7. The Lung

Question 1

Acute respiratory distress syndrome

Answer 1

• ARDS is a clinical syndrome of progressive respiratory insufficiency caused by diffuse alveolar damage in the setting of sepsis, severe trauma, or diffuse pulmonary infection.
• Neutrophils and their products have a crucial role in the pathogenesis of ARDs by causing endothelial and epithelial injury.
• The characteristic histologic picture is that of alveolar edema, epithelial necrosis, accumulation of neutrophils, and presence of hyaline membranes lining the alveolar wall and ducts.

Question 2

Emphysema

Answer 2

• Emphysema is a chronic obstructive airway disease characterized by enlargement of air spaces distal to terminal bronchioles.
• Subtypes include centriacinar (most common: smoking related), panacinar (seen in a1-anti-trypsin deficiency), distal acinar, and irregular.
• Smoking and inhaled pollutants cause ongoing accumulation of inflammatory cells, which are the source of proteases such as elastases that irreversibly damage alveolar walls.
• Patients with uncomplicated emphysema present with increased chest volumes, dysnpea, and relatively normal blood oxygenation at rest (”pink puffers”).
• Most patients with emphysema also have signs and symptoms of concurrent chronic bronchitis, since cigarette smoking is a risk factor for both.

Question 3

Chronic bronchitis

Answer 3

• Chronic bronchitis is defined as persistend productive cough for at least 3 consecutive months in at least 2 consecutive years.
• Cigarette smoking is the most important underlying risk factor; air pollutants also contribute.
• Chronic airway obstruction largely results from small airway disease (chronic bronchiolitis) and coexistent emphysema.
• Histologic examination demonstrates enlargement of mucus-secreting glands, goblet cell metaplasia, and bronchiolar wall fibrosis.

Question 4

Asthma

Answer 4

• Asthma is characterized by reversible bronchoconstriction caused by airway hyperresponsiveness to a variety of stimuli.
• Atopic asthma most often is caused by T(H)2 and IgE-mediated immunologic reaction to environmental allergens and is characterized by early-phase (immediate) and late-phase reactions. The T(H)2 cytokines IL4, IL5, and IL13 are important mediators. Non-T(H)2 inflammation also has roles in atopic asthma that are being defined.
• Triggers for nonatopic asthma are less clear but include viral infections and inhaled air pollutants, which also can trigger atopic asthma.
• Eosinophils are key inflammatory cells found in almost all subtypes of asthma: eosinophil products (such as major basic protein) are responsible for airway damage.
• Airway remodeling (sub-basement membrane thickening and hypertrophy of bronchial glands and smooth muscle) adds an irreversible component to the obstructive disease.

Question 5

Chronic interstitial lung diseases

Answer 5

• Diffuse interstitial fibrosis of the lung gives rise to restrictive lung diseases characterized by reduced lung compliance and reduced forced vital capacity (FVC). The ratio of FEV to FVC is normal.
• Disease that cause diffuse interstitial fibrosis are heterogeneous. The unifying pathogenic factor is injury to the alveoli leading to activation of macrophages and release of fibrogenic cytokines such as TGF-B.
• Idiopathic pulmonary fibrosis is prototypic of restrictive lung diseases. It is characterized by patchy interstitial fibrosis, firbroblastic foci, and formation of cystic spaces (honeycomb lung). This histologic pattern is known as usual interstitial pneumonia (UIP).

Question 6

Pneomococonioses

Answer 6

• Pneumoconioses encompass a group of chronic fibrosing diseases of the lung resulting from exposure to organic and inorganic particulates, most commonly mineral dust.
• Pulmonary alveolar macrophages play a central role in the pathogenesis of the lung injury by promoting inflammation and producing reactive oxygen species and fibrogenic cytokines.
• Coal dusted-induced disease varies from asymptomatic anthracosis, to simple coal worker’s pneumoconiosis (coal macules or nodules, and centrilobular emphysema), to progressive massive fibrosis (PMF), manifested by increasing pulmonary dysfunction, pulmonary hypertension, and cor pulmonale.
• Silicosis is the most common pneumoconiosis in the world, and crystalline silica (e.g. quartz) is the usual culprit)
• The manifestations of the silicosis range from asymptomatic silicotic nodules to PMF; individuals with silicosis also have an increased susceptibility to tuberculosis. The relationship between silica exposure and subsequent lung cancer is controversial.
• Asbestos exposure is linked with six disease processes: (1) parenchymal interstitial fibrosis (asbestos); (2) localized fibrous plaques or, rarely diffuse pleural fibrosis; (3) pleural effusions; (4) lung cancer; (5) malignant pleural and peritoneal mesothelioma; and (6) laryngeal cancer.
• Cigarette smoking increases the risk for lung cancer in the setting of asbestos exposure; moreover, even family members of workers exposed to asbestos are at increased risk for cancer.

Question 7

Sarcoidosis

Answer 7

• multisystem disease of unkown etiology; the diagnostic histopathologic feature is the presence of noncaseating granulomas in various tissues.
• Immunologic abnormalities include high levels of CD4+ T(H)1 cells in the lung that secrete cytokines such as IFN-y.
• Clinical manifestations: lymph node enlargement, eye involvement (sicca syndrome [dry eyes], iritis, or iridocyclitis), skin lesions (erythema nodosum, painless subcutaneous nodules), and visceral involvement (liver, skin, bone marrow). Lung involvement occurs in 90% of cases, with formation of granulomas and interstitial fibrosis.

Question 8

Pulmonary embolism

Answer 8

• Almost all large pulmonary artery thrombi are embolic in origin, usually arising from the deep veins of the lower leg.
• Risk factors include prolonged bed rest, knee or hip surgery, severe trauma, congestive heart failure, use of oral contraceptives (especially those with high estrogen content), disseminated cancer, and genetic causes of hypercoagulability.
• Most emboli (60% to 80%) are clinically silent; a minority (5%, typically large “saddle emboli”) cause acute right-sided heart failure, shock, or sudden death; and the remainder cause pulmonary infarction.
• Risk of recurrence is high.

Question 9

Acute pneumonias

Answer 9

• S. pneumoniae (the pneumococcus) is the most common cause of community-acquired bacterial pneumonia and usually has a lobar pattern of involvement.
• Morphologically, lobar pneumonias evolve through four stages: congestion, red hepatization, gray hepatization, and resolution.
• Other common causes of bacterial pneumonias in the community include H. influenzae and M. catarrhalis (both associated with acute exacerbations of COPD), S. aureus (usually secondary to viral respiratory infections), K. pneumoniae (observed in chronic alcoholics), P. aeruginosa (seen in individuals with cystic fibrosis, in burn victims, and in patients with neutropenia), and L. pneumophila, seen particularly in organ transplant recipients.
• Viral pneumonias are characterized by respiratory distress, and by inflammation that is predominantly confined to alveolar septa, with generally clear alveoli.
• Common causes of viral pneumonia include influenza A and B, respiratory syncytial virus, human metapneumovirus, parainfluenza virus, and adenovirus.

Question 10

Tuberculosis

Answer 10

• Tuberculosis is a chronic granulomatous disease caused by M. tuberculosis, usually affecting the lungs, but virtually any extrapulmonary organ can be involved.
• Initial exposure to mycobacteria results in development of a cellular immune response that confers resistance and leads to hypersensitivity (positive result on the tuberculin skin test).
• The T(H)1 subset of CD4+ T cells has a crucial role in cell-mediated immunity against mycobacteria; mediators of inflammation and bacterial containment include IFN-y, TNF, and nitric oxide.
• The histopathologic hallmark of host reaction to tuberculosis is in immunocompetent individuals is the presence of granulosmas, usually with caseous necrosis.
• Primary pulmonary tuberculosis in immunocompetent individuals is asymptomatic and results only in healed lesions, typically in a sub-pleural focus and a draining lymph node.
• Secondary (reactivation) tuberculosis arises in previously expossed individuals when host immune defenses are compromised, and usually manifests as cavitary lesions in the lung apices.
• Both progressive primary tuberculosis and secondary tuberculosis can result in systemic seeding, causing life-threatening forms of disease such as miliary tuberculosis and tuberculous meningitis.
• HIV-seropositive status is an important risk factor for development or recrudescence of active tuberculosis.

Question 11

Carcinoma of the lung

Answer 11

• adenocarcinoma (most common), squamous cell carcinoma, and small cell carcinoma, each clinically and genetically distinct. Adenocarcinomas are the most common cancers overall and are especially in women and in nonsmokers.
• Smoking is the most important risk factor for lung cancer.
• Precursor lesions include atypical adenomatous hyperplasia and adenocarcinoma in situ for adenocarcinomas and squamous dysplasia for squamous cancer.
• Tumors 3cm or less in diameter characterized by pure growth along preexisting structures without stromal invasion are called adenocarcinoma in situ.
• SCLCs are best treated with chemotherapy, because almost all are metastatic at presentation. The other carcinomas may be curable by surgery if limited to the lung. Targeted therapies, such as EGFR inhibitor therapy for adenocarcinomas with EGFR mutations, ca be effective, (example of personalized cancer therapy). Immunotherapies are under development.
• Lung cancers commonly cause a variety of paraneoplastic syndromes.