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Pathology (Pulmonary Infections (Community-Acquired Bacterial Pneumonias…

- - - - Major Fs
        genetic predisposition to type I hypersensitivity (atopy),
        acute and chronic airway infl,
        bronchial hyperresponsiveness to a variety of stimuli.
        subclassified as atopic (evidence of allergen sensitization) or nonatopic.
        In both: episodes of bronchospasm may be triggered by diverse exposures, such as respiratory infections (esp viral), airborne irritants (e.g., smoke, fumes), cold air, stress, and exercise.
        varying patterns of infl—eosinophilic (most common), neutrophilic, mixed infl, and pauci-granulocytic—that are a. w/ differing etiologies, immunopathologies, and responses to treatment.
        classic atopic form:
        excessive TH2 cell activation--> IL-4 and IL-13 (IgE production), IL-5 (activates eosinophils), and IL-13 (stimulates mucus production); IgE coats submucosal mast cells...
        Mast cell–derived mediators--> two waves of reaction:
        • early-phase reaction: dominated by bronchoconstriction, incr mucus production, and vasodilation; Bronchoconstriction triggered by mediators released from mast cells (histamine, PGD2, and LTC4, D4, and E4) and also by reflex neural pathways
        • late-phase reaction: infl in nature.
        Infl mediators--> epith cells produce chemokines (incl eotaxin, a potent chemoattractant and activator of eosinophils)--> recruitment of TH 2 cells, eosinophils, and etc--> amplifying an infl reaction that is initiated by resident immune cells.
        • Repeated bouts of infl--> structural changes in bronchial wall: airway remodeling: hypertrophy of bronchial smooth muscle and mucus glands + incr vascularity and deposition of subepith coll, which may occur as early as several yrs before initiation of symptoms.
        Asthma tends to “run” in families, but role of genetics complex.
        a number of genetic variants a.: genes enocoding factors like IL-4 R
      - Atopic Asthma:
        most common type
        classic example of type I IgE–mediated hypersensitivity reaction
        u. begins in childhood
        family hx of atopy and/or asthma common
        onset of asthmatic attacks often preceded by allergic rhinitis, urticaria, or eczema.
        triggers: allergens in dust, pollen, animal dander, or food, or by infections.
        A skin test w/ offending Ag--> positive, immediate wheal-and-flare reaction.
        also can be dx based on serum radioallergosorbent tests (RASTs) that identify presence of IgEs that recognize specific allergens.
        
        Non-Atopic Asthma
        pxs do not have evidence of allergen sensitization, and skin test results u. negative.
        family hx of asthma less common. Respiratory infections due to viruses (e.g., rhinovirus, parainfluenza virus) and inhaled air pollutants (e.g., sulfur dioxide, ozone, nitrogen dioxide) are common triggers; thought that virus-induced infl of the respiratory mucosa lowers threshold of subepith vagal Rs to irritants.
        the ultimate humoral and cellular mediators of airway obstruction (e.g., eosinophils) are common to both atopic and nonatopic variants of asthma, so they are treated in a similar way.
        
        Drug-Induced Asthma
        Several pharmacologic agents provoke asthma: aspirin: present w/ recurrent rhinitis, nasal polyps, urticaria, and bronchospasm; likely involves some abnormality in PG metabolism
        
        Occupational Asthma
        may be triggered by fumes (epoxy resins, plastics), organic and chemical dusts (wood, cotton, platinum), gases (toluene), and other chemicals. Asthma attacks usually develop after repeated exposure to the inciting antigen(s).
  - - - • Centriacinar (centrilobular):
        distinctive feature: central or proximal parts of acini affected, while distal alveoli spared--> both emphysematous and normal air spaces exist within same acinus and lobule
        lesions more common + severe in upper lobes, partic in apical segments.
        severe centriacinar emphysema: distal acinus also involved (thus, differentiation from panacinar becomes difficult)
        most common in cigarette smokers, often in a. w/ chronic bronchitis.
      - • Distal acinar (paraseptal) emphysema
        proximal portion of acinus normal but distal part primarily involved
        more striking adj to pleura, along lobular connective tissue septa, and at margins of the lobules; occurs adj to areas of fibrosis, scarring, or atelectasis + u. more severe in upper half of the lungs.
        charac finding: multiple, contiguous, enlarged air spaces ranging in diameter from < 0.5 mm to > 2.0 cm, sometimes forming cystic structures that, w/ progressive enlargement, give rise to bullae.
        cause: unknown; comes to attention most often in young adults who present w/ spontaneous pneumothorax; young tall smoking man
      - • Irregular emphysema
        accinus irregularly involved
        almost invariably a. w/ scarring, such as that resulting from healed infl diseases.
        clinically asymptomatic, may be most common form of emphysema.
      - • Panacinar (panlobular) emphysema.
        acini uniformly enlarged, from level of respiratory bronchiole to terminal blind alveoli
        In contrast to centriacinar emphysema, panacinar emphysema occurs more commonly in lower lung zones and is a. w/ α1-anti-trypsin deficiency
    - - Dyspnea u. first symptom; begins insidiously but steadily progressive.
        in pxs w/ underlying chronic bronchitis or chronic asthmatic bronchitis, cough and wheezing may be initial complaints.
        Weight loss common and may be severe enough to suggest an occult malignant tumor.
        reduced FEV1 w/ normal or near-normal FVC--> FEV1 to FVC ratio reduced.
        
        emphysema w/ no “bronchitic” component
        classic presentation: px barrel-chested and dyspneic, w/ obviously prolonged expiration, sitting forward in a hunched-over position.
        air space enlargement severe + diffusing capacity low.
        Dyspnea + hyperventilation prominent--> until very late, gas exchange adequate and blood gas values relatively normal.
        prominent dyspnea + adequate oxygenation of hemoglobin--> pxs sometimes called “pink puffers.”
        
        emphysema w/ pronounced chronic bronchitis + a hx of recurrent infections.
        Dyspnea u. less prominent, and in absence of incr respiratory drive--> px retains CO2--> hypoxic and often cyanotic.
        pxs tend to be obese--> “blue bloaters.”
        
        In most pxs w/ COPD symptoms fall in between these two extremes
        
        Hypoxia-induced pulmonary vascular spasm + loss of pulmonary capillary surface area from alveolar destruction--> gradual development of secondary pulmonary HTN--> in 20-30% of pxs leads to R-sided CHF (cor pulmonale)
        Death from emphysema is related to either respiratory or R-sided heart failure.
      - Conditions Related to Emphysema
        • Compensatory emphysema: dilation of residual alveoli in response to loss of lung substance elsewhere (ex after surgical removal of a diseased lung or lobe)
        • Obstructive overinflation: expansion of lung due to air trapping; common cause: subtotal obstruction of an airway by a tumor or foreign object; can be life-threatening if expansion of affected portion produces compression of remaining normal lung.
        • Bullous emphysema: any form of emphysema that produces large subpleural blebs or bullae (spaces >1 cm in diameter in distended state); Such blebs represent localized accentuations of one of the four forms of emphysema; most often blebs are subpleural, and on occasion they may rupture, leading to pneumothorax.
        • Mediastinal (interstitial) emphysema: caused by entry of air into interstitium of lung, from where it may track to mediastinum and sometimes the subcutaneous tissue.
        may occur spontaneously if a sudden incr in intraalveolar P (as w/ vomiting or violent coughing)--> alveolar rupture--> air into interstitium.
        Sometimes develops in children w/ whooping cough; may also occur in pxs on respirators who have partial bronchiolar obstruction or in individuals w/ a perforating injury (a fractured rib). When interstitial air gets into the subcutaneous tissue, px may literally blow up like a balloon, w/ marked swelling of head and neck and crackling crepitation over chest (subcutaneous emphysema). In most instances air resorbed spontaneously after site of entry seals.
- - - - Epidemiology
        • consistent predilection for <40 yrs
        • high incidence in Danish and Swedish and African Americans
        • A higher prevalence among nonsmokers: unique to sarcoidosis among pulmonary diseases.
      - Etiology and Pathogenesis
        disordered immune regulation + genetically predisposed + certain environmental agents.
        development of a cell-mediated response to an unidentified Ag, driven by CD4+ helper T cells.
        • Intraalveolar + interstitial accumulation of CD4+ TH 1 cells, w/ peripheral T cell cytopenia
        • Incr in TH1 cytokines (IL-2 and IFN-γ)
        • Anergy to common skin test antigens such as Candida or purified protein derivative (PPD)
        • Polyclonal hypergammaglobulinemia
        • Familial and racial clustering of cases, suggesting the involvement of genetic factors
      - multisystem disease of unknown etiology charac by noncaseating granulomatous infl
        Other diseases (mycobacterial or fungal infections and berylliosis) sometimes also produce noncaseating granulomas--> histologic dx of sarcoidosis: exclusion
        bilateral hilar lymphadenopathy or lung involvement (or both), visible on CXR: major finding at presentation in most cases
      - Clinical Features
        In many asymptomatic,
        In most symptomatic cases: gradual appearance of respiratory symptoms (dyspnea, dry cough,..) or constitutional signs and symptoms (fever, fatigue, weight loss, anorexia, night sweats)
        A definitive diagnostic test does not exist: presence of clinical and radiologic findings, exclusion of other disorders esp TB, noncaseating granulomas in tissues.
        follows an unpredictable course charac by either progressive chronicity or periods of activity interspersed w/ remissions.
        remissions may be spontaneous or initiated by steroid therapy and often permanent
        After lung transplantation, sarcoidosis recurs in new
        lungs in at least one-third of patients
  - - - most prevalent chronic occupational disease in world.
        inhalation of crystalline silica, mostly in occupational (sandblasting and hard-rock mining at partic high risk)
        forms:
        
        amorphous
        
        crystalline: quartz (most commonly implicated in silicosis), cristobalite, and tridymite; by far most toxic and fibrogenic.
        
        particles interact w/ epith cells + MQs--> activation of inflammasome--> release of infl mediators by pulmonary MQs (IL-1, TNF, fibronectin, lipid mediators, oxygen-derived free radicals, and fibrogenic cytokines)
        mixed w/ other minerals--> fibrogenic effect of quartz reduced
        ex: iron-containing ore hematite
      - MORPHOLOGY
        Silicotic nodules in early stages: tiny, barely palpable, discrete, pale-to-black (if coal dust present) nodules in upper zones of lungs
        Microscopic:
        first find silicotic nodules: concentrically arranged hyalinized coll fibers surrounding an amorphous center (“whorled” appearance, distinctive for silicosis) as opposed to carbon which fibrosis is behamrikhte:/
        then using polarized microscopy: weakly birefringent silica particles, primarily in center of nodules.
        disease progresses--> individual nodules may coalesce into hard, coll scars--> eventual progression to PMF.
        intervening lung parenchyma may be compressed or overexpanded, and a honeycomb pattern may develop.
        Fibrotic lesions also may occur in hilar lymph nodes + pleura (bc of MQ migration)
      - Clinical Features
        Silicosis u. detected in asymptomatic workers on routine chest radiographs: fine nodularity in upper zones of lung.
        Most do not develop shortness of breath until late in course, after PMF present.
        Many w/ PMF--> chronic hypoxia–induced vasoconstriction and parenchymal destruction--> pulmonary HTN and cor pulmonale
        disease slowly progressive, often impairing pulmonary function--> physical activity severely limited
        a. w/ an incr susceptibility to tuberculosis (quartz crystals--> MQ lysosomal dysfunction)
        depresses cell-mediated immunity, and crystalline silica may inhibit ability of pulmonary MQs to kill phagocytosed mycobacteria.
        Nodules of silicotuberculosis often contain a central zone of caseation.
        relationship betw silica and lung cancer: most studies suggest that silica exposure is a. w/ some incr in risk.
        bc of widespread fibrosis--> susceptible to tumors (adenocarcinoma and mesothelioma)
    - - Pathogenesis
        phagocytosed by MQs--> activate inflammasome + damage phagolysosomal membranes--> release of proinfl factors and fibrogenic mediators.
        also functions as both a tumor initiator and a promoter.
        Some oncogenic effects on mesothelium mediated by reactive free radicals generated by asbestos fibers, which preferentially localize in distal lung close to mesothelial layer.
        potentially toxic chemicals adsorbed onto asbestos fibers also undoubtedly contribute to pathogenicity of fibers.
        ex: adsorption of carcinogens in tobacco smoke onto asbestos fibers may be basis for remarkable synergy betw tobacco smoking + development of lung carcinoma in asbestos workers.
      - Asbestos: a family of crystalline hydrated silicates w/ a fibrous geometry.
        occupational exposure linked to (from highest frequency to lowest)
        (1) parenchymal interstitial fibrosis (asbestosis);
        (2) localized fibrous plaques, or, rarely, diffuse fibrosis in pleura;
        (3) pleural effusions;
        (4) lung carcinoma;
        (5) malignant pleural and peritoneal mesothelioma; and
        (6) laryngeal carcinoma.
        incr incidence of asbestos-related cancers in family members of asbestos workers
      - MORPHOLOGY
        diffuse pulmonary interstitial fibrosis,
        charac by asbestos bodies (seen as golden brown, fusiform or beaded rods w/ a translucent center): asbestos fibers coated w/ an iron-containing proteinaceous material; formed when MQs attempt to phagocytose asbestos fibers; iron “crust” derived from phagocyte ferritin.
        In contrast w/ CWP + silicosis, asbestosis begins in lower lobes and subpleurally, spreading to middle and upper lobes of lungs as fibrosis progresses.
        Contraction of fibrous tissue--> enlarged air spaces enclosed within thick fibrous walls; eventually, affected regions become honeycombed.
        Simultaneously, fibrosis develops in visceral pleura--> adhesions betw lungs + chest wall; scarring may trap and narrow pulmonary arteries and arterioles--> pulmonary HTN + cor pulmonale.
        Pleural plaques: most common manifestation of asbestos exposure; well-circumscribed plaques of dense coll, often containing Ca; develop most frequently on ant + postlat aspects of parietal pleura + over domes of diaphragm
        Uncommonly, asbestos exposure induces pleural effusion or diffuse pleural fibrosis
      - Clinical Features
        indistinguishable from those of any other chronic interstitial lung disease; Progressively worsening dyspnea appears 10 to 20 yrs after exposure: u. accompanied by a cough and production of sputum.
        disease may remain static or progress to CHF, cor pulmonale, and death.
        Pleural plaques u. asymptomatic + detected on radiographs as circumscribed densities.
        Both lung carcinoma + malignant mesothelioma develop in workers; risk for developing lung carcinoma incr about 5x for asbestos workers; relative risk for mesothelioma (a very rare tumor) >1000x
        Concomitant cigarette smoking greatly incr risk for lung carcinoma BUT NOT for mesothelioma
        Lung or pleural cancer a. w/ asbestos exposure: partic poor prognosis
    - - diseases induced by organic and inorganic particulates, and some also regard chemical fume- and vapor-induced lung diseases as pneumoconioses.
        mineral dust pneumoconioses—three most common: coal dust, silica, and asbestos—u. stem from exposure in workplace. Asbestos: exception: incr risk for cancer extends to family members of workers + to individuals exposed outside of workplace.
      - Pathogenesis
        
        reaction of the lung to mineral dusts depends on many variables, including the size, shape, solubility, and reactivity of the particles.
        
        particles
        .> 5 to 10 µm: unlikely to reach distal airways
        < 0.5 µm move into and out of alveoli, often w/o substantial deposition and injury.
        1 to 5 µm: most dangerous: get lodged at bifurcation of distal airways.
        Coal dust relatively inert--> large amounts deposited before lung disease clinically detectable.
        Silica, asbestos, and beryllium more reactive--> fibrotic reactions at lower [ ]s
        some inhaled dust become impacted at alveolar duct bifurcations, where MQs accumulate and engulf trapped particulates.
        pulmonary alveolar MQ: key cellular element in initiation and perpetuation of infl, lung injury and fibrosis.
        many activate inflammasome + induce production of IL-1 as well as release of other factors--> infl response--> fibroblast prolif + coll deposition.
        Some inhaled particles may reach lymphatics (direct drainage or within migrating MQs)--> immune response to components of particulates and/ or to self-prs modified by particles--> an amplification and extension of local reaction.
        Tobacco smoking worsens effects of all inhaled mineral dusts, more so with asbestos than other particles.
        
        Coal Worker’s Pneumoconiosis
        spectrum:
        asymptomatic anthracosis: pigment deposits w/o a perceptible cellular reaction;
        simple coal worker’s pneumoconiosis (CWP): MQs accumulate w/ little to no pulmonary dysfunction;
        complicated CWP or progressive massive fibrosis (PMF): fibrosis extensive and lung function compromised
        < 10% of simple CWP progress to PMF.
        PMF can be a complication of any of the pneumoconioses discussed here.
        coal mainly carbon, coal mine dust contains a variety of trace metals, inorganic minerals, and crystalline silica.
        ratio of carbon to contaminating chemicals and minerals (“coal rank”) incr from bituminous to anthracite coal; in general, anthracite mining has been a. w/ a higher risk for CWP.
      - MORPHOLOGY
        Pulmonary anthracosis: most innocuous coal-induced pulmonary lesion in coal miners and also commonly seen in urban dwellers and tobacco smokers.
        Inhaled carbon pigment engulfed by alveolar or interstitial MQs--> accumulate in connective tissue along pulmonary and pleural lymphatics and in draining lymph nodes.
        Simple CWP: charac by presence of coal macules and larger coal nodules.
        coal macule: dust-laden MQs + small amounts of coll fibers arrayed in a delicate network; lesions scattered throughout lung, upper lobes and upper zones of lower lobes are more heavily involved.
        centrilobular emphysema may occur.
        Complicated CWP (PMF) occurs on a background of simple CWP by coalescence of coal nodules and generally develops over many yrs.
        charac by multiple, dark black scars > 2 cm and sometimes up to 10 cm in greatest diameter that consist of dense coll and pigment
      - Clinical Features
        CWP u. a benign disease that produces little decrement in lung function.
        PMF--> decr vascular compliance: incr pulmonary dysfunction, pulmonary HTN, and cor pulmonale.
        Progression from CWP to PMF has been linked to a variety of variables including higher coal dust exposure levels and total dust burden.
        Unfortunately, once established PMF has a tendency to progress even in absence of further exposure.
        no incr frequency of lung carcinoma in coal miners (as opposed to silica and asbestos exposure)
    - - : a pulmonary disorder of unknown etiology charac by patchy, progressive bilateral interstitial fibrosis (also known as cryptogenic fibrosing alveolitis)
        Males>females affected, and it is a disease of aging (never < 50 yrs)
        radiologic and histologic pattern of fibrosis: usual interstitial pneumonia (UIP) (required for dx; similar pathologic changes in lung may be present in entities such as asbestosis, collagen vascular diseases, etc--> dx of exclusion)
      - Pathogenesis
        repeated injury (cause obscure) + defective repair of alveolar epith, often in a genetically predisposed--> interstitial fibrosis
        genetic:
        
        Germ line mutations--> loss of telomerase--> incr risk; --> cellular senescence contributes to profibrotic phenotype
        
        35% (50?) of affected: genetic variant in MUC5B gene (mucin production)
        
        a smaller number of affected: germ line mutations in surfactant genes
        
        These genes only expressed in lung epith cells--> epith cell abnorms primary initiators of IPF
        hypothesized: abnormal epith repair at sites of chronic injury + infl--> exuberant fibroblastic or myofibroblastic prolif--> charac fibroblastic foci; mechanisms of fibrosis: excessive activation of profibrotic factors such as TGF-β.
      - MORPHOLOGY
        Gross:
        pleural surfaces of lung cobblestoned (bc of retraction of scars along interlobular septa)
        cut surface: firm, rubbery white areas of fibrosis, which occurs preferentially within lower lobe, subpleural regions, and along interlobular septa.
        Histologic:
        hallmark: patchy interstitial fibrosis, worsens with time.
        earliest lesions: exuberant fibroblastic prolif (fibroblastic foci)
        Over time: become more collagenous and less cellular.
        Quite typical: existence of both early + late lesions (temporal heterogenity)
        dense fibrosis--> collapse of alveolar walls and formation of cystic spaces lined by hyperplastic type II pneumocytes or bronchiolar epith (honeycomb fibrosis).
        interstitial infl u. patchy and consists of an alveolar septal infiltrate of mostly lymphocytes and occasional plasma cells, mast cells, and eosinophils.
        Secondary pulmonary hypertensive changes (intimal fibrosis and medial thickening of pulmonary arteries) often present.
      - Clinical Features
        u. presents w/ gradual onset of a nonproductive cough and progressive dyspnea.
        P/E: most have characteristic “dry” or “Velcrolike” crackles during inspiration.
        Cyanosis, cor pulmonale, and peripheral edema may develop in later stages
        characteristic clinical and radiologic findings (subpleural and basilar fibrosis, reticular abnormalities, and “honeycombing”) often diagnostic.
        Antiinfl therapies: little use, infl of secondary pathogenic importance.
        anti-fibrotic therapies (nintedanib, a tyrosine kinase inhibitor, and pirfenidone, an inhibitor of TGF-β): approved for use
        overall prognosis: poor; survival is only 3-5 yrs, and lung transplantation only definitive treatment.
- - - - • In 5%: death, acute right-sided heart failure, or cardiovascular collapse (shock) occurs suddenly.
        Massive pulmonary embolism: virtually instantaneous death.
        typically happen when >60% of total pulmonary vasculature obstructed
      - • Obstruction of small to medium pulmonary branches (10% to 15% of cases): pulmonary infarction
      - • <3%: recurrent “showers” of emboli--> pulmonary HTN, chronic right-sided heart failure
      - • Most (60% to 80%): clinically silent; bronchial circulation sustains viability of affected lung parenchyma