertrophy of mucous cells and an increased ratio of mucous to serous cells.
    • 780. Thus, both the individual acini and the glands enlarge.
    • 781. Chronic inflammation of bronchial wall with predominantly lymphocytic infiltration.
    • 782. Reid index.
    • 783. Correlate severity and duration of chronic bronchitis with size of bronchial glands.
    • 784. Measure ratio of thickness of gland layer to thickness of wall. Normal value of 0.4.
    Emphysema <br />
    • Abnormal, permanent enlargement of air spaces distal to bronchioles, with destruction of walls without fibrosis.
    • 785. Airflow limitation in emphysema is due to loss of elastic recoil.
    • 786. Vesicular emphysema.
    • 787. Affects spaces that normally contain air, i.e., lungs.
    • 788. Chronic lung disease characterized by irreversible enlargement of airspaces distal to terminal bronchioles
    • 789. Destruction of their walls but without fibrosis.
    • 790. Primary degenerative disease with a poor prognosis -- destruction of gas-exchanging air spaces is irreversible.
    • 791. Interstitial (surgical) emphysema.
    • 792. Ingress of air into normally airless interstitial planes of lung and subcutaneous tissues (Subcutaneous emphysema)
    • 793. Complication of surgical procedures and trauma.
    • 794. Collection of gases outside of normal air passages and inside connective interstitial tissues due to rupture of alveoli.
    • 795. Subcutaneous emphysema usually occurs on chest, neck and face >> travel from chest cavity along fascia.
    • 796. Characteristic crackling feel to touch, a sensation that is known as subcutaneous crepitation.
    • 797. Most common causes: lead to pneumothorax and air spread to subcutaneous tissue of neck and face.
    • 798. Spontaneous rupture of pulmonary blebs
    • 799. Stab wounds to the chest
    • 800. Blunt trauma with a fractured rib which punctures the lung.
    Epidemiology<br />
    • Higher among males than females, among smokers and former smokers than nonsmokers, among those over 40 years old
    Types<br />
    • Classified according to its anatomic distribution within the pulmonary lobule.
    • 801. Centriacinar (centrilobular) emphysema.
    • 802. Central/proximal parts of acini, formed by respiratory bronchioles, are affected, whereas distal alveoli are spared.
    • 803. Most severe in upper zones of lung, upper lobe, and superior segment of the lower lobe.
    • 804. Far more common than Panacinar emphysema
    • 805. The walls of the emphysematous spaces often contain large amounts of black pigment.
    • 806. Occurs predominantly in heavy smokers, often in association with chronic bronchitis.
    • 807. Bronchi and bronchioles proximal to the emphysematous spaces are inflamed and narrowed.
    • 808. Panacinar (panlobular) emphysema.
    • 809. Acini are uniformly enlarged from the level of the respiratory bronchiole to the terminal blind alveoli.
    • 810. More commonly in the lower zones and in the anterior margins of the lung, and it is usually most severe at the bases
    • 811. Associated with alpha-1-antitrypsin (alpha1-AT) deficiency.
    • 812. Distal acinar (paraseptal) emphysema.
    • 813. Proximal portion of the acinus is normal, and the distal part is predominantly involved.
    • 814. More striking adjacent to the pleura, along the lobular connective tissue septa, and at the margins of the lobules.
    • 815. Occurs adjacent to areas of fibrosis, scarring, or atelectasis and is usually more severe in the upper half of the lungs.
    • 816. Characteristic findings are of multiple, continuous, enlarged airspaces, sometimes forming cystlike structures (bullae).
    • 817. This type of emphysema probably underlies many of the cases of spontaneous pneumothorax in young adults.
    • 818. Bullous emphysema.
    • 819. Exceptionally large air spaces, within uppermost portions of lungs that develop secondary to damaged alveoli.
    • 820. A bulla is an emphysematous space that is more than 1cm in diameter.
    • 821. Seen in association with centriacinar emphysema and paraseptal emphysema.
    • 822. Occurs when an abnormal air space ruptures, leaking air into pleural space and causing the affected lung to collapse.
    • 823. Often seen in young men in association with large, progressive upper-lobe bullae
    • 824. Paracicatricial (irregular) emphysema.
    • 825. Emphysematous destruction occurs adjacent to pulmonary scars
    • 826. Scars consequent to granulomatous inflammation (TB), healed pulmonary infarcts, pneumonia, or pneumoconiosis
    Morphology<br />
    • Gross morphologic changes.
    • 827. Begins as areas of destruction (holes in lung) just visible to the naked eye.
    • 828. Areas of emphysematous destruction are traversed by fine strands -- represent vasculature that once supplied area
    • 829. Increase in lung volume with progression of emphysema -- correlates with the degree of emphysematous destruction.
    • 830. Microscopic changes in emphysema.
    • 831. Early emphysematous changes can only be detected microscopically;
    • 832. Include loss of alveolar walls, resulting in fewer alveolar attachments to bronchioles.
    • 833. More severe changes characterized by complete loss of most of wall of air spaces, bronchiolar as well as alveolar.  
    Pathogenesis<br />
    • Destruction of alveolar walls due to protease-antiprotease mechanism, aided by imbalance of oxidants and antioxidants.
    • 834. Results when elastolytic activity increases or antielastolytic activity is reduced.
    • 835. Deficiency of antiprotease anzyme alpha-1 antitrypsin (AAT) -- enhanced tendency to develop pulmonary emphysema
    • 836. AAT is a major inhibitor of proteases (particularly elastase) secreted by neutrophils during inflammation
    • 837. Increases in leukocytes (neutrophils and macrophages) or release of granules >> increases pulmonary proteolytic activity.
    • 838. With low levels of serum AAT, elastic tissue destruction is unchecked and emphysema results.
    • 839. Emphysema results from the destructive effect of high protease activity in subjects with low antiprotease activity.
    • 840. In smokers, neutrophils and macrophages accumulate in alveoli
    • 841. Activate transcription of genes that encode TNF and chemokines >> attract and activate neutrophils.
    • 842. Accumulated neutrophils are activated and release their granules, resulting in tissue damage.
    • 843. Smoking enhances elastase activity in macrophages
    • 844. Oxidant-antioxidant imbalance
    • 845. Loss of elastic tissue in walls of alveoli that surround respiratory bronchioles causes bronchioles to collapse during expiration.
    • 846. Leads to functional airflow obstruction despite the absence of mechanical obstruction.
    • 847. Several changes are seen: narrow the bronchiolar lumen and contribute to airway obstruction
    • 848. Goblet cell metaplasia with mucus plugging of the lumen
    • 849. Inflammatory infiltration of the walls with neutrophils, macrophages, B cells, CD4 and CD8+ T cells
    • 850. Thickening of the bronchiolar wall due to smooth muscle hypertrophy and peribronchial fibrosis.
    Clinical Course<br />
    • Clinical manifestations of emphysema do not appear until at least 1/3 of functioning pulmonary parenchyma is damaged.
    • 851. Dyspnea
    • 852. First symptom; it begins insidiously but is steadily progressive. Minimal non-productive cough.
    • 853. Tachypneic, with prolonged expiratory phase, sits in a hunched-over position, and breathes through pursed lips.
    • 854. Weight loss
    • 855. Due to loss of muscle with or without loss of fat mass -- preferentially in the lower extremities.
    • 856. Increased proinflammatory mediators such as TNFalpha >> responsible for pulmonary cachexia and wasting process
    • 857. Physical examination findings
    • 858. Hyperinflation (barrel chest), wheezing, decreased breath sounds, hyperresonance, prolonged expiration.
    • 859. In advanced disease, signs of right heart failure (decompensated cor pulmonale)
    • 860. Cyanosis, elevated jugular venous pressure, and peripheral edema can be observed.
    Laboratory Studies<br />
    • ABG analysis: Mild-to-moderate hypoxemia without hypercapnia progresses to severe hypoxemia and hypercapnia
    • 861. Hematocrit value: Chronic hypoxemia may lead to polycythemia. Values > 52% in men and > 47% in women
    • 862. Bicarbonate value.
    • 863. Respiratory alkalosis is a clinical disturbance due to alveolar hyperventilation >> decreased PaCO2.
    • 864. Increases ratio of bicarbonate concentration to PCO2 and increases pH level beyond normal range of 7.35-7.45
    • 865. Alpha1-antitrypsin level.
    • 866. Serum levels below protective threshold of 11 mmol/L. Most common severe variant is the Z allele
    Imaging<br />
    • Chest radiography.
    • 867. Hyperinflation of lungs, flattening domes of hemidiaphragms, attenuation or absence of pulmonary vasculature, loss of vascular branching pattern, widened retrosternal space, large focal lucencies (bullae), bronchial wall thickening.
    • 868. Attenuation of vascular shadows accompanied by hyperlucency of the lungs are signs of emphysema.
    • 869. With complicating pulmonary hypertension, the hilar vascular shadows are prominent;
    • 870. With right ventricular enlargement, opacity in the lower retrosternal air space may occur. 
    • 871. CT scanning and HRCT are even better for assessment
    Pulmonary Function Tests<br />
    • Necessary for diagnosis of obstructive airway disease and for assessments of its severity.
    • 872. Spirometry is helpful for assessing responses to treatment and disease progression.
    • 873. Decrease of forced expiratory volume in 1 second (FEV1) is the key to diagnosis.
    • 874. Increase in total lung capacity, functional residual capacity, and residual volume. The vital capacity is decreased.
    Clinical Phenotypes<br />
    • Pink puffer.
    • 875. Emphysema is the primary underlying pathology.
    • 876. Results from destruction of airways distal to terminal bronchiole, includes gradual destruction of capillary bed
    • 877. Less surface area for gas exchange -- but less ventilation-perfusion mismatch than blue bloaters.  
    • 878. Compensate by hyperventilation ("puffer" part) -- less hypoxemia (compared to blue bloaters) with "reddish"
    • 879. Develop muscle wasting and weight loss.  
    • 880. Blue bloater.
    • 881. Primary underlying lung pathology is chronic bronchitis.
    • 882. Caused by excessive mucus production with airway obstruction
    • 883. Resulting from hyperplasia of mucus-producing glands, goblet cell metaplasia, and chronic inflammation.  
    • 884. Pulmonary capillary bed is undamaged.
    • 885. Body responds to the increased obstruction by decreasing ventilation and increasing cardiac output.
    • 886. Marked ventilation-to-perfusion mismatch leading to hypoxemia and polycythemia.  
    • 887. Increased CO2 retention (hypercapnia). 
    • 888. Because of increasing obstruction, their residual lung volume gradually increases (the "bloating" part). 
    • 889. Hypoxemic/cyanotic with worse hypoxemia than pink puffers >> manifests as bluish lips and faces--the "blue" part.
    • 890. Pulmonary Hypertension
    • 891. Hypoxemia produces constriction of pulmonary arterioles and thus a rise in pulmonary artery pressure.
    • 892. Increased afterload on the right ventricle causes hypertrophy and ultimately, right-sided heart failure (cor pulmonale)
    • 893. Causes dilatation and thickening of the wall of main pulmonary artery.
    Progression of Disease<br />
    • Inexorable decline in respiratory function and progressive dyspnea, for which no treatment is adequate.
    • 894. Development of cor pulmonale and eventually congestive heart failure, related to secondary pulmonary vascular hypertension,
    • 895. Death due to respiratory acidosis and coma, right heart failure, and massive collapse of lungs secondary to pneumothorax.
    • 896. Treatment options include bronchodilators, steroids, bullectomy, and lung volume reduction surgery and lung transplantation.
    Loading, Please Wait ... <br />DISORDERS OF PLEURA, DIAPHRAGM AND CHEST WALL<br /> <br />Disorders of Pleura<br />Pleural Effusions <br />
    • Accumulation of excess fluid in the pleural cavity
    • 897. Detected radiologically as obliteration of costophrenic angle, to a massive accumulation that shifts mediastinum and trachea
    • 898. Pleural fluid accumulates when pleural fluid formation exceeds pleural fluid absorption.
    • 899. May develop when there is excess pleural fluid formation or decreased fluid removal by the lymphatics.
    • 900. Accumulation of pleural fluid occurs in the following settings:
    • 901. Increased hydrostatic pressure, as in congestive heart failure
    • 902. Increased vascular permeability, as in pneumonia
    • 903. Decreased osmotic pressure, as in nephrotic syndrome
    • 904. Increased intrapleural negative pressure, as in atelectasis
    • 905. Decreased lymphatic drainage, as in mediastinal carcinomatosis
    • 906. Non-inflammatory pleural effusions (transudative).
    • 907. Noninflammatory collections of serous fluid within the pleural cavities are called hydrothorax
    • 908. Fluid is clear and straw colored.
    • 909. Most common cause is cardiac failure, usually accompanied by pulmonary congestion and edema.
    • 910. Also found in renal failure and cirrhosis of the liver.
    • 911. There are two special forms of non-inflammatory pleural effusions:
    • 912. Hemothorax: escape of blood into the pleural cavity
    • 913. Fatal complication of a ruptured aortic aneurysm or blunt or penetrating chest trauma.
    • 914. Identifiable by the large clots that accompany the fluid component of the blood.
    • 915. Associated with hypotension or shock and respiratory distress.
    • 916. Patients are tachycardic, tachypneic, PE reveals diminished breath sounds and dull percussion
    • 917. Chylothorax: presence of lymphatic fluid (chyle) in the pleural space secondary to leakage
    • 918. Chyle is milky white because it contains finely emulsified fats.
    • 919. Most common cause is trauma, but it also may result from tumors in mediastinum (lymphoma).
    • 920. Inflammatory pleural effusions (pleuritis) -- (exudative)
    • 921. Etiology
    • 922. Inflammation of pleura may result from extension of any pulmonary infection to the visceral pleura, rheumatoid arthritis, disseminated lupus erythematosus, collagen vascular disease, or pulmonary infarction
    • 923. Sharp, stabbing chest pain on inspiration. Associated with pleural effusion (exudates)
    • 924. Serous, serofibrinous and fibrinous pleuritis.
    • 925. Fibrinous exudations generally reflect a later, more severe exudative reaction
    • 926. Grossly, a grayish-white fibrinous membrane covers the inflamed pleura which lacks its normal luster.
    • 927. There is frequently a small amount of fluid serous exudate that is cloudy in appearance.
    • 928. Purulent pleuritis (Empyema)
    • 929. Results from infectious seeding of pleural space by contiguous, lymphatic or hematogenous dissemination
    • 930. Characterized by loculated, yellow-green, creamy pus composed of neutrophils admixed with leukocytes.
    • 931. Hemorrhagic pleuritis.
    • 932. Found especially in neoplastic involvement of the pleural cavity (such as pleural metastases).
    • 933. Lung carcinoma, breast carcinoma, and lymphoma.
    • 934. Most patients complain of dyspnea, which is frequently out of proportion to the size of the effusion.
    • 935. Pleural fluid is a sanguineous exudate which must be differentiated from hemothorax.
    • 936. Diagnosis of pleuritis. 
    • 937. First step is to determine whether the effusion is a transudate or an exudate.
    • 938. Distinguished by measuring the lactate dehydrogenase (LDH) and protein levels in the pleural fluid.
    • 939. Exudative pleural effusions meet at least one of following criteria, whereas transudative pleural effusions meet none:
    • 940. Pleural fluid protein/serum protein >0.5
    • 941. Pleural fluid LDH/serum LDH >0.6
    • 942. Pleural fluid LDH more than two-thirds normal upper limit for serum
    • 943. If exudative pleural effusion is determined, the following tests on the pleural fluid should be obtained:
    • 944. Description of the fluid, glucose level, differential cell count, microbiologic studies, and cytology.
    Pneumothorax <br />
    • Presence of air or gas in pleural cavity between the visceral and parietal pleura.
    • 945. Air can enter intrapleural space through a communication from chest wall or through lung parenchyma across visceral pleura.
    • 946. Classification: may be spontaneous, traumatic, iatrogenous or therapeutic.
    • 947. Primary spontaneous pneumothorax.
    • 948. Epidemiology: Occurs more frequently in men between 18 and 40 years of age.
    • 949. Pathogenesis: Occur from rupture of blebs and bullae.
    • 950. Risk factors
    • 951. Heavily associated with smoking,
    • 952. Physical height -- typical patients tend to have a tall and thin body habitus. 
    • 953. Familial forms
    • 954. Marfan syndrome is an autosomal dominant disease caused by mutations in the gene encoding fibrillin 1.
    • 955. Ehlers-Danlos syndrome, especially vascular subtype (type IV)
    • 956. Birt-Hogg-Dubé syndrome -- associated with pulmonary cysts and renal cancer. Mutations in folliculin gene.
    • 957. Secondary spontaneous pneumothorax.
    • 958. Epidemiology: COPD is a common cause of secondary spontaneous pneumothorax
    • 959. Pathogenesis. Air enters the pleural space via distended, damaged, or compromised alveoli.
    • 960. Etiology: emphysema in particular and COPD in general, asthma, CF, interstitial lung disease, TB, lung carcinoma
    • 961. Clinical relevance: may present with more serious clinical symptoms and sequelae due to comorbidity.
    • 962. Traumatic pneumothorax.
    • 963. Iatrogenic pneumothorax.
    • 964. Leading causes include transthoracic needle aspiration, subclavicular needle stick, thoracentesis, transbronchial biopsy, pleural biopsy and positive pressure ventilation.
    • 965. Therapeutic pneumothorax: designed to create pulmonary parenchymal collapse and has been used to treat lung tuberculosis.
    • 966. Pneumomediastinum.
    • 967. Condition in which air is present in the mediastinum.
    • 968. Etiology: alveolar rupture with dissection of air into the mediastinum, esophageal perforation, and bowel rupture
    • 969. Diagnosis: confirmed via chest radiograph showing a radiolucent outline around heart and mediastinum or via CT
    • 970. Clinical presentation
    • 971. Causes compression, collapse, and atelectasis of the lung and may be responsible for marked respiratory distress.
    • 972. Acute onset of chest pain and shortness of breath are the predominant symptoms.
    • 973. Primary spontaneous pneumothorax usually causes limited symptoms
    • 974. Symptoms of secondary spontaneous pneumothorax tend to be more severe,
    • 975. Hypoxia, cyanosis and tachycardia are usually present. Hypercapnia may cause confusion and coma.
    • 976. Physical examination: absent breath sounds, hyperresonance on percussion and decreased tactile fremitus.
    • 977. Tension pneumothorax.
    • 978. Secondary to blunt or penetrating injury of the lung which results in a one-way valve being created.
    • 979. Air leaks from the lung out into the pleural space and is unable to escape, resulting in increased intrapleural pressure.
    • 980. Increases to the point where it interferes with venous return
    • 981. Clinical presentation: respiratory distress with tachypnea, tachycardia, cyanosis, hypotension and confusion.
    • 982. Affected side of chest may be hyperexpanded and show decreased movement
    Pleural Tumors<br />
    • Secondary metastatic involvement is far more common than are primary tumors.
    • 983. Most frequent metastatic malignancies arise from primary neoplasms of the lung and breast.
    • 984. Hemorrhagic or serohemorrhagic effusion follows that often contains neoplastic cells.
    Solitary Fibrous Tumor of Pleura <br />
    • Rare mesenchymal neoplasm that most commonly involves the pleura, which probably derives from fibroblast.
    • 985. Epidemiology.
    • 986. Tends to occur in older individuals (45 - 65 years) without a specific gender predilection
    • 987. Most of them (about 80%) arise from the visceral pleura and the remainder from parietal pleura.
    • 988. Morphology.
    • 989. Gross appearance.
    • 990. Tumor is often attached to the pleural surface by a pedicle
    • 991. Tends to remain confined to the surface of the lung.
    • 992. Consists of dense fibrous tissue with occasional cysts filled with viscid fluid.
    • 993. Microscopic appearance
    • 994. Composed of a mixture of spindle shaped fibroblast like cells within collagenous stroma.  
    • 995. Tumor cells are CD34+ and keratin-negative by immunostaining.
    • 996. Arises from submesothelial connective tissue, rather than mesothelium.
    • 997. Clinical presentation.
    • 998. The majority of patients are asymptomatic at presentation, the tumor being an incidental finding.
    • 999. When symptoms are present they are nonspecific and are caused by compression.
    • 1000. Present with chest pain, shortness of breath, cough, hypoglycemia, weight loss, hemoptysis, fever, and night sweats.
    • 1001. Associated with hypertrophic pulmanary osteoarthropathy (the clinical syndrome of clubbing of the fingers and toes).
    • 1002. Associated with hypoglycemia possibly due to production of high levels of insulin like growth factor (IGF)
    • 1003. Outcome: Surgical resection cures about 90% of these patients but recurrent disease occurs in remaining 10%.
    Malignant Mesothelioma <br />
    • Aggressive malignant tumor of serosal surfaces, such as the pleura and the peritoneum.
    • 1004. Etiology.
    • 1005. Exposure to asbestos.
    • 1006. Long latent period of 25 to 45 years for the development of asbestos-related mesothelioma.
    • 1007. Simian virus 40.
    • 1008. DNA virus -- polyomavirus that is found in both monkeys and humans.
    • 1009. Potential to cause tumors, but most often persists as a latent infection.
    • 1010. Binds to and inactivates several critical regulators of growth, such as p53 and Rb.
    • 1011. Epidemiology.
    • 1012. More common in men, with a male-to-female ratio of 3:1. Most develop in the six to seventh decade of life (60 years)
    • 1013. Cytogenetic analysis: display loss of chromosome 22 and p16 mutations.
    • 1014. Morphology.
    • 1015. Gross appearance.
    • 1016. Begins as discrete nodules that coalesce to produce a sheetlike neoplasm.
    • 1017. First involves parietal pleura where foci are found, appearing there as multiple small grape-like masses.
    • 1018. Involvement of visceral pleura follows with pleural effusion and direct invasion of thoracic structures.
    • 1019. Progression of tumor results in coalescence of nodules to form plaques anda continuous sheet of tumor
    • 1020. Fusing the visceral and parietal pleura and obliterating the pleural space.
    • 1021. Late stage: tumor encases lung as a layer of dense white tissue
    • 1022. Extends into fissures and infiltrates the peripheral lung parenchyma
    • 1023. Microscopic appearance.
    • 1024. Epithelioid and sarcomatoid patterns.
    • 1025. Glands and tubules are admixed with sheets of spindle cells.
    • 1026. If it is epithelial, the tumor may be difficult to distinguish from adenocarcinoma.
    • 1027. Despite their epithelial appearance, mesothelial cells are of mesodermal origin.
    • 1028. Epithelioid mesothelioma is the most common, and has the best prognosis.
    • 1029. Less commonly, only a sarcomatous component is present.
    • 1030. Clinical presentation.
    • 1031. Nonpleuritic chest wall pain, dyspnea, and recurrent pleural effusions.
    • 1032. Easy fatigability, fever, sweats, and weight loss are the other common accompanying symptoms.
    • 1033. Concurrent pulmonary asbestosis (fibrosis) is present in only 20% of individuals with pleural mesothelioma.
    • 1034. Often metastatic spread to the hilar lymph nodes and, eventually, to the liver and other distant organs.
    • 1035. Imaging: Chest radiographs or CT scans show obliteration of the diaphragm, nodular thickening of the pleura, decreased size of the involved chest, radiolucent sheetlike encasement of the pleura, or a combination of these.
    • 1036. Prognosis: The prognosis is poor, with a median survival time of 12 months after diagnosis
    • 1037. Peritoneal mesothelioma.
    • 1038. Primary sites include the pleura, the peritoneum, and the pericardium.
    • 1039. Also have pulmonary fibrosis.
    Disorders of Diaphragm<br />Diaphragm Paralysis <br />
    • Diaphragm is a chief muscle of inspiration.
    • 1040. Paralysis can lead to dyspnea and can affect ventilatory function.
    • 1041. Ventilatory failure and cor pulmonale are usually seen in severe cases.
    • 1042. Etiology.
    • 1043. Unilateral diaphragmatic paralysis
    • 1044. Most common cause is a malignant lesion leading to phrenic nerve or brachial plexus compression
    • 1045. Idiopathic: Brachial plexus neuritis secondary to a viral infection
    • 1046. Other causes in the differential include surgical trauma, and cervical spondylosis.
    • 1047. Bilateral diaphragmatic paralysis.
    • 1048. Arises from neuropathies, myopathies, and other systemic disorders
    • 1049. Most common causes are ALS, MS, post-poliomyelitis sequelae and muscular dystrophy.
    • 1050. Clinical presentation.
    • 1051. Unilateral diaphragmatic paralysis.
    • 1052. Usually found incidentally in patients undergoing chest radiography for some other reason.
    • 1053. Asymptomatic at rest but experience dyspnea upon exertion with decrease in exercise performance.
    • 1054. PE reveals dullness to percussion and absent breath sounds over the lower chest on the involved side.
    • 1055. Excursion on the involved hemithorax is decreased when compared with the healthy side.
    • 1056. Bilateral diaphragmatic paralysis.
    • 1057. Usually symptomatic and may develop ventilatory failure without medical intervention.
    • 1058. Typically present with respiratory failure or dyspnea that worsens in the supine position.
    • 1059. Tachypnea and rapid, shallow breathing occur when the patient adopts the supine position.
    • 1060. Limitation of diaphragmatic excursions, bilateral lower chest dullness with absent breath sounds.
    • 1061. Patients are tachypneic and use accessory respiration muscles.
    • 1062. The diagnostic finding is a paradoxical inward movement of the abdomen with inspiration.
    • 1063. Laboratory studies.
    • 1064. Pulmonary function testing
    • 1065. Patients with diaphragm paralysis develop restrictive ventilatory impairment.
    • 1066. Decrease in vital capacity due to cephalad displacement of abdominal contents.
    • 1067. Arterial blood gas analysis
    • 1068. Demonstrates hypoxemia in persons with bilateral diaphragmatic paralysis.
    • 1069. Hypoxemia develops from atelectasis and ventilation-perfusion mismatching.
    • 1070. Progressive hypercapnia also develops with disease progression.
    • 1071. Imaging.
    • 1072. Workup usually begins with inspiratory and expiratory chest radiographs.
    • 1073. Fluoroscopic examination is the most practical method of assessing the movement of the diaphragm.
    • 1074. Unilateral paralysis, hemidiaphragm moves upward with rapid inspiration and downward with expiration.
    • 1075. Sniff test: performed to confirm that abnormal diaphragm excursion is the result of paralysis rather than of weakness.
    • 1076. During this test, the patient inhales forcefully and rapidly through the nose with the mouth closed.
    • 1077. A sharp and brief downward motion in both hemidiaphragms is normal response when paralysis is absent.
    • 1078. If an entire hemidiaphragm exhibits a paradoxical upward motion > 2 cm, diaphragmatic paralysis is likely.
    • 1079. Prognosis.
    • 1080. Unilateral diaphragmatic paralysis: excellent unless phrenic nerve compression due to lung cancer metastasis.
    • 1081. Bilateral diaphragmatic paralysis prognosis depends on the nature of the underlying disease.
    • 1082. Patients with neuropathies or myopathies may require long-term ventilatory support. 
    Disorders of Chest Wall<br />
    • Diseases that alter structure of chest wall affect function of the pump, and may result in respiratory compromise or failure.
    Kyphoscoliosis <br />
    • Abnormal curvature of the spine in both curonal and sagittal plane. It is a combination of kyphosis and scoliosis. 
    • 1083. Etiology.
    • 1084. Congenital kyphoscoliosis: result in infants whose spinal column has not developed correctly during embryonal period
    • 1085. Idiopathic kyphoscoliosis: etiology remains unknown.
    • 1086. Neuromuscular: develops as a secondary symptom of another condition
    • 1087. Clinical presentation.
    • 1088. Initially present due to perceived deformity. Traditionally, scoliosis has been described as a nonpainful condition.
    • 1089. Complications.
    • 1090. Restrictive lung disease
    • 1091. Ventilation-perfusion imbalances result in alveolar hypoventilation and hypoxic vasoconstriction
    • 1092. Paraplegia
    • 1093. Associated with kyphoscoliosis in upper thoracic area (part of spinal cord with poorest collateral circulation)
    Pectus Excavatum <br />
    • Also known as sunken or funnel chest
    • 1094. Congenital chest wall deformity consisting in depression of sternum/adjacent ribs producing a concave appearance
    • 1095. Epidemiology: Most frequent anterior chest wall deformity. Male-to-female ratio of approximately 4:1.
    • 1096. Etiology.
    • 1097. Overgrowth of costal cartilage, which displaces sternum posteriorly, producing a caved-in appearance of the chest
    • 1098. Coexistence of pectus excavatum with other skeletal disorders suggests that an abnormality of connective tissue
    • 1099. Familial history suggests a possible genetic predisposition.
    • 1100. Impact on the cardiovascular and respiratory function.
    • 1101. Severe compression of heart is noted in majority of patients >> impairment of function of the cardiovascular system
    • 1102. Pectus excavatum does not affect lung performance.
    Pectus Carinatum <br />
    • Also called pigeon chest -- deformity of chest characterized by a protrusion of the sternum and ribs.
    • 1103. Epidemiology: Second most common congenital chest wall deformity -- more common in boys than girls (ratio, 4:1).
    • 1104. Etiology: Represent an overgrowth of ribs or costochondral cartilage. Often accompany connective tissue disorders.
    • 1105. Gross appearance.
    • 1106. Deformity usually manifests in early teenage years.
    • 1107. Most common variety consists of anterior displacement of the sternal gladiolus with the appropriate cartilages in tow.
    • 1108. Result is a lateral depression of the ribs, known as Harrison grooves.
    • 1109. Termed chondrogladiolar protuberance -- looks like the result of a giant hand crushing chest from each side.
    • 1110. Clinical presentation.
    • 1111. Symptoms more common in adolescents
    • 1112. Range from a reduced endurance to severe shortness of breath on minimal exertion.
    • 1113. Pulmonary function >> increased residual volume, tachypnea, and compensatory diaphragmatic excursions.
    • 1114. Commonly concurrent is mild to moderate asthma.
    • 1115. Surgical repair can result in an improvement of 9% in vital capacity.Loading, Please Wait ...
    PULMONARY VASCULAR DISORDERS<br />Pulmonary Thromboembolism <br />
    • Blockage of pulmonary artery and branches by thromboemboli that originate in venous system.
    • 1116. Blood clots that occlude the large pulmonary arteries are almost always embolic in origin.
    • 1117. Usually due to deep venous thrombosis (DVT) from deep veins of the leg
    Epidemiology<br />
    • Incidence significantly higher in African Americans than in Caucasians.   
    • 1118. Age is a risk factor for thromboembolic disease -- greater in older patients than in younger patients.
    Deep Venous Thrombosis <br />
    • Epidemiology.
    • 1119. Deep venous thrombosis (DVT) occurs about 3 times more often than PTE.
    • 1120. Most DVT is occult and usually resolves spontaneously without complication.
    • 1121. DVT usually affects individuals older than 40 years.
    • 1122. Risk factors.
    • 1123. Acquired risk factors: immobilization, obesity, cigarette smoking, oral contraceptives, pregnancy, surgery, trauma, etc
    • 1124. Genetic factors: autosomal dominant genetic mutations are factor V Leiden and prothrombin gene mutations.
    • 1125. Sites of thrombosis.
    • 1126. Commonly affects proximal leg veins (femoral vein or popliteal vein) or deep veins of pelvis.
    • 1127. Embolize to pulmonary arterial circulation >> develop PTE, which is usually asymptomatic.
    • 1128. Pathophysiologic consequences of pulmonary embolism.
    • 1129. Response depends on extent to which the pulmonary artery blood flow is obstructed, the size of the occluded vessel(s), the number of emboli, the overall status of the cardiovascular system, and the release of vasoactive factors such as thromboxane A2 from platelets that accumulate at the site of the thrombus.
    • 1130. Respiratory consequences due to the nonperfused, though ventilated, lung segment
    • 1131. Increased alveolar dead space, hypoxemia (ventilation-perfusion mismatch), and hyperventilation.
    • 1132. Pulmonary infarction is an uncommon consequence because of the rich collateral circulation
    • 1133. Hemodynamic consequences due to increased resistance to pulmonary blood flow by embolic obstruction.
    • 1134. Reduction in cross-sectional area >> pulmonary vascular resistance >> increases right ventricular afterload.
    • 1135. Right ventricular failure may ensue.
    • 1136. Consequences of pulmonary thromboembolism.
    • 1137. Sudden death as a result of the blockage of the main pulmonary artery (blockage of blood flow through lungs)
    • 1138. Death may also be caused by acute failure of the right side of the heart (acute cor pulmonale)
    • 1139. Smaller emboli travel out into more peripheral pulmonary vessels that supply lobules >> may cause infarct.
    • 1140. Alveolar hemorrhage, but there is no infarction, if adequate cardiovascular function is present
    • 1141. Morphology of pulmonary infarction.
    • 1142. Affect the lower lobes, and, in more than half of cases, multiple lesions occur.
    • 1143. Distinguished from a post-mortem clot by the presence of the lines of Zahn in the thrombus. 
    • 1144. Pulmonary infarct is classically hemorrhagic and appears as a raised, firm, red-blue area.
    • 1145. Apposed pleural surface is covered by a fibrinous exudate.
    • 1146. Red cells begin to lyse and infarct becomes paler and eventually red-brown as hemosiderin is produced.
    • 1147. Fibrous replacement begins at margins as a gray-white peripheral zone and converts infarct into a contracted scar.
    • 1148. Ischemic necrosis of lung substance within area of hemorrhage, affecting alveolar walls, bronchioles, and vessels.
    • 1149. Septic infarcts: infarct caused by infected embolus with neutrophilic inflammatory reaction. May convert to abscesses.
    • 1150. Clinical manifestations of pulmonary thromboembolism.
    • 1151. Varies from sudden death, catastrophic hemodynamic collapse, gradually progressive dyspnea, asymptopmatic.
    • 1152. A large pulmonary embolus is one of the few causes of virtually instantaneous death.
    • 1153. Massive pulmonary embolism produces circulatory collapse and shock
    • 1154. Hypotension, rapid and faint peripheral pulses, cool skin, altered mental status and decreased urine output.
    • 1155. Acute pulmonary infarction
    • 1156. Present with acute onset of pleuritic chest pain, fever, dyspnea, and hemoptysis.
    • 1157. An overlying fibrinous pleuritis may produce a pleural friction rub.
    • 1158. Acute embolism without infarction
    • 1159. Nonspecific symptoms of unexplained dyspnea and/or substernal discomfort. Crackles may be heard
    • 1160. Most patients with pulmonary embolism have no obvious symptoms at presentation.
    • 1161. Laboratory findings in pulmonary thromboembolism.
    • 1162. D-dimer testing.
    • 1163. Detects cross-linked fibrin degradation fragment
    • 1164. Elevations in this fragment are seen in blood in after a thrombus is degraded by thrombolysis.
    • 1165. Clotting study. Clotting study results are normal in most patients with PTE.
    • 1166. Peripheral blood WBC count. The WBC count may be normal or elevated.
    • 1167. Arterial blood gases: reveal hypoxemia, hypocapnia, and respiratory alkalosis
    • 1168. Imaging studies in pulmonary thromboembolism.
    • 1169. Chest radiography
    • 1170. Hampton hump: wedge-shaped, pleura-based, triangular opacity with an apex pointing toward the hilus
    • 1171. Westermark sign: decreased vascularity.
    • 1172. Spiral computed tomographic angiography (CTA): Visualize main, lobar, and segmental pulmonary emboli
    • 1173. Ventilation-perfusion (V/Q) scanning: ventilation scan shows air flows and perfusion scan shows blood flows.  
    • 1174. Color-flow Doppler imaging ultrasonography for detection of proximal DVT.
    • 1175. Sequelae of pulmonary thromboembolism.
    • 1176. Often resolve spontaneously via contraction and fibrinolysis, particularly in the relatively young.
    • 1177. With anticoagulant therapy, most of lung scan defects are resolved.
    • 1178. Unresolved, multiple small emboli may lead to Pulmonary Hypertension, atherosclerosis, and chronic cor pulmonale.
    Pulmonary Arterial Hypertension (PAH)<br />
    • Progressive condition characterized by elevated pulmonary arterial pressures leading to right ventricular (RV) failure.
    Classification<br />
    • Pathophysiologic classification.
    • 1179. Precapillary hypertension
    • 1180. Left-to-right cardiac shunts as well as idiopathic pulmonary hypertension, thromboembolic pulmonary hypertension, and hypertension secondary to fibrotic lung disease, connective tissue diseases and hypoxia.
    • 1181. Postcapillary hypertension
    • 1182. Pulmonary veno-occlusive disease as well as hypertension secondary to left-sided cardiac disorders
    • 1183. Etiologic classification.
    • 1184. Primary: Unknown etiology -- idiopathic
    • 1185. Secondary: due to either intrinsic parenchymal disease of the lung or disease extrinsic to the lung.
    Idiopathic Pulmonary Hypertension <br />
    • Mean pulmonary artery pressure > 25 mm Hg at rest with normal pulmonary capillary wedge pressure and absence of causes
    • 1186. Epidemiology.
    • 1187. Rare disease -- female-to-male ratio of 4:1; affects young women of childbearing age; average age is about 35 years.
    • 1188. Pathogenesis.
    • 1189. Cause is unexplained -- mechanism most widely accepted is that of pulmonary vasoconstriction.
    • 1190. Insult to endothelium occurs resulting in vascular scarring, endothelial dysfunction, and smooth muscle proliferation
    • 1191. Sporadic form.
    • 1192. Familial form.
    • 1193. Autosomal dominant trait with incomplete penetrance
    • 1194. Bone morphogenetic protein receptor type 2 (BMPR2) gene mutations
    • 1195. Transforming growth factor-beta (TGF-beta) receptor involved in regulation of apoptosis and growth
    Pulmonary Veno-Occlusive Disease <br />
    • Characterized by extensive occlusion of small pulmonary veins and venules by loose, sparsely cellular, intimal fibrosis.
    • 1196. Reported to follow viral infections, exposure to toxic agents and chemotherapy.
    • 1197. Morphology.
    • 1198. Brown induration of lung and atherosclerosis of large pulmonary arteries.
    • 1199. Occlusion of small veins and venules and eccentric intimal thickening of larger veins.
    • 1200. Moderate fibrosis of alveolar walls is usually noted, and foci of hemosiderosis are common.
    • 1201. Clinical presentation.
    • 1202. Produces severe pulmonary hypertension and progressive dyspnea
    • 1203. Radiologic examination reveals scattered infiltrates in lung, representing hemorrhage and hemosiderosis
    • 1204. There is no effective therapy, and heart–lung transplantation should be contemplated.
    Secondary Pulmonary Hypertension <br />
    • More common than idiopathic pulmonary hypertension.
    • 1205. Pulmonary hypertension associated with left heart disease.
    • 1206. Left ventricular failure: increases pulmonary venous pressure and pulmonary arterial pressure.
    • 1207. Mitral stenosis: Produces severe venous hypertension and significant pulmonary artery hypertension.
    • 1208. Congenital heart disease: shunt from systemic to pulmonary circulation results in increased flow to the lungs.
    • 1209. Pulmonary hypertension associated with lung diseases and/or hypoxemia.
    • 1210. Obstructive and restrictive lung disease
    • 1211. Due to hypoxic pulmonary vasoconstriction, loss of small vessels in regions of emphysematous lung destruction and obliteration of the pulmonary vascular bed by interstitial fibrosis and lung destruction.
    • 1212. Sleep apnea: hypoxemia can result in constriction of small pulmonary arteries and pulmonary hypertension
    • 1213. Kyphoscoliosis or extreme obesity (Pickwickian syndrome)
    • 1214. Lead to hypoxemia and pulmonary hypertension.
    • 1215. Chronic hypoxia results in muscularization of the arterioles with minimal effects on the intima.
    • 1216. Pulmonary hypertension due to chronic thrombotic and/or embolic disease.
    • 1217. Rresults from asymptomatic, episodic showers of small emboli from the periphery.
    • 1218. Gradually restrict pulmonary circulation, and lead to pulmonary hypertension and right ventricular failure.
    • 1219. Evidence of peripheral venous thrombosis, in deep leg veins, or a history predisposition to venous thrombosis.
    Clinical Manifestations<br />
    • Symptoms.
    • 1220. Present with exertional dyspnea that increases in severity over months or even years.
    • 1221. Exertional chest pain, syncope, and lower extremity edema >> more severe with impaired right heart function.
    • 1222. Physical examination findings.
    • 1223. Increased pulmonic component of second heart sound, a right ventricular lift, and elevated jugular venous pulsations. Hepatomegaly, leg pitting edema and ascites are present in patients with decompensated right heart failure.
    Morphology<br />
    • Medial hypertrophy of muscular and elastic arteries, atherosclerosis of pulmonary artery and branches, and RV hypertrophy.  
    • 1224. Coexistence of diffuse pulmonary fibrosis, or severe emphysema and chronic bronchitis, points to chronic hypoxia
    • 1225. Atherosclerotic plaques form in pulmonary artery and its major branches, resembling systemic atherosclerosis.
    • 1226. Increases in muscular thickness of media (medial hypertrophy) and intimal fibrosis
    • 1227. Plexiform lesion: tuft of capillary formations, producing a network that spans lumens of dilated thin-walled, small arteries
    Diffuse Pulmonary Hemorrhage Syndromes<br />
    • Hemorrhage from the lung is a dramatic complication of some interstitial lung disorders.
    • 1228. Goodpasture syndrome
    • 1229. Idiopathic pulmonary hemosiderosis
    • 1230. Vasculitis-associated hemorrhage, found in hypersensitivity angiitis, Wegener granulomatosis, and SLE.
    Goodpasture Syndrome <br />
    • Triad of pulmonary hemorrhage, glomerulonephritis, and circulating anti–glomerular basement membrane (anti-GBM) Abs
    • 1231. Epidemiology.
    • 1232. Uncommon disorder; usually results in rapidly progressive glomerulonephritis
    • 1233. Most cases occur in the teens or 20s, and there is a male preponderance.
    • 1234. Pathogenesis.
    • 1235. Autoimmune disease -- kidney and lung are injured by circulating autoantibodies against alpha-3 chain of collagen IV.
    • 1236. Initiate inflammatory destruction of basement membrane in renal glomeruli and pulmonary alveoli
    • 1237. Rapidly progressive glomerulonephritis and a necrotizing hemorrhagic interstitial pneumonitis.
    • 1238. Presumed that some environmental insult is required to unmask the cryptic epitopes.
    • 1239. Genetic predisposition: indicated by association with certain HLA subtypes (HLA-DR2)
    • 1240. Morphology.
    • 1241. Gross appearance: lungs are heavy, with areas of red-brown consolidation.  
    • 1242. Microscopic appearance:
    • 1243. Focal necrosis of alveolar walls associated with intra-alveolar hemorrhages.
    • 1244. Often the alveoli contain hemosiderin-laden macrophages.
    • 1245. Fibrous thickening of the septae, hypertrophy of type II pneumocytes, and blood in alveolar spaces.
    • 1246. Renal lesions:
    • 1247. Rapidly progressive glomerulonephritis, with focal or complete necrosis
    • 1248. IgG and C3 along glomerular basement membrane can be observed with immunofluorescence testing.
    • 1249. Clinical presentation.
    • 1250. Begin with respiratory symptoms, principally hemoptysis, cough and dyspnea, and focal pulmonary consolidations.
    • 1251. Soon, glomerulonephritis appears, with gross or microscopic hematuria and edema >> progressive renal failure.
    • 1252. Laboratory studies.
    • 1253. Anemia (hemoglobin level less than 12 mg/dL) occurs out of proportion to hemoptysis or renal failure.
    • 1254. Leukocytosis with a left shift is present in about 50% of patients.
    • 1255. Urinalysis findings are characteristic of rapidly progressive glomerulonephritis
    • 1256. Demonstrating low-grade proteinuria, gross or microscopic hematuria, and red blood cell casts.
    • 1257. Serologic assays for anti-GMB antibodies are valuable for confirming diagnosis and monitoring adequacy of therapy.
    • 1258. Prognosis: Aggressive therapy with plasmapheresis, corticosteroids, and immunosuppressive agents improved prognosis
    Idiopathic Pulmonary Hemosiderosis <br />
    • Pulmonary hemorrhage without demonstrable immunologic association.
    • 1259. Epidemiology: Rare condition with an unknown incidence and prevalence in the population
    • 1260. Morphology.
    • 1261. Lungs are firm and darkly brown pigmented ("brown induration").
    • 1262. Alveolar walls are thickened, and interstitium contains collagen deposition in long-standing disease.  
    • 1263. Presence of intact erythrocytes in the distal airways and alveoli reflects recent/active alveolar hemorrhage
    • 1264. Multiple hemosiderin-laden macrophages (siderophages) reflect recurrent intra-pulmonary bleeding;
    • 1265. Prussian blue histochemical reaction (Perls staining method)
    • 1266. Immunohistochemistry tests exclude any intrapulmonary immunoglobulin or immune complex depositions.
    • 1267. Clinical presentation.
    • 1268. Acute phase
    • 1269. Corresponds to intra-alveolar bleeding episodes
    • 1270. Manifested by cough, dyspnea, various degrees of anemia, hemoptysis, alveolar infiltrates on CXR
    • 1271. Chronic phase.
    • 1272. Characterized by a slow resolution of the previous symptoms, with or without treatment.
    • 1273. Alveolar macrophages convert hemoglobin’s iron into hemosiderin within 36-72 hours >> hemosiderosis.
    • 1274. Pallor, emaciation, failure to thrive, hepatosplenomegaly and sometimes a normal examination.
    • 1275. In those with pulmonary fibrosis, bilateral crackles and clubbing may be present.
    • 1276. Laboratory studies.
    • 1277. CBC count reveals variable degrees of anemia.
    • 1278. Bone marrow biopsy typically shows hyperplasia of erytropoietic precursors and low intramedullary iron store.
    • 1279. Sputum examination can demonstrate intraalveolar bleeding (erythrocytes and hemosiderin-laden macrophages)
    • 1280. Bronchoalveolar lavage (BAL) from involved areas has a higher diagnostic yield than the sputum examination.
    • 1281. Lung function tests show in general a ventilatory restrictive pattern of variable severity.
    • 1282. Imaging.
    • 1283. Acute phase -- chest radiographs show diffuse alveolar type infiltrates in lower lung fields
    • 1284. Ground glass attenuation on the high resolution computed tomographic scan.
    • 1285. Remission -- alveolar infiltrates are reabsorbed and opacities ensue in same areas, with variable degree of fibrosis.
    • 1286. Etiology: Unknown, and no anti-basement membrane antibodies are detectable in serum or tissues.
    • 1287. Favorable response to long-term immunosuppression indicates that an immunological mechanism could be involved.Loading, Please Wait ...
    LUNG CANCER<br />Epidemiology<br />
    • Most common cause of cancer death worldwide, in both men and women.
    • 1288. Peak age between age 60 and 70 years with male predominance.
    Classification<br />
    • Relative proportions of major types of carcinomas are:
    • 1289. (1) adenocarcinoma (males 37%, females 47%)
    • 1290. (2) squamous cell carcinoma (males 32%, females 25%)
    • 1291. (3) small cell carcinoma (males 14%, females 18%)
    • 1292. (4) large cell carcinoma (males 18%, females 10%)
    Site of Origin<br />
    • Arise most often in large central bronchi (1st, 2nd and 3rd order bronchi) and about hilus of lung.
    • 1293. ~ 30% of lung carcinomas are peripheral, arising from the alveolar septal cells or terminal bronchioles.
    • 1294. Squamous cell carcinomas and small cell carcinomas tend to have more a central localization.
    • 1295. Adenocarcinomas tend to have a peripheral localization.
    Etiology<br />
    • Tobacco smoking
    • 1296. Association between frequency of lung cancer and:
    • 1297. Amount of daily smoking
    • 1298. Tendency to inhale
    • 1299. Duration of smoking habit.
    • 1300. Linked to histologic changes in epithelium of respiratory tract: dysplasia >> carcinoma in situ >> invasive carcinoma.
    • 1301. Carcinogens -- initiators (polycyclic aromatic hydrocarbons ie. benzopyrene) and promoters (phenol derivatives)
    • 1302. Strongest association with squamous cell carcinoma and small cell carcinoma.
    • 1303. Nonsmokers usually develop adenocarcinoma.
    • 1304. Industrial hazards
    • 1305. High-dose ionizing radiation is carcinogenic.
    • 1306. Uranium is weakly radioactive
    • 1307. Asbestos
    • 1308. Air pollution
    • 1309. Radon is a ubiquitous radioactive gas -- low-level indoor exposure (e.g., in homes in areas of high radon in soil)
    Precursor Lesions<br />
    • Squamous metaplasia.
    • 1310. Replacement of columnar bronchial epithelium by squamous stratified epithelium >> pulmonary SCC.
    • 1311. Atypical adenomatous hyperplasia.
    • 1312. Solitary lesion in which atypical bronchiole-alveolar cuboidal cells proliferate along alveolar septa >> adenocarcinoma
    • 1313. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia.
    • 1314. Proliferation associated with the bronchiolar epithelium >> pulmonary carcinoid tumor.
    Clinical Presentation<br />
    • General symptoms and signs: Cough (most common), dyspnea, chest pain, and hemoptysis.
    • 1315. Symptoms and signs according to location.
    • 1316. Lung cancer growing endobronchially.
    • 1317. Cough;  
    • 1318. Hemoptysis;
    • 1319. Bronchial obstruction: stridor, and wheezing;
    • 1320. Post Obstruction >> atelectasis, asymmetric breath sounds, CXR infiltrate, pneumonia, pleural effusion
    • 1321. Mediastinal spread
    Superior vena cava syndrome due to obstruction >> upper extremity and facial edema, dilated neck veins<br />Left vocal cord paralysis due to recurrent laryngeal nerve impingement: hoarseness;<br />Nerve entrapment syndromes due to invasion of extreme lung apex (Pancoast tumor): <br />Involvement of brachial plexus >> shoulder pain radiating in ulnar nerve distribution down arm<br />Involvement of stellate ganglion may cause Horner syndrome<br />Characterized by enophthalmos, ptosis of upper eyelid, miosis, and anhidrosis <br />Compression of middle third of esophagus due to enlargement of subcarinal lymph nodes: dysphagia;<br />Compression of thoracic duct: chylothorax<br />
    • Pleural spread: Chest pain and pleural effusion.
    • 1322. Paraneoplastic syndromes.
    • 1323. Collections of symptoms that result from substances produced by tumor, and they occur remotely from tumor itself.
    • 1324. May be endocrine, neuromuscular, musculoskeletal, cardiovascular, cutaneous, hematologic, gastrointestinal, renal.
    • 1325. Paraneoplastic syndromes associated with lung cancer include:
    • 1326. Cushing syndrome (due to secretion of ACTH) is associated with small cell carcinoma;
    • 1327. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is associated with small cell carcinoma;
    • 1328. Hypercalcemia (due to secretion of a parathyroid-hormone-like substance) is associated with SCC
    • 1329. Acanthosis nigricans, i.e. thickened brown velvety pigmentation of skin due to hypersecretion of TGF-alpha
    • 1330. Dermatomyositis/polymyositis,
    • 1331. Clubbing of fingers
    • 1332. Myasthenic syndromes, such as Eaton-Lambert syndrome and progressive multifocal encephalopathy.
    Prognosis: Tumor stage remains the single most important predictor of prognosis.<br />Small Cell Carcinoma <br />
    • Highly malignant epithelial tumor that exhibits neuroendocrine features.
    • 1333. Paraneoplastic syndromes: diabetes insipidus, ectopic ACTH syndrome (Cushing syndrome), and Eaton-Lambert syndrome.
    • 1334. Arises in major airways, grows very rapidly, metastasizes early and is sensitive to chemotherapy, but most aggressive
    Morphology<br />
    • Gross.
    • 1335. Appears as a perihilar mass, frequently with extensive lymph node metastases.
    • 1336. Soft and white but often shows extensive hemorrhage and necrosis.
    • 1337. Typically spreads along bronchi in a submucosal and circumferential fashion.
    • 1338. Microscopic appearance. 
    • 1339. Consists of sheets of small, round, oval or spindle-shaped cells.
    • 1340. Display scant cytoplasm, finely granular nuclear chromatin, absent or inconspicuous nucleoli, high mitotic rate
    • 1341. Necrosis is frequent and extensive
    • 1342. Electron microscopy:
    • 1343. Neuroendocrine differentiation, with small cytoplasmic granules – round, electrondense core and electronlucent halo
    • 1344. Immunohistochemistry:
    • 1345. No completely satisfactory marker of neuroendocrine differentiation is available.
    • 1346. Chromogranin A and synaptophysin: specific protein component of endocrine granules
    Squamous Cell Carcinoma<br />
    • Injury to bronchial epithelium >> squamous metaplasia >> dysplasia, carcinoma in situ, and invasive tumor
    Morphology<br />
    • Gross appearance.
    • 1347. Arise as a granular or friable polypoid mass within lumen of central bronchi (mainstem, lobar and segmental bronchi)
    • 1348. Invade lung parenchyma in later stages.
    • 1349. Cavitation due to central necrosis.
    • 1350. Hilar lymph nodes are often directly invaded.
    • 1351. Histopathology.
    • 1352. Irregular nests and strands of tumor cells separated by varying amounts of fibrous stroma.
    • 1353. Keratinization
    • 1354. Forms concentrically laminated ‘keratin pearls’ with refractile eosinophilic cytoplasm.
    • 1355. Intercellular bridges
    • 1356. Represent desmosomal cell junctions evident at light microscopic level because of artifactual cell shrinkage
    • 1357. Histological grading.
    • 1358. Variation within a tumor >> small biopsies are in adequate for tumor grading.
    • 1359. Well-differentiated squamous cell carcinomas (grade 1) show prominent keratinization throughout
    • 1360. Poorly differentiated tumors (grade 3 and 4) require careful scrutiny to identify keratinization or intercellular bridging.
    • 1361. Immunohistochemistry.
    • 1362. Stain strongly for low molecular weight cytokeratins.
    • 1363. In better differentiated tumors, high molecular weight cytokeratins and carcinoembryonic antigen are also found.
    • 1364. Electron microscopy.
    • 1365. Tonofibrils converge on desmosomes and extend into intercellular bridges.
    • 1366. Keratin pearls consist of large keratin plaques surrounded by necrotic cells with pyknotic nuclei.  
    Adenocarcinoma <br />Morphology<br />
    • Gross appearance.
    • 1367. Arise in periphery of lung as a subpleural mass with central depressed scarring with indrawing of overlying pleura.
    • 1368. ‘Scar cancer’: central sclerosis is result rather than the cause of cancer.
    • 1369. Microscopic appearance.
    • 1370. Acinar adenocarcinoma: predominance of glandular structures, well- differentiated
    • 1371. Papillary and solid adenocarcinoma: Less well diferentiated subtypes.
    • 1372. Solid with mucus formation
    • 1373. Intracellular mucin takes form of small droplets or larger vacuoles, giving a ‘signet-ring’ appearance.
    • 1374. Extracellular mucin accumulates within glandular lumina of varying size and shape.
    • 1375. Large pools of mucin containing sparse clumps of free cells that show little atypia >> ‘colloid’ carcinoma.
    • 1376. Mixed adenocarcinoma: heterogeneous group of tumors histologically and often show a mixed subtype.
    • 1377. Immunohistochemistry.
    • 1378. Express a wide range of cytokeratins and stain for carcinoembryonic antigen (CEA).
    • 1379. Staining for epithelial membrane antigen and vimentin is also usually positive.
    • 1380. Many primary adenocarcinomas stain for surfactant apoprotein and thyroid transcription factor-1.
    • 1381. Electron microscopy – Heterogeneous and may appear as one of the following
    • 1382. Cells are rich in cytoplasmic organelles that indicate active mucin synthesis and storage.
    • 1383. Composed of cells resembling type II pneumocytes, sometimes containing tubulolamellar nuclear inclusions.
    • 1384. Entirely composed of cells resembling Clara cells.
    • 1385. Type II pneumocytes may be seen alongside mucous or Clara cells.
    Bonchioloalveolar Carinoma<br />
    • Arise in periphery of lung; characterized by tumor cells growth along alveolar walls without destruction, architecture retained.
    Morphology<br />
    • Mucinous type
    • 1386. Tumor cells are high columnar, mucin producing, and show little atypia.
    • 1387. Accumulation of large amounts of mucus in pulmonary parenchyma leads to bronchorrhea.
    • 1388. Consolidation of large parts of a lobe or entire lung, with a glistening, slimy cut surface,.
    • 1389. Non-mucinous type
    • 1390. Exhibits cuboidal tumor cells with a higher degree of nuclear atypia, and producing little or no mucin.
    • 1391. Consists of Clara cells or type II pneumocytes
    • 1392. Growth pattern only at periphery, center being sclerotic.  
    • 1393. Mixed
    Large Cell Carcinoma <br />
    • Diagnosis of exclusion
    • 1394. Poorly differentiated -- does not show squamous or glandular differentiation and shown not to be small cell carcinoma
    • 1395. Cells are large and exhibit ample cytoplasm. Nuclei show prominent nucleoli and vesicular chromatin.
    • 1396. Histologic variant >> large cell neuroendocrine carcinoma: solid, trabecular, rosette-like, and palisading patterns
    Carcinoid Tumors<br />Pulmonary Neuroendocrine Cells<br />
    • The normal lung contains neuroendocrine cells within the bronchial epithelium as single cells or as clusters.
    • 1397. Neoplasms of neuroendocrine cells
    • 1398. Benign tumorlets: small, hyperplastic nests of neuroendocrine cells seen in areas of chronic lung damage (scarring)
    • 1399. Carcinoid tumors
    • 1400. Highly aggressive small cell carcinoma and large cell neuroendocrine carcinoma
    • 1401. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: precursor to development of multiple tumorlets and carcinoids.
    Epidemiology: Most patients are younger than 40 years of age, and the incidence is equal for both sexes. <br />Classification<br />
    • Low-grade malignant epithelial neoplasms classified into:
    • 1402. Typical: no p53 mutations or abnormalities of BCL2 and BAX expression
    • 1403. Atypical carcinoids: show these changes in a large proportion of tumors
    Morphology<br />
    • Gross appearance.
    • 1404. Central tumors
    • 1405. Grow as finger-like or spherical polypoid masses that commonly project into lumen of bronchus
    • 1406. Most are confined to main stem bronchi.
    • 1407. Others produce little intraluminal mass but instead penetrate bronchial wall, producing collar-button lesion.
    • 1408. Peripheral tumors are solid and nodular. 
    • 1409. Microscopic appearance.
    • 1410. Solid, trabecular, palisading, ribbon, or rosette-like arrangements of cells separated by delicate fibrovascular stroma.
    • 1411. Cells are quite regular and have uniform round nuclei and a moderate amount of eosinophilic cytoplasm.
    • 1412. Typical carcinoids have fewer than two mitoses per ten high-power fields and lack necrosis
    • 1413. Atypical carcinoids have between two and ten mitoses per ten high-power fields and/or foci of necrosis
    • 1414. Show increased pleomorphism, prominent nucleoli, and grow in a disorganized fashion > invade lymphatics
    • 1415. Ultrastructural studies
    • 1416. Cells exhibit dense-core granules and are found to contain serotonin, neuron-specific enolase, bombesin, calcitonin.
    Clinical Presentation<br />
    • Persistent cough, hemoptysis, impairment of drainage with secondary infections, bronchiectasis, emphysema, and atelectasis
    • 1417. Intermittent attacks of diarrhea, flushing, and cyanosis.
    • 1418. Follow a relatively benign course for long periods and are therefore amenable to resection.
    Loading, Please Wait ... <br />IMMUNOLOGY OF CARDIAC AND PULMONARY TRANSPLANT<br />  <br />Immunopathology of Organ Transplantation<br />Types of Grafts<br />
    • Degree of immune response depends on degree of genetic disparity (histocompatibility) between grafted organ and host.
    • 1419. Xenografts: grafts between members of different species -- most disparity and elicit the maximal immune response
    • 1420. Autografts, grafts from one part of the body to another (e.g., skin grafts), are not foreign tissue and do not elicit rejection.
    • 1421. Isografts, which are grafts between genetically identical individuals (e.g., monozygotic twins), also undergo no rejection.
    • 1422. Allografts are grafts between members of the same species that differ genetically -- most common form of transplantation.
    Immunobiology of Rejections <br />
    • Genetic incompatibility of components of tissue that are antigenic between the donor and the recipient.
    • 1423. Major histocompatibility antigens (MHC antigens)
    • 1424. Minor histocompatibility antigens (mHags);
    • 1425. Tissue specific antigens (non MHC).
    Major Histocompatibility Antigens <br />
    • Strongest antigens expressed by tissues -- act as primary antigens responsible for induction of immune response
    • 1426. MHC (or “human leukocyte antigen or HLA system) located on the short arm of chromosome 6.
    • 1427. Function is to present antigenic peptides to T cells
    • 1428. Divided into 2 classes.
    • 1429. HLA class I molecules
    • 1430. Normally expressed on all nucleated cells.
    • 1431. Responsible for presenting antigenic peptides from within the cell to CD8 T cells.
    • 1432. HLA class II molecules present extracellular antigens such as extracellular bacteria to CD4 T cells.
    • 1433. Expressed only on antigen-presenting cells (APCs) (dendritic cells, activated macrophages, and B cells)
    Minor Histocompatibility Antigens <br />
    • Cause problems of rejection less frequently than those of the major histocompatibility complex.
    • 1434. >19 autosomal and Y-chromosome-encoded minor histocompatibility antigens have been identified in humans:
    • 1435. H-Y, an antigen encoded on the Y chromosome and thus present in male, but not female, tissue
    • 1436. HA-2, an antigen derived from the contractile protein myosin.
    • 1437. Minor histocompatibility antigens cause only weaker reactions, but combinations of several can elicit strong rejection
    • 1438. mHags are presented as peptides on the cell surface primarily by MHC class I molecules.
    Tissue Specific Antigens<br />
    • Exhibit some degree of polymorphism among individuals due to variation in their primary or secondary structures.
    Mechanism of Transplant Rejection<br />
    • Antigens responsible for such rejection are primarily MHCs with a smaller contribution of mHags and tissue specific antigens.
    • 1439. Immune response consists of both cellular (lymphocyte mediated) and humoral (antibody mediated) mechanisms.
    T- cell Mediated Reactions <br />
    • Called cellular rejection and is induced by two mechanisms:
    • 1440. Destruction of graft cells by CD8+ cytotoxic lymphocytes
    • 1441. Delayed hypersensitivity reactions triggered by activated CD4+ helper cells.
    • 1442. Recipient T cells recognize antigens in the graft (alloantigens) by two pathways:
    • 1443. Direct pathway.
    • 1444. T cells of transplant recipient recognize donor MHC molecules on the surface of APCs in the graft
    • 1445. Both the CD4+ and the CD8+ T cells are involved in this reaction.
    • 1446. CD8+ T cells recognize class I MHC molecules and differentiate into active cytotoxic T cells
    • 1447. CD4+ helper T cells recognize allogeneic class II molecules, proliferate/differentiate into TH1 cells.
    • 1448. Major pathway in acute cellular rejection
    • 1449. Indirect pathway.
    • 1450. Recipient T lymphocytes recognize MHC antigens of graft after they are presented by recipient's own APCs.
    • 1451. Generates CD4+ T cells >> result is a delayed hypersensitivity type of reaction.
    • 1452. Important in chronic rejection.
    Antibody-Mediated Reactions <br />
    • Antibodies produced against alloantigens in graft are important mediators of rejection -- humoral rejection
    • 1453. Recipients are previously sensitized to transplantation antigens.
    • 1454. Preformed antidonor antibodies are present in circulation of recipient before transplantation >> hyperacute rejection
    • 1455. Occurs due to previously rejected transplant, pregnancy , and Prior blood transfusions
    • 1456. Complement fixation occurs, resulting in endothelial cell death, thrombosis of vessels in graft and ischemic death
    • 1457. Recipients are not previously sensitized to transplantation antigens.
    • 1458. Exposure to the class I and class II HLA antigens of the donor graft may evoke antibodies.
    • 1459. Initial target of these antibodies in rejection seems to be the graft vasculature >> rejection vasculitis.
    Host-Versus-Graft Reaction<br />
    • Donor-derived MHCs, mHags and tissue specific antigens are recognized as foreign by the recipient.
    • 1460. Hyperacute rejection.
    • 1461. Occurs within minutes of transplantation due to antibodies in organ recipient’s blood stream that react with new organ
    • 1462. Results in organ failure within the first hours after transplantation.
    • 1463. Acute rejection: Occurs in first 6 months after transplantation. T-cells are blamed for causing acute rejection.
    • 1464. Chronic rejection.
    • 1465. Caused by multiple factors: antibodies as well as lymphocytes.
    • 1466. Definitive diagnosis is made by biopsy of the organ in question.
    • 1467. Chronic rejection in heart grafts is manifested by accelerated graft arteriosclerosis.
    • 1468. Kidneys with chronic rejection have fibrosis (scarring) and damage to the microcirculation
    • 1469. Livers with chronic rejection have decreased number of bile ducts -- ‘vanishing bile duct syndrome’
    • 1470. Transplanted lungs with chronic rejection -- ‘bronchiolitis obliterans’: scarring leads to narrowing of bronchi
    Graft-Versus-Host Reactions<br />
    • Common complication of allogeneic hematopoietic stem cell transplantation
    • 1471. Dependent on transfer of a high “innoculum” of donor lymphocytes through lymphoid tissue within organ being transplanted.
    • 1472. Principal targets are skin, liver, gut and lymphoid tissues.
    • 1473. Immunodeficiency is a frequent risk factor for graft-versus-host disease -- result of prior treatment
    • 1474. Acute graft-versus-host disease.
    • 1475. Occurs within days to weeks after allogeneic bone marrow transplantation.
    • 1476. Clinical manifestations: skin rash, jaundice, and mucosal ulceration of the intestines resulting in bloody diarrhea.
    • 1477. Infections, especially cytomegalovirus-induced pneumonitis can be a fatal complication.
    • 1478. Chronic graft-versus-host disease.
    • 1479. Cutaneous injury resembling systemic sclerosis (scleroderma), with fibrosis of dermis and destruction of skin
    • 1480. Chronic liver disease manifested by cholestatic jaundice is frequents.
    • 1481. Damage to the gastrointestinal mucosa may cause esophageal strictures.
    • 1482. Thymus involutes and lymphocytes are depleted in lymph nodes.
    • 1483. Patients experience recurrent life-threatening infections. 
    Clinical Stages of Rejection<br />Hyperacute Rejection<br />
    • Occurs within minutes or hours after transplantation because vascularization is rapidly destroyed.
    • 1484. Gross signs of rejection: Recognized by surgeon just after graft vasculature is anastomosed to recipient’s.
    • 1485. Pathogenesis.
    • 1486. Humorally mediated and occurs because recipient has preexisting anti-HLA antibodies against graft
    • 1487. Induced by prior blood transfusions, multiple pregnancies, or prior transplantation.
    • 1488. ABO antibodies also may be involved in antibody-mediated hyperacute rejection.
    • 1489. Mechanism is an antibody-antigen reaction at the level of vascular endothelium.
    • 1490. Antigen-antibody complexes activate complement system
    • 1491. Immunoglobulins and complement deposited in vessels wall >> endothelial injury with fibrin-platelet thrombi.
    • 1492. Thrombosis develops in microcirculation, which prevents the vascularization of the graft >> fibrinoid necrosis
    • 1493. Most susceptible organs.
    • 1494. Kidney is most susceptible to hyperacute rejection -- undergoes necrosis (infarction) and have to be removed.
    • 1495. Liver is relatively resistant, possibly because of its dual blood supply
    Acute Rejection<br />
    • Manifests commonly in the first 6 months after transplantation.
    • 1496. Antibody-mediated acute rejection.
    • 1497. Derives from underlying anti-donor antibody that is formed de novo following implantation of graft.
    • 1498. Antibody is either class IgM or IgG and binds specifically to allopeptides present in the graft.
    • 1499. Activation of complement cascade releasing factors that can attract and activate T cells and macrophages.
    • 1500. Process results in necrotizing vasculitis associated with extensive necrosis of the graft parenchyma.
    • 1501. Cell-mediated acute rejection.
    • 1502. Most common form of rejection.
    • 1503. Accumulation of chronic inflammatory cells (such as T lymphocytes and macrophages) within the interstitial spaces.
    • 1504. Lymphocytes are both CD4+ cells and CD8+ cells -- cause injury to parenchymal and vascular structures.
    • 1505. T cells cause injury and apoptosis to graft cells via perforin/granzyme molecules >> cause lysis of cells.
    Chronic Rejection<br />
    • Appears as fibrosis and scarring in all transplanted organs
    • 1506. In heart transplants, chronic rejection manifests as accelerated coronary artery arteriosclerosis.
    • 1507. Lesion is diffusely distributed, has minimal lipid deposition, and has concentric lamination due to intimal hyperplasia.
    • 1508. Result in luminal narrowing, obliteration, ischemia, interstitial fibrosis, shrinkage of organ, atrophy of parenchyma.
    • 1509. There are numerous plasma cells in the interstitium, eosinophils.
    • 1510. In transplanted lungs, it manifests as bronchiolitis obliterans.
    • 1511. In liver transplants, chronic rejection is characterized by the vanishing bile duct syndrome.
    • 1512. In kidney recipients, chronic rejection manifests as fibrosis and glomerulopathy.
    • 1513. Pathogenesis: Ongoing vascular reaction of mainly humoral type, which results in endothelial damage
    Cardiac Transplantation <br />
    • Reserved for patients with end-stage CHF with ejection fraction < 20% and prognosis of < 1 year to live without transplant.
    • 1514. Patients undergo cardiac transplantation or the following heart diseases:
    • 1515. Dilated cardiomyopathy
    • 1516. Chronic coronary artery disease
    • 1517. Valvular heart disease
    • 1518. Congenital heart disease
    Surgical Technique<br />
    • Ventricles are excised, leaving right atrium, left atrium and great vessels of recipient.
    • 1519. Donor left and right atria are anastomosed to the recipient atrioventricular groove.
    • 1520. Immunosuppression is started soon after surgery.
    • 1521. After transplant endomyocardial biopsies are performed to assess for allograft rejection.
    Hyperacute Rejection<br />
    • Occurs within minutes to hours after blood flow is restored to allograft and results in extremely rapid destruction of allograft.
    • 1522. Pathogenesis.
    • 1523. Due to preformed antibodies to HLA or ABO antigens.
    • 1524. Antibody-mediated complement activation leading to destruction of endothelial cells
    • 1525. Secondary hemorrhage, thrombosis and necrosis of the allograft.
    • 1526. Gross signs of rejection: The cardiac allograft looks hemorrhagic with minimal contractility shortly after being reperfused.
    Acute Rejection<br />
    • Acute cellular rejection.
    • 1527. Incidence
    • 1528. Two to three episodes of acute cellular rejection in the first year after transplantation
    • 1529. Most likely to occur in the first three to six months
    • 1530. Pathogenesis: Mediated by host cytotoxic and helper T cells targeting donor graft antigens.
    • 1531. Morphology
    • 1532. Interstitial inflammatory infiltrate (T lymphocytes and macrophages) and myocyte damage.
    • 1533. Often asymptomatic and are diagnosed by surveillance endomyocardial biopsy.
    • 1534. Symptoms, when present, are vague and nonspecific, and include low grade fever, myalgia and flu-like symptoms.
    • 1535. LV dysfunction >> orthopnea, dyspnea, paroxysmal nocturnal dyspnea, palpitations of syncope.
    • 1536. Antibody-mediated rejection.
    • 1537. Targets the microcirculatory vessels of cardiac allograft.
    • 1538. Pathogenesis
    • 1539. Deposition of donor reactive antibodies in microvasculature of allograft and complement activation.
    • 1540. Antibodies develop de novo after transplantation, and are absent pre-transplantation.
    • 1541. Consequences: thrombosis, interstitial hemorrhage, necrosis, edema, and inflammatory cell infiltration.
    • 1542. Clinical presentation
    • 1543. Antibody-mediated rejection is seen within the first months after transplantation.
    • 1544. May be asymptomatic or manifest evidence of allograft dysfunction such as CHF, shock, or hypotension.
    • 1545. Morphology
    • 1546. Heart is swollen with intramyocardial bleeding, areas of coagulation necrosis and neutrophilic infiltration
    • 1547. Diffuse linear staining in capillaries for IgG or IgM and complement is considered diagnostic
    Cardiac Allograft Vasculopathy. <br />
    • Manifested by accelerated form of coronary arteriosclerosis affecting both intramyocardial and epicardial coronary vessels.
    • 1548. Characterized by concentric fibromuscular proliferation of the intima that progressively obliterates the coronary vasculature.
    • 1549. Incidence: Troublesome long-term complication -- major cause of death in patients surviving 1 year after transplantation.
    • 1550. Morphology.
    • 1551. Diffusely involves larger epicardial as well as the smaller intramyocardial coronary vessels.
    • 1552. Both coronary arteries and veins are involved in this process.
    • 1553. Lesions consist of uniform, concentric intimal proliferation of smooth muscle cells
    • 1554. Unlike native coronary artery atherosclerosis, lesions lack cholesterol accumulation and calcification.
    • 1555. Distal myocardium supplied by narrowed coronary arteries may exhibit changes of ischemic injury.
    • 1556. Lesion reflects changes of MI including coagulative necrosis, granulation tissue and healed scar.
    • 1557. Pathogenesis.
    • 1558. Suggested primarily an immune-mediated disease.
    • 1559. Initial event is probably coronary endothelial injury >> predispose artery to inflammation, thrombosis, vasoconstriction
    • 1560. Clinical diagnosis
    • 1561. Patients present late in the course of their disease with CHF, silent AMI, cardiac arrhythmias or sudden death.
    Lung Transplantation <br />
    • Major indications include COPD, idiopathic pulmonary fibrosis, cystic fibrosis, alpha-1-antitrypsin deficiency, etc.
    • 1562. One of the most difficult organs to transplant
    Surgical Technique<br />
    • Lung is exposed via posterolateral thoracotomy, native lung is excised. The donor lung is placed into the hemithorax
    • 1563. Surveillance bronchoscopy with biopsy at specified time intervals after transplantation.
    Hyperacute Rejection<br />
    • Rare -- associated with the presence in the recipient of antibodies directed against major HLA or ABO allograft antigens.
    • 1564. Pulmonary edema and hypoxemia develop one hour after completion of vascular anastomosis, and pink, frothy fluid is noted in
    • 1565. Grafted lung reveals acute diffuse alveolar damage.
    Acute Rejection<br />
    • Occurs during the first 3 weeks after transplantation
    • 1566. Clinical presentation: Dyspnea, fever, leukocytosis, and a widened alveolar-arterial oxygen gradient
    • 1567. Pulmonary function testing.
    • 1568. Decrease in forced expiratory volume in 1 second (FEV1), vital capacity (VC) and diffusing capacity of the lung.
    • 1569. Imaging.
    • 1570. Findings on chest radiograph are normal or nonspecific
    • 1571. New perihilar and basal reticular interstitial disease and/or consolidations 5-10 days after the transplant.
    • 1572. Findings observed on CT scans include ground-glass opacities, septal thickening, nodules, and consolidations.
    • 1573. Morphology.
    • 1574. Transbronchial biopsy usually is performed to establish the diagnosis and exclude infection.  
    • 1575. Mononuclear inflammatory infiltrates with perivascular localization, most typically affecting venules.
    • 1576. Primary inflammatory cell constituent of these infiltrates is the T lymphocyte -- mixture of CD4+ and CD8+ T cells.
    • 1577. Lymphocytes are associated with plasma cells, neutrophils and eosinophils.
    • 1578. Severe cases demonstrate extension of inflammatory cells from the perivascular zones into the alveolar septa.
    Chronic Rejection<br />
    • Characterized as bronchiolitis obliterans
    • 1579. Morphology.
    • 1580. Lymphocytic infiltration of respiratory bronchioles and deposition of collagen leading to luminal occlusion.
    • 1581. Fibrosing may cause replacement of bronchiolar smooth muscle and extention into peribronchiolar tissues.  
    • 1582. Incidence.
    • 1583. Highest after the first year following lung transplantation.
    • 1584. Most important complication that adversely affects the long-term survival of graft recipients.
    • 1585. Clinical presentation.
    • 1586. Due to airflow obstruction that progresses over time
    • 1587. Extertional dyspnea, non-productive cough, wheezing and low grade fever.
    • 1588. Symptoms resemble bronchial asthma, but the response to bronchodilator therapy is ineffective.
    • 1589. Pulmonary function studies reveal expiratory obstruction -- decrement of > 20% in FEV1 and FEV1 to FVC ratio
    • 1590. Pathogenesis.
    • 1591. Develops secondary to a fibroproliferative response, mediated by immune inflammation of bronchiolar structures