ALTERATIONS OF PULMONARY FUNCTION

Cough

Cough is an important reflex that helps clear the airways of large amounts of inhaled material, excessive secretions, or abnormal substances, such as edema or pus. Individuals with an inability to cough normally are at greater risk for pneumonia. The cough reflex results from a complex interaction of sensory receptors in the upper and lower airways, including stimulation of mechanical and chemical “irritant” receptors.^1,2 There are few such receptors in the most distal bronchi and the alveoli; thus it is possible for significant amounts of secretions to accumulate in the distal respiratory tree without cough being initiated. Other cough receptors are located in the external auditory canal, diaphragm, pericardium, pleura, and stomach. Stimulation of cough receptors is transmitted centrally through the vagus nerve, and central modulation of the cough reflex can be influenced by opiates and serotonergic agents.³

Acute cough is cough that resolves within 2 to 3 weeks of the onset of illness or resolves with treatment of the underlying condition. It is most commonly the result of upper respiratory infections, allergic rhinitis, acute bronchitis, pneumonia, congestive heart failure, pulmonary embolus, or aspiration.⁴ Chronic cough is defined as cough that has persisted for more than 3 weeks, although some researchers have suggested that 7 or 8 weeks is a more appropriate timeframe because acute cough and bronchial hyperreactivity can be prolonged in some cases of viral infection. In nonsmokers, chronic cough is almost always caused by postnasal drainage syndrome, nonasthmatic eosinophilic bronchitis, asthma, or gastroesophageal reflux disease.^4,5 In smokers, chronic bronchitis is the most common cause of chronic cough, although lung cancer must always be considered. Up to 33% of individuals taking angiotensin-converting enzyme inhibitors for cardiovascular disease develop chronic cough that resolves with discontinuation of the drug.

Dyspnea

Dyspnea is the subjective sensation of being unable to get enough air. It is often described as breathlessness, air hunger, shortness of breath, labored breathing, and preoccupation with breathing. Dyspnea is a common symptom of respiratory disease.

The severity of the sensation of dyspnea may not directly correlate with the severity of underlying pulmonary disease.^6,7 Either diffuse or focal disturbances of ventilation, gas exchange, or ventilation-perfusion relationships can cause dyspnea, as can increased work of breathing or diseases that damage lung tissue (lung parenchyma). Many mechanisms have been proposed to explain the complex sensation of dyspnea, but no single mechanism has been found to be responsible in all situations. One commonly accepted mechanism involves an impaired sense of effort. This is a situation in which the perceived work of breathing is greater than the actual motor response generated. Mechanoreceptors in the chest wall respond to the length and tension in muscles and can contribute to the sensation of dyspnea as can upper airway receptors that signal the brain through trigeminal nerve fibers.⁷ A second explanation involves the stimulation of central and peripheral chemoreceptors. It has long been known that decreased pH, hypercapnia, and hypoxemia can cause dyspnea.^6,7 (The neurochemical control of ventilation is described in Chapter 32.) Stimulation of chemoreceptors causes dyspnea in many lung diseases in which oxygenation and gas exchange are impaired.

A third explanation is stimulation of the afferent receptors in the lung (the stretch receptors, irritant receptors, and J-receptors), which send impulses to the central nervous system through the vagus nerve.^6,7 Stretch receptors are stimulated in asthma and may be the primary cause of the sensation of dyspnea and chest tightness in that disorder. J-receptors also trigger dyspnea in individuals with pulmonary edema and pulmonary microemboli. Finally, the sensation of dyspnea also can be caused by increased work of breathing, respiratory muscle fatigue, decreased breathing reserve, and strong emotions, particularly anxiety and anger. There is general agreement that neurologic control and function of respiratory muscles are the common elements in most clinical experiences of dyspnea and that the sensation perceived is that of increased respiratory effort.

The signs of dyspnea include flaring of the nostrils, use of accessory muscles of respiration, and retraction (pulling back) of the intercostal spaces. In dyspnea caused by parenchymal disease (e.g., pneumonia), retractions of tissue between the ribs (subcostal and intercostal retractions) are observed more often than supercostal retractions (retractions of tissues above the ribs), which predominate in upper airway obstruction. Retractions of any type are more commonly seen in children or in adults who are thin and have poorly developed thoracic musculature. Dyspnea can be quantified by the use of ordinal rating scales or visual analog scales.⁷

Dyspnea can occur transiently or can become chronic. The first episode commonly occurs with exercise and is called dyspnea on exertion. Dyspnea also can be associated with body positioning. Orthopnea is dyspnea that occurs when an individual lies flat and is common in individuals with heart failure. The recumbent position redistributes body water, causes the abdominal contents to exert pressure on the diaphragm, and decreases the efficiency of the respiratory muscles. Orthopnea is generally relieved by sitting up in a forward-leaning posture or supporting the upper body on several pillows. Another type of positional dyspnea is termed paroxysmal nocturnal dyspnea (PND) in which individuals with heart failure or lung disease wake up at night gasping for air and must sit up or stand to relieve the dyspnea.

Pain

Pain caused by pulmonary disorders originates in the pleurae, airways, or chest wall. Pleural pain is the most common pain caused by pulmonary disease and is usually sharp or stabbing in character. Infection and inflammation of the parietal pleura (pleuritis or pleurisy) cause pain when the pleura stretch during inspiration. The pain is usually localized to a portion of the chest wall, where a unique breath sound called a pleural friction rub may be heard over the painful area. Laughing or coughing makes pleural pain worse. Pleural pain is also common with pulmonary infarction (tissue death) caused by pulmonary embolism and emanates from the area around the infarction.

Pulmonary pain is central chest pain that is pronounced after coughing and occurs in individuals with infection and inflammation of the trachea or bronchi (tracheitis or tracheobronchitis). Central chest pain can be difficult to differentiate from cardiac pain (see Chapter 30). High blood pressure in the pulmonary circulation (pulmonary hypertension) can cause pain during exercise that is often mistaken for cardiac pain (angina pectoris).

Pain in the chest wall is muscle pain or rib pain. The common causes of chest wall pain are excessive coughing, which makes the muscles sore, and rib fractures. Inflammation of the costochondral junction (costochondritis) also can cause chest wall pain. Chest wall pain can often be reproduced by pressing on the sternum or ribs.

Abnormal Sputum

The color, consistency, odor, and amount of sputum vary with different pulmonary disorders. A distinctive color or odor may suggest infection by a specific microorganism. Changes in the amount and consistency of sputum provide information about progression of disease and effectiveness of therapy. The gross and microscopic appearances of sputum enable the clinician to identify cellular debris or microorganisms that aid in diagnosis and choice of therapy.

Hemoptysis

Hemoptysis is the coughing up of blood or bloody secretions. Hemoptysis is sometimes confused with hematemesis, which is the vomiting of blood. Blood that is coughed up is usually bright red, has an alkaline pH, and is mixed with frothy sputum, whereas blood that is vomited is dark, has an acidic pH, and is mixed with food particles.

The most common causes of hemoptysis are bronchiectasis, lung cancer, bronchitis, and pneumonia. Tuberculosis remains an important cause of hemoptysis but is less common in the United States than in many other parts of the world. Hemoptysis results from damage to the lung parenchyma with rupture of pulmonary vessels or from inflammation, injury, or cancer of the bronchial tree. The amount and duration of bleeding (i.e., a sudden large amount versus a persistent slight amount) provide important clues about the source of the bleeding.⁸ Bronchoscopy, combined with chest computed tomography (CT), can identify the cause in the majority of cases of hemoptysis.

Abnormal Breathing Patterns

Normal breathing (eupnea) is rhythmic and effortless. Ventilatory rate is 8 to 16 breaths per minute, and tidal volume ranges from 400 to 800 ml. A short expiratory pause occurs with each breath, and the individual takes an occasional deeper breath or sigh. Sigh breaths, which help maintain normal lung function, are usually 1.5 to 2 times the normal tidal volume and occur approximately 10 to 12 times per hour.

The rate, depth, regularity, and effort of breathing undergo characteristic alterations in response to physiologic and pathophysiologic conditions. Patterns of breathing automatically adjust to minimize the work of respiratory muscles. Strenuous exercise or metabolic acidosis induces Kussmaul respiration (hyperpnea). Kussmaul respiration is characterized by a slightly increased ventilatory rate, very large tidal volume, and no expiratory pause.

Labored breathing occurs whenever there is an increased work of breathing, especially if the airways are obstructed, as in chronic obstructive pulmonary disease (COPD). If the large airways are obstructed, a slow ventilatory rate, increased effort, prolonged inspiration or expiration, and stridor (high-pitched sounds made during inspiration) or audible wheezing (whistling sounds on expiration) are typical. In small airway obstruction, like that seen in asthma and chronic obstructive pulmonary disease, a rapid ventilatory rate, small tidal volume, increased effort, prolonged expiration, and wheezing are often present.

Restricted breathing is commonly caused by disorders such as pulmonary fibrosis that stiffen the lungs or chest wall and decrease compliance. Restricted breathing is characterized by small tidal volumes and rapid ventilatory rate (tachypnea).

Shock and severe cerebral hypoxia (insufficient oxygen in the brain) contribute to gasping respirations that consist of irregular, quick inspirations with an expiratory pause. Anxiety can cause sighing respirations that consist of irregular breathing characterized by frequent, deep sighing inspirations.

Cheyne-Stokes respirations are characterized by alternating periods of deep and shallow breathing. Apnea lasting 15 to 60 seconds is followed by ventilations that increase in volume until a peak is reached, after which ventilation (tidal volume) decreases again to apnea. Cheyne-Stokes respirations result from any condition that slows the blood flow to the brainstem, which in turn slows impulses sending information to the respiratory centers of the brainstem. Neurologic impairment above the brainstem is also a contributing factor (see Table 16-5).

Hypoventilation and Hyperventilation

Hypoventilation is inadequate alveolar ventilation in relation to metabolic demands. It is caused by alterations in pulmonary mechanics or in the neurologic control of breathing such that minute volume (tidal volume times respiratory rate) is reduced. When alveolar ventilation is normal, carbon dioxide (CO₂) is removed from the lungs at the same rate at which it is produced by cellular metabolism. This maintains arterial CO₂ (PaO₂) at normal levels (40 mmHg). With hypoventilation, CO₂ removal does not keep up with CO₂ production and PaCO₂ increases, causing hypercapnia (PaCO₂ greater than 44 mmHg). (Table 32-2 contains the definition of gas partial pressure and other pulmonary abbreviations.) This results in an increase in hydrogen ion in the blood, termed respiratory acidosis, which can affect the function of many tissues throughout the body.

Hypoventilation is often overlooked until it is severe because breathing pattern and ventilatory rate may appear normal. Blood gas analysis (i.e., measurement of the PaCO₂ of arterial blood) reveals the hypercapnia. Pronounced hypoventilation can cause somnolence or disorientation. In addition, hypoventilation with hypercapnia results in secondary hypoxemia.

Hyperventilation is alveolar ventilation that exceeds metabolic demands. The lungs remove CO₂ at a faster rate than it is produced by cellular metabolism, resulting in decreased PaCO₂ or hypocapnia (PaCO₂ less than 36 mmHg). Hypocapnia results in a respiratory alkalosis that also can interfere with tissue function. Like hypoventilation, hyperventilation can be determined only by arterial blood gas analysis. Hyperventilation commonly occurs with severe anxiety, acute head injury, and conditions that cause insufficient oxygenation of the blood.

Cyanosis

Cyanosis is a bluish discoloration of the skin and mucous membranes caused by increasing amounts of desaturated or reduced hemoglobin (which is bluish) in the blood. Cyanosis generally develops when 5 g of hemoglobin is desaturated, regardless of hemoglobin concentration. For example, if total hemoglobin concentration is 15 g/dl of blood, 5 g/dl must be desaturated to cause cyanosis. If total hemoglobin is 11 g/dl, 5 g/dl must still be desaturated for cyanosis to occur.

Peripheral cyanosis is most often caused by poor circulation resulting from intense peripheral vasoconstriction, like that seen in Raynaud disease, cold environments, or severe stress. Central cyanosis is caused by decreased arterial oxygenation (low PaO₂) from pulmonary diseases or pulmonary or cardiac right-to-left shunts. In adults, cyanosis is not evident until severe hypoxemia is present and therefore is an insensitive indicator of respiratory distress. Lack of cyanosis does not necessarily indicate that oxygenation is normal. For example, severe anemia (inadequate hemoglobin concentration) and carbon monoxide poisoning (in which hemoglobin binds to carbon monoxide instead of binding to oxygen) can cause inadequate oxygenation of tissues without causing cyanosis. Individuals with polycythemia (an abnormal increase in numbers of red blood cells), however, may have cyanosis when tissue oxygenation is adequate. Because polycythemia causes hemoglobin concentration to be greater than normal, 5 g/dl can be desaturated, causing cyanosis, without having much effect on oxygenation. Therefore, the significance of cyanosis as a clinical finding must be interpreted in relation to the underlying pathophysiology. Central cyanosis is best seen in buccal mucous membranes and lips. Peripheral cyanosis is best seen in nail beds. If cyanosis is suggested, the PaO₂ should be measured.

Clubbing

Clubbing is the selective bulbous enlargement of the end (distal segment) of a digit (finger or toe) (Figure 33-1) whose severity can be graded from 1 to 5 based on the extent of nail bed hypertrophy and the amount of changes in the nails themselves. Usually it is painless. Clubbing is commonly associated with diseases that interfere with oxygenation, such as bronchiectasis, cystic fibrosis, pulmonary fibrosis, lung abscess, and congenital heart disease. It is usually reversible with treatment of the underlying pulmonary condition. Lung cancer is sometimes associated with clubbing even in the absence of significant hypoxemia. This syndrome is called hypertrophic osteoarthropathy (HOA) and its pathogenesis is unknown, although tumor-associated production of inflammatory cytokines and growth factors have been implicated.

Hypercapnia

Hypercapnia, or increased CO₂ in the arterial blood (increased PaCO₂), is caused by hypoventilation of the alveoli. As discussed in Chapter 32, CO₂ is easily diffused from the blood into the alveolar space; thus minute volume (respiratory rate × tidal volume) determines not only alveolar ventilation but also PaCO₂. Hypoventilation is often overlooked because breathing pattern and ventilatory rate may appear normal; it is important to obtain blood gas analysis to determine the severity of hypercapnia and resultant respiratory acidosis (acid-base balance is described in Chapter 3).

There are many causes of hypercapnia. Most are a result of decreased drive to breathe or an inadequate ability to respond to ventilatory stimulation. Causes include (1) depression of the respiratory center by drugs; (2) diseases of the medulla, including infections of the central nervous system or trauma; (3) abnormalities of the spinal conducting pathways, as in spinal cord disruption or poliomyelitis; (4) diseases of the neuromuscular junction or of the respiratory muscles themselves, as in myasthenia gravis or muscular dystrophy; (5) thoracic cage abnormalities, as in chest injury or congenital deformity; (6) large airway obstruction, as in tumors or sleep apnea; and (7) increased work of breathing or physiologic dead space, as in emphysema.

Hypercapnia and the associated respiratory acidosis can result in several important clinical manifestations. Of greatest concern are electrolyte abnormalities that occur in response to the low pH that may cause dysrhythmias. Individuals also may have somnolence and even be in a coma because of changes in intracranial pressure associated with high levels of arterial carbon dioxide, which causes cerebral vasodilation. Alveolar hypoventilation with increased alveolar carbon dioxide limits the amount of oxygen available for diffusion into the blood, leading to secondary hypoxemia.

Hypoxemia

Hypoxemia, or reduced oxygenation of arterial blood (reduced PaO₂), is caused by respiratory alterations, whereas hypoxia, or reduced oxygenation of cells in tissues, may be caused by alterations of other systems as well. Although hypoxemia can lead to tissue hypoxia, tissue hypoxia can result from other abnormalities, such as low cardiac output or cyanide poisoning, that have no relation to alterations of pulmonary function.

Hypoxemia results from problems with one or more of the major mechanisms of oxygenation:

Table 33-1 lists some of the common clinical causes of these problems.

The amount of oxygen in the alveoli is called the PAO₂ and is dependent on two factors. The first factor is the presence of adequate oxygen content of the inspired air. The amount of oxygen in inspired air is expressed as the percentage or fraction of air that is composed of oxygen called the FiO₂. The FiO₂ of air at sea level is approximately 21% or 0.21. Anything that decreases the FiO₂ (such as high altitude) decreases the PAO₂. The second factor is the amount of alveolar minute ventilation (tidal volume × respiratory rate). Hypoventilation results in an increase in P_ACO₂ and a decrease in PAO₂ such that there is less oxygen available in the alveoli for diffusion into the blood. This type of hypoxemia can be completely corrected if alveolar ventilation is improved by increases in the rate and depth of breathing. Hypoventilation causes hypoxemia in unconscious persons; in people with neurologic, muscular, or bone diseases that restrict chest expansion; and in individuals who have COPD.

Diffusion of oxygen from the alveoli into the blood is also dependent on two factors. The first is the balance between the amount of air getting into alveoli () and the amount of blood perfusing the capillaries around the alveoli (). An abnormal ventilation-perfusion ratio () is the most common cause of hypoxemia (Figure 33-2). Normally, alveolocapillary lung units receive almost equal amounts of ventilation and perfusion. The normal is 0.8 to 0.9 because perfusion is somewhat greater than ventilation in the lung bases and because some blood is normally shunted to the bronchial circulation. mismatch refers to an abnormal distribution of ventilation and perfusion. Hypoxemia can be caused by inadequate ventilation of well-perfused areas of the lung (low ). Mismatching of this type, called shunting, occurs in atelectasis, in asthma as a result of bronchoconstriction, and in pulmonary edema and pneumonia when alveoli are filled with fluid. When blood passes through portions of the pulmonary capillary bed that receive no ventilation, right-to-left shunt occurs, resulting in decreased systemic PaO₂ and hypoxemia. Hypoxemia also can be caused by poor perfusion of well-ventilated portions of the lung (high ), resulting in wasted ventilation. The most common cause of high is a pulmonary embolus that impairs blood flow to a segment of the lung. An area where alveoli are ventilated but not perfused is termed alveolar dead space.

The second factor affecting diffusion of oxygen from the alveoli into the blood is the alveolocapillary barrier. Diffusion of oxygen through the alveolocapillary membrane is impaired if the alveolocapillary membrane is thickened or the surface area available for diffusion is decreased. Abnormal thickness, as occurs with edema (tissue swelling) and fibrosis (formation of fibrous lesions), increases the time required for diffusion across the alveolocapillary membrane. If diffusion is slowed enough, the oxygen in the alveolar gas (PAO₂) and capillary blood does not have time to equilibrate during the fraction of a second that blood remains in the capillary. Destruction of alveoli, such as that which occurs in emphysema, decreases the surface area available for diffusion. Hypercapnia is rarely produced by impaired diffusion because carbon dioxide diffuses so easily from capillary to alveolus that the individual with impaired diffusion would die from hypoxemia before hypercapnia could occur.

Hypoxemia most often is associated with a compensatory hyperventilation and resultant respiratory alkalosis (i.e., decreased PaCO₂ and increased pH). However, in individuals with associated ventilatory difficulties, hypoxemia may be complicated by hypercapnia and respiratory acidosis. Hypoxemia results in widespread tissue dysfunction and, when severe, can lead to organ infarction. In addition, hypoxic pulmonary vasoconstriction can contribute to increased pressures in the pulmonary artery and lead to right-sided heart failure and cor pulmonale (see p. 1298). Clinical manifestations of acute hypoxemia may include cyanosis, confusion, tachycardia, edema, and decreased renal output.

Acute Respiratory Failure

Respiratory failure is defined as inadequate gas exchange, that is, hypoxemia, in which PaO3 is ≤50 mmHg, or hypercapnia, in which PaCO₂ is ≥50 mmHg with a pH of ≤7.25. Respiratory failure can result from direct injury to the lungs, airways, or chest wall or indirectly because of injury to another body system such as the brain. It can occur in individuals who have an otherwise normal respiratory system or in those with underlying chronic pulmonary disease. Most pulmonary diseases can cause episodes of acute respiratory failure. If the respiratory failure is primarily hypercapnic, it is the result of inadequate alveolar ventilation (see Hypercapnia, p. 1269) and the individual must receive ventilatory support, such as with a bag-valve mask, noninvasive positive pressure ventilation, or intubation and placement on mechanical ventilation. If the respiratory failure is primarily hypoxemic, it is the result of inadequate exchange of oxygen between the alveoli and the capillaries (see Hypoxemia, p. 1269) and the individual must receive supplemental oxygen therapy. Many individuals have a combined hypercapnic and hypoxemic respiratory failure and require both kinds of support.

Respiratory failure is an important potential complication of any major surgical procedure, especially those that involve the central nervous system, thorax, or upper abdomen. Smokers are at risk, particularly if they have preexisting lung disease. Limited cardiac reserve, chronic renal failure, chronic hepatic disease, and infection also increase the tendency to develop postoperative respiratory failure. The most common postoperative pulmonary problems are atelectasis, pneumonia, pulmonary edema, and pulmonary emboli (these conditions are discussed later in this chapter).

Prevention of postoperative respiratory failure includes frequent turning, deep breathing, and early ambulation to prevent atelectasis and accumulation of secretions. Humidification of inspired air can help loosen secretions. Incentive spirometry gives individuals immediate feedback about tidal volumes, which encourages them to breathe deeply. Supplemental oxygen is given for hypoxemia, and antibiotics are given as appropriate to treat infection. If respiratory failure develops, the individual may require mechanical ventilation for a time.

Chest Wall Restriction

If the chest wall is deformed, traumatized, immobilized, or made heavy by fat, the work of breathing is increased and ventilation may be compromised because of a decrease in tidal volume. The degree of ventilatory impairment depends on the severity of the chest wall abnormality. Grossly obese individuals are often dyspneic on exertion or when recumbent. Individuals with severe kyphoscoliosis (lateral bending and rotation of the spinal column with distortion of the thoracic cage) often have dyspnea on exertion that can progress to respiratory failure. Such individuals are also susceptible to lower respiratory tract infections. Obesity and kyphoscoliosis are risk factors for respiratory disease in individuals admitted to a hospital for other problems, particularly those who require surgery. Other musculoskeletal abnormalities that can impair ventilation are ankylosing spondylitis and pectus excavatum (a deformity characterized by depression of the sternum) (see Chapters 42 and 43, respectively). Pain from chest wall injury, surgery, or disease is also an important cause of restriction and decreased tidal volume. This can cause significant hypoventilation, especially in those with underlying lung disease.

Impairment of respiratory muscle function caused by neuromuscular disease also can restrict the chest wall or impair pulmonary function. Muscle weakness can result in hypoventilation and hypercapnia, inability to remove secretions, and hypoxemia. The most common cause of hospital admission for individuals with neuromuscular diseases, such as poliomyelitis, muscular dystrophy, myasthenia gravis, and Guillain-Barré syndrome, is respiratory difficulty. (See Unit V for a more complete discussion of these disorders.)

Because chest wall restriction results in a decrease in tidal volume, an increase in respiratory rate can temporarily compensate and restore minute ventilation. However, many individuals will eventually progress to hypercapnic respiratory failure. Diagnosis of chest restriction is made by pulmonary function testing (reduction in forced vital capacity [FVC]), arterial blood gas measurement (hypercapnia), and radiographs. Treatment is aimed at any reversible underlying cause but is otherwise supportive. In severe cases, mechanical ventilation may be indicated.

Flail Chest

Flail chest results from the fracture of several consecutive ribs in more than one place, or the fracture of the sternum plus several consecutive ribs. These multiple fractures result in instability of a portion of the chest wall, causing paradoxical movement of the chest with breathing. During inspiration the unstable portion of the chest wall moves inward and during expiration it moves outward, impairing movement of gas in and out of the lungs (Figure 33-3). Flail chest is usually associated with significant underlying lung contusion.

The clinical manifestations of flail chest are pain, dyspnea, unequal chest expansion, hypoventilation, and hypoxemia. Treatment is internal fixation by controlled mechanical ventilation until the chest wall has stabilized.

Pneumothorax

Pneumothorax is the presence of air or gas in the pleural space caused by a rupture in the visceral pleura (which surrounds the lungs) or the parietal pleura and chest wall (see Chapter 32). As air separates the visceral and parietal pleurae, it destroys the negative pressure of the pleural space. This disrupts the state of equilibrium that normally exists between elastic recoil forces of the lung and chest wall. No longer held in check by the recoil forces of the chest wall, the lung fulfills its tendency to recoil by collapsing toward the hilum (Figure 33-4).

Primary (spontaneous) pneumothorax, which occurs unexpectedly in healthy individuals (usually men) between ages 20 and 40 years, is most often caused by the spontaneous rupture of blebs (blister-like formations) on the visceral pleura.^9,10 The cause of bleb formation is not known, although more than 80% of these individuals have been found to have emphysema-like changes in their lungs even if they have never smoked or have no known genetic disorder. Approximately 10% of affected individuals have a significant family history of primary pneumothorax that has been linked to mutations in the folliculin gene.¹¹ Bleb rupture can occur during sleep, rest, or exercise. The ruptured bleb or blebs are usually located in the apexes of the lungs. A secondary pneumothorax can be caused by chest trauma, such as a rib fracture, stab or bullet wounds, or surgical procedure that tears the pleura; rupture of a bleb or bulla (larger vesicle) as occurs in COPD; or mechanical ventilation, particularly if it includes positive end-expiratory pressure (PEEP).¹⁰

Spontaneous and secondary pneumothorax can present as either open or tension. In open pneumothorax (communicating pneumothorax), air pressure in the pleural space equals barometric pressure because air that is drawn into the pleural space during inspiration (through the damaged chest wall and parietal pleura or through the lungs and damaged visceral pleura) is forced back out during expiration. In tension pneumothorax, however, the site of pleural rupture acts as a one-way valve, permitting air to enter on inspiration but preventing its escape by closing up during expiration. As more and more air enters the pleural space, air pressure in the pneumothorax begins to exceed barometric pressure. The pathophysiologic effects of tension pneumothorax are life threatening. Air pressure in the pleural space pushes against the already recoiled lung, causing compression atelectasis, and against the mediastinum, compressing and displacing the heart and great vessels.

Clinical manifestations of spontaneous or secondary pneumothorax begin with sudden pleural pain, tachypnea, and possibly mild dyspnea. The manifestations depend on the size of the pneumothorax. Physical examination may reveal absent or decreased breath sounds and hyperresonance to percussion on the affected side. Clinical manifestations of tension pneumothorax may also include severe hypoxemia, dyspnea, tracheal deviation away from the affected lung, and hypotension (low blood pressure).

Diagnosis of open pneumothorax is made with chest radiographs and CT. A thoracostomy (chest) tube is placed, and its efficacy in relieving the pneumothorax is documented on repeat chest radiograph. The diagnosis of tension pneumothorax is made on physical examination alone. It requires immediate treatment and a chest tube must be placed quickly. If a chest tube is not readily available, a large-bore needle is inserted into the pleural space to decompress it until a chest tube can be placed. An outward gush of air as the needle or chest tube is inserted confirms the presence of tension pneumothorax. For both open and tension pneumothorax, the chest tube is connected to a water-seal drainage and suction until the damaged pleura is healed.

In some situations, the pleural tear does not heal spontaneously and it is necessary to prevent recurrence of the pneumothorax by a process called pleurodesis. This procedure uses the chest tube to instill a caustic substance, such as talc, into the pleural space. The resultant inflammation and scarring as the pleura heals result in closure of the pleural tear. Some individuals require thoracotomy with pleurectomy.

Pleural Effusion

Pleural effusion is the presence of fluid in the pleural space. The source of the fluid is usually blood vessels or lymphatic vessels lying beneath either pleura, but occasionally an abscess or other lesion may drain into the pleural space. Because the pleura is a relatively permeable membrane, fluids that accumulate in the lung can cross into the pleural space.

The most common mechanism of pleural effusion is migration of fluids and other blood components through the walls of intact capillaries bordering the pleura. Pleural effusions that enter the pleural space from the intact blood vessels can be transudative or exudative. In transudative effusion, the fluid, or transudate, is watery and diffuses out of the capillaries as a result of disorders that increase intravascular hydrostatic pressure or decrease capillary oncotic pressure. Examples are congestive heart failure, in which venous and left atrial pressures are increased, and liver or kidney disorders that cause hypoproteinemia. Hypoproteinemia decreases capillary oncotic pressure, which promotes diffusion of water out of the capillaries. (This mechanism is discussed in Chapter 3).

Exudative effusion is less watery and contains high concentrations of white blood cells and plasma proteins. Exudative effusion occurs in response to inflammation, infection, or malignancy and involves inflammatory processes that increase capillary permeability (see Chapter 6). When stimulated by biochemical mediators of inflammation, junctions in the capillary endothelium separate slightly, enabling leukocytes and plasma proteins to migrate out into affected tissues. Other types of pleural effusion are characterized by the presence of pus (empyema), blood (hemothorax), or chyle (chylothorax). Mechanisms of pleural effusion are summarized in Table 33-2.

Small pleural effusions may not affect lung function and go undetected. Most will be removed by the lymphatic system once the underlying condition is resolved. Like pneumothorax, larger pleural effusions can cause compression atelectasis and displace mediastinal contents. Unlike pneumothorax, however, pleural effusion does not cause the lung to collapse. Because there is no communication between the pleural space and environmental air, pressure in the pleural space remains negative and atelectasis is caused solely by pressure exerted by the effusion.

The most common symptom associated with pleural effusion is dyspnea. Pleuritic chest pain may be present if the pleura is inflamed. Physical examination usually reveals decreased breath sounds and dullness to percussion on the affected side, and a pleural friction rub may be heard. In large, rapidly developing effusions, compression atelectasis may cause hypoxemia and mediastinal shift. Inability to expand the lungs may impair ventilation, leading to hypercapnia. Diagnosis is confirmed by chest x-ray and thoracentesis (needle aspiration) with pleural fluid analysis, which can determine the type of effusion and provide symptomatic relief.¹² Small effusions will usually resolve with treatment of the underlying disorder. Large pleural effusions can contain several liters of fluid and require the placement of a thoracostomy (chest) tube.

Empyema

Empyema (infected pleural effusion) is the presence of pus in the pleural space. It is thought to develop when the pulmonary lymphatics become blocked, leading to an outpouring of contaminated lymphatic fluid into the pleural space. Empyema occurs most commonly in older adults and children and usually develops as a complication of pneumonia, surgery, trauma, or bronchial obstruction from a tumor.¹³ Commonly documented infectious microorganisms include Staphylococcus aureus, Escherichia coli, anaerobic bacteria, and Klebsiella pneumoniae.

Individuals with empyema are usually quite ill and may have cyanosis, fever, tachycardia (rapid heart rate), cough, and pleural pain. Breath sounds are decreased directly over the empyema. Diagnosis is made by chest radiographs and thoracentesis. Identification of the causative microorganism by positive cultures from the pleural fluid is obtained only about 50% of the time, and empiric antibiotics may be needed. The treatment for empyema includes the administration of appropriate antimicrobials, and thoracentesis is performed to drain the pleural space. Continuous drainage with a chest tube may be required. In severe cases, instillation of fibrinolytic agents or deoxyribonuclease (DNase) into the pleural space may be required to mobilize the fluid and facilitate drainage. Surgical débridement of the pleural space also may be performed to prevent reaccumulation and achieve adequate drainage.

Aspiration

Aspiration is the passage of fluid and solid particles into the lung. It tends to occur in individuals whose normal swallowing mechanism and cough reflex are impaired by a decreased level of consciousness or central nervous system abnormalities. It has been estimated that more than 10% of all hospital admissions for community-acquired pneumonias and up to 30% of admissions for pneumonia in residents of long-term facilities are the result of aspiration.¹³ Predisposing factors include altered level of consciousness caused by substance abuse, sedation, or anesthesia; seizure disorders; cerebrovascular accident; and neuromuscular disorders that cause dysphagia. In individuals who require enteral feeding (through a nasogastric feeding tube), aspiration is common and frequently leads to bacterial pneumonia.¹⁴ The right lung, particularly the right lower lobe, is more susceptible to aspiration than the left lung because the branching angle of the right mainstem bronchus is straighter than the branching angle of the left mainstem bronchus.

The effects of aspiration depend on the material aspirated. The aspiration of large food particles or gastric fluid with pH of less than 2.5 has serious consequences. Solid food particles can obstruct a bronchus, resulting in bronchial inflammation and collapse of airways distal to the obstruction. If the aspirated solid is not identified and removed by bronchoscopy, a chronic, local inflammation develops that may lead to recurrent infection and bronchiectasis (permanent dilation of the bronchus). Once the pathologic process has progressed to bronchiectasis, surgical resection of the affected area is usually required.

Aspiration of oral or pharyngeal secretions can lead to aspiration pneumonia, especially if the oral cavity is colonized with bacteria (e.g., individuals with poor dentition). Intubation of the trachea also can cause aspiration and bacterial pneumonia. Aspiration of acidic gastric fluid may cause severe pneumonitis. Bronchial damage includes inflammation, loss of ciliary function, and bronchospasm. In the alveoli, acidic fluid damages the alveolocapillary membrane. This allows plasma and blood cells to move from capillaries into the alveoli, resulting in hemorrhagic pneumonitis. The lung becomes stiff and noncompliant as surfactant production is disrupted, leading to further edema and collapse. Hypoventilation may develop as this progresses, and systematic complications, such as hypotension, may occur.

The clinical manifestations of aspiration include the sudden onset of choking and intractable cough with or without vomiting, fever, dyspnea, and wheezing. Some individuals have no symptoms acutely; instead they have recurrent lung infections, chronic cough, or persistent wheezing over months and even years.

Preventive measures for individuals at risk are more effective than treatment of known aspiration. The most important preventive measures include a semirecumbent position, surveillance of enteral feeding, use of promotility agents, and avoidance of excessive sedation. Individuals undergoing general anesthesia should not receive food or fluid for several hours before or after surgery. Antacids are sometimes given to individuals at risk for aspiration to keep gastric pH greater than 2.5. Individuals who have difficulty swallowing are fed with extreme caution and positioned to minimize the likelihood of aspiration. Nasogastric tubes, which often are used to remove stomach contents and reduce the risk for aspiration, also can cause aspiration if fluid and particulate matter are regurgitated as the tube is being placed. For those who suffer from swallowing difficulties, speech-language pathologists can often improve swallowing abilities and prevent recurrence.

The rate of deaths resulting from aspiration-caused pneumonitis has been estimated to be as high as 50%. Treatment includes supplemental oxygen and may require mechanical ventilation with PEEP. Fluids are restricted to decrease blood volume and minimize pulmonary edema. Steroids often are administered during the first 72 hours after aspiration, although their effectiveness is not well documented. Bacterial pneumonia may develop as a complication of aspiration pneumonitis and must be treated with broad-spectrum antibiotics.

Atelectasis

Atelectasis is the collapse of lung tissue. There are three types of atelectasis: compression, absorption, and surfactant impairment¹⁵:

Atelectasis tends to occur after surgery. Intraoperative high-dose supplemental oxygen in combination with general anesthesia increases the likelihood of postoperative atelectasis.¹⁵ In addition, individuals are often in pain, breathe shallowly, are reluctant to change position, and produce viscous secretions that tend to pool in dependent portions of the lung after surgical procedures, especially those involving the thorax or upper abdomen.

Clinical manifestations of atelectasis are similar to those of pulmonary infection: dyspnea, cough, fever, and leukocytosis. Prevention and treatment of postoperative atelectasis usually include deep breathing (often with the aid of an incentive spirometer), frequent position changes, and early ambulation. Deep breathing is beneficial because it (1) promotes the ciliary clearance of secretions, (2) stabilizes the alveoli by redistributing surfactant, and (3) permits collateral ventilation of the alveoli through pores of Kohn in the alveolar septa. The pores of Kohn, which open only during deep breathing, allow air to pass from well-ventilated alveoli to obstructed alveoli, minimizing their tendency to collapse and facilitating expectoration of the bronchial obstruction (Figure 33-5).

Bronchiectasis

Bronchiectasis is persistent abnormal dilation of the bronchi. It usually occurs in conjunction with other respiratory conditions that are associated with chronic bronchial inflammation. Causes include obstruction of an airway with mucous plugs, atelectasis, aspiration of a foreign body, infection, cystic fibrosis, tuberculosis, congenital weakness of the bronchial wall, or impaired defense mechanisms. Bronchiectasis is also associated with a number of systemic disorders such as rheumatologic disease, inflammatory bowel disease, and immunodeficiency syndromes (e.g., acquired immunodeficiency syndrome [AIDS]).¹⁶

Chronic inflammation of the bronchi leads to destruction of elastic and muscular components of their walls and permanent dilation.¹⁶ Bronchial dilation (Figure 33-6) may be cylindrical (cylindrical bronchiectasis), with symmetrically dilated airways as can be seen after pneumonia and is reversible; saccular (saccular bronchiectasis), in which the bronchi become large and balloon-like; or varicose (varicose bronchiectasis), in which constrictions and dilations deform the bronchi. In both varicose and saccular bronchiectasis, the smaller bronchial divisions are plugged with secretions or obliterated by fibrosis. Large anastomoses (connections) develop between the bronchial and pulmonary blood vessels, increasing blood flow through the bronchial circulation. These anastomoses are thought to cause the hemoptysis experienced by individuals with bronchiectasis. Airway damage leads to bronchospasm and copious production of purulent mucus. Ventilation-perfusion abnormalities develop and result in hypoxemia. In severe cases, minute ventilation is also compromised and PaCO₂ may become elevated.

The primary symptom of bronchiectasis is chronic productive cough. The symptoms of bronchiectasis may date back to a childhood illness or infection. The disease is commonly associated with recurrent lower respiratory tract infections and expectoration of voluminous amounts of purulent sputum (measured in cupfuls). If the individual is not receiving antibiotics, the sputum has a foul odor. Hemoptysis and clubbing of the fingers are common. Pulmonary function studies show decreases in FVC and expiratory flow rates. The diagnosis is usually confirmed by the use of high-resolution CT. Bronchiectasis is treated with antibiotics, bronchodilators, chest physiology, and supplemental oxygen.¹⁶ In selected individuals with localized areas of involvement, surgery may be indicated to remove the affected portion of the lung.

Bronchiolitis

Bronchiolitis is inflammation of the small airways or bronchioles. It is most common in children (see Chapter 34). In adults it usually occurs with chronic bronchitis but can occur in otherwise healthy individuals in association with an upper or lower airway viral infection (e.g., respiratory syncytial virus [RSV]), or with inhalation of toxic gases. Atelectasis or emphysematous destruction of the alveoli may develop distal to the inflammatory lesion. Bronchiolitis is usually diffuse. The resulting decrease in the ventilation-perfusion ratio results in hypoxemia. A decrease in minute ventilation with resulting carbon dioxide retention also may occur as lung restriction worsens.

Clinical manifestations include a rapid ventilatory rate; marked use of accessory muscles; low-grade fever; dry, nonproductive cough; and hyperinflated chest. If bronchiolitis is caused by an inhalation injury, pulmonary edema occurs rapidly and then quickly clears. One to 2 weeks later, respiratory distress develops, and infiltrates are seen on chest radiographs. Bronchiolitis is treated with appropriate antibiotics, steroids, and chest physical therapy (humidified air, coughing and deep breathing, postural drainage).

Bronchiolitis obliterans is a late-stage fibrotic process that occludes the airways and causes permanent scarring of the lungs. This process can occur in all causes of bronchiolitis but is most common after lung transplantation. Bronchiolitis obliterans can be further complicated by the development of pneumonia (called bronciolitis obliterans organizing pneumonia [BOOP]) in which the alveoli and bronchioles become filled with plugs of connective tissue.¹⁶ This complication of lung transplant has a high morbidity. Diagnosis is made by spirometry and bronchoscopy with biopsy. Treatment includes corticosteroids and other immunosuppressive agents.¹⁷

Pulmonary Fibrosis

Pulmonary fibrosis is an excessive amount of fibrous or connective tissue in the lung. When no specific cause for the development of fibrosis is known, it is called idiopathic pulmonary fibrosis. Although fibrosis can complicate healing after active pulmonary diseases, such as ARDS or tuberculosis, specific causes most often include inhalation of harmful substances, such as toxic gases, inorganic dusts, or organic dusts, and underlying autoimmune systemic disorders, such as rheumatologic disease. The fibrotic process results from chronic inflammation, alveolar epithelialization, and myofibroblast proliferation. Fibrosis causes a marked loss of lung compliance. The lung becomes stiff and difficult to ventilate, and the diffusing capacity of the alveolocapillary membrane may decrease, causing hypoxemia.

Systemic Disorders

Several systemic diseases affect the airways, pleurae, or lung parenchyma, causing fibrosis, vasculitis, pulmonary hemorrhage, or granuloma formation. Clinical manifestations of lung involvement are usually nonspecific, and the diagnosis is based on involvement of other organs. There is usually no specific treatment, although corticosteroids often are used. Some of the systemic diseases affecting the lung are granulomatous disorders such as sarcoidosis, Wegener granulomatosis, lymphomatoid granulomatosis, and eosinophilic granuloma; connective tissue diseases such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis or dermatomyositis, Sjögren syndrome, and polyarteritis nodosa; angioimmunoblastic or immunoblastic lymphadenopathy (a disease of the lymph nodes); cystic fibrosis (see Chapter 34); and Goodpasture syndrome (a pulmonary and renal disorder).

Pulmonary Edema

Pulmonary edema is excess water in the lung. The normal lung contains very little fluid. It is kept dry by lymphatic drainage and a balance among capillary hydrostatic pressure, capillary oncotic pressure, and capillary permeability. In addition, surfactant lining the alveoli repels water, keeping fluid from entering the alveoli. Predisposing factors for pulmonary edema include heart disease, ARDS, and inhalation of toxic gases. The pathogenesis of pulmonary edema is illustrated in Figure 33-7.

The most common cause of pulmonary edema is heart disease (see Chapter 30). When the left ventricle fails, filling pressures on the left side of the heart increase and cause a concomitant increase in pulmonary capillary hydrostatic pressure. When the hydrostatic pressure exceeds oncotic pressure, fluid moves out into the interstitium, or interstitial space (the space within the alveolar septum between alveolus and capillary). Fluid is initially picked up by lymphatic vessels and removed from the lung. When the flow of fluid out of the capillaries exceeds the lymphatic system’s ability to remove it, pulmonary edema develops. Pulmonary edema usually begins to develop at a pulmonary capillary wedge pressure or left atrial pressure of 20 mmHg. If the capillary oncotic pressure is decreased for any reason (e.g., anemia or decreased plasma proteins), pulmonary edema develops at a lower hydrostatic pressure.

Another cause of pulmonary edema is capillary injury that increases capillary permeability. Capillary injury causes edema in cases of ARDS or inhalation of toxic gases, such as ammonia. Capillary injury causes water and plasma proteins to leak out of the capillary and move into the interstitium. When plasma proteins move into the lung interstitium, they increase the interstitial oncotic pressure, which is usually very low. As the interstitial oncotic pressure begins to equal capillary oncotic pressure, water moves out of the capillary and into the lung. (Mechanisms of edema are discussed in Chapter 3.)

Pulmonary edema also can result from obstruction of the lymphatic system. Drainage can be blocked by compression of lymphatic vessels caused by edema, tumors, and fibrotic tissue or by increased systemic venous pressure that elevates hydrostatic pressure of the large pulmonary veins into which the pulmonary lymphatic system drains. This can happen in left-sided heart failure.

Clinical manifestations of pulmonary edema include dyspnea, orthopnea, hypoxemia, and increased work of breathing. Physical examination may reveal inspiratory crackles (rales), dullness to percussion over the lung bases, and evidence of ventricular dilation (S₃ gallop and cardiomegaly). In severe edema, pink, frothy sputum is expectorated, hypoxemia worsens, and hypoventilation with hypercapnia may develop.

The treatment of pulmonary edema depends on its cause. If the edema is caused by increased hydrostatic pressure caused by heart failure, therapy is geared toward improving cardiac output and volume status with diuretics, vasodilators, and drugs that improve the contraction of the heart muscle. If edema is the result of increased capillary permeability resulting from injury, the treatment is focused on removing the offending agent and supportive therapy to maintain adequate oxygenation, ventilation, and circulation. Individuals with either type of pulmonary edema require supplemental oxygen. Mechanical ventilation may be needed if edema significantly impairs ventilation and oxygenation.

Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is a fulminant form of respiratory failure characterized by acute lung inflammation and diffuse alveolocapillary injury. In the United States, acute lung injury (a slightly milder form of lung injury) and ARDS complicate more than 30% of all intensive care unit (ICU) admissions.²⁷ Advances in therapy have decreased the overall mortality rate to approximately 40%, although older people and those with severe infections or are immunocompromised continue to have a much higher mortality rate.²⁷ Most survivors, however, have almost normal lung function 1 year after the acute illness. ARDS is the result of injury to the lung by numerous unrelated causes. The most common predisposing factors are sepsis and multiple trauma (especially when multiple transfusions are received); however, there are many other causes, including pneumonia, burns, aspiration, cardiopulmonary bypass surgery, pancreatitis, drug overdose, smoke or noxious gas inhalation, oxygen toxicity, radiation therapy, and disseminated intravascular coagulation.²⁷

Asthma

Asthma is defined as “a chronic disorder of the airways that involves a complex interaction of airway obstruction, bronchial hyperresponsiveness and an underlying inflammation.”³³ Many cells and cellular elements contribute to the inflammatory response including mast cells, eosinophils, neutrophils, T lymphocytes, macrophages, and damaged epithelial cells (especially in sudden onset, fatal exacerbations, occupational asthma, and individuals who smoke). In susceptible individuals, this inflammation causes recurrent episodes of coughing (particularly at night or early in the morning), wheezing, breathlessness, and chest tightness. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment.³³

Asthma occurs at all ages, with approximately half of all cases developing during childhood and another third before age 40. In the United States, asthma affects more than 22 million persons and is a major global health problem affecting more than 300 million people worldwide.^33,34 With the projected increase in the proportion of the world’s population that lives in cities, it is estimated that there may be an additional 100 million people with asthma by 2025.³⁴ Mortality rates have declined since 1995 in the United States, but the incidence of asthma has increased over the past two decades, especially in urban areas.³³

Asthma is a familial disorder and more than 100 genes have been identified that may play a role in the susceptibility and pathogenesis of asthma, including those that influence the production of IL-4, IL-5, and IL-13; IgE; eosinophils; mast cells; adrenergic receptors; leukotrienes; and bronchial hyperresponsiveness.^35–36 The ADAM 33 (a disintegrin and metalloprotease)³³ gene is particularly associated with asthma and bronchial hyperresponsiveness.³⁷ Furthermore, there is increasing understanding of the specific interactions of susceptibility genes with the environment that can guide prevention and treatment interventions.^38–40 Risk factors for asthma, in addition to family history, include allergen exposure, urban residence, exposure to air pollution and cigarette smoke, recurrent respiratory viral infections, and obesity.^33,41

There is significant evidence that allergy and inflammation involving the upper airway (allergic rhinitis) can contribute to lower airway inflammation and bronchospasm (“one airway hypothesis”) (see What’s New? The Link Between the Upper and Lower Airways in Asthma and COPD).⁴² Based on this understanding, it has been shown that prevention and treatment of allergic rhinitis may prevent the development of asthma.⁴³

Of great interest in recent years has been the effect of recurrent allergen exposure during childhood on the subsequent development of asthma. A significant amount of evidence indicates that exposure to high levels of most allergens (e.g., dust mites) is correlated with an increased risk of asthma, although the age at the time of exposure may influence the risk.³³ It also has been noted that children who live on farms or have certain childhood infections may have a decreased

risk for asthma, theoretically because they become less immunologically “primed” to be allergic (see What’s New? New Understandings of Gene and Environmental Interactions in Asthma).^33,41,44 These relationships have been described as the hygiene hypothesis, and many studies are being conducted to further elucidate the relationship between allergen exposure and infection and asthma risk and to see if asthma can be prevented through allergen reduction and exposure to probiotics.^33,41,44,45

Inflammation resulting in hyperresponsiveness of the airways is the major pathologic feature of asthma. Airway epithelial cell irritation combined with exposure to antigens initiates both an innate and an adaptive immune response (see Chapter 8). In sensitized individuals, allergen exposure leads to activation of T-helper cells. These cells release what are called T-helper 2 cytokines, especially IL-4, IL-5, IL-8, and IL-13. IL-4 stimulates B-cell activation, proliferation, and production of antigen-specific IgE. IgE causes mast cell degranulation with the release of a large number of inflammatory

mediators, such as histamine, prostaglandins, and leukotrienes^33,41,46 (Figure 33-11; see Figure 34-14, p. 1331, for additional detail). IL-5 stimulates the activation, migration, and proliferation of eosinophils, which cause direct tissue injury and release toxic neuropeptides that contribute to increased bronchial hyperresponsiveness, fibroblast proliferation, and airway scarring.^33,47 IL-8 activates polymorphonucleocytes that contribute to a more exaggerated inflammatory response. IL-13 impairs mucociliary clearance, enhances fibroblast secretion, and contributes to bronchoconstriction. The resulting inflammatory process produces bronchial smooth muscle spasm, vascular congestion, increased vascular permeability, edema formation, production of thick tenacious mucus, impaired mucociliary function (see Figure 33-10), thickening of airway walls, and increased contractile response of bronchial smooth muscle.⁴⁸ Other inflammatory cytokines, such as TNF and IL-1, have been found to alter muscarinic receptor function, leading to increased levels of acetylcholine, which cause bronchial smooth muscle contraction and mucus secretion.^33,49,50 These changes, combined with the epithelial cell damage caused by eosinophil infiltration, produce acute airway hyperreponsiveness and obstruction. Recent studies have identified important roles for nitric oxide and reduced airway pH in the pathogenesis of asthma and airway inflammation.^51,52 Untreated inflammation can lead to long-term airway damage that is irreversible (airway remodeling).^33,49

Airway obstruction increases resistance to airflow and decreases flow rates, especially expiratory flow. Impaired expiration causes air trapping, hyperinflation distal to obstructions, altered pulmonary mechanics, and increased work of breathing. Changes in resistance to airflow are not uniform throughout the lungs and the distribution of inspired air is uneven, with more air flowing to the less resistant portions. Continued air trapping increases intrapleural and alveolar gas pressures and causes decreased perfusion of the alveoli. Increased alveolar gas pressure, decreased ventilation, and decreased perfusion lead to variable and uneven ventilation-perfusion relationships within different lung segments. Hyperventilation is triggered by lung receptors responding to increased lung volume and obstruction. The result is early hypoxemia without CO₂ retention. Hypoxemia further increases hyperventilation through stimulation of the respiratory center, causing PaCO₂ to decrease and pH to increase (respiratory alkalosis). As the obstruction becomes more severe, the number of alveoli being inadequately ventilated and perfused increases. As air trapping in the lungs because of obstruction of expiratory airflow progresses, the lungs and thorax become hyperexpanded putting the respiratory muscles at a mechanical disadvantage. This leads to CO₂ retention and respiratory acidosis. Respiratory acidosis signals respiratory failure.

Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) has been defined as pathologic lung changes consistent with emphysema or chronic bronchitis. A recent consensus report defines COPD as a “preventable and treatable disease with some significant extrapulmonary effects that may contribute to the severity in individual patients. Its pulmonary component is characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases.”⁵⁷ It is the fourth leading cause of death in the United States and is the sixth leading cause of death worldwide.⁵⁷ Overall mortality from COPD has increased 103% in the United States over the past 30 years; however, mortality in women has increased more than twice that much.⁵⁸ COPD is primarily caused by cigarette smoke, and active as well as passive smoking have been implicated. Other risks include occupational exposures, indoor and outdoor air pollution, and history of severe childhood respiratory infections. Genetic susceptibilities have been identified, including polymorphisms of genes that code

for TNF, surfactant, proteases, and antiproteases.^59,60 Gender differences in the genes that code for the breakdown and removal of cigarette smoke metabolites may explain the increased susceptibility of women smokers to COPD and lung cancer.⁵⁸ An inherited mutation in the α₁-antitrypsin gene results in the development of COPD at an early age, even in nonsmokers.

Pneumonia

Pneumonia is infection of the lower respiratory tract caused by bacteria, viruses, fungi, protozoa, or parasites. It is the sixth leading cause of death in the United States and is responsible for more disease and death than any other infection.⁷³ More than half of those hospitalized for pneumonia are older than age 65; mortality from pneumonia is highest in older adults.^74,75 Risk factors for pneumonia include advanced age, immunocompromise, underlying lung disease (especially COPD), alcoholism, altered consciousness, impaired swallowing, smoking, endotracheal intubation, malnutrition, immobilization, underlying cardiac or liver disease, and residence in a nursing home. The causative microorganism influences the symptoms and signs with which the patient presents, how the pneumonia should be treated, and the prognosis.⁷³ Community-acquired pneumonia tends to be caused by different microorganisms than those infections acquired in the hospital (nosocomial).⁷⁶ In addition, the characteristics of the individual are important in determining which etiologic microorganism is likely; for example, immunocompromised persons tend to be susceptible to opportunistic infections that are uncommon in normal adults. In general, nosocomial infections and those affecting immunocompromised individuals have a higher mortality rate than community-acquired pneumonias.⁷⁷ Some of the most common causal microorganisms include the following^74–77:

The most common community-acquired pneumonia is caused by S. pneumoniae (also known as pneumococcus), which has a relatively high mortality in older adults.^74,75,78 M. pneumoniae and C. pneumoniae are common causes of pneumonia in young people, especially those living in group housing, such as dormitories and army barracks.⁷⁹ Influenza is the most common viral community-acquired pneumonia in adults and causes more than 200,000 hospitalizations and more than 30,000 deaths annually in the United States.⁸⁰ Legionella species can contaminate cooling systems and are an important cause of community-acquired pneumonia. Legionnaire disease has increased in incidence since it was first described in water supplies leading to outbreaks of disease, such as the 1976 incident at the American Legion convention in Philadelphia.⁸¹ Nosocomial pneumonia is a frequent complication in the ICU, most often in individuals placed on mechanical ventilation (ventilator-associated pneumonia [VAP]). P. aeruginosa, other gram-negative microorganisms, and S. aureus (including methicillin-resistant Staphylococcus aureus [MRSA]) are the most common etiologic agents in nosocomial pneumonia.⁸² Immunocompromised individuals are especially susceptible to P. jiroveci, other fungal infections, viruses, and mycobacterial infections of the respiratory tract.^83–85

Tuberculosis

Tuberculosis (TB) is an infection caused by M. tuberculosis, an acid-fast bacillus that usually affects the lungs but may invade other body systems. TB is the leading cause of death from a curable infectious disease throughout the world. TB cases increased greatly during the mid-1990s because of AIDS.⁹⁹ Many ambitious programs for prevention and treatment have been initiated worldwide and the World Health Organization (WHO) 2008 Global Tuberculosis Control Report indicates that global TB incidence and prevalence have declined in most regions of the world in recent years, although southern Africa continues to carry a huge portion of the burden of TB infection and mortality.¹⁰⁰ In the United States, the incidence of TB has reached its lowest level since 1953, but the rate of decline has begun to slow with more than half of new cases of TB occurring in foreign-born individuals, especially those from Mexico, the Philippines, India, and Vietnam.¹⁰¹ Individuals with AIDS are highly susceptible to respiratory infections, including multidrug-resistant TB. Emigration of infected individuals from high-prevalence countries, transmission in crowded institutional settings, homelessness, substance abuse, and lack of access to medical care have contributed to the spread of TB.^100,101

Abscess Formation and Cavitation

An abscess is a circumscribed area of suppuration and destruction of lung parenchyma. Abscess formation follows consolidation of lung tissue, in which inflammation causes alveoli to fill with fluid, pus, and microorganisms. Necrosis (death and decay) of consolidated tissue may progress proximally until it communicates with a bronchus. If this occurs, the abscess empties into the bronchus, leaving a cavity that has a radiographic appearance similar to that of a lesion of tuberculosis. Cavitation is the process of abscess emptying and cavity formation. Diagnosis is made by radiography.

Pneumonia caused by aspiration, Klebsiella, or Staphylococcus is the most common cause of abscess formation. Aspiration abscess is usually associated with alcohol abuse, seizure disorders, general anesthesia, and swallowing disorders. Immunocompromised individuals also are at greater risk for lung abscesses and may be infected with opportunistic microorganisms, such as fungi and mycobacteria. The clinical manifestations of abscess formation are similar to those of pneumonitis: fever, cough, chills, sputum production, and pleural pain. Abscess communication with a bronchus causes a severe cough, copious amounts of often foul-smelling sputum, and occasionally hemoptysis.

Treatment includes the administration of appropriate antibiotics and chest physical therapy, including chest percussion and postural drainage. Bronchoscopy is sometimes performed to drain the abscess. Mortality rates are influenced by the severity of the primary disease that initially caused consolidation and by the virulence of the causative microorganism.

Acute Bronchitis

Acute bronchitis is acute infection or inflammation of the airways or bronchi. The vast majority of acute bronchitis is caused by viruses.¹¹² Many of the clinical manifestations are similar to those of pneumonia (i.e., fever, cough, chills, malaise), but physical examination does not reveal signs of pulmonary consolidation and chest radiographs do not show infiltrates. Individuals with viral bronchitis usually have a nonproductive cough that occurs in paroxysms and is aggravated by cold, dry, or dusty air. However, purulent sputum may be produced with some viral infections. Chest pain often develops from the effort of coughing. Treatment consists of rest, aspirin, humidity, and a cough suppressant, such as codeine.

Individuals with bacterial bronchitis have a productive cough, fever, and pain behind the sternum (breast bone) that is aggravated by coughing. It is rare in previously healthy adults except after viral infection but is common in those with COPD. Bacterial bronchitis is treated with rest, aspirin, humidity, and antibiotics.¹¹²

Pulmonary Embolism

Pulmonary embolism (PE) is occlusion of a portion of the pulmonary vascular bed by an embolus that can be a thrombus (blood clot), a tissue fragment, lipids (fats), or an air bubble (Figure 33-16). The most common emboli are thrombi dislodged from deep veins in the thigh and pelvis, termed venous thromboembolism. Symptomatic pulmonary embolism occurs in approximately 50% of cases of untreated deep venous thrombosis (DVT).¹¹³ PE has an incidence of nearly 300,000 cases per year in the United States, although it is estimated that if undiagnosed cases also were counted, the number would be closer to 900,000. Many with PE die before reaching the hospital, and mortality at 3 months remains at 15% to 18% despite adequate anticoagulation therapy.¹¹⁴

Risk factors for pulmonary thromboembolism include many conditions and disorders that promote blood clotting (see Chapter 25). The three categories of pathologic risks are called the Virchow triad and include (1) venous stasis (slowing or stagnation of blood flow through the veins), (2) hypercoagulability (increased tendency of the blood to form clots), and (3) injuries to the endothelial cells that line the vessels. Venous stasis is usually caused by immobility with prolonged bed rest or sitting, for example, with air travel, neurologic disorders, advanced age, or immobilzer and cast use. Other causes of venous stasis include obesity, pregnancy, congestive heart failure, and sickle cell disease. Hypercoagulability can result from inherited or acquired conditions. Some of the most important acquired hypercoagulable states include malignancy, antiphospholipid antibody syndrome, heparin-induced thrombocytopenia, polycythemia vera, hyperhomocysteinemia, and hormone use (oral contraceptives or hormone replacement therapy).^113–115 Some of the most common inherited clotting disorders include factor V Leiden or prothrombin mutations and deficiencies of antithrombin III, protein C, protein S, or plasminogen.^113–115 Endothelial injury and clot formation also proceed if vessel damage occurs, as in traumatic injury, surgery (especially obstetric or orthopedic procedures), indwelling venous catheters, or caustic intravenous medication use. No matter what its source, a blood clot becomes an embolus when all or part of it breaks away from the site of formation and begins to travel in the bloodstream. (Thromboembolism is described further in Chapter 30.)

Pulmonary Artery Hypertension

Pulmonary artery hypertension (PAH) is defined as a mean pulmonary artery pressure above 25 mmHg at rest or 30 mmHg with exercise.¹²⁶ Pulmonary artery pressure is lower than systemic arterial pressure and is normally 15 to 18 mmHg. Box 33-1 contains the WHO¹²⁷ categories for PAH. Idiopathic PAH (IPAH) is rare with only one or two cases per million people. It is more common in women than in men and presents in women in the third decade of life and in men in the fourth decade.^126,127 Familial PAH (FPAH) describes those individuals with PAH who have a family history of the disorder, most often due to mutations in the gene encoding the bone morphogenetic protein receptor type II (BMPR2).^127,128 Associated PAH (APAH) is a leading cause of mortality in many connective tissue disorders and affects up to 1 in 200 individuals infected with HIV.¹²⁷ Diet drugs, amphetamines, and cocaine also have been linked to an increased risk for PAH. Pulmonary artery hypertension associated with left heart failure or valvular disease is caused by increased pulmonary venous pressure and is discussed in Chapter 30. COPD is the most common lung disease associated with PAH, but any condition that causes chronic hypoxemia can result in pulmonary hypertension. Recurrent pulmonary embolism may be subclinical in its presentation and unrecognized until the signs and symptoms of PAH are detected.

Cor Pulmonale

Cor pulmonale is secondary to pulmonary artery hypertension and consists of right ventricular enlargement (hypertrophy, dilation, or both).

Lip Cancer

Cancer of the lip is more prevalent in men, with 3100 new cases per year accounting for about 1% of all cancers in men.¹³² Long-term exposure to sun, wind, and cold over a period of years results in dryness, chapping, hyperkeratosis, and predisposition to malignancy. The lower lip is the most common site.

Laryngeal Cancer

Cancer of the larynx represents approximately 2% to 3% of all cancers in the United States. There were an estimated 12,290 new cases in 2009, 9920 of them in men.¹³² The risk of laryngeal cancer is increased by the amount of tobacco smoked; risk is further heightened with the combination of smoking and alcohol consumption. Gastroesophageal reflux disease is also a risk factor.¹³³ The human papillomavirus (HPV) has been linked to both benign and malignant disease of the larynx.¹³⁴ The highest incidence is in men between 50 and 75 years of age.

Lung Cancer

Lung cancers (bronchogenic carcinomas) arise from the epithelium of the respiratory tract. As such, the term lung cancer excludes other pulmonary tumors, including sarcomas, lymphomas, blastomas, hematomas, and mesotheliomas. Lung cancer is the number one cancer killer in the United States and the world. In the United States, there were an estimated 219,440 new cases and 159,390 deaths in 2009. It accounts for 15% of all cancers in men and 14% in women but is responsible for 31% of all cancer deaths in men and 26% of all cancer deaths in women (Box 33-2). Lung cancer is more common in blacks, for whom survival rates are lower.¹³² Although the mortality rate for lung cancer has leveled off in men, it is still rising in women. Overall 5-year survival remains low at 20%.

The most common cause of lung cancer is cigarette smoking, and approximately 10% to 15% of active smokers will develop lung cancer.¹³⁸ About 10% of lung cancers occur in never-smokers and it is estimated that one fourth of lung cancer cases among never-smokers could be attributed to exposure to passive cigarette smoke.^138,139 Cigarette smoke contains several organ-specific carcinogens, and smoking has been causally related to carcinogenesis at several sites, including the larynx, oral cavity, esophagus, and urinary bladder. Underlying smoking-related COPD is also a risk factor.^138,139 Many genes have been implicated in the risk for lung cancer including genes for glutathione S-transferase M1, growth factors, tumor suppressor, detoxification enzymes, proteases, addiction, and deoxyribonucleic acid (DNA) repair have been identified^138–141 (see What’s New? The Genetics of Lung Cancer). Theories of carcinogenesis are discussed in Chapter 11.

Environmental or occupational risk factors associated with lung cancer include benzopyrene and radon particles associated with uranium mining, radiation, and nuclear bombs. Others are polycyclic aromatic hydrocarbons and arsenicals, asbestos fibers, diesel exhaust, nitrogen mustard gases, nickel, silica, vinyl chloride, and chloromethyl methyl ether. Air pollution, coal, and iron mining are also considered risk factors.¹³⁹

Primary lung cancers arise from the bronchi within the lungs and are therefore called bronchogenic carcinomas. Although there are many types of lung cancer, they are divided into two major categories: non–small cell lung carcinoma (NSCLC, 75% to 85% of all lung cancers) and small cell lung carcinoma (SCLC, 15% to 20% of all lung cancers). The NSCLC can be subdivided into three common types of lung cancer: squamous cell carcinoma, adenocarcinoma, and large cell undifferentiated carcinoma.¹⁴¹ The clinical and pathologic features that most commonly characterize these cancer types are illustrated in Figure 33-21 and described in Table 33-4. Many cancers that arise in other organs of the body metastasize to the lungs; however, these are not considered lung cancers and are categorized by their primary site of origin.