Pathology_Robbins

Pathology_Robbins. Asthma is a chronic inflammatory disorder of the airways that causes recurrent episodes of wheezing, breathlessness, chest tightness, and cough, particularly at night and/or early in the morning. The hallmarks of asthma are intermittent, reversible airway obstruction; chronic bronchial inflammation with eosinophils; bronchial smooth muscle cell hypertrophy and hyperreactivity; and increased mucus secretion. Sometimes trivial stimuli are sufficient to trigger attacks in patients, because of airway hyper-reactivity. Many cells play a role in the inflammatory response, in particular eosinophils, mast cells, macrophages, lymphocytes, neutrophils, and epithelial cells. Of note, asthma has increased in incidence significantly in the Western world over the past 4 decades. One explanation for this troubling trend is the hygiene hypothesis, according to which a lack of exposure to infectious organisms (and possibly nonpathogenic microorganisms as well) in early childhood results in defects in


Pathology_Robbins

Pathology_Robbins. troubling trend is the hygiene hypothesis, according to which a lack of exposure to infectious organisms (and possibly nonpathogenic microorganisms as well) in early childhood results in defects in immune tolerance and subsequent hyperreactivity to immune stimuli later in life.


Pathology_Robbins

Pathology_Robbins. Major factors contributing to the development of asthma include genetic predisposition to type I hypersensitivity (atopy), acute and chronic airway inflammation, and bronchial hyperresponsiveness to a variety of stimuli. Asthma may be subclassified as atopic (evidence of allergen sensitization) or nonatopic. In both types, episodes of bronchospasm may be triggered by diverse exposures, such as respiratory infections (especially viral), airborne irritants (e.g., smoke, fumes), cold air, stress, and exercise. There also are varying patterns of inflammation—eosinophilic (most common), neutrophilic, mixed inflammatory, and pauci-granulocytic—that are associated with differing etiologies, immunopathologies, and responses to treatment.


Pathology_Robbins

Pathology_Robbins. The classic atopic form is associated with excessive type 2 helper T (TH2) cell activation. Cytokines produced by TH2 cells account for most of the features of atopic asthma— IL-4 and IL-13 stimulate IgE production, IL-5 activates eosinophils, and IL-13 also stimulates mucus production. IgE coats submucosal mast cells, which on exposure to allergen release their granule contents and secrete cytokines and other mediators. Mast cell–derived mediators produce two waves of reaction: an early (immediate) phase and a late phase ( Fig. 13.10 The early-phase reaction is dominated by bronchoconstriction, increased mucus production, and vasodilation. Bronchoconstriction is triggered by mediators released from mast cells, including histamine, prostaglandin D2, and leukotrienes LTC4, D4, and E4, and also by reflex neural pathways.


Pathology_Robbins

Pathology_Robbins. The late-phase reaction is inflammatory in nature. Inflammatory mediators stimulate epithelial cells to produce chemokines (including eotaxin, a potent chemoattractant and activator of eosinophils) that promote the recruitment of TH2 cells, eosinophils, and other leukocytes, thus amplifying an inflammatory reaction that is initiated by resident immune cells. • Repeated bouts of inflammation lead to structural changes in the bronchial wall that are collectively referred to as airway remodeling. These changes include hypertrophy of bronchial smooth muscle and mucus glands and increased vascularity and deposition of sub-epithelial collagen, which may occur as early as several years before initiation of symptoms.


Pathology_Robbins

Pathology_Robbins. Asthma tends to “run” in families, but the role of genetics in asthma is complex. Genome-wide association studies have identified a number of genetic variants associated with asthma risk, some in genes enocding factors like the IL-4 receptor that are clearly involved in asthma pathogenesis. However, the precise contribution of asthma-associated genetic variants to the development of disease remains to be determined.


Pathology_Robbins

Pathology_Robbins. This is the most common type of asthma and is a classic example of type I IgE–mediated hypersensitivity reaction (Chapter 5). It usually begins in childhood. A positive family history of atopy and/or asthma is common, and the onset of asthmatic attacks is often preceded by allergic rhinitis, urticaria, or eczema. Attacks may be triggered by allergens in dust, pollen, animal dander, or food, or by infections. A skin test with the offending antigen results in an immediate wheal-and-flare reaction. Atopic asthma also can be diagnosed based on serum radioallergosorbent tests (RASTs) that identify the presence of IgEs that recognize specific allergens.


Pathology_Robbins

Pathology_Robbins. Patients with nonatopic forms of asthma do not have evidence of allergen sensitization, and skin test results usually are negative. A positive family history of asthma is less common. Respiratory infections due to viruses (e.g., rhino-virus, parainfluenza virus) and inhaled air pollutants (e.g., sulfur dioxide, ozone, nitrogen dioxide) are common triggers. It is thought that virus-induced inflammation of the respiratory mucosa lowers the threshold of the subepithelial vagal receptors to irritants. Although the connections are not well understood, the ultimate humoral and cellular mediators of airway obstruction (e.g., eosinophils) are common to both atopic and nonatopic variants of asthma, so they are treated in a similar way.


Pathology_Robbins

Pathology_Robbins. Several pharmacologic agents provoke asthma, aspirin being the most striking example. Patients with aspirin sensitivity present with recurrent rhinitis, nasal polyps, urticaria, and bronchospasm. The precise pathogenesis is unknown but is likely to involve some abnormality in prostaglandin metabolism stemming from inhibition of cyclooxygenase by aspirin. Occupational asthma may be triggered by fumes (epoxy resins, plastics), organic and chemical dusts (wood, cotton, platinum), gases (toluene), and other chemicals. Asthma attacks usually develop after repeated exposure to the inciting antigen(s). http://ebooksmedicine.net Release of granules and mediators


Pathology_Robbins

Pathology_Robbins. Fig.13.10 (AandB)Comparisonofanormalairwayandanairwayinvolvedbyasthma.Theasthmaticairwayismarkedbyaccumulationofmucusinthe bronchiallumensecondarytoanincreaseinthenumberofmucus-secretinggobletcellsinthemucosaandhypertrophyofsubmucosalglands;intensechronic inflammationduetorecruitmentofeosinophils,macrophages,andotherinflammatorycells;thickenedbasementmembrane;andhypertrophyandhyperplasia ofsmoothmusclecells.(C)Inhaledallergens(antigen)elicitaTH2-dominatedresponsefavoringIgEproductionandeosinophilrecruitment.(D)Onreexposure toantigen(Ag),theimmediatereactionistriggeredbyAg-inducedcross-linkingofIgEboundtoFcreceptorsonmastcells.Thesecellsreleasepreformed mediatorsthatdirectlyandvianeuronalreflexesinducebronchospasm,increasedvascularpermeability,mucusproduction,andrecruitmentofleukocytes. (E) Leukocytes recruited to the site of reaction (neutrophils, eosinophils, and basophils; lymphocytes and monocytes) release additional mediators that initiatethelatephaseofasthma.Severalfactorsrelease


Pathology_Robbins

Pathology_Robbins. ) Leukocytes recruited to the site of reaction (neutrophils, eosinophils, and basophils; lymphocytes and monocytes) release additional mediators that initiatethelatephaseofasthma.Severalfactorsreleasedfromeosinophils(e.g.,majorbasicprotein,eosinophilcationicprotein)alsocausedamagetothe epithelium.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. An attack of asthma is characterized by severe dyspnea and wheezing due to bronchoconstriction and mucus plugging, which leads to trapping of air in distal airspaces and progressive hyperinflation of the lungs. In the usual case, attacks last from 1 to several hours and subside either spontaneously or with therapy. Intervals between attacks are characteristically free from overt respiratory difficulties, but persistent, subtle deficits can be detected by pulmonary function tests. Occasionally a severe paroxysm occurs that does not respond to therapy and persists for days and even weeks (status asthmaticus). The associated hypercapnia, acidosis, and severe hypoxia may be fatal, although in most cases the condition is more disabling than lethal. Standard therapies include anti-inflammatory drugs, particularly glucocorticoids, and bronchodilators such as beta-adrenergic drugs and leukotriene inhibitors (recall that leukotrienes are potent bronchoconstrictors). Agents that block specific


Pathology_Robbins

Pathology_Robbins. drugs, particularly glucocorticoids, and bronchodilators such as beta-adrenergic drugs and leukotriene inhibitors (recall that leukotrienes are potent bronchoconstrictors). Agents that block specific immune mediators, such as IL-4 and IL-5, are of modest benefit in some patients but are not broadly efficacious, perhaps because of disease heterogeneity. Another approach called bronchial thermoplasty, which involves controlled delivery of thermal energy during bronchoscopy to reduce the mass of smooth muscle and airway responsiveness, is being evaluated in patients with severe, poorly controlled asthma.


Pathology_Robbins

Pathology_Robbins. Airwayremodeling(sub-basementmembranethickeningandhypertrophyofbronchialglandsandsmoothmuscle)addsanirreversiblecomponenttotheobstructivedisease. Bronchiectasis is the permanent dilation of bronchi and bronchioles caused by destruction of smooth muscle and the supporting elastic tissue; it typically results from or is associated with chronic necrotizing infections. It is not a primary disorder, as it always occurs secondary to persistent infection or obstruction caused by a variety of conditions. Bronchiectasis gives rise to a characteristic symptom complex dominated by cough and expectoration of copious amounts of purulent sputum. Diagnosis depends on an appropriate history and radiographic demonstration of bronchial dilation. The conditions that most commonly predispose to bronchiectasis include:


Pathology_Robbins

Pathology_Robbins. Bronchial obstruction. Common causes are tumors, foreign bodies, and impaction of mucus. In these conditions, bronchiectasis is localized to the obstructed lung segment. Bronchiectasis also may complicate atopic asthma and chronic bronchitis. Congenital or hereditary conditions—for example: Cystic fibrosis, in which widespread severe bronchiectasis results from obstruction caused by abnormally viscid mucus and secondary infections (Chapter 7). Immunodeficiency states, particularly immunoglobulin deficiencies, in which localized or diffuse bronchiectasis often develops because of recurrent bacterial infections. http://ebooksmedicine.net Primary ciliary dyskinesia (also called the immotile cilia syndrome). This is a rare autosomal recessive disorder that is frequently associated with bronchiectasis and with sterility in males. It is caused by inherited abnormalities of cilia that impair mucociliary clearance of the airways, leading to persistent infections.


Pathology_Robbins

Pathology_Robbins. Necrotizing, or suppurative, pneumonia, particularly with virulent organisms such as Staphylococcus aureus or Klebsiella spp., predispose affected patients to development of bronchiectasis. Posttuberculosis bronchiectasis continues to be a significant cause of morbidity in endemic areas. Two intertwined processes contribute to bronchiectasis: obstruction and chronic infection. Either may be the initiator. For example, obstruction caused by a foreign body impairs clearance of secretions, providing a favorable substrate for superimposed infection. The resultant inflammatory damage to the bronchial wall and the accumulating exudate further distend the airways, leading to irreversible dilation. Conversely, a persistent necrotizing infection in the bronchi or bronchioles may lead to poor clearance of secretions, obstruction, and inflammation with peribronchial fibrosis and traction on the bronchi, culminating again in full-blown bronchiectasis.


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYBronchiectasisusuallyaffectsthelowerlobesbilaterally,particularlythoseairpassagesthataremostvertical.Whencausedbytumorsoraspirationofforeignbodies,theinvolvementmaybesharplylocalizedtoasinglesegmentofthelungs.Usually,themostsevereinvolvementisfoundinthemoredistalbronchiandbronchioles.The airways may be dilated to as much as four times their usual diameter andcanbeseenongrossexaminationalmostouttothepleuralsurface( Fig.13.12 ).Bycontrast,innormallungs,thebronchiolescannotbefollowedbyeyebeyondapoint2to3cmfromthepleura.


Pathology_Robbins

Pathology_Robbins. Bronchiectasis is characterized by severe, persistent cough associated with expectoration of mucopurulent, sometimes fetid, sputum. Other common symptoms Fig. 13.12 Bronchiectasisinapatientwithcysticfibrosiswhounderwentlungresectionfortransplantation.Cutsurfaceoflungshowsmarkedlydilatedbronchifilledwithpurulentmucusthatextendtosubpleuralregions. include dyspnea, rhinosinusitis, and hemoptysis. Symptoms often are episodic and are precipitated by upper-respiratory tract infections or the introduction of new pathogenic agents. Severe, widespread bronchiectasis may lead to significant obstructive ventilatory defects, with hypoxemia, hypercapnia, pulmonary hypertension, and cor pulmonale. However, with current treatment outcomes have improved and severe complications of bronchiectasis, such as brain abscess, amyloidosis (Chapter 5), and cor pulmonale, occur less frequently now than in the past. CHRONICINTERSTITIAL(RESTRICTIVE,INFILTRATIVE)LUNGDISEASES


Pathology_Robbins

Pathology_Robbins. CHRONICINTERSTITIAL(RESTRICTIVE,INFILTRATIVE)LUNGDISEASES Chronic interstitial diseases are a heterogeneous group of disorders characterized by bilateral, often patchy, pulmonary fibrosis mainly affecting the walls of the alveoli (see Fig. 13.1 ). Many of the entities in this group are of unknown cause and pathogenesis; some have an intraalveolar and an interstitial component. Chronic interstitial lung diseases are categorized based on clinicopathologic features and characteristic histology ( Table 13.2 ). However, it must be acknowledged that there is frequent overlap in histologic features among the different conditions. The shared histologic features and the similarity in clinical signs, symptoms, radiographic alterations, and pathophysiologic changes justify their consideration as a http://ebooksmedicine.net Table 13.2 Major Categories of Chronic Interstitial Lung Disease


Pathology_Robbins

Pathology_Robbins. Table 13.2 Major Categories of Chronic Interstitial Lung Disease Usualinterstitialpneumonia(idiopathicpulmonaryfibrosis)NonspecificinterstitialpneumoniaCryptogenicorganizingpneumoniaCollagenvasculardisease-associatedPneumoconiosisTherapy-associated(drugs,radiation) group. The hallmark of these disorders is reduced compliance (stiff lungs), which in turn necessitates increased effort to breathe (dyspnea). Furthermore, damage to the alveolar epithelium and interstitial vasculature produces abnormalities in the ventilation–perfusion ratio, leading to hypoxia. Chest radiographs show small nodules, irregular lines, or “ground-glass shadows.” With progression, patients may develop respiratory failure, pulmonary hypertension, and cor pulmonale (Chapter 11). When advanced, the etiology of the underlying diseases may be difficult to determine because they all result in diffuse scarring and gross destruction of the lung, referred to as end-stage or “honeycomb” lung.


Pathology_Robbins

Pathology_Robbins. Idiopathic pulmonary fibrosis (IPF) refers to a pulmonary disorder of unknown etiology that is characterized by patchy, progressive bilateral interstitial fibrosis. Because its etiology is unknown, it is also known as cryptogenic fibrosing alveolitis. Males are affected more often than females, and it is a disease of aging, virtually never occurring before 50 years of age. The radiologic and histologic pattern of fibrosis is referred to as usual interstitial pneumonia (UIP), which is required for the diagnosis of IPF. Of note, similar pathologic changes in the lung may be present in entities such as asbestosis, collagen vascular diseases, and other conditions. Therefore, IPF is a diagnosis of exclusion. The interstitial fibrosis that characterizes IPF is believed to result from repeated injury and defective repair of alveolar epithelium, often in a genetically predisposed individual (


Pathology_Robbins

Pathology_Robbins. Fig. 13.13 ). The cause of the injury is obscure, and a variety of sources have been proposed, including chronic gastroesophageal reflux. However, only a small fraction of individuals suffering from reflux or exposed to other proposed environmental triggers develop IPF; thus, other factors must have a predominant role. The clearest etiologic clues come from genetic studies. Germ line mutations leading to loss of telomerase are associated with increased risk, suggesting that cellular senescence contributes to a profibrotic phenotype. The link to cellular aging also is in line with the observation that IPF is a disorder of older adults, rarely occurring before the age of 55 years. Other genetic associations also point to the primary defect residing in epithelial cells. Specifically, approximately 35% of affected individuals have a genetic variant in the MUC5B gene that alters the production of mucin, while a smaller number of affected patients have germ line mutations in surfactant


Pathology_Robbins

Pathology_Robbins. 35% of affected individuals have a genetic variant in the MUC5B gene that alters the production of mucin, while a smaller number of affected patients have germ line mutations in surfactant genes. These genes are only expressed in lung epithelial cells, indicating that epithelial cell abnormalities can be the primary initiators of IPF. It is hypothesized that abnormal epithelial repair at the sites of chronic injury and inflammation gives rise to exuberant fibroblastic or myofibroblastic proliferation, leading to the characteristic fibroblastic foci. Although the mechanisms of fibrosis are incompletely understood, recent data point to excessive activation of profibrotic factors such as TGF-β.


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYGrossly,thepleuralsurfacesofthelungarecobblestonedduetoretractionofscarsalongtheinterlobularsepta.Thecutsurfaceshowsfirm,rubberywhiteareasoffibrosis,whichoccurspreferentiallywithinthelowerlobe,thesubpleuralregions,andalongtheinterlobularsepta.Histologically,thehallmarkispatchy interstitial fibrosis, whichvariesinintensity( Fig.13.14 Environmental factors: Other irritants, toxins At risk epithelium: Genetics: FibrosisProliferation, collagen production Fig. 13.13 Proposedpathogenicmechanismsinidiopathicpulmonaryfibrosis.Seetextfordetails. http://ebooksmedicine.net Fig. 13.14 Usualinterstitialpneumonia.Thefibrosis,whichvariesininten-sity,ismorepronouncedinthesubpleuralregion. worsenswithtime.Theearliestlesionsdemonstrateexuberantfibroblasticproliferation(fibroblastic foci)(


Pathology_Robbins

Pathology_Robbins. IPF usually presents with the gradual onset of a nonproductive cough and progressive dyspnea. On physical examination, most patients have characteristic “dry” or “Velcrolike” crackles during inspiration. Cyanosis, cor pulmonale, and peripheral edema may develop in later stages of the disease. The characteristic clinical and radiologic findings (subpleural and basilar fibrosis, reticular abnormalities, and “honeycombing”) often are diagnostic. Anti-inflammatory therapies have proven to be of little use, in line with the idea that inflammation is of secondary pathogenic importance. By contrast, anti-fibrotic therapies such as nintedanib, a tyrosine kinase inhibitor, and pirfenidone, an inhibitor of TGF-β, have produced positive outcomes in clinical trials and are now approved for use in patients with IPF. The overall prognosis remains poor, however; survival is only 3 to 5 years, and lung transplantation is the only definitive treatment.


Pathology_Robbins

Pathology_Robbins. Fig. 13.15 Usualinterstitialpneumonia.Fibroblasticfocuswithfibersrunningparalleltosurfaceandbluishmyxoidextracellularmatrix.Honey-combingispresenttotheleft.


Pathology_Robbins

Pathology_Robbins. Other rare pulmonary diseases associated with fibrosis need to be considered in the differential diagnosis of IPF, several of which are worthy of brief mention. One is nonspecific interstitial pneumonia (NSIP). NSIP is a chronic bilateral interstitial lung disease of unknown etiology, which (despite its name) has distinct radiologic, histologic, and clinical features, including a frequent association with collagen vascular disorders such as rheumatoid arthritis. It is important to recognize NSIP because it has a much better prognosis than IPF. It is characterized by mild to moderate interstitial chronic inflammation and/or fibrosis that is patchy but uniform in the areas involved. A second uncommon entity associated with fibrosis is cryptogenic organizing pneumonia. It presents with cough and dyspnea, and chest radiographs demonstrate subpleural or peribronchial patchy areas of airspace consolidation which are due to intraalveolar plugs of loose organizing connective tissue. Some


Pathology_Robbins

Pathology_Robbins. and dyspnea, and chest radiographs demonstrate subpleural or peribronchial patchy areas of airspace consolidation which are due to intraalveolar plugs of loose organizing connective tissue. Some patients recover spontaneously while most require treatment, usually with oral steroids. Also in the differential diagnosis of fibrosing pulmonary disorders are several rheumatologic entitiies, such as systemic sclerosis, rheumatoid arthritis and systemic lupus erythematosus, which may be complicated by diffuse pulmonary fibrosis.


Pathology_Robbins

Pathology_Robbins. Diffuseinterstitialfibrosisofthelunggivesrisetorestrictivelungdiseasescharacterizedbyreducedlungcomplianceandreducedforcedvitalcapacity(FVC).TheratioofFEVtoFVCisnormal. Diseasesthatcausediffuseinterstitialfibrosisareheterogeneous.TheunifyingpathogenicfactorisinjurytothealveolileadingtoactivationofmacrophagesandreleaseoffibrogeniccytokinessuchasTGF-β. Idiopathicpulmonaryfibrosisisprototypicofrestrictivelungdiseases.Itischaracterizedbypatchyinterstitialfibrosis,fibroblasticfoci,andformationofcysticspaces(honeycomblung).Thishistologicpatternisknownasusualinterstitialpneumonia(UIP). Pneumoconiosis is a term originally coined to describe lung disorders caused by inhalation of mineral dusts. The term has been broadened to include diseases induced by organic and inorganic particulates, and some experts also regard http://ebooksmedicine.net Table 13.3 Mineral Dust–Induced Lung Disease


Pathology_Robbins

Pathology_Robbins. Table 13.3 Mineral Dust–Induced Lung Disease CoaldustSimplecoalworker’spneumoconiosis:maculesandnodulesCoalminingComplicatedcoalworker’spneumoconiosis:PMF SilicaSilicosisSandblasting,quarrying,mining,stonecutting,foundrywork,ceramics chemical fumeand vapor-induced lung diseases as pneumoconioses. The mineral dust pneumoconioses—the three most common of which are caused by inhalation of coal dust, silica, and asbestos—usually stem from exposure in the workplace. Asbestos is the exception, as with this mineral the increased risk for cancer extends to family members of asbestos workers and to individuals exposed outside of the workplace. Table 13.3 indicates the pathologic conditions associated with each mineral dust and the major industries in which the dust exposure may produce disease.


Pathology_Robbins

Pathology_Robbins. The reaction of the lung to mineral dusts depends on many variables, including the size, shape, solubility, and reactivity of the particles. For example, particles greater than 5 to 10 µm are unlikely to reach distal airways, whereas particles smaller than 0.5 µm move into and out of alveoli, often without substantial deposition and injury. Particles that are 1 to 5 µm in diameter are the most dangerous, because they get lodged at the bifurcation of the distal airways. Coal dust is relatively inert, and large amounts must be deposited in the lungs before lung disease is clinically detectable. Silica, asbestos, and beryllium are more reactive than coal dust, resulting in fibrotic reactions at lower concentrations. Most inhaled dust is entrapped in the mucus blanket and rapidly removed from the lung by ciliary movement. However, some of the particles become impacted at alveolar duct bifurcations, where macrophages accumulate and engulf the trapped particulates.


Pathology_Robbins

Pathology_Robbins. The pulmonary alveolar macrophage is a key cellular element in the initiation and perpetuation of inflammation, lung injury and fibrosis. Following phagocytosis by macrophages, many particles activate the inflammasome and induce production of the pro-inflammatory cytokine IL-1 as well as the release of other factors, which initiates an inflammatory response that leads to fibroblast proliferation and collagen deposition. Some of the inhaled particles may reach the lymphatics either by direct drainage or within migrating macrophages and thereby initiate an immune response to components of the particulates and/ or to self-proteins that are modified by the particles. This then leads to an amplification and extension of the local reaction. Tobacco smoking worsens the effects of all inhaled mineral dusts, more so with asbestos than other particles.


Pathology_Robbins

Pathology_Robbins. Worldwide dust reduction in coal mines has greatly reduced the incidence of coal dust–induced disease. The spectrum of lung findings in coal workers is wide, ranging from asymptomatic anthracosis, in which pigment deposits without a perceptible cellular reaction; to simple coal worker’s pneumoconiosis (CWP), in which macrophages accumulate with little to no pulmonary dysfunction; to complicated CWP or progressive massive fibrosis (PMF), in which fibrosis is extensive and lung function is compromised (see Table 13.3 ). Although statistics vary, it seems that less than 10% of cases of simple CWP progress to PMF. Of note, PMF is a generic term that applies to a confluent fibrosing reaction in the lung; this can be a complication of any of the pneumoconioses discussed here.


Pathology_Robbins

Pathology_Robbins. Although coal is mainly carbon, coal mine dust contains a variety of trace metals, inorganic minerals, and crystalline silica. The ratio of carbon to contaminating chemicals and minerals (“coal rank”) increases from bituminous to anthracite coal; in general, anthracite mining has been associated with a higher risk for CWP. MORPHOLOGYPulmonary anthracosis isthemostinnocuouscoal-inducedpulmonarylesionincoalminersandalsoiscommonlyseeninurbandwellersandtobaccosmokers.Inhaledcarbonpigmentisengulfedbyalveolarorinterstitialmacrophages,whichthenaccumulateintheconnectivetissuealongthepulmonaryandpleurallymphaticsandindraininglymphnodes.


Pathology_Robbins

Pathology_Robbins. Simple CWP ischaracterizedbythepresenceofcoal macules andlargercoal nodules. Thecoalmaculeconsistsofdust-ladenmacrophagesandsmallamountsofcollagenfibersarrayedinadelicatenetwork.Althoughtheselesionsarescatteredthroughoutthelung,theupperlobesandupperzonesofthelowerlobesaremoreheavilyinvolved.Induecourse,centrilobular emphysema mayoccur.FunctionallysignificantemphysemaismorecommonintheUnitedKingdomandEurope,probablybecauseintheselocalesthecoalrankishigherthanintheUnitedStates. Complicated CWP (PMF) occursonabackgroundofsimpleCWPbycoalescenceofcoalnodulesandgenerallydevelopsovermanyyears.Itischaracterizedbymultiple,darkblackscarslargerthan2cmandsometimesupto10cmingreatestdiameterthatconsistofdensecollagenandpigment( Fig.13.16


Pathology_Robbins

Pathology_Robbins. Fig.13.16 CWP usually is a benign disease that produces little decrement in lung function. In those in whom PMF develops, there is increasing pulmonary dysfunction, pulmonary hypertension, 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 the absence of further exposure. After taking smoking-related risk into account, there is no increased frequency of lung carcinoma in coal miners, a feature that distinguishes CWP from both silica and asbestos exposures (discussed next). http://ebooksmedicine.net Fig. 13.16 Progressivemassivefibrosisinacoalworker.Alargeamountofblackpigmentisassociatedwithfibrosis.(From Klatt EC: RobbinsandCotranatlasofpathology,ed 2, Elsevier, Philadelphia, p 121.)


Pathology_Robbins

Pathology_Robbins. Silicosis is currently the most prevalent chronic occupational disease in the world. It is caused by inhalation of crystalline silica, mostly in occupational settings. Workers involved in sandblasting and hard-rock mining are at particularly high risk. Silica occurs in both crystalline and amorphous forms, but crystalline forms (including quartz, cristobalite, and tridymite) are by far the most toxic and fibrogenic. Of these, quartz is most commonly implicated in silicosis. After inhalation, the particles interact with epithelial cells and macrophages. Ingested silica particles cause activation of the inflammasome and the subsequent release of inflammatory mediators by pulmonary macrophages, including IL-1, TNF, fibronectin, lipid mediators, oxygen-derived free radicals, and fibrogenic cytokines. When mixed with other minerals, the fibrogenic effect of quartz is reduced. This fortuitous situation is commonplace, as quartz in the workplace is rarely pure. Thus, for example, miners of


Pathology_Robbins

Pathology_Robbins. When mixed with other minerals, the fibrogenic effect of quartz is reduced. This fortuitous situation is commonplace, as quartz in the workplace is rarely pure. Thus, for example, miners of the iron-containing ore hematite may have abundant quartz in their lungs yet have relatively mild lung disease because of the protective effect of hematite.


Pathology_Robbins

Pathology_Robbins. Fig. 13.17 Advancedsilicosis,seeninatransectedlung.Scarringhascontractedtheupperlobeintoasmalldarkmass(arrow). Notethedensepleuralthickening.(Courtesy of Dr. John Godleski,Brigham and Women’s Hospital,Boston, Massachusetts.) MORPHOLOGYSilicotic nodules intheirearlystagesaretiny,barelypalpable,discrete,pale-to-black(ifcoaldustispresent)nodulesintheupperzonesofthelungs( Fig.13.17 ).Microscopically,thesilicoticnoduledemonstratesconcentrically arranged hyalinized collagen fibers surroundinganamorphouscenter.The“whorled”appearanceofthecollagenfibersisquitedistinctiveforsilicosis( Fig.13.18 ).Examinationofthenodulesbypolarized microscopy reveals weakly birefringent silica particles,primarilyinthecenterofthenodules.Asthediseaseprogresses,individualnodulesmaycoalesceintohard,collagenousscars,witheventualprogressiontoPMF.Theinterveninglungparenchymamaybecompressedoroverexpanded,andahoneycombpatternmaydevelop.Fibroticlesionsalsomayoccurinhilarlymphnodesandthepleura.


Pathology_Robbins

Pathology_Robbins. Fig. 13.18 Coalescentcollagenoussilicoticnodules.(Courtesy of Dr. John Godleski, Brigham and Women’s Hospital, Boston, Massachusetts.) http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Silicosis usually is detected in asymptomatic workers on routine chest radiographs, which typically show a fine nodularity in the upper zones of the lung. Most patients do not develop shortness of breath until late in the course, after PMF is present. Many patients with PMF develop pulmonary hypertension and cor pulmonale as a result of chronic hypoxia–induced vasoconstriction and parenchymal destruction. The disease is slowly progressive, often impairing pulmonary function to such a degree that physical activity is severely limited. Silicosis is associated with an increased susceptibility to tuberculosis. It is postulated that silicosis depresses cell-mediated immunity, and crystalline silica may inhibit the ability of pulmonary macrophages to kill phagocytosed mycobacteria. Nodules of silicotuberculosis often contain a central zone of caseation. The relationship between silica and lung cancer is unsettled, but most studies suggest that silica exposure is associated with some


Pathology_Robbins

Pathology_Robbins. of silicotuberculosis often contain a central zone of caseation. The relationship between silica and lung cancer is unsettled, but most studies suggest that silica exposure is associated with some increase in risk.


Pathology_Robbins

Pathology_Robbins. Asbestos is a family of crystalline hydrated silicates with a fibrous geometry. On the basis of epidemiologic studies, occupational exposure to asbestos is linked to (1) parenchymal interstitial fibrosis (asbestosis); (2) localized fibrous plaques, or, rarely, diffuse fibrosis in the pleura; (3) pleural effusions; (4) lung carcinoma; (5) malignant pleural and peritoneal mesothelioma; and (6) laryngeal carcinoma. An increased incidence of asbestos-related cancers in family members of asbestos workers has alerted the general public to the potential hazards of asbestos in the environment.


Pathology_Robbins

Pathology_Robbins. As with silica crystals, once phagocytosed by macrophages, asbestos fibers activate the inflammasome and damage phagolysosomal membranes, stimulating the release of proinflammatory factors and fibrogenic mediators. In addition to cellular and fibrotic lung reactions, asbestos probably also functions as both a tumor initiator and a promoter. Some of the oncogenic effects of asbestos on the mesothelium are mediated by reactive free radicals generated by asbestos fibers, which preferentially localize in the distal lung close to the mesothelial layer. However, potentially toxic chemicals adsorbed onto the asbestos fibers also undoubtedly contribute to the pathogenicity of the fibers. For example, the adsorption of carcinogens in tobacco smoke onto asbestos fibers may be the basis for the remarkable synergy between tobacco smoking and the development of lung carcinoma in asbestos workers. Fig. 13.19 High-powerdetailofanasbestosbody,revealingthetypicalbeadingandknobbedends(arrow).


Pathology_Robbins

Pathology_Robbins. Fig. 13.19 High-powerdetailofanasbestosbody,revealingthetypicalbeadingandknobbedends(arrow). MORPHOLOGYAsbestosisismarkedbydiffuse pulmonary interstitial fibrosis,characterizedbythepresenceofasbestos bodies, whichareseenasgoldenbrown,fusiformorbeadedrodswithatranslucentcenter.Theyconsistofasbestosfiberscoatedwithaniron-containingproteinaceousmaterial( Fig.13.19 ).Asbestosbodiesapparentlyareformedwhenmacrophagesattempttophagocytoseasbestosfibers;theiron“crust”isderivedfromphagocyteferritin.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. The clinical findings in asbestosis are indistinguishable from those of any other chronic interstitial lung disease. Progressively worsening dyspnea appears 10 to 20 years after exposure. It is usually accompanied by a cough and production of sputum. The disease may remain static or progress to congestive heart failure, cor pulmonale, and death. Pleural plaques are usually asymptomatic and are detected on radiographs as circumscribed densities. Both lung carcinoma and malignant mesothelioma develop in workers exposed to asbestos. The risk for developing lung carcinoma is increased about 5-fold for asbestos workers; the relative risk for mesothelioma, normally a very rare tumor (2–17 cases per 1 million individuals), is more than 1000 times greater. Concomitant cigarette smoking greatly increases the risk for lung carcinoma but not for mesothelioma. Lung or pleural cancer associated with asbestos exposure carries a particularly poor prognosis. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Drugs can cause a variety of acute and chronic alterations in respiratory structure and function. For example, bleomycin, an anti-cancer agent, causes pneumonitis and interstitial fibrosis as a result of direct toxicity of the drug and by stimulating the influx of inflammatory cells into the alveoli. Amiodarone, an anti-arrhythmic agent, also is associated with risk for pneumonitis and fibrosis. Radiation pneumonitis is a well-known complication of irradiation of pulmonary and other thoracic tumors. Acute radiation pneumonitis, which typically occurs 1 to 6 months after therapy in as many as 20% of the patients, is manifested by fever, dyspnea out of proportion to the volume of irradiated lung, pleural effusion, and pulmonary infiltrates in the irradiated lung bed. These signs and symptoms may resolve with corticosteroid therapy or progress to chronic radiation pneumonitis, associated with pulmonary fibrosis.


Pathology_Robbins

Pathology_Robbins. Sarcoidosis is a multisystem disease of unknown etiology characterized by noncaseating granulomatous inflammation in many tissues and organs. We discuss it here because one presentation of sarcoidosis is as a restrictive lung disease. Other diseases, including mycobacterial or fungal infections and berylliosis, sometimes also produce noncaseating granulomas; therefore, the histologic diagnosis of sarcoidosis is one of exclusion. Although sarcoidosis can manifest in many different ways, bilateral hilar lymphadenopathy or lung involvement (or both), visible on chest radiographs, is the major finding at presentation in most cases. Eye and skin involvement each occurs in about 25% of cases, and either may occasionally be the presenting feature of the disease. Sarcoidosis occurs throughout the world, affecting both genders and all races and age groups. There are, however, certain interesting epidemiologic trends: A consistent predilection for adults younger than 40 years of age.


Pathology_Robbins

Pathology_Robbins. A consistent predilection for adults younger than 40 years of age. A high incidence in Danish and Swedish populations, and in the United States among African Americans (in whom the frequency is 10 times higher than in whites). A higher prevalence among nonsmokers, an association that is virtually unique to sarcoidosis among pulmonary diseases. Although the etiology of sarcoidosis remains unknown, several lines of evidence suggest that it is a disease of disordered immune regulation in genetically predisposed individuals exposed to certain environmental agents. The role of each of these contributory influences is summarized in the following discussion. http://ebooksmedicine.net Several immunologic abnormalities in sarcoidosis suggest the development of a cell-mediated response to an unidentified antigen. The process is driven by CD4+ helper T cells. These immunologic “clues” include the following:


Pathology_Robbins

Pathology_Robbins. Intraalveolar and interstitial accumulation of CD4+ TH1 cells, with peripheral T cell cytopenia Oligoclonal expansion of CD4+ TH1 T cells within the lung as determined by analysis of T cell receptor rearrangements Increases in TH1 cytokines such as IL-2 and IFN-γ, resulting in T cell proliferation and macrophage activation, respectively Increases in several cytokines in the local environment (IL-8, TNF, macrophage inflammatory protein-1α) that favor recruitment of additional T cells and monocytes and contribute to the formation of granulomas Anergy to common skin test antigens such as Candida or purified protein derivative (PPD) Familial and racial clustering of cases, suggesting the involvement of genetic factors


Pathology_Robbins

Pathology_Robbins. Anergy to common skin test antigens such as Candida or purified protein derivative (PPD) Familial and racial clustering of cases, suggesting the involvement of genetic factors After lung transplantation, sarcoidosis recurs in the new lungs in at least one-third of patients, but without any effect on survival. Finally, several putative “antigens” have been proposed as the inciting agent for sarcoidosis (e.g., viruses, mycobacteria, Borrelia, pollen), but there is no “smoking gun” linking sarcoidosis to any specific antigen or infectious agent. MORPHOLOGYThecardinalhistopathologicfeatureofsarcoidosis,irrespectiveoftheorganinvolved,isthenonnecrotizing epithelioid granuloma (


Pathology_Robbins

Pathology_Robbins. Thelungs areinvolvedatsomestageofthediseasein90%ofpatients.Thegranulomaspredominantlyinvolvetheinterstitiumratherthanairspaces,withsometendencytolocalizeintheconnectivetissuearoundbronchiolesandpulmonaryvenulesandinthepleura(“lymphangitic”distribution).ThebronchoalveolarlavagefluidcontainsabundantCD4+ Tcells.In5%to15%ofpatients,thegranulomaseventuallyarereplacedbydiffuse interstitial fibrosis, resultinginaso-called“honeycomblung”. Fig. 13.21 Sarcoid.Characteristicperibronchialnoncaseatinggranulomaswithmanygiantcellsarepresent. Intrathoracichilar and paratracheal lymph nodes areenlargedin75%to90%ofpatients,whileone-thirdpresentwithperipherallymphadenopathy.Thenodesarecharacteristicallypainlessandhaveafirm,rubberytexture.Unlikeintuberculosis,lymphnodesinsarcoidosisare“nonmatted”(nonadherent)anddonotulcerate.


Pathology_Robbins

Pathology_Robbins. Involvement of the eye and lacrimal glands occurs in about one-fifth to one-half of patients. Theocularinvolvementtakestheformofiritis oriridocyclitis andmaybeunilateralorbilateral.Asaconsequence,cornealopacities,glaucoma,and(lesscommonly)totallossofvisionmaydevelop.Theposterioruvealtractalsoisaffected,withresultantchoroiditis, retinitis, andoptic nerve involvement. Theseocularlesionsarefrequentlyaccompaniedbyinflammationinthelacrimalglands,withsuppressionoflacrimation(sicca syndrome). Unilateral or bilateral parotitis with painful enlargement of the parotid glands occursinlessthan10%ofpatientswithsarcoidosis;somegoontodevelopxerostomia(drymouth).CombineduveoparotidinvolvementisdesignatedMikulicz syndrome.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net In many affected individuals, the disease is entirely asymptomatic, discovered on routine chest films as bilateral hilar adenopathy or as an incidental finding at autopsy. In others, peripheral lymphadenopathy, cutaneous lesions, eye involvement, splenomegaly, or hepatomegaly may be presenting manifestations. In about two-thirds of symptomatic cases, there is gradual appearance of respiratory symptoms (shortness of breath, dry cough, or vague sub-sternal discomfort) or constitutional signs and symptoms (fever, fatigue, weight loss, anorexia, night sweats). A definitive diagnostic test for sarcoidosis does not exist, and establishing a diagnosis requires the presence of clinical and radiologic findings that are consistent with the disease, the exclusion of other disorders with similar presentations, and the identification of noncaseating granulomas in involved tissues. In particular, tuberculosis must be excluded.


Pathology_Robbins

Pathology_Robbins. Sarcoidosis follows an unpredictable course characterized by either progressive chronicity or periods of activity interspersed with remissions. The remissions may be spontaneous or initiated by steroid therapy and often are permanent. Overall, 65% to 70% of affected individuals recover with minimal or no residual manifestations. Another 20% develop permanent lung dysfunction or visual impairment. Of the remaining 10% to 15%, most succumb to progressive pulmonary fibrosis and cor pulmonale. Sarcoidosisisamultisystemdiseaseofunknownetiology;thediagnostichistopathologicfeatureisthepresenceofnoncaseatinggranulomasinvarioustissues. ImmunologicabnormalitiesincludehighlevelsofCD4+ TH1cellsinthelungthatsecretecytokinessuchasIFN-γ.


Pathology_Robbins

Pathology_Robbins. ImmunologicabnormalitiesincludehighlevelsofCD4+ TH1cellsinthelungthatsecretecytokinessuchasIFN-γ. Clinicalmanifestationsincludelymphnodeenlargement,eyeinvolvement(siccasyndrome[dryeyes],iritis,oriridocyclitis),skinlesions(erythemanodosum,painlesssubcutaneousnodules),andvisceralinvolvement(liver,skin,bonemarrow).Lunginvolvementoccursin90%ofcases,withformationofgranulomasandinterstitialfibrosis. Hypersensitivity pneumonitis is an immunologically mediated inflammatory lung disease that primarily affects the alveoli and is therefore often called allergic alveolitis. Most often it is an occupational disease that results from heightened sensitivity to inhaled antigens such as those found in moldy hay (


Pathology_Robbins

Pathology_Robbins. Table 13.4 ). Unlike bronchial asthma, in which bronchi are the focus of immunologically mediated injury, the damage in hypersensitivity pneumonitis occurs at the level of alveoli. Hence, it manifests predominantly as a restrictive lung disease with the typical decreases in diffusion capacity, lung compliance, and total lung volume. The responsible occupational and household exposures are diverse, but the syndromes share common clinical and pathologic findings and probably have a very similar pathophysiologic basis. Table 13.4 Sources of Antigens Causing Hypersensitivity Pneumonitis Source of Antigen Types of Exposures Mushrooms,fungi,yeastsContaminatedwood,humidifiers,centralhotairheatingducts,peatmossplants MycobacteriaMetalworkingfluids,sauna,hottub BirdsPigeons,dovefeathers,ducks,parakeets ChemicalsIsocyanates(autopainters),zinc,dyes FromLacasseY,GirardM,CormierY:Recentadvancesinhypersensitivitypneumonitis,Chest 142:208,2012.


Pathology_Robbins

Pathology_Robbins. BirdsPigeons,dovefeathers,ducks,parakeets ChemicalsIsocyanates(autopainters),zinc,dyes FromLacasseY,GirardM,CormierY:Recentadvancesinhypersensitivitypneumonitis,Chest 142:208,2012. Several lines of evidence suggest that hypersensitivity pneumonitis is an immunologically mediated disease: Bronchoalveolar lavage specimens consistently show increased numbers of CD4+ and CD8+ T lymphocytes. Most affected patients have specific antibodies against the offending antigen in their serum. Complement and immunoglobulins have been demonstrated within vessel walls by immunofluorescence. Noncaseating granulomas are found in the lungs of two-thirds of affected patients.


Pathology_Robbins

Pathology_Robbins. Complement and immunoglobulins have been demonstrated within vessel walls by immunofluorescence. Noncaseating granulomas are found in the lungs of two-thirds of affected patients. MORPHOLOGYThehistopathologicpictureinbothacuteandchronicformsofhypersensitivitypneumonitisincludespatchymononuclearcellinfiltratesinthepulmonaryinterstitium,withacharacteristicperibronchiolaraccentuation.Lymphocytespredominate,butplasmacellsandepithelioidmacrophagesalsoarepresent.Inacuteformsofthedisease,variablenumbersofneutrophilsalsomaybeseen.“Loose,” poorly formed granulomas, withoutnecrosis,arepresentinmorethantwo-thirdsofcases,usuallyinaperibronchiolarlocation( Fig.13.22 ).Inadvancedchroniccases,bilateral,upper-lobe–dominantinterstitialfibrosis(UIPpattern)occurs. Fig. 13.22 Hypersensitivitypneumonitis,histologicappearance.Looselyformedinterstitialgranulomasandchronicinflammationarecharacteristic. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Fig. 13.22 Hypersensitivitypneumonitis,histologicappearance.Looselyformedinterstitialgranulomasandchronicinflammationarecharacteristic. http://ebooksmedicine.net Hypersensitivity pneumonitis may manifest either as an acute reaction, with fever, cough, dyspnea, and constitutional signs and symptoms arising 4 to 8 hours after exposure, or as a chronic disease characterized by insidious onset of cough, dyspnea, malaise, and weight loss. With the acute form, the diagnosis is usually obvious because of the temporal relationship of symptom onset and exposure to the incriminating antigen. If antigenic exposure is terminated after acute attacks of the disease, complete resolution of pulmonary symptoms occurs within days. Failure to remove the inciting agent from the environment eventually results in an irreversible chronic interstitial pulmonary disease.


Pathology_Robbins

Pathology_Robbins. A number of disorders are characterized by pulmonary infiltrates rich in eosinophils, which are recruited to the lung by local release of chemotactic factors. These diverse diseases generally are of immunologic origin, but the etiology is not understood. Pulmonary eosinophilia is divided into the following categories: Acute eosinophilic pneumonia with respiratory failure, characterized by rapid onset of fever, dyspnea, hypoxia, and diffuse pulmonary infiltrates on chest radiographs. The bronchoalveolar lavage fluid typically contains more than 25% eosinophils. There is prompt response to corticosteroids. Simple pulmonary eosinophilia (Loeffler syndrome), characterized by transient pulmonary lesions, eosinophilia in the blood, and a benign clinical course. The alveolar septa are thickened by an infiltrate containing eosinophils and occasional giant cells. Tropical eosinophilia, caused by infection with microfilariae and helminthic parasites


Pathology_Robbins

Pathology_Robbins. Tropical eosinophilia, caused by infection with microfilariae and helminthic parasites Secondary eosinophilia, seen, for example, in association with asthma, drug allergies, and certain forms of vasculitis Idiopathic chronic eosinophilic pneumonia, characterized by aggregates of lymphocytes and eosinophils within the septal walls and the alveolar spaces, typically in the periphery of the lung fields, and accompanied by high fever, night sweats, and dyspnea. This is a disease of exclusion, once other causes of pulmonary eosinophilia have been ruled out.


Pathology_Robbins

Pathology_Robbins. In addition to obstructive lung disease (COPD), smoking is also is associated with restrictive or interstitial lung diseases. Desquamative interstitial pneumonia (DIP) and respiratory bronchiolitis are two related examples of smoking-associated interstitial lung disease. The most striking histologic feature of DIP is the accumulation of large numbers of macrophages containing dusty-brown pigment (smoker’s macrophages) in the air spaces ( Fig.


Pathology_Robbins

Pathology_Robbins. Fig. 13.23 ). The alveolar septa are thickened by a sparse inflammatory infiltrate (usually lymphocytes); interstitial fibrosis, when present, is mild. Pulmonary function tests usually show a mild restrictive abnormality. Overall, patients with DIP have a good prognosis and an excellent response to steroids and smoking cessation; however, some patients progress despite therapy. Respiratory bronchiolitis is a common lesion found in smokers that is characterized by the presence of pigmented intraluminal macrophages akin to those in DIP, but in a “bronchiolocentric” distribution (first-and second-order respiratory bronchioles). Mild peribronchiolar fibrosis also is seen. As with DIP, affected patients present with gradual onset of dyspnea and dry cough, and the symptoms recede with smoking cessation. Fig. 13.23 Desquamativeinterstitialpneumonia.Thereisaccumulationoflargenumbersofmacrophageswithinthealveolarspaceswithonlyslightfibrousthickeningofthealveolarwalls.


Pathology_Robbins

Pathology_Robbins. Fig. 13.23 Desquamativeinterstitialpneumonia.Thereisaccumulationoflargenumbersofmacrophageswithinthealveolarspaceswithonlyslightfibrousthickeningofthealveolarwalls. PulmonaryEmbolism,Hemorrhage,andInfarction Thromboembolism causes approximately 50,000 deaths per year in the United States and even when not directly fatal often complicates the course of other diseases. The true incidence of nonfatal pulmonary embolism is not known. Some cases undoubtedly occur outside the hospital in ambulatory patients, in whom the emboli are small and clinically silent. Even among hospitalized patients, no more than one-third are diagnosed before death. Autopsy data on the incidence of pulmonary embolism vary widely, ranging from 1% in the general hospitalized population, to 30% in individuals dying after severe burns, trauma, or fractures.


Pathology_Robbins

Pathology_Robbins. Blood clots that occlude the large pulmonary arteries are almost always embolic in origin. More than 95% of all pulmonary emboli arise from thrombi within the large deep veins of the legs, most often those that have propagated to involve the popliteal vein and larger veins above it. The influences that predispose to venous thrombosis in the legs are discussed in Chapter 4, but the following risk factors are paramount: (1) prolonged bed rest (particularly with immobilization of the legs); (2) surgery, especially orthopedic surgery on the knee or hip; (3) severe trauma (including burns or multiple fractures); (4) congestive heart failure; (5) in women, the period around parturition or the use of oral contraception pills with high estrogen content; http://ebooksmedicine.net (6) disseminated cancer; and (7) primary disorders of hypercoagulability (e.g., factor V Leiden) (Chapter 4).


Pathology_Robbins

Pathology_Robbins. The pathophysiologic consequences of pulmonary thromboembolism depend largely on the size of the embolus, which in turn dictates the size of the occluded pulmonary artery, and the cardiopulmonary status of the patient. There are two important consequences of pulmonary arterial occlusion: (1) an increase in pulmonary artery pressure from blockage of flow and, possibly, vasospasm caused by neurogenic mechanisms and/or release of mediators (e.g., thromboxane A2, serotonin); and (2) ischemia of the downstream pulmonary parenchyma. Thus, occlusion of a major vessel results in an abrupt increase in pulmonary artery pressure, diminished cardiac output, right-sided heart failure (acute cor pulmonale), and sometimes sudden death. If smaller vessels are occluded, the result is less catastrophic and may even be clinically silent. Hypoxemia develops as a result of multiple mechanisms:


Pathology_Robbins

Pathology_Robbins. Perfusion of atelectatic lung zones. Alveolar collapse occurs in ischemic areas because of a reduction in surfactant production and because pain associated with embolism leads to reduced movement of the chest wall. The decrease in cardiac output causes a widening of the difference in arterial-venous oxygen saturation. Right-to-left shunting of blood may occur through a patent foramen ovale, present in 30% of normal individuals. Recall that the lungs are oxygenated not only by the pulmonary arteries but also by bronchial arteries and directly from air in the alveoli. Thus, ischemic necrosis (infarction) is the exception rather than the rule, occurring in as few as 10% of patients with thromboemboli. It occurs only if there is compromise in cardiac function or bronchial circulation, or if the region of the lung at risk is underventilated as a result of underlying pulmonary disease.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Fig. 13.24 Largesaddleembolusfromthefemoralveinlyingastridethemainleftandrightpulmonaryarteries.(Courtesy of Dr. Linda Margraf, Department of Pathology, University of Texas Southwestern Medical School, Dallas, Texas.) The clinical consequences of pulmonary thromboembolism are summarized as follows: • Most (60% to 80%) are clinically silent because they are small; the bronchial circulation sustains the viability of the affected lung parenchyma, and the embolic mass is rapidly removed by fibrinolytic activity. Fig. 13.25 Asmall,roughlywedge-shapedhemorrhagicpulmonaryinfarctofrecentoccurrence. http://ebooksmedicine.net In 5% of cases, death, acute right-sided heart failure, or cardiovascular collapse (shock) occurs suddenly. Massive pulmonary embolism is one of the few causes of virtually instantaneous death. These severe consequences typically happen when more than 60% of the total pulmonary vasculature is obstructed by a large embolus or multiple simultaneous small emboli.


Pathology_Robbins

Pathology_Robbins. Obstruction of small to medium pulmonary branches (10% to 15% of cases) causes pulmonary infarction if some element of circulatory insufficiency also is present. Typically, individuals who sustain infarctions present with dyspnea. In a small but significant subset of patients (accounting for <3% of cases), recurrent “showers” of emboli lead to pulmonary hypertension, chronic right-sided heart failure, and, in time, pulmonary vascular sclerosis with progressively worsening of dyspnea.


Pathology_Robbins

Pathology_Robbins. Emboli usually resolve after the initial acute event, as endogenous fibrinolytic activity often leads to their complete dissolution. However, in the presence of an underlying predisposing factor, a small, innocuous embolus may presage a larger one, and patients who have experienced one pulmonary embolism have a 30% chance of developing a second. Prophylactic therapy may include anticoagulation, early ambulation for postoperative and postparturient patients, application of elastic stockings, intermittent pneumatic calf compression, and isometric leg exercises for bedridden patients. Those who develop pulmonary embolism are given anti-coagulation therapy. Patients with massive pulmonary embolism who are hemodynamically unstable (shock, acute right heart failure) are candidates for thrombolytic therapy.


Pathology_Robbins

Pathology_Robbins. Nonthrombotic pulmonary emboli come in several uncommon but potentially lethal forms, such as air, fat, and amniotic fluid embolism (Chapter 4). Intravenous drug abuse often is associated with foreign body embolism in the pulmonary microvasculature; the presence of magnesium trisilicate (talc) in the intravenous mixture elicits a granulomatous response within the interstitium or pulmonary arteries. Involvement of the interstitium may lead to fibrosis, while vascular involvement leads to pulmonary hypertension. Residual talc crystals can be demonstrated within the granulomas using polarized light. Bone marrow embolism (denoted by the presence of hematopoietic and fat elements within a pulmonary artery) can occur after massive trauma and in patients with bone infarction secondary to sickle cell anemia. Almostalllargepulmonaryarterythrombiareembolicinorigin,usuallyarisingfromthedeepveinsofthelowerleg.


Pathology_Robbins

Pathology_Robbins. Riskforrecurrenceishigh. The pulmonary circulation normally is one of low resistance, and pulmonary blood pressures are only about one-eighth of systemic pressures. Pulmonary hypertension (defined as pressures of 25 mm Hg or more at rest) may be caused by a decrease in the cross-sectional area of the pulmonary vascular bed or, less commonly, by increased pulmonary vascular blood flow. Based on shared features, the World Health Organization has classified pulmonary hypertension into the following five groups: Pulmonary arterial hypertension, a diverse collection of disorders that includes heritable forms of pulmonary hypertension and diseases that cause pulmonary hypertension by affecting small pulmonary muscular arterioles; these include connective tissue diseases, human immunodeficiency virus, and congenital heart disease with left to right shunts Pulmonary hypertension due to left-sided heart disease, including systolic and diastolic dysfunction and valvular disease


Pathology_Robbins

Pathology_Robbins. Pulmonary hypertension due to left-sided heart disease, including systolic and diastolic dysfunction and valvular disease Pulmonary hypertension due to lung diseases and/or hypoxia, including COPD and interstitial lung disease Pulmonary hypertension with unclear or multifactorial mechanisms As can be gathered from this classification, pulmonary hypertension has diverse causes. Some of the more common causes are the following: Chronic obstructive or interstitial lung diseases (group 3). These diseases obliterate alveolar capillaries, increasing pulmonary resistance to blood flow and, secondarily, pulmonary blood pressure. Antecedent congenital or acquired heart disease (group 2). Mitral stenosis, for example, causes an increase in left atrial pressure and pulmonary venous pressure that is eventually transmitted to the arterial side of the pulmonary vasculature, leading to hypertension.


Pathology_Robbins

Pathology_Robbins. Recurrent thromboemboli (group 4). Recurrent pulmonary emboli may cause pulmonary hypertension by reducing the functional cross-sectional area of the pulmonary vascular bed, which in turn leads to an increase in pulmonary vascular resistance. Autoimmune diseases (group 1). Several of these diseases (most notably systemic sclerosis) involve the pulmonary vasculature and/or the interstitium, leading to increased vascular resistance and pulmonary hypertension. Obstructive sleep apnea (also group 3) is a common disorder that is associated with obesity and hypoxemia. It is now recognized to be a significant contributor to the development of pulmonary hypertension and cor pulmonale. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Uncommonly, pulmonary hypertension is encountered in patients in whom all known causes are excluded; this is referred to as idiopathic pulmonary arterial hypertension. This name is a misnomer, however, as up to 80% of “idiopathic” pulmonary hypertension (sometimes referred to as primary pulmonary hypertension) has a genetic basis, sometimes being inherited in families as an autosomal dominant trait. Within these families, there is incomplete penetrance, and only 10% to 20% of the family members develop overt disease. As is often the case, investigating the molecular basis of an uncommon familial form of the disease has provided new pathogenic insights, in this instance by shining a spotlight on the role of the bone morphogenetic protein (BMP)–signaling pathway. Inactivating germ line mutations in the gene encoding bone morphogenetic protein receptor 2 (BMPR2) are found in 75% of the familial cases of pulmonary hypertension and 25% of sporadic cases. More recently, mutations in other


Pathology_Robbins

Pathology_Robbins. in the gene encoding bone morphogenetic protein receptor 2 (BMPR2) are found in 75% of the familial cases of pulmonary hypertension and 25% of sporadic cases. More recently, mutations in other genes that are involved in the BMPR2 pathway also have been identified in affected patients. Details remain to be worked out, but it appears that defects in BMPR2 signaling leads to dysfunction of endothelium and proliferation of vascular smooth muscle cells in the pulmonary vasculature. Because only 10% to 20% of individuals with BMPR2 mutations develop disease, it is likely that modifier genes and/or environmental triggers also contribute to the pathogenesis of the disorder.


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYRegardlessoftheiretiology,allformsofpulmonaryhypertensionareassociatedwithmedial hypertrophy of the pulmonary muscular and elastic arteries, pulmonary arterial atherosclerosis, and right ventricular hypertrophy. Thepresenceoforganizingorrecanalizedthrombifavorsrecurrentpulmonaryemboliasthecause,andthecoexistenceofdiffusepulmonaryfibrosis,orsevereemphysemaandchronicbronchitis,pointstochronichypoxiaastheinitiatingevent.Thevesselchangescaninvolvetheentirearterialtree,fromthemainpulmonaryarteriesdowntothearterioles( Fig.13.26 ).Inseverecases,atheromatousdepositsforminthepulmonaryarteryanditsmajorbranches.Thearteriolesandsmallarteriesaremostprominentlyaffectedbymedialhypertrophyandintimalfibrosis,sometimesnarrowingthelumenstopinpointchannels.Anuncommonbutcharacteristicpathologicchangeistheplexiform lesion, socalledbecauseatuftofcapillaryformationsispresent,producinganetwork,orweb,thatspansthelumensofdilatedthin-walled,smallarteriesandmayextendoutsidethevessel.


Pathology_Robbins

Pathology_Robbins. Pulmonary hypertension produces symptoms when the disease is advanced. Idiopathic pulmonary hypertension is most common in women 20 to 40 years of age and occurs occasionally in young children. The presenting features are usually dyspnea and fatigue, but some patients have anginal chest pain. Over time, respiratory distress, cyanosis, and right ventricular hypertrophy appear, and death from decompensated cor pulmonale, often with superimposed thromboembolism and pneumonia, ensues within 2 to 5 years in 80% of patients. Fig. 13.26 Vascularchangesinpulmonaryhypertension.(A)Atheromafor-mation,achangeusuallylimitedtolargepulmonaryarteries.(B)Markedmedialhypertrophy.(C)Plexiformlesioncharacteristicofadvancedpulmo-naryhypertensionseeninsmallarteries.


Pathology_Robbins

Pathology_Robbins. Treatment choices depend on the underlying cause. For those with secondary disease, therapy is directed at the trigger (e.g., thromboembolic disease or hypoxemia). A variety of vasodilators have been used with varying success in those with group 1 disease or refractory disease belonging to other groups. Lung transplantation is the definitive treatment for selected patients. http://ebooksmedicine.net Pulmonary hemorrhage is a dramatic complication of some interstitial lung disorders. Among these so-called “pulmonary hemorrhage syndromes” are (1) Goodpasture syndrome, (2) idiopathic pulmonary hemosiderosis, and (3) granulomatosis with polyangiitis.


Pathology_Robbins

Pathology_Robbins. Goodpasture syndrome is an uncommon autoimmune disease in which lung and kidney injury are caused by circulating autoantibodies against certain domains of type IV collagen that are intrinsic to the basement membranes of renal glomeruli and pulmonary alveoli. The antibodies trigger destruction and inflammation of the basement membranes in pulmonary alveoli and renal glomeruli, giving rise to necrotizing hemorrhagic interstitial pneumonitis and rapidly progressive glomerulonephritis. MORPHOLOGYThelungsareheavyandhaveareasofred-brownconsolidationduetodiffuse alveolar hemorrhage. Microscopicexaminationshowsfocalnecrosisofalveolarwallsassociatedwithintra-alveolarhemorrhage,fibrousthickeningofsepta,andhypertrophictypeIIpneumocytes.Thereisabundanthemosiderin duetoearlierepisodesofhemorrhage(


Pathology_Robbins

Pathology_Robbins. Fig.13.27 ).Thecharacteristiclinear pattern of immunoglobulin deposition (usuallyIgG,sometimesIgAorIgM)thatisthehallmarkdiagnosticfindinginrenalbiopsyspecimens(Chapter14)alsomaybeseenalongthealveolarsepta. Most cases of Goodpasture syndrome occur in patients in their teens or twenties. In contrast to many other autoimmune diseases, there is a male preponderance. The majority of patients are active smokers. Plasmapheresis and immunosuppressive therapy have markedly improved a once-dismal prognosis. Plasma exchange removes offending antibodies, and immunosuppressive drugs inhibit antibody production. With severe renal disease, renal transplantation is eventually required.


Pathology_Robbins

Pathology_Robbins. More than 80% of patients with granulomatosis and polyangiitis (GPA; formerly Wegener granulomatosis) develop upper-respiratory or pulmonary manifestations at some time in their course. This is discussed in Chapter 10. Here we list the salient pulmonary features. The lung lesions are characterized by a combination of necrotizing vasculitis (“angiitis”) and parenchymal necrotizing granulomatous inflammation. The signs and symptoms stem from involvement of the upper-respiratory tract (chronic sinusitis, epistaxis, nasal perforation) and the lungs (cough, hemoptysis, chest pain). Anti-neutrophil cytoplasmic antibodies (PR3ANCAs) are present in close to 95% of cases (Chapter 10).


Pathology_Robbins

Pathology_Robbins. Pulmonary infections in the form of pneumonia are responsible for one sixth of all deaths in the United States. Pneumonia can be broadly defined as any infection in the lung. Normally, the lung parenchyma remains sterile because of a number of highly effective immune and non-immune defense mechanisms that extend throughout the respiratory system from the nasopharynx to the alveolar air spaces ( Fig. 13.28 ). The vulnerability of the lung to infection dsepite these defenses is not surprising because (1) many microbes are airborne and readily inhaled into the lungs; (2) nasopharyngeal flora are regularly aspirated during sleep, even by healthy individuals; and (3) lung diseases often lower local immune defenses. The importance of immune defenses in preventing pulmonary infections is emphasized by patients with inherited or acquired defects in innate immunity (including neutrophil and complement defects) or adaptive immunity (e.g., humoral immunodeficiency), all of which lead to an


Pathology_Robbins

Pathology_Robbins. Fig. 13.27 Diffusealveolarhemorrhagesyndrome.(A)Lungbiopsyspecimendemonstrateslargenumbersofintraalveolarhemosiderin-ladenmacrophagesonabackgroundofthickenedfibroussepta.(B)ThetissuehasbeenstainedwithPrussianblue,anironstainthathighlightstheabundantintracellularhemosiderin.(From the Teaching Collection of the Department of Pathology,Children’s Medical Center,Dallas,Texas.) http://ebooksmedicine.net


Pathology_Robbins

Fig.

Pathology_Robbins. Fig.


Pathology_Robbins

Pathology_Robbins. 13.28 Lung defense mechanisms. (A) Innate defenses against infection: 1, In the normal lung, removal of microbial organisms depends on entrapment in the mucous blanket and removal by means of the mucociliary elevator; 2, Phagocytosis by alveolar macrophages can kill and degrade organisms and remove them from the air spaces by migrating onto the mucociliary elevator; or 3, phagocytosis and killing by neutrophils recruited by macrophage factors; 4, Complement may enter the alveoli and be activated by the alternative pathway to produce the opsonin C3b, which enhances phagocytosis; 5, Organisms, including those ingested by phagocytes, may reach the draining lymph nodes to initiate immune responses. (B) Additional mechanisms operate after development of adaptive immunity: 1, Secreted IgA can block attachment of the microorganism to epithelium in the upper-respiratory tract; 2, In the lower-respiratory tract, serum antibodies (IgM, IgG) are present in the alveolar lining fluid and activate


Pathology_Robbins

Pathology_Robbins. lock attachment of the microorganism to epithelium in the upper-respiratory tract; 2, In the lower-respiratory tract, serum antibodies (IgM, IgG) are present in the alveolar lining fluid and activate complement more efficiently by the classic pathway, yielding C3b (not


Pathology_Robbins

Pathology_Robbins. shown); In addition, IgG is an opsonin; 3, The accumulation of immune T cells is important for controlling infections by viruses and other intracellular microorganisms.


Pathology_Robbins

Pathology_Robbins. PMN, neutrophil. increased incidence of infections with pyogenic bacteria. For example, patients with mutations in MYD88, an adaptor protein required for signaling by Toll-like receptors, are extremely susceptible to severe necrotizing pneumococcal infections, while patients with congenital defects in IgA production (the major immunoglobulin in airways secretions) are at increased risk for pneumonias caused by encapsulated organisms such as pneumococcus and H. influenzae. On the other hand, defects in TH1 cell–mediated immunity lead mainly to increased infections with intracellular microbes such as atypical mycobacteria. Much more commonly, lifestyle choices interfere with host immune defense mechanisms and facilitate infections. For example, cigarette smoke compromises mucociliary clearance and pulmonary macrophage activity, and alcohol impairs neutrophile function as well as cough and epiglottic reflexes (thereby increasing the risk for aspiration).


Pathology_Robbins

Pathology_Robbins. Bacterial pneumonias are classified according to the specific etiologic agent or, if no pathogen can be isolated, by the clinical setting in which the infection occurs. Altogether, seven distinct clinical settings are recognized, each associated with a fairly distinct group of pathogens (summarized in Table 13.5 ). Thus, consideration of the clinical setting can be a helpful guide when anti-microbial therapy has to be given empirically. Bacterial pneumonias often follow a viral upper-respiratory tract infection. S. pneumoniae (i.e., the pneumococcus) is the most common cause of community-acquired acute pneumonia and is discussed first, followed by other relative common pathogens.


Pathology_Robbins

Pathology_Robbins. Pneumococcal infections occur with increased frequency in two clinical settings: (1) chronic diseases such as CHF, COPD, or diabetes; and (2) congenital or acquired defects in immunoglobulin production (e.g., acquired immune deficiency syndrome [AIDS]). In addition, decreased or absent splenic function (e.g., sickle cell disease or after splenectomy) greatly increases the risk for overwhelming pneumococcal sepsis. You will recall that the spleen contains the largest collection of phagocytes in the body and is the major organ responsible for removing pneumococci from the blood. The spleen also is an important site for Table 13.5 The Pneumonia Syndromes and Implicated Pathogens Streptococcus pneumoniae Haemophilus influenzae Moraxella catarrhalis Staphylococcus aureus Legionella pneumophila Enterobacteriaceae(Klebsiella pneumoniae) andPseudomonas spp. Mycoplasma pneumoniae Chlamydia pneumoniae Coxiella burnetii (Qfever)


Pathology_Robbins

Pathology_Robbins. Respiratorysyncytialvirus,humanmetapneumovirus,parainfluenzavirus(children);influenzaAandB(adults);adenovirus(militaryrecruits) Gram-negativerodsbelongingtoEnterobacteriaceae (Klebsiella spp.,Serratia marcescens, Escherichia coli)andPseudomonas spp. S. aureus (usuallymethicillin-resistant) Anaerobicoralflora(Bacteroides, Prevotella, Fusobacterium, Peptostreptococcus),admixedwithaerobicbacteria(S. pneumoniae, S. aureus, H. influenzae, andPseudomonas aeruginosa) NocardiaActinomycesGranulomatous:Mycobacteriumtuberculosisandatypicalmycobacteria, Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis Anaerobicbacteria(extremelycommon),withorwithoutmixedaerobicinfection S. aureus, K. pneumoniae, Streptococcus pyogenes, andtype3pneumococcus(uncommon)


Pathology_Robbins

Pathology_Robbins. Anaerobicbacteria(extremelycommon),withorwithoutmixedaerobicinfection S. aureus, K. pneumoniae, Streptococcus pyogenes, andtype3pneumococcus(uncommon) Mycobacteriumaviumcomplex(MAC)InvasiveaspergillosisInvasivecandidiasis“Usual”bacterial,viral,andfungalorganisms(listedabove) production of antibodies against polysaccharides, which are the dominant protective antibodies against encapsulated bacteria.


Pathology_Robbins

Pathology_Robbins. The presence of numerous neutrophils in sputum containing the typical gram-positive, lancet-shaped diplococci supports the diagnosis of pneumococcal pneumonia, but it must be remembered that S. pneumoniae is a part of the endogenous flora in 20% of adults, and therefore false-positive results may be obtained. Isolation of pneumococci from blood cultures is more specific but less sensitive (in the early phase of illness, only 20% to 30% of patients have positive blood cultures). Pneumococcal vaccines containing capsular polysaccharides from the common serotypes are used in individuals at high risk for pneumococcal sepsis.


Pathology_Robbins

Pathology_Robbins. Both encapsulated and unencapsulated forms of H. influenzae are important causes of community-acquired pneumonias. The former can cause a particularly life-threatening form of pneumonia in children, often after a respiratory viral infection. Adults at risk for developing infections include those with chronic pulmonary diseases such as chronic bronchitis, cystic fibrosis, and bronchiectasis. H. influenzae is the most common bacterial cause of acute exacerbations of COPD. Encapsulated H. influenzae type b was formerly an important cause of epiglottitis and suppurative meningitis in children, but vaccination against this organism in infancy has significantly reduced the risk.


Pathology_Robbins

Pathology_Robbins. M. catarrhalis is being increasingly recognized as a cause of bacterial pneumonia, especially in older adults. It is the second most common bacterial cause of acute exacerbation of COPD in adults. Along with S. pneumoniae and H. influenzae, M. catarrhalis is one of the three most frequent causes of otitis media (infection of the middle ear) in children. S. aureus is an important cause of secondary bacterial pneumonia in children and healthy adults after viral respiratory illnesses (e.g., measles in children and influenza in both children and adults). Staphylococcal pneumonia is associated with a high incidence of complications, such as lung abscess and empyema. Staphylococcal pneumonia occurring in association with right-sided staphylococcal endocarditis is a serious complication of intravenous drug abuse. It is also an important cause of nosocomial pneumonia (discussed later).


Pathology_Robbins

Pathology_Robbins. K. pneumoniae is the most frequent cause of gram-negative bacterial pneumonia. Klebsiella-related pneumonia frequently afflicts debilitated and malnourished individuals, particularly chronic alcoholics. Thick and gelatinous sputum is characteristic, because the organism produces an abundant viscid capsular polysaccharide, which the patient may have difficulty coughing up.


Pathology_Robbins

Pathology_Robbins. Although discussed here with community-acquired pathogens because of its association with infections in cystic fibrosis, P. aeruginosa infection is most commonly is seen in nosocomial settings (discussed later). Pseudomonas pneumonia also is common in individuals who are neutropenic, usually secondary to chemotherapy; in victims of extensive burns; and in patients requiring mechanical ventilation. P. aeruginosa has a propensity to invade blood vessels at the site of infection, with consequent extrapulmonary spread. Pseudomonas bacteremia is a fulminant disease, with death often occurring within a matter of days. Histologic examination reveals organisms invading the walls of necrotic blood vessels (Pseudomonas vasculitis), leading to secondary coagulative necrosis of the pulmonary parenchyma.


Pathology_Robbins

Pathology_Robbins. L. pneumophila is the agent of Legionnaire disease, an eponym for the epidemic and sporadic forms of pneumonia caused by this organism. Pontiac fever is a related self-limited upper-respiratory tract infection caused by L. pneumophila, without pneumonic symptoms. L. pneumophila flourishes in artificial aquatic environments, such as water-cooling towers and within the tubing system of domestic (potable) water supplies. The mode of transmission is thought to be either inhalation of aerosolized organisms or aspiration of contaminated drinking water. Legionella pneumonia is common in individuals with some predisposing condition such as cardiac, renal, immunologic, or hematologic disease. Organ transplant recipients are particularly susceptible. Legionella pneumonia may be quite severe, frequently requiring hospitalization and producing a fatality rate of 30% to 50% in immunosuppressed individuals. Rapid diagnosis is facilitated by demonstration of Legionella antigens in the urine or by a


Pathology_Robbins

Pathology_Robbins. requiring hospitalization and producing a fatality rate of 30% to 50% in immunosuppressed individuals. Rapid diagnosis is facilitated by demonstration of Legionella antigens in the urine or by a positive fluorescent antibody test on sputum samples; culture remains the standard diagnostic modality. PCR-based tests can be used on bronchial secretions in atypical cases.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Mycoplasma infections are particularly common among children and young adults. They occur sporadically or as local epidemics in closed communities (schools, military camps, prisons). Tests for Mycoplasma antigens and polymerase chain reaction (PCR) testing for Mycoplasma DNA are available. MORPHOLOGYBacterialpneumoniahastwopatternsofanatomicdistribution:lobularbronchopneumoniaandlobarpneumonia( Fig.13.29 ).Inthecontextofpneumonias,theterm“consolidation,”usedfrequently,refersto“solidification”ofthelungduetoreplacementoftheairbyexudateinthealveoli.Patchyconsolidationofthelungisthedominantcharacteristicofbronchopneumonia,whileconsolidationofalargeportionofalobeorofanentirelobedefineslobar pneumonia (Fig.13.30 ).Theseanatomiccategorizationsmaybedifficulttoapplyinindividualcasesbecausepatternsoverlap,andpatchyinvolvementmayevolvetobecome Fig. 13.29 Theanatomicdistributionofbronchopneumoniaandlobarpneumoniaaffectingthelowerlobesofthelung.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. (C)Advancedorganizingpneumonia,featuringtransformationofexudatestofibromyxoidmassesrichlyinfiltratedbymacrophagesandfibroblasts. Complicationsofpneumoniainclude(1)tissuedestructionandnecrosis,causingabscess formation;(2)spreadofinfectiontothepleuralcavity,causingtheintrapleuralfibrinosuppurativereactionknownasempyema;and(3)bacteremic dissemination totheheartvalves,pericardium,brain,kidneys,spleen,orjoints,causingmetastaticabscesses,endocarditis,meningitis,orsuppurativearthritis. The major symptoms of typical community-acquired acute bacterial pneumonia are abrupt onset of high fever, shaking chills, and cough producing mucopurulent sputum; occasional patients have hemoptysis. When pleuritis is present, it is accompanied by pleuritic pain and pleural friction rub. The whole lobe is radiopaque in lobar pneumonia, whereas there are focal opacities in bronchopneumonia.


Pathology_Robbins

Pathology_Robbins. The clinical picture is markedly modified by the administration of effective antibiotics. Treated patients may be relatively afebrile with few clinical signs 48 to 72 hours after the initiation of antibiotics. The identification of the organism and the determination of its antibiotic sensitivity are the keystones of therapy. Less than 10% of patients with pneumonia severe enough to merit hospitalization now succumb, and in most such instances death results from a complication, such as empyema, meningitis, endocarditis, or pericarditis, or to some predisposing influence, such as debility or chronic alcoholism. The most common causes of community-acquired viral pneumonias are influenza types A and B, the respiratory syncytial viruses, human metapneumovirus, adenovirus, rhinoviruses, rubeola virus, and varicella virus (see 13.5 ). Nearly all of these agents also cause upper-respiratory tract infections (“common cold”).


Pathology_Robbins

Pathology_Robbins. These pathologic viruses share a propensity to infect and damage resspiratory epithelium, producing an inflammatory response. When the process extends to alveoli, there is usually interstitial inflammation, but some outpouring of fluid into alveolar spaces may also occur, so that on chest films the changes may mimic those of bacterial pneumonia. As a result, it is not possible to distinguish bacterial and viral pneumonia based on radiologic appearance alone. Moreover, damage leading to necrosis of the respiratory epithelium inhibits mucociliary clearance and predisposes to secondary bacterial infections. Such serious complications of viral infection are more likely in infants, older adults, malnourished patients, alcoholics, and immunosuppressed individuals.


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYThemorphologicpatternsinviralpneumoniasaresimilar.Theprocessmaybepatchy,oritmayinvolvewholelobesbilaterallyorunilaterally.Macroscopically,theaffectedareasarered-blue,congested,andsubcrepitant.Onhistologicexamination,the inflammatory reaction is largely confined to the walls of the alveoli ( Fig.13.32 ).Theseptaarewidenedandedematous;theyusuallycontainamononuclearinflammatoryinfiltrateoflymphocytes,macrophagesand,occasionally,plasmacells.Intheclassiccase,alveolarspacesinviralpneumoniasarefreeofcellularexudate.Inseverecases,however,full-blowndiffusealveolardamagewithhyalinemembranesmaydevelop.Inlesssevere,uncomplicatedcases,subsidenceofthediseaseisfollowedbyreconstitutionofthenormalarchitecture.Superimposedbacterialinfection,asexpected,resultsinamixedhistologicpicture. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig. 13.32 Viralpneumonia.Thethickenedalveolarwallsareinfiltratedwithlymphocytesandsomeplasmacells,whicharespillingoverintoalveolarspaces.Notethefocalalveolaredema(center) andearlyfibrosis(upper right).


Pathology_Robbins

Pathology_Robbins. The clinical course of viral pneumonia is extremely varied. It may masquerade as a severe upper-respiratory tract infection or “chest cold” that goes undiagnosed, or manifest as a fulminant, life-threatening infection in immunocompromised patients. The initial presentation usually is that of an acute, nonspecific febrile illness characterized by fever, headache, and malaise and, later, cough with minimal sputum. The localization of the inflammatory exudate to the alveolar walls, prevents oxygenation of blood flowing through the affected air spaces which in turn causes mismatch of ventilation and perfusion. As a result, the degree of respiratory distress often seems out of proportion to the physical and radiographic findings. Identifying the causative agent can be difficult.


Pathology_Robbins

Pathology_Robbins. Perhaps no other communicable disorder causes as much public concern in the developed world as the threat of an influenza epidemic. The influenza virus is a single-stranded RNA virus, bound by a nucleoprotein that determines the virus type—A, B, or C. The viral surface has a lipid bilayer containing the viral hemagglutinin and neuraminidase, which determine the subtype (e.g., H1N1, H3N2). Host antibodies to the hemagglutinin and neuraminidase prevent and ameliorate, respectively, future infection with the influenza virus. The type A viruses infect humans, pigs, horses, and birds and are the major cause of pandemic and epidemic influenza infections. Epidemics of influenza occur through mutations of the hemagglutinin and neuraminidase antigens that allow the virus to escape most host antibodies (antigenic drift). Pandemics, which last longer and are more widespread than epidemics, may occur when both the hemagglutinin and neuraminidase are replaced through recombination of RNA segments


Pathology_Robbins

Pathology_Robbins. (antigenic drift). Pandemics, which last longer and are more widespread than epidemics, may occur when both the hemagglutinin and neuraminidase are replaced through recombination of RNA segments with those of animal viruses, making all animals susceptible to the new influenza virus (antigenic shift). Commercially available influenza vaccines provide reasonable protection against the disease, especially in vulnerable infants and in older adults.


Pathology_Robbins

Pathology_Robbins. Insight into future pandemics has come from studying those past. DNA analysis of viral genomes retrieved from the lungs of a soldier who died in the great 1918 influenza pandemic that killed 20 million to 40 million individuals worldwide identified swine influenza sequences, consistent with this virus having its origin in an antigenic shift. The first flu pandemic of this century, in 2009, also resulted from an antigenic shift involving a virus of swine origin. It caused particularly severe infections in young adults, apparently because older adults had antibodies against past influenza strains that conveyed partial protection. Comorbidities such as diabetes, heart disease, lung disease, and immunosuppression also were associated with a higher risk for severe infection.


Pathology_Robbins

Pathology_Robbins. What then might be the source of the next great pandemic? One concern is centered on avian influenza, which normally infects birds. One avian strain, type H5N1, has spread throughout the world in wild and domestic birds. As of September 2015, approximately 700 H5N1 influenza virus infections and 400 deaths in humans (from 15 countries) have been reported to the World Health Organization (WHO). Nearly all cases have been acquired by close contact with domestic birds; most deaths resulted from pneumonia. Fortunately, the transmission of the current H5N1 avian virus is inefficient. However, if H5N1 influenza recombines with an influenza that is highly infectious for humans, a strain might emerge that is capable of sustained human-to-human transmission (and, thus, of causing the next great pandemic). S. pneumoniae (thepneumococcus)isthemostcommoncauseofcommunity-acquiredbacterialpneumoniaandusuallyhasalobarpatternofinvolvement.


Pathology_Robbins

Pathology_Robbins. S. pneumoniae (thepneumococcus)isthemostcommoncauseofcommunity-acquiredbacterialpneumoniaandusuallyhasalobarpatternofinvolvement. Morphologically,lobarpneumoniasevolvethroughfourstages:congestion,redhepatization,grayhepatization,andresolution. OthercommoncausesofbacterialpneumoniasinthecommunityincludeH. influenzae andM. catarrhalis (bothassociatedwithacuteexacerbationsofCOPD),S. aureus (usuallysecondarytoviralrespiratoryinfections),K. pneumoniae (observedinchronicalcoholics),P. aeruginosa (seeninindividualswithcysticfibrosis,inburnvictims,andinpatientswithneutropenia),and L. pneumophila, seenparticularlyinorgantransplantrecipients. Viral pneumonias arecharacterizedbyrespiratorydistressoutofproportiontotheclinicalandradiologicsigns,andbyinflammationthatispredominantlyconfinedtoalveolarsepta,withgenerallyclearalveoli. CommoncausesofviralpneumoniaincludeinfluenzaAandB,respiratorysyncytialvirus,humanmetapneumovirus,parainfluenzavirus,andadenovirus.


Pathology_Robbins

Pathology_Robbins. CommoncausesofviralpneumoniaincludeinfluenzaAandB,respiratorysyncytialvirus,humanmetapneumovirus,parainfluenzavirus,andadenovirus. Nosocomial, or hospital-acquired, pneumonias are defined as pulmonary infections acquired in the course of a hospital stay. These infections not only have an adverse impact on the clinical course of ill patients, but http://ebooksmedicine.net also add considerably to the burgeoning costs of health care. Nosocomial infections are common in hospitalized individuals with severe underlying disease, those who are immunosuppressed, or those on prolonged antibiotic regimens. Patients on mechanical ventilation are a particularly high-risk group, and infections acquired in this setting are given the designation ventilator-associated pneumonia. Gram-negative rods (members of Enterobacteriaceae and Pseudomonas spp.) and S. aureus are the most common isolates; unlike community-acquired pneumonias, S. pneumoniae is not a common pathogen in the hospital setting.


Pathology_Robbins

Pathology_Robbins. Aspiration pneumonia occurs in debilitated patients or those who aspirate gastric contents while unconscious (e.g., after a stroke) or during repeated vomiting. Those affected have abnormal gag and swallowing reflexes that facilitate aspiration. The resultant pneumonia is partly chemical, due to the extremely irritating effects of the gastric acid, and partly bacterial. Typically, more than one organism is recovered on culture, aerobes being more common than anaerobes (see Table 13.5 ). Aspiration pneumonia is often necrotizing, pursues a fulminant clinical course, and is a frequent cause of death in individuals predisposed to aspiration. In those who survive, abscess formation is a common complication. Microaspiration, by contrast, occurs in many individuals, especially those with gastroesophageal reflux, and may exacerbate other lung diseases but does not lead to pneumonia.


Pathology_Robbins

Pathology_Robbins. Lung abscess refers to a localized area of suppurative necrosis within the pulmonary parenchyma, resulting in the formation of one or more large cavities. The causative organism may be introduced into the lung by any of the following mechanisms: Aspiration of infective material from carious teeth or infected sinuses or tonsils. This may occur during oral surgery, anesthesia, coma, or alcoholic intoxication, and in debilitated patients with depressed cough reflexes. Aspiration of gastric contents, usually accompanied by infectious organisms originating in the oropharynx. As a complication of necrotizing bacterial pneumonias, particularly those caused by S. aureus, Streptococcus pyogenes, K. pneumoniae, Pseudomonas spp., and, rarely, type 3 pneumococci. Mycotic infections and bronchiectasis also may lead to lung abscesses.


Pathology_Robbins

Pathology_Robbins. Bronchial obstruction, particularly with bronchogenic carcinoma obstructing a bronchus or bronchiole. Impaired drainage, distal atelectasis, and aspiration of blood and tumor fragments all contribute to the development of abscesses. An abscess also may form within an excavated necrotic portion of a tumor. Septic embolism, from infective endocarditis of the right side of the heart. In addition, lung abscesses may result from hematogenous spread of bacteria in disseminated pyogenic infection. This occurs most characteristically in staphylococcal bacteremia and often results in multiple lung abscesses. Anaerobic bacteria are present in almost all lung abscesses, and they are the exclusive isolates in one-third to two-thirds of cases. The most frequently encountered anaerobes are commensals normally found in the oral cavity, principally species of Prevotella, Fusobacterium, Bacteroides, Peptostreptococcus, and microaerophilic streptococci.


Pathology_Robbins

Pathology_Robbins. The manifestations of a lung abscess are much like those of bronchiectasis and include a prominent cough that usually yields copious amounts of foul-smelling, purulent, or sanguineous sputum; occasionally, hemoptysis occurs. Spiking fever and malaise are common. Clubbing of the fingers, weight loss, and anemia may all occur. Abscesses occur in 10% to 15% of patients with bronchogenic carcinoma; thus, when a lung abscess is suspected in an older adult, underlying carcinoma must be considered. Secondary amyloidosis (Chapter 5) may develop in chronic cases. Treatment includes antibiotic therapy and, if needed, surgical drainage. Overall, the mortality rate is in the range of 10%. Chronic pneumonia most often is a localized lesion in an immunocompetent individual, with or without regional lymph node involvement. There is typically granulomatous inflammation, which may be due to bacteria (e.g.,


Pathology_Robbins

Pathology_Robbins. M. tuberculosis) or fungi. In immunocompromised patients, such as those with debilitating illness, on immunosuppressive regimens, or with human immunodeficiency virus (HIV) infection (see later), the usual presentation is widespread disease due to systemic dissemination of the causative organism. Tuberculosis is by far the most important entity within the spectrum of chronic pneumonias. http://ebooksmedicine.net Tuberculosis is a communicable chronic granulomatous disease caused by Mycobacterium tuberculosis. It usually involves the lungs but may affect any organ or tissue in the body.


Pathology_Robbins

Pathology_Robbins. The World Health Organization (WHO) considers tuberculosis to be the most common cause of death resulting from a single infectious agent. It is estimated that 1.7 billion individuals are infected worldwide, with 8 to 10 million new cases and 1.5 million deaths per year. In the Western world, deaths from tuberculosis peaked in 1800 and steadily declined throughout the 1800s and 1900s. However, in 1984 the decline in new cases stopped abruptly, a change that resulted from the increased incidence of tuberculosis in HIV-infected individuals. As a consequence of intensive public health surveillance and tuberculosis prophylaxis among immunosuppressed individuals, the incidence of tuberculosis in U.S.-born individuals has declined since 1992. In 2014, there were approximately 9400 new cases of active tuberculosis in the United States, with nearly 60% of these occurring in immigrants from countries where tuberculosis is endemic.


Pathology_Robbins

Pathology_Robbins. Tuberculosis flourishes under conditions of poverty, crowding, and chronic debilitating illness. In the United States, tuberculosis is a disease of older adults, the urban poor, patients with AIDS, and members of minority communities. African Americans, Native Americans, the Inuit (from Alaska), Hispanics, and immigrants from Southeast Asia have higher rates of disease than other segments of the population. Certain disease states also increase the risk, such as diabetes mellitus, Hodgkin lymphoma, chronic lung disease (particularly silicosis), chronic renal failure, malnutrition, alcoholism, and immunosuppression. In areas of the world where HIV infection is prevalent, HIV infection is the dominant risk factor for the development of tuberculosis.


Pathology_Robbins

Pathology_Robbins. It is important that infection be differentiated from disease. Infection implies seeding of a focus with organisms, which may or may not cause clinically significant tissue damage (i.e., disease). Although other routes may be involved, most infections are acquired by direct person-toperson transmission of airborne droplets of organisms from an active case to a susceptible host. In most individuals, an asymptomatic focus of pulmonary infection appears that is self-limited, although uncommonly, primary tuberculosis may result in the development of fever and pleural effusions. Generally, the only evidence of infection, if any remains, is a tiny, telltale fibrocalcific nodule at the site of the infection. Viable organisms may remain dormant in such loci for decades, and possibly for the life of the host. Such individuals are infected but do not have active disease and therefore cannot transmit organisms to others. Yet, if their immune defenses are lowered, the infection may reactivate to


Pathology_Robbins

Pathology_Robbins. of the host. Such individuals are infected but do not have active disease and therefore cannot transmit organisms to others. Yet, if their immune defenses are lowered, the infection may reactivate to produce communicable and potentially life-threatening disease.


Pathology_Robbins

Pathology_Robbins. Infection with M. tuberculosis typically leads to the development of delayed hypersensitivity, which can be detected by the tuberculin (Mantoux) test. About 2 to 4 weeks after the infection has begun, intracutaneous injection of 0.1 mL of sterile purified protein derivative (PPD) induces a visible and palpable induration (at least 5 mm in diameter) that peaks in 48 to 72 hours. Sometimes, more PPD is required to elicit the reaction, and unfortunately, in some responders, the standard dose may produce a large, necrotizing lesion. A positive tuberculin skin test result signifies cell-mediated hypersensitivity to tubercular antigens, but does not differentiate between infection and disease. A well-recognized limitation of this test is that false-negative reactions (or skin test anergy) may be produced by certain viral infections, sarcoidosis, malnutrition, Hodgkin lymphoma, immunosuppression, and (notably) overwhelming active tuberculous disease. False-positive reactions may result from


Pathology_Robbins

Pathology_Robbins. produced by certain viral infections, sarcoidosis, malnutrition, Hodgkin lymphoma, immunosuppression, and (notably) overwhelming active tuberculous disease. False-positive reactions may result from infection by atypical mycobacteria.