Chapter 35. The Lung: II. Toxic, Immunologic, & Vascular Diseases

Infections of the Air Passages

Acute Tracheobronchitis

Acute tracheobronchitis commonly complicates a severe upper respiratory tract infection, particularly Haemophilus influenzae infection of the larynx in young children and influenza in adults and children (see Chapter 32: The Ear, Nose, Pharynx, & Larynx). Viral tracheobronchitis may also be complicated by secondary bacterial infection, most commonly with Staphylococcus aureus.

Acute Bronchiolitis

Acute bronchiolitis is a common, often epidemic, infection of the small airways that occurs mainly in children under the age of 2 years. Most cases are mild, but 1–2% require hospitalization, and about 1% of these children die. Most cases are caused by respiratory syncytial virus; more rarely, parainfluenza virus and adenoviruses are responsible. The bronchioles show acute epithelial damage and lymphocytic infiltration of the walls. Their lumens are filled with mucus plugs, which cause distal alveolar air trapping. In patients who recover, the bronchiolar epithelium regenerates within 2 weeks. Patients present with acute-onset tachypnea and wheezing; fever is low-grade and may be absent. Cases caused by adenoviruses tend to have greater degrees of necrosis and a higher mortality rate.

Whooping Cough (Pertussis)

Caused by Bordetella pertussis, whooping cough is an extremely serious acute respiratory tract infection of the young. Prior to immunization (the “P” of diphtheria-pertussis-tetanus [Vaccine] (DPT)), it accounted for 40% of all deaths in the first 6 months of life. Clinically, it is an acute tracheobronchitis, characterized by paroxysmal coughing and an inspiratory whoop (most often seen in older children). Otitis media, bronchitis, and bronchiectasis are serious complications. Tetracycline is effective in therapy.

Bronchial Asthma

Bronchial asthma is a disease in which there is increased responsiveness of the tracheobronchial tree to a variety of stimuli. Exposure to these stimuli leads to bronchiolar smooth muscle contraction (bronchospasm). The cause of the increased responsiveness of the air passages is unknown but is believed to be related to bronchial inflammation. Bronchospasm causes obstruction to air flow—maximal in expiration—and a high-pitched wheeze. Expiration is prolonged because of airflow obstruction. Attacks of asthma are usually of short duration and reverse completely. Rarely, they may be severe and prolonged (status asthmaticus), and may lead to acute ventilatory failure and even death.

Etiology & Classification

Extrinsic Allergic Asthma

Extrinsic allergic asthma is a reagin-mediated type I hypersensitivity (atopic) reaction. It is common in childhood and has a familial tendency. Many different antigens may be involved (Table 35-1). Serum IgE is increased, and skin tests against the offending antigens are positive.

Intrinsic (Nonallergic) Asthma

It has been suggested that patients with intrinsic asthma have hyperreactive airways that constrict in response to a variety of nonspecific stimuli, due in part to abnormal β-adrenergic responses. Aspirin, cold, exercise, and respiratory infections are common precipitants of attacks. Serum IgE levels are normal, and skin tests are negative. Intrinsic asthma occurs in older patients.

Pathology

In extrinsic allergic asthma, the inhaled antigen combines with specific IgE on the surface of mast cells in the respiratory mucosa, releasing histamine (Figure 35-1). Other mediators such as bradykinin, leukotrienes, prostaglandins, and platelet-aggregating factor are produced, leading to bronchoconstriction and acute inflammation. Bronchioles show vascular congestion, edema, and infiltration by neutrophils and eosinophils. The bronchioles become filled with thick mucous secretions (Figure 35-2).

Bronchiolar obstruction due to smooth muscle contraction, mucoid plugs, and inflammatory edema is maximal in expiration. This results in distal air trapping and alveolar distention. Vital capacity and Forced expiratory volume in one second (FEV1) decrease, and residual volume increases. Patients who present for therapy have an FEV1 that is < 30% of predicted. Hypoxia is always present and is often associated with hypocapnia and a respiratory alkalosis due to hyperventilation. An increased Pco2 and acidosis indicates severe obstruction and ventilatory failure.

Clinical Features

Bronchial asthma is characterized by episodic attacks of dyspnea and wheezing. A dry cough is common during the acute attack and may produce thick, tenacious, scanty sputum that is stringy, forming casts of the bronchioles (Curschmann's spirals). In severe attacks, there is frequently secondary bacterial infection. Allergic asthma occurs in childhood and tends to disappear as the child grows. Intrinsic asthma occurs in older individuals and tends to produce a more chronic disease.

Treatment & Prevention

Treatment of the acute attack is with bronchodilator drugs. These drugs may be given as aerosol sprays. Corticosteroids are effective in severe cases.

Further treatment consists of control of secondary infection when it complicates a severe attack and identification of allergens followed by their avoidance. Skin testing to identify allergens may be followed by desensitization (hyposensitization), which involves serial injection of increasing doses of the responsible antigen; IgG blocking antibodies probably form, and the severity of disease is reduced in about 20% of patients.

COPD is characterized by features of chronic obstruction to air flow in the lungs. It is diagnosed by abnormalities in tests of ventilatory function. The FEV1:forced vital capacity (FVC) ratio (see Chapter 34: The Lung: I. Structure & Function; Infections) is the most widely used test. Normally, the FEV1:FVC ratio is over 75%. In COPD, the ratio is decreased (Figure 35-3), with the degree of reduction correlating well with disease severity and survival.

Incidence

COPD is a common disease second only to ischemic heart disease as a cause of chronic disability in older individuals. The incidence is increasing.

Pathology

COPD, as defined by the ventilatory abnormality, is associated with two distinctive pathologic conditions: chronic bronchitis and emphysema. These two conditions contribute in variable degree to COPD in individual patients.

Chronic Bronchitis

Chronic bronchitis is defined clinically as a persistent presence of increased bronchial mucus secretion that leads to chronic cough productive of mucoid sputum. Pathologic examination shows hypertrophy of bronchial wall mucous glands associated with chronic inflammation and fibrous replacement of the muscular walls of small bronchioles (Figure 35-4). The Reid index—the ratio of mucous gland thickness to bronchial wall thickness—is increased above the normal value of 0.5. Fibrotic bronchioles tend to collapse in expiration under the influence of the positive intrathoracic pressure, resulting in ventilatory obstruction in expiration (chronic obstructive bronchitis).

Emphysema in COPD

Emphysema is defined in pathologic terms as permanent dilation of the air spaces distal to the terminal bronchiole, usually with destruction of lung parenchyma. To produce clinical COPD, large areas of the lung must be involved by emphysema. Two principal types of emphysema are recognized (Figure 35-5): (1) centrilobular emphysema, in which dilation and destruction primarily involve the central part of the acinus formed by the respiratory bronchioles; and (2) panacinar emphysema, in which dilation and destruction involve the entire acinus, including the alveoli and alveolar ducts as well as the respiratory bronchioles (Figure 35-5).

Accurate recognition of the gross and microscopic features of emphysema at autopsy requires fixation of the lungs in a state of inflation. This technique permits the gross demonstration of dilated air spaces and microscopic documentation of alveolar destruction (Figure 35-6).

Other Forms of Emphysema

Several other types of emphysema are recognized but are not usually associated with COPD (Table 35-2). These conditions fit the pathologic definition of emphysema—dilation and destruction of the small airways and alveoli—but usually do not involve a large enough area of lung parenchyma to produce clinical effects.

Pathogenesis of Chronic Bronchitis

(Table 35-2)

Chronic bronchitis is 5–10 times more common in heavy cigarette smokers than in nonsmokers, even after correction for other factors such as age, sex, place of residence, and occupation. Cigarette smoking acts as a local irritant, causing hypertrophy of bronchial mucous glands, increase in the number of mucous cells, hypersecretion of mucus, and increased numbers of neutrophils. Other inhaled irritants such as sulfur dioxide and oxides of nitrogen associated with heavy air pollution cause exacerbation of chronic bronchitis.

The hypersecretion of mucus increases the susceptibility to bacterial infection. In cigarette smokers, this predisposition is further aggravated by interference with ciliary action that results from smoking. Haemophilus influenzae, pneumococci, and Streptococcus viridans are common pathogens. These organisms cause both a chronic low-grade inflammation of the bronchiolar wall and acute exacerbations with suppuration manifested clinically as fever and expectoration of purulent sputum. Inflammation leads to progressive destruction of the muscle of the bronchiolar wall, with replacement by collagen.

In heavy smokers, the initial changes of chronic bronchitis are present from an early age, but COPD usually does not become clinically apparent until the fourth or fifth decade of life.

Pathogenesis of Emphysema

(Table 35-2)

(Figure 35-5)

The destruction of lung parenchyma in emphysema is believed to be due to the action of proteolytic enzymes (proteases, mainly elastase). One important source of these proteases is leukocytes associated with pulmonary inflammation. Normally, antiproteolytic substances such as antitrypsins in the plasma inactivate these proteolytic enzymes as they are released and thereby protect tissues from damage. However, lung destruction—and emphysema—occur in patients who either produce an excess of proteolytic enzymes (chronic neutrophil infiltration) or have too little antiproteolytic activity in the plasma (α1-antiprotease deficiency; see below). Hypersecretion of mucus in chronic bronchitis and emphysema favors inflammation and local leukocyte enzyme release.

Cigarette smoking is an important etiologic factor in emphysema. Chronic irritation resulting from smoking results in increased numbers of neutrophils, and cigarette smoke directly promotes elastase release from neutrophils. The chronic bacterial infection associated with chronic bronchitis in smokers also contributes to the increased levels of leukocyte-derived proteolytic enzymes. The lungs of heavy smokers show inflammation and destruction of the respiratory bronchioles, with centrilobular emphysema beginning at a relatively young age.

Alpha1-antiprotease (α1-antitrypsin) deficiency predisposes to emphysema because α1-antiprotease is responsible for the major part of plasma antiproteolytic activity. The α1-antiprotease level in serum is determined by inheritance at a single (Pi, or protease inhibitor) locus. A normal individual has two M alleles at this locus (PiMM). The Z allele is the most common of several abnormal alleles that may be inherited. PiZZ homozygotes have severe deficiency of α1-antiprotease and almost invariably develop panacinar emphysema by age 40 years.

PiZZ occurs with a frequency of 1:4000 and thus is a very rare cause of emphysema; it cannot account for most of the cases of COPD in the population. The heterozygous PiMZ state occurs in about 5% of the population in the United States and Europe and is potentially a factor in the genesis of the common type of COPD. The PiMZ state is associated with a moderate reduction in serum α1-antiprotease. While PiMZ has been associated with emphysema in some families, general population studies have not confirmed a causal association between emphysema and the PiMZ genotype.

Clinical Features

(Table 35-3)

Patients with COPD are asymptomatic in the early stages of the disease because of pulmonary reserve; however, the FEV1:FVC ratio is decreased, as is vital capacity and maximal ventilatory volume. The total lung capacity and residual volume are often increased as a result of air trapping in the distended air spaces.

In the later symptomatic phase, COPD patients present with a spectrum of symptoms, the 2 extremes of which are sometimes designated types A and B. In most cases, features of both type A and type B are present.

Type A patients present with chronic cough—either dry or productive of mucoid sputum—progressive dyspnea, and wheezing. They hyperventilate, and often sit hunched forward (to bring accessory respiratory muscles into action) with mouth open and nostrils dilated in an attempt to overcome the ventilatory difficulty. Their lungs are overinflated, with increased anteroposterior diameter of the chest (barrel chest) and flattened diaphragm on chest x-ray. These patients successfully maintain oxygenation of the blood by hyperventilation. Patients with type A COPD are sometimes called “pink puffers.”

Type B patients have marked chronic obstructive bronchitis and cannot hyperventilate. There is decreased oxygenation of blood (cyanosis) and increased arterial carbon dioxide content. They also have pulmonary hypertension caused by changes in the microvasculature of the lung parenchyma. This leads to right ventricular hypertrophy and failure (cor pulmonale), and peripheral edema due to right heart failure is a dominant clinical feature. Type B patients are sometimes called “blue bloaters.”

The correlation between these clinical types and pathologic changes is inexact. Type A patients frequently have dominant emphysematous changes, while type B patients usually have dominant chronic obstructive bronchitis. Most patients, however, have varying mixtures of both pathologic changes and clinical features.

Changes in blood gases in patients with COPD are variable. In the early stages, blood gases are normal at rest, but hypoxemia develops during exercise due to the decreased pulmonary reserve. Blood gas changes result from decreased alveolar ventilation and imbalanced ventilation and perfusion, with the latter the dominant abnormality in many cases.

In type B patients with chronic hypercapnia (elevated Pco2), the respiratory center becomes insensitive to the Pco2 stimulus and is driven by the hypoxemia. Administration of oxygen in these patients can remove the respiratory center drive and cause carbon dioxide retention and death (carbon dioxide narcosis).

Treatment

Cessation of smoking and prevention and early treatment of infections are the only methods available to prevent progression of COPD. Bronchodilators are useful in some patients who have reversible bronchial obstruction, particularly in the early stages of COPD. When hypoxemia becomes persistent and severe (PaO2 <60 mm Hg) or associated with cor pulmonale, continuous oxygen therapy is indicated.

Bronchiectasis is abnormal and irreversible dilation of the bronchial tree proximal to the terminal bronchioles—in contrast to emphysema, which involves the bronchial tree distal to the terminal bronchioles.

Etiology

Bronchiectasis is the result of chronic infection with resulting parenchymal destruction, fibrosis, and abnormal permanent dilation of damaged bronchi. Several causes act singly or in concert.

1. Long-standing bronchial obstruction, as occurs in bronchial tumors and stenosis. Stagnation of mucus is followed by bronchopneumonia distal to the obstruction, progressing to localized fibrosis and bronchiectasis.

2. Mucoviscidosis (Fibrocystic Disease of the Pancreas): (See Chapter 45: The Exocrine Pancreas.) In this condition, mucus is abnormally thick and viscous; it plugs the smaller bronchi, causing obstruction and predisposing to recurrent infection.

3. Bronchopneumonia, particularly following childhood infections such as measles and whooping cough, which in the past were common antecedents of bronchiectasis. Bronchiectasis occurs today in immunodeficient children who are susceptible to recurrent pulmonary infections.

4. Kartagener's Syndrome: Kartagener's syndrome is due to a congenital defect in ciliary motion caused by absence of the dynein arms in cilia. The lack of ciliary action interferes with clearance of mucus and bacteria in the bronchi, predisposing to bronchopneumonia and therefore bronchiectasis. Chronic infection of the paranasal sinuses also results in absence of the frontal sinuses in this condition. In the male, absence of dynein arms in the microtubules of the sperm tail leads to loss of sperm motility and infertility. Dextrocardia (location of the heart on the right side) completes the syndrome.

   Kartagener's syndrome is inherited as an autosomal recessive trait and has an incidence of 1:20,000.

5. Intralobar Sequestration of the Lung (Congenital): In this rare condition a part of the lung receives either no pulmonary arterial supply or no communication with the bronchial tree. The sequestered lobe maintains nutrition via its bronchial arterial supply. The bronchi within the area, however, have no drainage and therefore undergo infection and dilation.

Pathology

(Figure 35-7)

Bronchiectasis usually has a patchy distribution, depending on the extent of bronchial obstruction. The lower lobes are the most commonly affected. The dilated bronchi and bronchioles may be cylindric, fusiform, or saccular and are made more conspicuous by extensive destruction and fibrosis of the intervening lung parenchyma. An important diagnostic feature is the finding of large bronchi near the pleura.

The walls of the distended bronchi show inflammation and fibrosis. The mucosa may be ulcerated, and the lumen is commonly filled with pus.

Clinical Features

Bronchiectasis is a chronic illness with cough, usually productive of a large volume of foul-smelling sputum, and episodic fever. The chronic infection commonly causes clubbing of fingers and hyperglobulinemia and may cause secondary amyloidosis.

Common bacteria cultured from bronchiectatic cavities include Staphylococcus aureus, Staphylococcus epidermidis; streptococci of all types, including pneumococci; Haemophilus influenzae; enteric gram-negative bacilli; and anaerobes. Several of these organisms can usually be grown at any one time. Rarely, bacteremia may occur.

Treatment

The treatment of bronchiectasis consists of control of infection with antibiotics and removal of predisposing causes such as bronchial obstruction by surgery, when possible. Surgical removal of bronchiectatic areas is important because the permanently dilated bronchi represent foci of almost continuous infection.

Chronic diffuse interstitial lung diseases are noninfectious disorders characterized by diffuse inflammation and fibrosis involving the interstitium of the alveolar septum (Figure 35-8). The end stage is associated with extensive parenchymal destruction, fibrosis, and often the formation of abnormal cystic spaces (honeycomb lung).

General Clinical & Pathologic Features

Patients with diffuse interstitial lung disease present with dyspnea, tachypnea, and cyanosis. Pulmonary function abnormalities are of the restrictive type, with reduced vital capacity but no airway obstruction. The FEV1:FVC ratio is normal. Thickening of the alveolar membrane affects diffusion of oxygen, leading to hypoxemia. This stimulates the respiratory center, resulting in increased ventilation. Carbon dioxide, which is much more diffusible than oxygen, is washed out, resulting in lowered Pco2 levels. Chest x-ray shows a characteristic reticulonodular pattern of interstitial involvement.

Etiology

Diffuse infiltrative lung disease has many causes (Table 35-4). While all produce the general picture described above, some have individual features that permit specific diagnosis.

Immunologic Interstitial Pneumonitis & Fibrosis

Idiopathic Pulmonary Fibrosis (Fibrosing Alveolitis; Hamman-Rich Syndrome)

Idiopathic pulmonary fibrosis is actually a group of diseases characterized by diffuse interstitial fibrosis occurring without recognized cause. About half the cases of chronic diffuse interstitial lung disease fall into this category. Alhough the cause is unknown, the presence of circulating immune complexes, immunoglobulin deposition in the interstitium in many patients, and the response of early disease to treatment with steroids strongly suggest an immunologic basis.

The alveolar macrophage is thought to be responsible for mediating fibrosis. In idiopathic pulmonary fibrosis, alveolar macrophages express several genes that encode for mediators such as fibronectin and platelet-derived growth factor that recruit and stimulate fibroblasts. The production of platelet-derived growth factor by alveolar macrophages in idiopathic pulmonary fibrosis correlates with activation of the c-sis gene in these cells. The c-sis gene encodes for the B chain of platelet-derived growth factor.

Clinically, patients present with progressive dyspnea and cough and ventilatory failure of the restrictive type. A defect in oxygen diffusion across the abnormal alveolar membrane may also contribute. The rate of progression is quite variable; a rapidly progressive variant that may cause death in 1–2 years is sometimes called Hamman-Rich syndrome.

Idiopathic pulmonary fibrosis is classified according to the histologic appearance of the lung, as discussed below.

Usual Interstitial Pneumonitis

This accounts for the majority of cases. In the acute phase, there is interstitial infiltration with lymphocytes, plasma cells, and macrophages; pulmonary edema; acute alveolar damage; and proteinaceous hyaline membranes. The damaged alveoli are lined by type II pneumocytes, which can appear so atypical cytologically as to mimic the appearance of an adenocarcinoma. In the acute phase, the disease may respond to treatment with immunosuppressive agents such as corticosteroids. The acute phase is followed by proliferation of fibroblasts and laying down of collagen in the alveolar interstitium (Figure 35-8). The rate of fibrosis is variable, but the occurrence of fibrosis represents irreversibility.

The course is characteristically protracted, with respiratory failure occurring many years after onset. When interstitial fibrosis (honeycomb lung) is present, the clinical response to steroids is poor.

Desquamative Interstitial Pneumonitis

The desquamative form is similar to the foregoing except for the aggregation of desquamated cells in alveoli—a variable mixture of macrophages and type II pneumocytes. Controversy exists about whether this is a variant of usual interstitial pneumonitis or a completely different disease. The course is similar to that of slowly progressive usual interstitial pneumonitis.

Lymphocytic Interstitial Pneumonitis (Pseudolymphoma)

Lymphocytic interstitial pneumonitis is characterized by extensive infiltration of the interstitium with lymphocytes and plasma cells. It may be diffuse or may involve a single area of lung, producing a mass lesion (pseudolymphoma). The disorder is associated with an increased incidence of primary pulmonary malignant lymphoma; in some cases, the process appears to be a primary low-grade malignant lymphoma.

Hypersensitivity Pneumonitis (Extrinsic Allergic Alveolitis)

Hypersensitivity pneumonitis results from inhalation by susceptible individuals of small organic particles (antigens), most commonly spores of thermophilic fungi. These fungi grow best at 50–60 °C in decaying vegetation such as hay and sugar cane or in heated water in air-conditioning and heating systems.

Individuals working in a variety of occupations are at risk, and the disease frequently bears the name of these occupations (see Chapter 8: Immunologic Injury). Thermophilic actinomycete spores occur in moldy hay (farmer's lung), moldy sugar cane residue (bagassosis), and compost for mushroom growing (mushroom worker's disease). In urban areas, the spores are most frequently found in contaminated forced-air-heating and air-conditioning systems. Antigenic products are also found in bird droppings (bird-fancier's lung), dead wood (maple bark stripper's disease), and barley malt used in brewing (malt worker's lung).

Pathogenesis

Hypersensitivity pneumonitis is caused by a combination of type III hypersensitivity associated with precipitating IgG antibodies, which are present in the serum of 70% of patients, producing a local Arthus type immune complex reaction with complement deposition in the lung; and T lymphocyte-mediated type IV hypersensitivity, leading to the formation of small, noncaseating epithelioid cell granulomas in the alveolar septa (Table 35-5). Bronchoalveolar lavage demonstrates an increase in T lymphocytes.

Pathology

Hypersensitivity pneumonitis is characterized by an acute interstitial pneumonitis. The alveolar septa are expanded by neutrophils, lymphocytes, and plasma cells. Poorly formed alveolar granulomas with giant cells are typically present. Fibrous obliteration of bronchioles (bronchiolitis obliterans) is a characteristic change.

If the disease is recognized early and the patient removed from the source of antigen, the disease is reversible. With continued exposure, diffuse interstitial fibrosis occurs, leading to end-stage honeycomb lung. As fibrosis becomes more advanced, the disease becomes irreversible.

Clinical Features

Patients present with acute dyspnea, fever, and cough 4–6 hours after exposure to the antigen. Initially, these symptoms subside spontaneously in 12–18 hours. As pulmonary fibrosis ensues, the disease goes into its chronic phase, with all the features of diffuse interstitial lung disease.

Eosinophilic Pneumonias

Eosinophilic pneumonias are a group of diseases characterized by eosinophilic pulmonary interstitial infiltrates and peripheral blood eosinophilia. These disorders may be idiopathic or may be due to (1) allergic bronchopulmonary aspergillosis, in which there is also bronchial asthma, elevated serum IgE, and evidence of bronchial infection by Aspergillus fumigatus; (2) parasitic (larval) infections, including filariasis, ascariasis, and strongyloidiasis; or (3) drug reactions to nitrofurantoin, sulfonamides, penicillin, gold, and antituberculous agents.

Idiopathic eosinophilic pneumonia may be acute and self-limiting, with minimal clinical effect (Löffler's syndrome), or chronic, with cough, fever, and weight loss lasting several months (chronic eosinophilic pneumonia).

Allergic angiitis and granulomatosis of Churg and Strauss shows features of eosinophilic pneumonia with asthma combined with a multisystem vasculitis that frequently involves the skin, kidney, and nervous system. Allergic angiitis and granulomatosis of Churg and Strauss is a serious disease with a high mortality rate and requires aggressive immunosuppressive therapy.

Interstitial Pneumonitisin Connective Tissue Diseases

Diffuse interstitial pneumonitis with fibrosis leading to honeycomb lung indistinguishable from usual interstitial pneumonitis occurs in progressive systemic sclerosis (scleroderma) and rheumatoid arthritis. Systemic lupus erythematosus may also be complicated by immune complex deposition in the alveoli, transient patchy lung infiltrates, vasculitis, and acute alveolar damage.

Goodpasture's Syndrome

Goodpasture's syndrome is a rare disease characterized by a combination of hemoptysis and pulmonary infiltrates, glomerulonephritis, and the presence of anti-basement membrane antibodies in the circulation. There is a striking male predominance.

Pathology

The circulating anti-basement membrane antibody, which is thought to be an autoantibody, fixes onto the basement membrane of pulmonary alveoli and renal glomeruli, causing a complement-mediated type II hypersensitivity reaction (Table 35-5). Immunofluorescence shows linear deposition of IgG and complement in the alveoli, a finding that is diagnostic of Goodpasture's syndrome. In the lung, hemorrhage into the alveoli is the dominant feature; hemosiderin-containing macrophages may be found in the sputum.

In the acute phase, the lungs are grossly consolidated, heavy, and hemorrhagic. In the chronic phase, the lung is firm because of marked interstitial fibrosis, brown because of hemosiderin, and may show changes of honeycomb lung.

Clinical Features

Onset is most frequently in the second or third decade of life. Patients present with recurrent hemoptysis. Massive pulmonary hemorrhage occurs rarely.

In the chronic phase, there is progressive dyspnea, cough, and right heart failure due to pulmonary fibrosis. Iron deficiency anemia may result from chronic blood loss. Chest x-ray shows pulmonary infiltrates due to intra-alveolar hemorrhage. Changes of increasing pulmonary fibrosis dominate chronic disease.

Patients almost invariably have evidence of glomerulonephritis, most frequently microscopic hematuria. In many cases of Goodpasture's syndrome, the renal disease dominates the clinical picture and generally determines the prognosis, which is poor. Renal changes are described in Chapter 48: The Kidney: II. Glomerular Diseases. Treatment by plasmapheresis (to remove the antibody) and steroids has proved effective in a minority of cases.

Idiopathic Pulmonary Hemosiderosis

Idiopathic pulmonary hemosiderosis is morphologically identical to Goodpasture's syndrome and considered by some to be a variant of Goodpasture's syndrome without renal involvement. It differs from Goodpasture's syndrome in that it tends to affect a younger age group; there is no male preponderance; and anti-basement membrane antibodies cannot be demonstrated in the blood, although they are present on the alveolar membranes.

Pneumoconioses (Inorganic Dust Diseases)

The term pneumoconiosis literally means “dust in the lungs” and denotes pulmonary disease secondary to inhalation of various inorganic dusts (Table 35-6). Changes that occur in the lung vary with the type and amount of dust inhaled, particle size, and the presence of other lung diseases, most importantly those associated with cigarette smoking. Genetic factors play an uncertain role in susceptibility. Some dusts such as coal dust do not evoke a fibrous response (noncollagenous pneumoconioses), whereas others such as silica do (collagenous pneumoconioses). In some patients, inhalation of several different kinds of dust results in mixed disease (eg, anthracosilicosis).

There is a variable latent period between exposure to dust and onset of clinical disease that may be as long as 20–30 years. Rarely, acute disease develops within weeks after a massive exposure.

Coal Worker's Pneumoconiosis (Anthracosis)

Anthracosis results from exposure to coal (carbon) dust and is seen in its most extensive form in coal miners and workers in old coal-burning railways. Lesser degrees of anthracosis occur in almost all urban dwellers.

The basic pathologic lesion is the coal dust macule, which is a collection of carbon-laden macrophages around the respiratory bronchiole (Figure 35-9). This dust accumulation induces only a very small amount of delicate fibrosis. There may also be insignificant dilation of the respiratory bronchiole (“focal dust emphysema”). There are usually no symptoms and no detectable abnormalities in lung function.

Rarely, coal workers develop progressive massive fibrosis when heavy exposure is coupled with a complicating factor such as infection with Mycobacterium tuberculosis (found in 40% of patients with massive fibrosis), significant silica contamination (silica induces fibrosis), or development of allergic responses to various proteins that have passively adsorbed onto the coal dust. Progressive massive fibrosis is characterized by the presence of multiple irregular, firm, homogeneous black fibrous masses in both lungs.

There is also a peculiar relationship between coal workers' pneumoconiosis and rheumatoid arthritis. When coal miners develop rheumatoid arthritis, they tend to develop large rheumatoid nodules in the lung (Caplan's syndrome).

Silicosis

Silicosis is caused by inhalation of crystalline silicon dioxide (silica) dust particles in the range of 1–5 μm. Silica exists in nature as quartz, chrystobalite, and tridymite. Occupations at increased risk for silicosis are hardrock, gold, tin, and copper mining; sand-blasting; and iron, steel, and granite working. More than 1 million workers in the United States are at risk for developing silicosis. Significant pulmonary disease usually occurs with 10–15 years of exposure but may rarely occur after as little as 1 year. Silicotic lesions may be found long after exposure has been terminated.

Pathology

Small silica crystals, when inhaled, reach the lung acinus. Larger crystals (> 5 μm) are caught in the bronchial mucus layer and wafted upward by the ciliary action to be expelled; particles less than 1 μm remain airborne and are exhaled.

In the alveoli, the silica crystals are phagocytosed by macrophages. Silica is toxic to the internal organelle membranes of the macrophages and causes phagolysosomal disruption, cell death, and liberation of free silica particles. Inflammation and fibrosis follow, leading to formation of a nodule composed of hyalinized collagen around the crystals (Figure 35-10). Silica crystals are also carried in lymphatics to the hilar lymph nodes, where similar silicotic nodules form. One hypothesis suggests that fibrosis is the result of a fibroblast-stimulating factor liberated by macrophages upon phagocytosis of silica particles. A second hypothesis attributes fibrosis to a lymphokine produced by silica-activated T lymphocytes.

Grossly, the silicotic nodule is gray-black (due to associated carbon pigment), hard, and brittle and has concentric rings of hyalinized collagen in cross section. Nodules are found mainly along lymphatic pathways, especially around the hilum and in the upper lobes. Microscopically, the nodules are composed of a solid mass of macrophages, fibroblasts, and collagen (Figure 35-10). Silica particles are recognized as birefringent needle-shaped crystals in the nodules when examined by polarized light.

Clinical Features

Silicosis is often asymptomatic, being found incidentally at chest x-ray or histologic examination of lungs and hilar lymph nodes removed for an unrelated reason. Rarely, when patients are exposed to massive amounts of dust, acute lung disease may occur, with alveolar thickening and accumulation of proteinaceous material in the alveoli (acute silicotic proteinosis). More often, there is chronic pulmonary fibrosis with a mild restrictive ventilatory defect, slowly progressive dyspnea, and pulmonary hypertension (cor pulmonale).

Complications

Progressive massive fibrosis may complicate chronic silicosis, particularly when the level of exposure to dust is high. The disorder is characterized by confluence of silicotic nodules into large masses of fibrous tissue that cause obliteration of vessels and bronchioles. Central necrosis and cavitation may occur in these masses as a result of ischemia. Progressive massive fibrosis commonly involves the upper lobes and is associated with a significant ventilatory defect and respiratory failure.

Patients with silicosis have a greatly increased incidence of tuberculosis, believed to be due to the adverse effects of silica dust on macrophage function. Tuberculosis causes extensive necrosis in the nodules, and large numbers of tubercle bacilli can be found in such lesions.

Silicosis is also associated with an increased incidence of autoimmune disease, especially progressive systemic sclerosis.

Asbestosis

Asbestos is a fibrous silicate found in nature as the minerals chrysotile, amosite, and crocidolite. It is present in such diverse components of the modern environment as insulation, flame retardants, flooring and roofing materials, water and sewage pipes, and brake linings in vehicles, making low-grade exposure almost universal among urban dwellers. It is estimated that up to 11 million workers in the United States have had significant asbestos exposure since 1940.

Asbestos-related disease was first recognized in those with the highest levels of exposure, ie, workers in shipyards and the construction industry. Approximately 40% of World War II shipyard pipe fitters now have evidence of asbestosis. It is becoming clear, however, that lower levels of exposure are also associated with significant risk. Asbestos-related neoplasms occur in families of shipyard workers—due presumably to the presence in the home of contaminated clothing—and in communities with asbestos-based industries (air pollution by asbestos dust). It is estimated that about 10,000 deaths every year in the United States are due to asbestos-related diseases.

Pathology

One of the most common changes associated with asbestos exposure is thickening of the parietal pleura by a plaque-like deposition of hyalinized collagen, maximal in the lateral and diaphragmatic pleura. This change on chest x-ray provides epidemiologic evidence of significant asbestos exposure. Pleural fibrosis does not cause symptoms and does not fall within the definition of asbestos pneumoconiosis because it does not involve lung parenchyma.

Asbestos fibers, when inhaled into the alveoli, are taken up by macrophages and evoke a diffuse interstitial fibrosis. The mechanism of stimulation of pulmonary fibrosis by asbestos is poorly understood. Asbestos, unlike silica, is not cytotoxic to macrophages; there is evidence of activation of macrophages by asbestos. Asbestos, when added to in vitro cultures of fibroblasts, stimulates increased collagen synthesis by these cells. Initially, fibrosis occurs around bronchioles but eventually extends into the alveolar interstitium. Advanced asbestosis causes end-stage fibrosis (honeycomb lung).

Microscopically, asbestos fibers are visible as ferruginous bodies (asbestos bodies) composed of a thin central asbestos fiber 5–10 μm long encased in an iron-containing glycoprotein coat which is brown and typically beaded (shish kebab appearance; Figure 35-11). Ferruginous bodies are best seen in sections that have been stained for iron with Prussian blue. While ferruginous bodies are most commonly seen in asbestosis, they are not diagnostic because a similar iron-glycoprotein coat may form on other types of inhaled fibers.

Asbestos fibers that do not have the iron-glycoprotein coat are not visible microscopically, but they outnumber coated fibers 10:1. The amount of asbestos in the lung thus cannot be accurately estimated by microscopy. A quantitative evaluation of asbestos is best made by chemical analysis of lung tissue.

Clinical Features

Asbestos-induced lung disease presents with the features of diffuse interstitial lung disease, ie, chronic cough, progressive dyspnea, a diffuse infiltrative pattern on chest x-ray, decreased vital capacity with no obstructive element, and blood gas changes of restrictive lung disease (hypoxemia with a normal or reduced arterial Pco2). Asbestosis rarely causes sufficient lung destruction to result in respiratory failure.

The most significant effect of asbestos exposure is the greatly increased risk of malignant neoplasms. (1) Bronchogenic carcinoma is the most common neoplasm associated with asbestosis. Cigarette smoking has a profound additive effect to asbestos exposure in causing bronchogenic carcinoma. (2) Malignant mesothelioma of the pleura, peritoneum, and pericardium, although less common than bronchogenic carcinoma, represents the most specific neoplasm associated with asbestos exposure; most patients with malignant mesotheliomas give a history of asbestos exposure. Malignant mesothelioma has a 100% mortality rate, and 90% of patients die within 2 years of diagnosis.

Berylliosis

Berylliosis is rarely seen today because beryllium use has declined. Beryllium was used in the past in fluorescent lights and in the aerospace industry.

Acute exposure to beryllium results in a nonspecific acute pneumonitis. Chronic exposure is characterized by pulmonary fibrosis and the formation of noncaseating epithelioid cell granulomas resembling those of sarcoidosis. Beryllium can be demonstrated in these lesions as refractile crystalline material using polarized light. The formation of granulomas is due to activation of helper T cells in the lung as a direct result of beryllium exposure in susceptible individuals.

The diagnosis is made by a history of exposure and confirmed by chemical analysis of lung tissue.

Iatrogenic Drug-, Chemical-, or Radiation-Induced Interstitial Fibrosis

A large number of drugs—notably the anticancer drugs bleomycin, busulfan, melphalan, methotrexate, and cyclophosphamide—cause diffuse interstitial pulmonary disease with fibrosis. The pulmonary changes are usually dose-related. Lung fibrosis occurs insidiously, often appearing several months after treatment. The fibrosis progresses even after the drug is withdrawn and may cause death if excessive dosages of the drug have been used.

Paraquat, a commonly used herbicide, causes a severe toxic reaction in the lung when ingested or inhaled. In the acute phase there is pulmonary edema, hemorrhage, and interstitial inflammation. This progresses rapidly to interstitial pulmonary fibrosis, often leading to respiratory failure and death.

Radiation pneumonitis may complicate cancer therapy if the lungs are included in the field of radiation. High doses cause acute radiation pneumonitis, characterized by necrosis of epithelial cells, intra-alveolar hemorrhage, and formation of hyaline membranes. With lower doses, chronic pulmonary fibrosis occurs.

Toxic gases (mustard gas, 100% oxygen) also produce diffuse fibrosis that may be severe.

The pulmonary fibrosis that complicates intravenous heroin use by addicts may be more a response to impurities in the injected material than to the heroin itself. Foreign body granulomas are commonly present in the thickened alveolar septa in addicts who use intravenous drugs.

Interstitial Diseases of Uncertain Etiology

Sarcoidosis

Sarcoidosis is a systemic disorder of uncertain cause that is commonly manifested in the lungs. Although the cause is unknown, immunologic mechanisms have been implicated, and abnormalities of the immune system are usually present: (1) Depressed cell mediated immunity is manifested by decreased numbers of T cells in the peripheral blood and by anergy (failure of delayed hypersensitivity to antigens injected in intradermal skin tests). (2) Exaggerated T helper cell activity at sites of disease, associated with the formation of epithelioid cell granulomas. (3) Hyperactive humoral immunity is probably the result of removal of T suppressor activity. There is an increased number of B lymphocytes in the peripheral blood, and most patients have hyperimmunoglobulinemia.

Pathology

The hallmark of sarcoidosis is the presence of small, noncaseating epithelioid cell granulomas (Figure 35-12). The granulomas contain Langhans-type giant cells and are associated with fibrosis. Several types of inclusions may be present, but although characteristic of sarcoidosis they are not pathognomonic. Schaumann (conchoidal) bodies are round, calcified, laminated bodies in the cytoplasm of giant cells. Asteroid bodies are smaller and have a central pink zone surrounded by a clear halo that is traversed by fine radial pink lines.

In the lung, granulomas are found in the alveolar septa (Figure 35-12) and along the pulmonary lymphatics in the bronchial wall. Granulomas are associated with interstitial inflammation and fibrosis. Chronic disease progresses to end-stage honeycomb lung. Granulomas may also be found in lymph nodes, liver, spleen, skin, and many other organs.

The diagnosis of sarcoidosis is made on clinical grounds. A finding of noncaseating epithelioid granulomas on histologic examination of biopsies provides confirmatory evidence when cultures of these tissues do not grow out mycobacteria and fungi. The cells in the granuloma release angiotensin-converting enzyme into the serum; the detection of elevated levels of this enzyme in serum (seen in 60% of patients) is a useful test for sarcoidosis. High serum levels of angiotensin-converting enzyme indicate activity of sarcoidosis and, when present, provide an important method of monitoring the course of disease.

Clinical Features

(Table 35-7)

In the United States, sarcoidosis occurs 10 times more frequently in blacks than in whites. Women are more commonly affected, and the most common age at onset is between 20 and 35 years. In Europe, sarcoidosis is more common in the Scandinavian countries.

An abnormality in the chest x-ray is present in over 90% of patients with sarcoidosis. Bilateral hilar lymphadenopathy is the most common finding. Pulmonary infiltrates due to interstitial pneumonitis may also be present.

Sarcoidosis has a variable course. About 65% of patients with hilar adenopathy alone undergo spontaneous remission. Pulmonary parenchymal involvement usually signifies progressive chronic disease. Disability and death from pulmonary fibrosis occur in a minority of patients. Steroids are effective in controlling the disease and are indicated when there is symptomatic lung involvement, ocular lesions, cardiac disease, or neurologic disease.

Wegener's Granulomatosis

Wegener's granulomatosis is a disease of unknown cause, although a hypersensitivity reaction to an unknown antigen has been postulated. Anti-neutrophil cytoplasmic autoantibodies (ANCA) are present in more than 95% of patients with Wegener's granulomatosis. ANCAs are not specific, however, as they are also found in polyarteritis nodosa. There are two distinct immunofluorescence patterns of ANCA: (1) diffuse cytoplasmic ANCA (c-ANCA) and (2) perinuclear ANCA (p-ANCA). The pattern of c-ANCA is more specific for Wegener's granulomatosis than p-ANCA. The way these autoantibodies are related to the pathologic lesion is unknown. Wegener's granulomatosis is characterized by necrotizing vasculitis of small arteries. The inflammatory reaction around the affected vessel is granulomatous, with scattered neutrophils, eosinophils, and lymphocytes.

The classic form of the disease involves (1) the nose, paranasal sinuses, and nasopharynx; (2) the lungs; and (3) the kidneys. Variants with involvement of other organs or sparing of one or two of the classic sites also occur.

Pulmonary involvement is characterized by a rapidly expanding infiltrate that tends to be bilateral, with multiple nodular mass lesions that tend to cavitate. The renal disease is a necrotizing glomerulitis that frequently progresses to crescentic glomerulonephritis and renal failure. Nasal lesions are usually ulcerating granulomas.

Clinical progression is rapid, with death from either the renal or pulmonary lesions in the majority of cases. Immunosuppressive drugs such as cyclophosphamide have prolonged survival.

Lymphomatoid Granulomatosis

Lymphomatoid granulomatosis is a poorly defined entity of uncertain cause. It is a systemic disorder affecting the lung, nervous system, kidney, skin, and many other organs. Histologically, there are necro-tizing granulomas in the lung that are infiltrated by atypical lymphocytes resembling immunoblasts. Lymphomatoid granulomatosis is a premalignant lesion with a high risk for pulmonary malignant lymphoma; some authorities hold that the process is an indolent form of malignant lymphoma from the outset. The prognosis is poor.

Bronchocentric Granulomatosis

Bronchocentric granulomatosis is a disease of uncertain cause characterized by granulomatous inflammation centered around the airways. The walls of the airways are destroyed, and their lumens are filled with necrotic material. No infectious agent can be isolated. Patients present with dyspnea, wheezing, and the consequences of bronchial obstruction such as pneumonia, lung abscess, and bronchiectasis.

Pulmonary Alveolarproteinosis

Although traditionally included with infiltrative lung diseases, pulmonary alveolar proteinosis is neither an interstitial pneumonitis nor is it associated with fibrosis. It is characterized by filling of the alveolar spaces with a homogeneous, proteinaceous, lipid-rich material thought to be composed of surfactant and cellular debris. Few or no inflammatory cells are present.

The cause is unknown. Increased production or decreased clearance of surfactant has been suggested as the cause.

Patients with alveolar proteinosis present with dyspnea and dry cough. The chest x-ray shows consolidation first affecting the lung bases. The infiltrates have a typical ground-glass appearance on chest x-ray. Hypoxemia is common and often severe.

While a few deaths have been reported, alveolar proteinosis is usually a benign disease, with most patients undergoing spontaneous remission. There is a good clinical response to treatment with pulmonary lavage.

Pulmonary Edema

Edema fluid may enter the alveolar septa and alveolar spaces as a result of (1) changes in the permeability of the lung capillaries (in acute inflammation) or (2) increased capillary blood pressure in acute left heart failure. Acute edema, if extensive, interferes with respiratory gas exchange and is a medical emergency. Histologically, alveoli contain pale pink fluid. The pathophysiology is discussed in Chapter 2: Abnormalities of Interstitial Tissues.

Adult Respiratory Distress Syndrome (ARDS; “Shock Lung”)

Respiratory distress syndrome of the newborn (also called hyaline membrane disease) has many features in common with ARDS and is discussed in Chapter 34: The Lung: I. Structure & Function; Infections.

ARDS is an acute diffuse alveolar injury that is caused by a variety of etiologic factors (Table 35-8). An estimated 150,000 patients in the United States develop ARDS annually. The mortality rate is about 50%.

Pathogenesis

The mechanisms by which ARDS occurs are complex and varied. In patients with hypovolemic shock, the acute alveolar injury is secondary to the prolonged vasoconstriction that occurs as a compensatory phenomenon; the vasoconstriction results in ischemic injury to the alveolar epithelium. In gram-negative bacteremia, alveolar damage is caused by endotoxins, which stimulates release of tumor necrosis factor by alveolar macrophages and activates complement. These and other mediators are chemotactic to neutrophils and cause endothelial and alveolar epithelial cell necrosis. In acute pancreatitis, the acute alveolar injury is caused by enzymes liberated into the bloodstream from the injured pancreas. These phospholipases damage alveolar epithelium and antagonize the action of surfactant. With toxic gas inhalation, the alveolar damage is direct; with oxygen at toxic levels, the damage is caused by oxygen-based free radicals.

Pathology

ARDS is characterized by acute diffuse alveolar damage leading to necrosis and loss of type I pneumocytes. Endothelial damage also occurs, leading to exudation of protein-rich fluid into the alveoli and resulting in pulmonary edema, hemorrhage, and formation of hyaline membranes. Hyaline membranes are composed of a pink proteinaceous material that lines the alveoli in any condition where there is acute loss of alveolar lining epithelium. They are composed of fibrin together with coagulated cell debris from necrotic cells.

Grossly, the lungs are purple, heavy, and solid. Hemorrhagic fluid exudes from the cut surface.

If the patient recovers, the alveolar epithelium regenerates, initially with hyperplasia of the type II pneumocytes. Residual interstitial fibrosis is present in severe cases.

Clinical Features

Patients with ARDS are often seriously ill with some other disease, and the features of ARDS are superimposed. The respiratory symptoms of ARDS are rapidly increasing dyspnea, hypoxemia, and cyanosis. These usually occur 1–2 days after the onset of acute injury or disease that has become complicated by ARDS. Chest x-ray shows diffuse interstitial or alveolar edema but may be normal in the early stages. ARDS is commonly the terminal event in many of these patients. Where the underlying cause is reversible, the recognition of ARDS and its aggressive management may reduce the frequency of death.

Pulmonary Embolism

Pulmonary embolism (see also Chapter 9: Abnormalities of Blood Supply) causes over 50,000 deaths per year in the United States and occurs as a complication in as many as 30% of hospitalized patients.

Pulmonary emboli originate from deep-leg-vein thrombi in over 90% of cases. Thrombi in pelvic veins are second in frequency. Deep vein thrombosis and pulmonary embolism occur most commonly (1) after surgery; (2) after childbirth; (3) in patients who are immobilized for any reason; (4) in patients with cardiovascular diseases, such as myocardial infarction and congestive heart failure; and (5) in patients receiving oral contraceptives. The risk of thromboembolism with oral contraceptives is less with newer pills, which contain smaller amounts of estrogen. The mechanisms leading to deep vein thrombosis and pulmonary embolism have been considered fully in Chapter 9: Abnormalities of Blood Supply.

Effects of Pulmonaryembolism

Sudden Death

Sudden death may occur with a large embolus that becomes impacted in the right ventricular outflow tract or main pulmonary artery (saddle embolus), effectively obstructing the circulation of blood. When circulatory obstruction is incomplete, the patient may survive long enough for emergency surgical removal of the thromboembolus from the pulmonary artery.

Pulmonary Infarction

Pulmonary infarction occurs when a medium-sized embolus obstructs a peripheral pulmonary artery in a patient whose bronchial arterial circulation is also impaired (patients with left heart failure and pulmonary hypertension).

Pathologically, pulmonary infarcts are hemorrhagic (red) and have a wedge shape with the base at the pleura and the apex directed toward the occluded vessel. The lower lobes are most commonly affected. Microscopically, alveolar necrosis and hemorrhage are present in the infarcted area. Pulmonary infarcts heal by fibrosis, leading to a subpleural scar.

Clinically, patients present with pleuritic chest pain, dyspnea, fever, and hemoptysis. A hemorrhagic pleural effusion may be present.

Pulmonary Hypertension

Isolated small emboli lodging in small pulmonary arterial branches produce no immediate effect because the bronchial artery supply is sufficient for oxygenation of tissues. Multiple small emboli over a long period may cause diffuse alveolar fibrosis and pulmonary hypertension.

Pulmonary Hypertension

Pulmonary hypertension is elevation of the mean pulmonary arterial pressure.

Most patients with pulmonary hypertension have a recognizable cause for the elevated pressure (secondary pulmonary hypertension) (Table 35-9). In a small number of patients, there is no recognizable cause; this is called primary (idiopathic) pulmonary hypertension and occurs mainly in young women in the second and third decades. Primary pulmonary hypertension is frequently associated with immunologically mediated collagen diseases such as rheumatoid arthritis. The pathogenesis of primary pulmonary hypertension is unknown. An intrinsic abnormality of the pulmonary vasculature is the most likely cause.

Pathology

The pathologic features of both primary and secondary pulmonary hypertension are similar. There is fibrous thickening of pulmonary arteries of all sizes, with medial hypertrophy and atherosclerosis in the large pulmonary arteries. Atherosclerosis occurs in the pulmonary circulation only in patients with pulmonary hypertension. Abnormal plexiform arteriolar structures may be present in the lungs.

Clinical Features

The elevated mean pulmonary arterial pressure causes right ventricular hypertrophy and a loud pulmonary valve closure sound with increased separation from the sound of aortic valve closure (split S2). Pulmonary valve closure is delayed because right ventricular output is prolonged. Right ventricular failure with peripheral edema ensues and is the common presenting feature.

Primary pulmonary hypertension is irreversible and slowly progressive. Few patients survive 10 years after diagnosis. In some, disease progression is more rapid. In patients with secondary pulmonary hypertension, treatment of the cause—eg, surgical replacement of a diseased mitral valve—if it is undertaken early enough, may halt progression of the hypertension.