DISEASES AND PATHOLOGY

PECTUS EXCAVATUM

Pectus excavatum is also called funnel chest, chonechondrosternon, or trichterbrust. It is a deformity of the anterior chest wall characterized by depression of the lower sternum and adjacent cartilages. The lowest point of the depression is at the junction of the xiphoid process and the body of the sternum. The trait is inherited and may coexist with other musculoskeletal malformations such as clubfoot, syndactyly, and Klippel-Feil syndrome. The cause of funnel chest remains obscure. A short central tendon and muscular imbalance of the diaphragm have been blamed. Most current writers attribute the deformity to unbalanced growth in the costochondral regions.

Symptoms are very uncommon. However, a child with an obvious deformity may experience unfortunate psychological effects. Funnel chest is usually associated with postural disorders such as forward displacement of the neck and shoulders, upper thoracic kyphosis, and a protuberant abdomen. Functional heart murmurs and benign cardiac arrhythmias are frequently seen in these individuals, and the electrocardiogram may show right-axis deviation because of the displacement of the heart. In older patients, there may be an appreciable incidence of chronic bronchitis and bronchiectasis.

Depression of the sternum begins typically at the junction of the manubrium and the gladiolus. The xiphoid process may be bifid, twisted, or displaced to one side. Costal cartilages are angulated internally, beginning with the second or third and extending caudally to involve the remainder. In general, the defect tends to be symmetric, but one side may be more depressed than the other so that the sternum deviates from the middle line. An estimate of the cavitary volume may be obtained by filling the depression with water while the patient lies supine. Standard radiographic films reveal that the heart is displaced toward the left side, and lateral films show the displacement of the body of the sternum posteriorly.

In patients who are symptomatic or who show a significant progression of pectus excavatum, the deformity should be corrected surgically. Because most of the operations are carried out with a cosmetic end in mind, the results are best when surgery is performed between 3 and 7 years of age. Surgical correction consists of excision of the hypertrophied costal cartilages on both sides; osteotomy of the sternum at the junction of the manubrium and body; and then internal fixation by pins or rods, which are removed later. Fixation by a metal strut or wire is required in older patients to prevent recurrence of the deformity, which, in some degree, may occur despite initial overcorrection.

PECTUS CARINATUM

Also known as pigeon breast, chicken breast, or keel breast, this is a protrusion deformity of the anterior chest wall that is unrelated to pectus excavatum and occurs about one-tenth as often. Two principal types are recognized: (1) chondromanubrial, in which the protuberance is maximal at the xiphoid and the gladiolus is directed posteriorly so that a secondary saucerization is evident, and (2) chondrogladiolar, in which the greatest prominence is at or near the gladiolus. The pathogenesis is no better understood than that of pectus excavatum, but the theory of unbalanced or excessive growth of the cartilages makes sense. Although functional cardiac and respiratory difficulties have been observed, the chief reason for surgical correction is cosmetic. If the deformity is minor, no treatment is required. When operation is necessary, the procedure should be tailored to the particular deformity, taking into account the full life circumstances of the patient. When the deformity causes embarrassment, the surgical procedure is aimed at achieving psychological as well as physiologic improvement.

BIFID STERNUM

Failure of fusion of the sternal bands may occur, creating a defect of the anterior chest wall. Separation of the sternum may be complete or incomplete and may be associated with an ectopia cordis. When the defect is incomplete, surgical correction of the abnormality may be accomplished. If the repair cannot be effected by primary approximation of the sternal segments, a prosthesis or a cartilage autograft may be used.

Other deformities of the chest wall occasionally seen include cervical ribs (with or without compression of the brachial plexus and artery), partial absence of ribs, supernumerary ribs, and thoracic-pelvic-phalangeal dystrophy.

SKELETAL DISORDERS PRESENTING WITH NEONATAL RESPIRATORY DISTRESS

Respiratory distress may result from abnormal lung growth caused by restriction by limited rib growth such as from osteochondrodysplasias (e.g., asphyxiating dystrophy, thanatrophic dwarfism, upper airway obstruction [diastrophic dysplasia]) or abnormal bone, cartilage, or collagen development, leading to a small or abnormal thoracic cage (hypophosphatasia, achondrogenesis, osteogenesis imperfecta).

ANOMALIES AND STRICTURES OF THE TRACHEA

Tracheal anomalies are very rare. With stricture of the trachea, there is local obstruction of the passage of air. In the absence of cartilage, the trachea can collapse and therefore obstruct on expiration. With deformity of cartilage, there is obstruction on inspiration and expiration. When abnormal bifurcations are present, the right upper or left upper lobe bronchi (or both) arise independently from the trachea.

Clinically, stenosis may be localized or diffuse. The localized form is caused by a web of the respiratory mucosa or by excessive growth of tracheal cartilage. The diffuse form is caused by a congenital absence of elastic fibrous tissue between the cartilage and its rings in the trachea or by an absence of cartilage. Clinically, obstruction of the trachea causes chronic dyspnea; cyanosis, especially on exercise; and repeated attacks of respiratory tract infection. The diagnosis is established by bronchoscopy and by radiography.

For localized obstruction, surgery is advisable, either dilatation or excision with end-to-end anastomosis. Resection and anastomosis of the trachea can be carried out, including up to six tracheal rings. For generalized stenosis, only supportive therapy is available.

CONGENITAL CYSTIC ADENOMATOID MALFORMATION OF THE LUNG

This lesion consists of a mass of cysts lined by proliferating bronchial and cuboidal epithelium. It is divided into three types: type I, which includes multiple large, thin-walled cysts; type II, which includes multiple, evenly spaced cysts; and type III, which includes a bulky firm mass with small, evenly spaced cysts. The lesion is now frequently diagnosed by antenatal ultrasonography, but some so detected may regress during the third trimester. Approximately 25% of patients are stillborn; they are usually hydropic and have a type III lesion. Fifty percent are born prematurely. Infants may develop respiratory distress immediately after birth, depending on the size of the lesion; other presentations include recurrent infection, hemoptysis, and an incidental finding on the chest radiograph. The lesion may also be premalignant. Infants with life-threatening respiratory distress require surgery in the perinatal period. The treatment of patients with asymptomatic disease is controversial, but intervention in infancy should be considered because of the increased risk of infection, pneumothorax, and malignancy.

CONGENITAL PULMONARY LYMPHANGIECTASIS

In this condition, there is dilatation of the lymphatic vessels of the lungs and obstruction to their drainage. It may be associated with lymphedema in other portions of the body. Most infants with this problem develop severe respiratory distress at birth, and the majority of them die. Radiologic findings include a ground-glass appearance with fine, diffuse, granular densities representing dilated lymphatics; as with other congenital pulmonary abnormalities, there may be delayed resolution of lung fluid. On examination, the lungs are bulky, with pronounced lobulation, and they contain many thin-walled cystic space–dilated lymphatic vessels.

INTRALOBAR SEQUESTRATION

This type comprises a nonfunctioning portion of lung within the visceral pleura of a pulmonary lobe. In the majority of cases, it derives its systemic arterial supply from the descending thoracic aorta or the abdominal aorta. The venous drainage is invariably by way of the pulmonary veins, producing an arterio-arterial communication. Embryologically, it appears to be a failure of the normal pulmonary artery to supply a peripheral portion of the lung; hence, the arterial supply is derived from a persistent ventral branch of the primitive dorsal aorta.

EXTRALOBAR SEQUESTRATION

This malformation may represent a secondary and more caudal development from the primitive foregut that is then sealed off and migrates caudally as the lung grows. Venous drainage is to the systemic circulation, usually the azygos, hemiazygos, or caval veins. Anatomically, it is related to the left hemidiaphragm in more than 90% of cases. It may be situated between the diaphragmatic surface of the lower lobe and the diaphragm or within the substance of the diaphragm.

On pathologic examination, the affected mass is cystic, and the spaces are filled either with mucus or, if infected, with purulent material. The cystic spaces are lined by either columnar or flat cuboidal epithelium.

Only 20% of intralobar sequestrations present in the neonatal period; occasionally, there may be heart failure caused by massive arteriovenous shunting. Extralobar sequestration rarely presents in the neonatal period but may be found incidentally at operation to repair a congenital diaphragmatic hernia. Later presentations include secondary infection, pneumonia, pleural effusion, and empyema. When the sequestered lung becomes infected, it often appears to be a chronic pulmonary abscess accompanied by episodes of fever, chest pain, cough, and bloody mucopurulent sputum.

On antenatal ultrasonography, the abnormal lung can be seen as an echogenic intrathoracic or intraabdominal mass. In 50% of cases, there is a pleural effusion, and polyhydramnios is a frequent complication. Postnatally, on radiographic examination the diagnosis should be suspected if there is a dense lesion on the posteromedial part of the left zone of the chest radiograph. Extralobar sequestration is usually seen as a dense triangular lesion close to the diaphragm.

Treatment for either type consists of surgical resection. Because of the threat of secondary infection and hemorrhage, surgery should be recommended even though the patient is asymptomatic at the time. When infection occurs, complete removal is mandatory.

CLINICAL FORMS OF BRONCHIAL ASTHMA

Asthma is a syndrome because, although the clinical presentation is often quite characteristic, its etiologic factors vary. Previous descriptors of asthma included the terms extrinsic asthma , implying that an external stimulus was responsible for causing the disease, and intrinsic asthma , in which no obvious external cause could be identified. It is now recognized that likely all asthma is initiated by some external stimulus, the most commonly identified of which are environmental allergens.

Allergic Asthma

Allergic asthma most often affects children and young adults ( Plate 4-14 ). A personal history of other allergic manifestations (atopy), such as allergic rhinitis, conjunctivitis, or eczema is common, as is a family history of atopy. Atopy is identified by positive dermal responses to environmental and occupational allergens and elevated serum immunoglobulin E (IgE) levels.

Nonallergic Asthma

Nonallergic asthma is usually identified in patients who develop asthma symptoms as adults (see Plate 4-15 ). The symptoms may develop after a respiratory tract infection, and occasionally infective agents such as Chlamydia pneumoniae or Mycoplasma spp. are implicated. Occupational sensitizers are other important causes of nonallergic asthma, and a detailed occupational history is a critical component of the evaluation of the patient. Nonallergic asthma is also commonly associated with comorbidities such as chronic sinusitis, obesity, or gastroesophageal reflux.

INDUCERS AND INCITERS OF ASTHMA

An important distinction needs to be made between stimuli that are inducers of asthma (cause the disease), such as environmental allergens and occupational sensitizers, and inciters of asthma, which are stimuli that cause exacerbations or transient symptoms (see Plate 4-16 ).

CLINICAL PRESENTATION

DIAGNOSIS OF ASTHMA

Because asthma is a lifelong disease in most patients, it is important to make the correct diagnosis when symptoms first present. Unfortunately, this is sometimes not done, and patients are inappropriately treated. None of the symptoms of asthma are pathognomonic, and the adage “all that wheezes is not asthma” serves as a reminder that wheezing but also cough, chest tightness, and dyspnea are symptoms of other respiratory or cardiac diseases. The diagnosis of asthma must be made by the presence of the characteristic symptoms associated with the presence of variable airflow obstruction or airway hyperresponsiveness to inhaled bronchoconstrictor mediators.

Variable airflow obstruction is best measured using spirometry with a flow-volume loop and demonstrating a reduced FEV ₁ and ratio of FEV ₁ to forced vital capacity (FVC), which improves after inhalation of β2agonists ( Plate 4-17 ). An improvement in FEV ₁ of more than 12%, with a minimal change of 200 mL, is usually accepted as documentation of reversible airflow obstruction. Some clinics may not have access to spirometry, so variability in peak expired flow (PEF) measurements can also be used for both diagnosis and monitoring asthma. An improvement of more than 20% (or >60 L/min) after inhalation of a β2-agonist or diurnal variation in PEF of more than 20% over 2 weeks of measurements also confirms variable airflow obstruction.

AIRWAY HYPERRESPONSIVENESS

For patients with symptoms consistent with asthma but normal lung function, measurements of airway responsiveness to direct airway challenges (e.g., inhaled methacholine and histamine) or indirect airway challenges (e.g., inhaled mannitol or exercise challenge) may help establish a diagnosis of asthma ( Plate 4-17 ). Measurements of airway responsiveness reflect the “sensitivity” of the airways to factors that can cause asthma symptoms, and the test results are usually expressed as the provocative concentration (or dose) of the agonist causing a given decrease in FEV ₁ . These tests are sensitive for a diagnosis of asthma but have limited specificity. This means that a negative test result can be useful to exclude a diagnosis of persistent asthma in a patient who is not taking inhaled glucocorticosteroid treatment, but a positive test result does not always mean that a patient has asthma. This is because airway hyperresponsiveness has been described in patients with allergic rhinitis and in those with airflow limitation caused by conditions other than asthma, such as cystic fibrosis, bronchiectasis, and chronic obstructive pulmonary disease (COPD).

INVESTIGATIONS THAT MAY BE CONSIDERED TO ESTABLISH A DIAGNOSIS

Sputum

Spontaneously produced as well as induced sputum can be helpful in confirming the diagnosis of asthma and in deciding treatment requirements ( Plate 4-18 ). Spontaneously produced sputum may be mucoid, purulent, or a mixture of both. Importantly, purulent sputum does not always indicate the presence of a bacterial infection in asthmatic patients.

Thin spiral bronchiolar casts (Curschmann spirals) in sputum, measuring up to several centimeters in length, are strongly indicative of asthma. Ciliated columnar bronchial epithelial cells are frequently found. Creola bodies are clumps of such bronchial epithelial cells with moving cilia and are seen in severe asthma.

In asthma, both sputum eosinophils and neutrophils may be increased or the cellular infiltrate may be predominantly eosinophilic or neutrophilic or occasionally paucigranulocytic. The importance of a sputum eosinophilia is that it indicates inadequate treatment with or poor adherence to inhaled corticosteroids (ICS). Acute exacerbations of asthma are usually associated with an increase in eosinophil or neutrophil cell numbers in sputum.

Skin Prick Tests

It is important to establish the presence of atopy in asthmatic subjects, particularly, whether environmental allergens are important triggers of asthma symptoms. Preferably, skin tests are performed by a skin prick using aqueous extracts of common antigens, such as molds, pollens, fungi, house dusts, feathers, foods, or animal dander technique ( Plate 4-19 ). If skinsensitizing antibodies to the antigen are present, a wheal-and-flare reaction develops within 15 to 30 minutes; a control test with saline diluent should show little or no reaction.

Optimally, both the history and dermal reactivity will give corresponding results. However, some patients have positive histories but negative skin test results. In other patients, negative histories and positive skin test results indicate immunologic reactivity that is clinically insignificant.

DIFFERENTIAL DIAGNOSIS

Diseases to be considered in the differential evaluation are depicted in Plate 4-20 . In children, diseases that may be misdiagnosed as asthma also include chronic rhinosinusitis, gastroesophageal reflux, cystic fibrosis, bronchopulmonary dysplasia, congenital malformation causing narrowing of the intrathoracic airways, foreign body aspiration, primary ciliary dyskinesia syndrome, immune deficiency, and congenital heart disease. In adult patients, pulmonary disorders, other than those illustrated in Plate 4-20 , include cystic fibrosis, pneumoconiosis, and systemic vasculitis involving the lungs.

PHYSIOLOGIC ABNORMALITIES IN ASTHMA

Spirometry and Ventilatory Function in Asthma

In asthma, the prime physiologic disturbance is obstruction to airflow, which is more marked in expiration. This obstruction is variable in severity and in its site of involvement and is, by definition, reversible to some degree. Various combinations of smooth muscle constriction, inflammation, edema, and mucus hypersecretion produce this airflow impediment. In addition, low lung volumes with terminal airspace collapse may compound the airway obstruction. In the larger airways, the rigid cartilaginous rings help maintain patency. In the peripheral airways, however, there is little opposition to the smooth muscle action because of the paucity of cartilage. Instead, the patency of these airways is influenced by lung volume because they are imbedded in and partially supported by the lung parenchyma.

At the onset of an asthmatic attack, or in mild cases, obstruction is not extensive. As asthma progresses, airways resistance significantly increases. Although inspiratory resistance also increases, the abnormality is more pronounced during expiration because of narrowing or closure of the airways as the lung empties. At this point, further expiratory effort does not produce any increase in expiratory flow rate and may even intensify airway collapse.

Because of these mechanical resistances, the respiratory muscles must produce a greater degree of chest expansion. More important, the elastic recoil of the lungs is insufficient for “passive” expiration. The respiratory muscles, therefore, must now play an active role in expiration. If obstruction is severe, air trapping will occur, with an increase in residual volume (RV) and functional residual capacity (FRC).

Airway obstruction is uneven and results in unequal distribution of gases to alveoli. This and other stimuli result in tachypnea and a consequently shortened respiratory cycle even though the bronchial obstruction requires a lengthened respiratory time for adequate ventilation. These conflicting demands cannot be reconciled while the asthmatic attack continues.

The severity of the obstruction is reflected in the spirometric measurements of expiratory volume and airflow. The FEV ₁ , FVC, and inspiratory capacity (IC) are all reduced during an acute attack.

The peripheral airways have a proportionately large total cross-sectional area. For this reason, the resistance of the peripheral airways normally accounts for only 20% of the total airway resistance. Thus, extensive obstruction in these smaller airways may go undetected if the physician relies only on clinical findings. The reduction in FVC and FEV ₁ shows a good correlation with the decrease in PaO ₂ , although carbon dioxide retention does not occur until the FEV ₁ is about 1 L or 25% of the level predicted.

With progressive obstruction, expiration becomes increasingly prolonged. Increases in RV and FRC occur (see Plate 4-39 ). These volume changes may represent an inherent physiologic response by the patient because breathing at higher lung volumes prevents the closure of terminal airways. The overall effect of these events is alveolar hyperinflation, which tends to further increase the diameter of the airways by exerting a greater lateral force on their walls. This hyperinflation may partially preserve gas exchange. It is disadvantageous because much more work is required, resulting in an increase in O ₂ consumption. Moreover, such a state compromises IC and vital capacity (VC). The symptoms of dyspnea and fatigue may also arise in part from this process. Finally, the effectiveness of cough is impaired because the velocity of respiratory airflow is seriously reduced.

As a result of the nonhomogeneous airway obstruction in asthma, the distribution of inspired air to the terminal respiratory units is not uniform throughout the lungs. Alveoli that are hypoventilated because they are supplied by obstructed airways are interspersed with normal or hyperventilated alveoli; hence, the severity of asthma is directly related to the ratio of poorly ventilated to well-ventilated alveolar groups. Arterial hypoxemia, which is the primary defect in gas exchange in asthma, is caused by this a / c nonhomogeneity ( Plate 4-21 ). As the population of alveolar units with a low a / c ratio increases (because of advancing obstruction), the degree of arterial hypoxemia also intensifies. The a / c disturbance is compounded if some airways are completely obstructed. The right-to-left intrapulmonary shunt effect results in arterial hypoxemia.

Carbon dioxide elimination is not impaired when the number of alveolar-capillary units with normal a / c ratios remains large relative to the number of those with low a / c ratios. As airway obstruction progresses, there are more and more hypoventilated alveoli. Simultaneously, appropriate increases in respiratory work, rate, and depth occur. Such a response initially minimizes the increase in physiologic dead space but eventually becomes limited, and alveolar ventilation finally fails to support the metabolic needs of the body. Carbon dioxide retention now occurs together with increasing hypoxemia. This is a state of ventilatory failure, and it commonly arises when the FEV ₁ is less than 25% predicted.

PATHOGENESIS OF ASTHMA

Cellular Inflammation

Persistent airway inflammation is considered the characteristic feature of severe, mild, and even asymptomatic asthma. The characteristic features include infiltration of the airways by inflammatory cells, hypertrophy of the airway smooth muscle, and thickening of the lamina reticularis just below the basement membrane (see Plate 4-22 ).

An important feature of the airway inflammatory infiltrate in asthma is its multicellular nature, which is mainly composed of eosinophils but also includes neutrophils, lymphocytes, and other cells in varying degrees. Whereas neutrophils, eosinophils, and T lymphocytes are recruited from the circulation, mast cells are resident cells of the airways. Histologic evidence of mast cell degranulation and eosinophil vacuolation reveals that the inflammatory cells are activated. The mucosal mast cells are not increased but show signs of granule secretion in asthmatic patients. Postmortem studies have shown an apparent reduction in the number of mast cells in the asthmatic bronchi as well as in the lung parenchyma, which reflects mast cell degranulation rather than a true reduction in their numbers.

Eosinophils are considered to be the predominant and most characteristic cells in asthma, as observed from both bronchoalveolar lavage (BAL) and bronchial biopsy studies. The bronchial epithelium is infiltrated by eosinophils, which is evident in both large and small airways, with a greater intensity in the proximal airways in acute severe asthma. However, some studies report the virtual absence of eosinophils in severe or fatal asthma, suggesting some heterogeneity in this process. Alveolar macrophages are the most prevalent cells in the human lungs, both in normal subjects and in asthmatic patients and, when activated, secrete a wide array of mediators. Lymphocytes are critical for the development of asthma and are found in the airways of asthmatic subjects in relationship to disease severity. The function and contribution of lymphocytes in asthma are multifactorial and center on their ability to secrete cytokines. Activated T cells are a source of Th2 cytokines (e.g., IL-4, IL-13), which may induce the activated B cell to produce IgE and enhance expression of cellular adhesion molecules, in particular vascular cell adhesion molecule-1 (VCAM-1) and IL-5, which is essential for eosinophil development and survival in tissues.

IMMUNOLOGIC ABNORMALITIES

Allergic asthma and other allergic diseases, such as allergic rhinitis and anaphylaxis, develop as a result of sensitization to environmental allergens and subsequent immunologically mediated responses when the allergens are encountered. These allergic reactions take place in specific target organs, such as the lungs, gastrointestinal tract, or skin. These immune processes leading to allergic reactions represent the disease state referred to clinically as “atopy.” The immune sequence consists of the sensitization phase followed by a challenge reaction, which produces the clinical syndrome concerned (see Plate 4-23 ).

Sensitization to an allergen occurs when the otherwise innocuous allergen is encountered for the first time. Professional antigen-presenting cells (APCs) such as monocytes, macrophages, and immature dendritic cells capture the antigen and degrade it into short immunogenic peptides. Cleaved antigenic fragments are presented to naïve CD4+ T-helper (Th) cells on MHC class II molecules. Depending on a multitude of factors, particularly the cytokine microenvironment, these naïve T-helper cells are subsequently polarized into Th1 or Th2 lymphocytes. Th1 lymphocytes predominantly secrete IL-2, INF-γ, and tumor necrosis factor (TNF)-β to induce a cellular immune response. In contrast, Th2 lymphocytes secrete IL-4, IL-5, IL-9, and IL-13 cytokines to induce a humoral immune response, particularly the B-cell class switch to allergen-specific immunoglobulin E (IgE) production. In allergic asthma, an imbalance exists between Th1 and Th2 lymphocytes, with a shift in immunity from a Th1 pattern toward a Th2 profile. Accordingly, allergic asthma is often referred to a Th2-mediated disorder, with a persistent Th2-skewed immune response to inhaled allergens ( Plate 4-23 ).

IgE is a γ-l-glycoprotein and is the least abundant antibody in serum, with a concentration of 150 ng/mL compared with 10 mg/mL for IgG in normal individuals. However, IgE concentrations in the circulation may reach more than 10 times the normal level in “atopic” individuals. IgE levels are also increased in patients with parasitic infestations and hyper-IgE-syndrome. Increased serum concentration is not necessarily a specific indicator of the extent or severity of allergy in the individual concerned. The IgE molecules attach to the surfaces of the mast cells or other cells such as basophils. The mast cells containing IgE are distributed in the mucosa of the upper and lower respiratory tract and perivascular connective tissues of the lung.

After sensitization to an allergen has occurred, reexposure of the patient to the allergen may result in an acute allergic reaction, also known as an immediate hypersensitivity reaction ( Plate 4-23 ). IgEsensitized mast cells in contact with the specific antigen secrete preformed and newly synthesized mediators, including histamine, cysteinyl leukotrienes, kinins, prostaglandins and thromboxane, and platelet activating factor. Also, mast cells are sources of proinflammatory cytokines. Each antigen molecule has to bridge at least two of the IgE molecules bound to the surface of the cell. The subsequent airway smooth muscle contraction, vasoconstriction, and hypersecretion of mucus, together with an inflammatory response of increased capillary permeability and cellular infiltration with eosinophils and neutrophils follows, producing asthma symptoms.

PATHOLOGIC CHANGES IN ASTHMA

The initial knowledge of the pathology of asthma came from postmortem studies of fatal asthma or airways of patients with asthma who have died of other causes or who had undergone lung resections. All showed similar, although variably severe, pathologic changes and provided key directives as to the causes and consequences of the inflammatory reactions in the airway (see Plate 4-24 ).

The characteristic mucus plugs in asthmatic airways can cause airway obstruction, leading to ventilation-perfusion mismatch and contributing to hypoxemia. Mucus plugs are composed of mucus, serum proteins, inflammatory cells, and cellular debris, which include desquamated epithelial cells and macrophages often arranged in a spiral pattern (Curschmann spirals). The excessive mucus production in fatal asthma is attributed to hypertrophy and hyperplasia of the submucosal glands. The mucus also contains increased quantities of nucleic acids, glycoproteins, and albumin, making it more viscous. This altered mucous rheology, coupled with the loss of ciliated epithelium, impairs mucociliary clearance.

The airway wall thickness is increased in asthma and is related to disease severity. Compared with nonasthmatic subjects, the airway wall thickness is increased from 50% to 300% in patients with fatal asthma and from 10% to 100% in nonfatal asthma. The greater thickness results from an increase in most tissue compartments, including smooth muscle, epithelium, submucosa, adventitia, and mucosal glands. The inflammatory edema involves the whole airway, particularly the submucosal layer, with marked hypertrophy and hyperplasia of the submucosal glands and goblet cell hyperplasia. Goblet cell hyperplasia and hypertrophy accompany the loss of epithelial cells. There is hyperplasia of the muscularis layer and microvascular vasodilation in the adventitial layers of the airways. Also, morphometric studies have shown that the bronchial lamina propria of asthmatic subjects had a larger number of vessels occupying a larger percentage area than in nonasthmatic subjects and in some circumstances correlated with the severity of disease.

LONG-TERM MANAGEMENT OF ASTHMA

Asthma treatment guidelines have been remarkably consistent in identifying the goals and objectives of asthma treatment. These are to (1) minimize or eliminate asthma symptoms, (2) achieve the best possible lung function, (3) prevent asthma exacerbations, (4) do the above with the fewest possible medications, (5) minimize short- and long-term adverse effects, and (6) educate the patient about the disease and the goals of management. One other important objective should be the prevention of the decline in lung function and the development of fixed airflow obstruction, which occur in some asthmatic patients. In addition to these goals and objectives, each of these documents has described what is meant by the term asthma control . This includes the above objectives but also includes minimizing the need for rescue medications, such as inhaled β ₂ agonists, to less than daily use; minimizing the variability of flow rates that is characteristic of asthma; and having normal activities of daily living. Achieving this level of asthma control should be an objective from the very first visit of the patient to the treating physician. The pharmacologic treatment of patients with asthma must only be considered in the context of asthma education and avoidance of inducers of the disease (see Plate 4-25 ).

Mild Persistent Asthma

Low doses of inhaled corticosteroids (ICS) can often provide ideal asthma control and reduce the risks of severe asthma exacerbations in both children and adults with mild persistent asthma, and they should be the treatment of choice. ICS are the most effective antiinflammatory medications for asthma treatment. The mechanisms of action of asthma medications are depicted in Plate 4-26 . There is no convincing evidence that regular use of combination therapy with ICS and inhaled long-acting β ₂ -agonists (LABA) provides any additional benefit. Leukotriene receptor antagonists (LTRAs) are another treatment option in this population, but they are also less effective than low-dose ICS. There are considerable inter- and intraindividual differences in responses to any therapy. This is also true for response to treatment with ICS and LTRAs in both adults and in children. Although on average, ICS improve almost all asthma outcomes more than LTRAs some patients may show a greater response to LTRAs. Currently, it is not possible to accurately identify these responders based on their clinical, physiologic, or pharmacogenomic characteristics.

The other issue that needs to be considered when making a decision to start ICS treatment in patients with mild asthma is the potential for side effects. ICS are not metabolized in the lungs, and every molecule of ICS that is administered into the lungs is absorbed into the systemic circulation. All of the studies in patients with mild persistent asthma have used low doses of ICS (maximal doses, 400 μg/d). A wealth of data are available demonstrating the safety of these low doses, even used long term, in adults. However, a significant reduction in growth velocity has been demonstrated with low doses of ICS in children. This is unlikely to have any effect on the final height of these children because the one study that has followed children treated with ICS to final height did not show any detrimental effect even with a moderate daily ICS doses.

TREATMENT OF SEVERE ASTHMA EXACERBATIONS

Episodes of acute severe asthma (asthma exacerbations) are episodes of progressive increase in shortness of breath, cough, wheezing, chest tightness, or some combination and are characterized by airflow obstruction that can be quantified by measurement of PEF or FEV ₁ . These measurements are more reliable indicators of the severity of airflow limitation than is the degree of symptoms. Severe exacerbations are potentially life threatening, and their treatment requires close supervision. Patients with severe exacerbations should be encouraged to see their physicians promptly or to proceed to the nearest hospital that provides emergency access for patients with acute asthma. Close objective monitoring of the response to therapy is essential.

The primary therapies for severe asthma exacerbations include repetitive administration of rapid-acting inhaled β ₂ -agonists, 2 to 4 puffs every 20 minutes for the first hour (see Plate 4-27 ). After the first hour, the dose of β ₂ -agonists required depends on the severity of the exacerbation and the response of the previously administered inhaled β ₂ -agonists. A combination of inhaled β ₂ -agonist with an anticholinergic (ipratropium bromide) may produce better bronchodilation than either drug alone. Oxygen should be administered by nasal cannula or by mask and should be titrated against pulse oximetry to maintain a satisfactory oxygen saturation of 90% or above (≥95% in children).

Systemic glucocorticosteroids speed resolution of exacerbations and should be used in all but the mildest exacerbations, especially if the initial rapid-acting inhaled β ₂ -agonist therapy fails to achieve lasting improvement. Oral glucocorticosteroids are usually as effective as those administered intravenously and are preferred because this route of delivery is less invasive. The aims of treatment are to relieve airflow obstruction and hypoxemia as quickly as possible and to plan the prevention of future relapses. Sedation should be strictly avoided during exacerbations of asthma because of the respiratory depressant effect of anxiolytic and hypnotic drugs.

Patients at high risk of asthma-related death should be encouraged to seek urgent care early in the course of their exacerbations. These patients include those with a previous history of near-fatal asthma requiring intubation and mechanical ventilation, who have had a hospitalization or emergency care visit for asthma in the past year, who are currently using or have recently stopped using oral glucocorticosteroids, who are overdependent on rapid-acting inhaled β ₂ -agonists, who have a history of psychiatric disease or psychosocial problems, and who have a history of noncompliance with an asthma medication plan.

The response to treatment may take time, and patients should be closely monitored using clinical as well as objective measurements. The increased treatment should continue until measurements of lung function return to their previous best level or there is a plateau in the response to the inhaled β ₂ -agonists, at which time a decision to admit or discharge the patient can be made based on these values. Patients who can be safely discharged will have responded within the first 2 hours, at which time decisions regarding patient disposition can be made. Patients with a pretreatment FEV ₁ or peak expiratory flow (PEF) below 25% percent predicted or those with a posttreatment FEV ₁ or PEF below 40% percent predicted usually require hospitalization. Patients with posttreatment lung function of 40% to 60% predicted can often be discharged from the emergency setting provided that adequate follow-up is available in the community and their compliance with treatment is assured.

For patients discharged from the emergency department, a minimum of a 7-day course of oral glucocorticosteroids for adults and a shorter course (3-5 days) for children should be prescribed along with continuation of bronchodilator therapy. The bronchodilator can be used on an as-needed basis, based on both symptomatic and objective improvement. Patients should initiate or continue inhaled glucocorticosteroids. The patient's inhaler technique and use of peak flow meter to monitor therapy at home should be reviewed. The factors that precipitated the exacerbation should be identified and strategies for their future avoidance implemented. The patient's response to the exacerbation should be evaluated, and an asthma action plan should be reviewed and written guidance provided.

SUBTYPES

COPD is a disorder that is characterized by slow emptying of the lung during a forced expiration (see Plate 4-39 ). In practice, this is measured as the ratio of forced expiratory volume in 1 second (FEV ₁ ) to forced vital capacity (FVC), and the arbitrary definition of airflow obstruction is generally taken to be an FEV ₁ /FVC ratio lower than 0.70. Because the rate of emptying of the lung decreases with advancing age, many elderly individuals demonstrate airflow obstruction even in the absence of a clinical diagnosis of COPD. The diagnosis of COPD usually describes individuals who have chronic airflow obstruction associated with tobacco smoke or some other environmental insult, although aging of the lung has many features that are similar to those of COPD.

COPD encompasses several clinical subtypes, including chronic bronchitis, emphysema, and some forms of long-standing asthma. Chronic bronchitis is defined by cough and sputum production for at least 3 months of the year for more than 2 consecutive years in the absence of other kinds of endobronchial disease such as bronchiectasis. In practice, though, most patients with chronic bronchitis have perennial chronic productive coughs that are dismissed as “smokers' cough.” Emphysema is defined as enlargement of the distal airspaces as a consequence of destruction of alveolar septa. The resultant loss of elasticity of the lung (i.e., increased distensibility) causes slowing of maximal airflow, hyperinflation, and air trapping that are the pathophysiologic hallmarks of COPD. Asthma is defined by completely reversible airflow obstruction and airway hyperresponsiveness. Chronic persistent asthma may lead to irreversible airflow obstruction and a subset of those with asthma smoke and have incompletely reversible airflow obstruction, resulting in a population that meets the definition of COPD. Because most patients have features of more than one subtype and because the treatment approaches are similar, physicians and epidemiologists usually do not distinguish among the various subcategories of COPD. In the future, however, as molecular and imaging methods permit finer distinction of COPD subgroups, it may be possible to more precisely tailor treatments and define prognosis for individual patients.

Patients with COPD often seek medical attention after their disease is already severe. Typically, patients have incurred several decades of damage caused by cigarette smoking before they experience dyspnea limiting their functional capacity. Patients may be treated for recurrent lower respiratory tract infections before a diagnosis of COPD is considered. Clinical presentations vary in the severity of the underlying lung disease, the rate of progression of disease, and the frequency of exacerbations.

EPIDEMIOLOGY

COPD is the fourth leading cause of death in the United States, and mortality related to COPD is projected to increase as cigarette smoking increases in developing countries. COPD is also among the leading causes of chronic medical disability and health care costs in the United States. Morbidity and mortality attributable to COPD have continued to increase, in contrast with other chronic diseases. COPD accounts for a great burden of health care costs, including direct costs of health care and indirect costs related to missed work and caregiver support. Historically, COPD was described as a disease that predominantly affected white men. However, the prevalence of COPD among women and minorities has grown in recent decades as the rate of increase in white men has leveled off. In the United States, morbidity and mortality from COPD in women now exceeds in men, which is largely attributable to increases in the prevalence of cigarette smoking among women. The most rapid increase in COPD mortality is among elderly women. In developing nations, indoor burning of biomass fuel has been an important risk factor for COPD among women. As tobacco use has become more widespread in the developing world, the prevalence of COPD has risen among both men and women (see Plate 4-28 ).

RISK FACTORS

COPD is caused by a combination of environmental exposures and genetic susceptibility. α ₁ -Antitrypsin deficiency is the best documented genetic risk factor for COPD and demonstrates the interaction between genetic predisposition and environmental exposures that results in clinical manifestations of COPD. Other genetic associations have been suggested but are not as well substantiated. Inhalational exposures are the major environmental risk factor for COPD, and cigarette smoking is by far the most common risk factor worldwide. Other inhalational exposures include outdoor atmospheric pollution and indoor air pollution from heating and cooking, especially with the use of biomass fuels in developing countries. Occupational exposures and recurrent bronchial infections have also been implicated as pathogenic factors. Socioeconomic status and poor nutrition are other factors that may predispose individuals to developing COPD, and individuals with reduced maximal lung function in early life are more likely to develop COPD later in life.

NATURAL HISTORY

COPD is a heterogeneous disorder with the unifying feature of incompletely reversible airflow obstruction, demonstrated by slow emptying of the lungs during a forced expiration. The natural history of the decline in FEV ₁ in patients with COPD was described by Fletcher and Peto (see Plate 4-28 ). These investigators reported that most cigarette smokers have a relatively normal rate of decline in FEV ₁ with aging, but a certain subset of smokers is especially susceptible to cigarette smoke, as demonstrated by an accelerated rate of FEV ₁ decline. More recent studies have confirmed that normal nonsmoking adults lose FEV ₁ at a rate of 30 mL per year, a consequence of aging-related loss of elastic recoil of the lung. Studies of patients with COPD show an average annual decline of FEV ₁ of 45 to 69 mL per year. Smokers that quit may revert to the normal state of decline ( Plate 4-28 ). Persons who develop COPD may start early adulthood with lower levels of lung function and have increased rates of decline. The decline in lung function is asymptomatic for a period of years, and patients adjust their activities to limit strenuous exercise. In middle age, the onset of an intercurrent respiratory infection, ascent to altitude, or progression of the disease beyond a critical threshold may lead to impairment of routine daily activities or even acute respiratory failure. These events lead the patients with COPD to seek medical attention. Thus, the onset of COPD may appear precipitous even though it is the cumulative result of decades of progression.

CLINICAL FEATURES

COPD is a heterogeneous disease that presents with a spectrum of clinical manifestations. Although end-stage COPD has classically been described as having features typical of emphysema or chronic bronchitis, most patients have features of both (see Plates 4-28 to 4-31 ). Although COPD represents a spectrum of clinical presentations, the presence of airflow limitation is a unifying feature, and spirometry serves as a diagnostic tool and a means of assessing disease severity (see Plates 4-39 and 4-42 ). Patients typically have some degree of dyspnea and may also experience cough and wheezing. COPD is progressive, and symptoms and clinical features worsen over time despite available treatments.

PREDOMINANCE OF EMPHYSEMA

The classic representation of a patient with a predominance of emphysema is an asthenic patient with a long history of exertional dyspnea and minimal cough productive of only scant amounts of mucoid sputum (see Plate 4-29 ). Weight loss is common, and the clinical course is characterized by marked, progressive dyspnea.

On physical examination, the patient appears distressed and is using accessory muscles of respiration, which serve to lift the sternum in an anterior-superior direction with each inspiration. The sternomastoid muscles are well-developed, but the limbs show evidence of muscle atrophy. The patient has tachypnea, with relatively prolonged expiration through pursed lips, or expiration is begun with a grunting sound. Patients who have active grunting expiration may exhibit well-developed, tense abdominal musculature. The hyperinflation of the chest leads to widening of the costal angle of the lower ribcage and elevation of the lateral clavicles. The flattened diaphragm causes the lateral ribcage to move inward with each breath. While sitting, the patient often leans forward, extending the arms to brace him- or herself in the so-called “tripod” position. Patients who brace themselves on their thighs may develop hyperkeratosis of the upper thighs. The neck veins may be distended during expiration, yet they collapse with inspiration. The lower intercostal spaces and sternal notch retract with each inspiration. The percussion note is hyperresonant, and the breath sounds on auscultation are diminished, with faint, high-pitched crackles early in inspiration, and wheezes heard in expiration. The cardiac impulse, if visible, is seen in the subxiphoid regions, and cardiac dullness is either absent or severely narrowed. The cardiac impulse is best palpated in the subxiphoid region. If pulmonary hypertension is present, a murmur of tricuspid insufficiency may be heard in the subxiphoid region.

The minute ventilation is maintained, the arterial Po ₂ is often above 60 mm Hg, and the Pco ₂ is low to normal. Pulmonary function testing demonstrates an increased total lung capacity (TLC) and residual volume (RV), with a decreased vital capacity. The DL _CO (diffusing capacity for carbon monoxide) is decreased, reflecting the destruction of the alveolar septa causing reduction of capillary surface area. When the DL _CO decreases below 50% predicted, many patients with emphysema have arterial oxygen desaturation with exercise.

PREDOMINANCE OF CHRONIC BRONCHITIS

Patients with a predominance of chronic bronchitis typically have a history of cough and sputum production for many years along with a history of heavy cigarette smoking (see Plate 4-30 ). Initially, the cough may be present only in the winter months, and the patient may seek medical attention only during the more severe of his or her repeated attacks of purulent bronchitis. Over the years, the cough becomes continuous, and episodes of illness increase in frequency, duration, and severity. After the patient begins to experience exertional dyspnea, he or she often seeks medical help and is found to have a severe degree of obstruction. Frequently, such patients do not seek out a physician until the onset of acute or chronic respiratory failure. Many of these patients report nocturnal snoring and daytime hypersomnolence and demonstrate sleep apnea syndrome, which may contribute to the clinical manifestations.

Patients with a predominance of bronchitis are often overweight and cyanotic. There is often no apparent distress at rest; the respiratory rate is normal or only slightly increased. Accessory muscle usage is not apparent. The chest percussion note is normally resonant and, on auscultation, one can usually hear coarse rattles and rhonchi, which change in location and intensity after a deep breath and productive cough. Wheezing may be present during resting breathing or may be elicited with a forced expiration.

The minute ventilation is either normal or only slightly increased. Failure to increase minute ventilation in the face of ventilation-perfusion mismatch leads to hypoxemia. Because of impaired chemosensitivity, such patients do not compensate properly and permit hypercapnia to develop with Paco ₂ levels above 45 mm Hg. The low Pao ₂ produces desaturation of hemoglobin, which causes hypoxic pulmonary vasoconstriction and eventually irreversible pulmonary hypertension. Desaturation may lead to visible cyanosis, and hypoxic pulmonary vasoconstriction leads to right-sided heart failure (see Plate 4-32 ). Because of the chronic systemic inflammatory response that occurs with COPD, these patients often do not have a normal erythrocytic response to hypoxemia, so the serum hemoglobin may be normal, elevated, or even decreased.

The TLC is often normal, and the RV is moderately elevated. The vital capacity (VC) is mildly diminished. Maximal expiratory flow rates are invariably low. Lung elastic recoil properties are normal or only slightly impaired; the DL _CO is either normal or minimally decreased.

PATHOLOGY

Large Airways Disease (see Plate 4-33 )

Chronic bronchitis is associated with hyperplasia and hypertrophy of the mucus-secreting glands found in the submucosa of the large cartilaginous airways. Because the mass of the submucous glands is approximately 40 times greater than that of the intraepithelial goblet cells, it is thought that these glands produce most airway mucus. The degree of hyperplasia is quantitatively assessed as the ratio of the submucosal gland thickness to the overall thickness of the bronchial wall from the cartilage to the airway lumen. This ratio is known as the Reid index . Although the Reid index is often low in the bronchi of patients who do not have symptoms of COPD during life and is frequently high in those with chronic bronchitis, there is sufficient overlap of Reid index values to suggest that a gradual change in the submucous glands may take place. Thus, the sharp distinction of the clinical definition of chronic bronchitis cannot correlate completely with the pathologic changes in large airways. Although patients with chronic mucus hypersecretion with cough and sputum are more prone to respiratory infections and exacerbations of COPD, the presence of cough and sputum are not, by themselves, indicative of a poor prognosis in the absence of airflow obstruction. The magnitude of airflow obstruction is better correlated with the pathologic involvement of the small airways.

EMPHYSEMA

The several types of emphysema are classified according to patterns of septal destruction and airspace enlargement within terminal respiratory units, or acini (see Plates 4-34 to 4-36 ). The normal acinus is supplied by a terminal bronchiole . The terminal bronchiole undergoes three orders of branching—first into respiratory bronchioles with alveolated walls, into alveolar ducts , and finally into alveolar sacs .

If the septal destruction and dilatation are limited to the central portion of the acinus in the region of the terminal bronchiole and respiratory bronchioles, the disorder is called centriacinar or centrilobular emphysema (see Plate 4-35 ). Because of septal destruction, there is free communication between all orders of respiratory bronchioles. Alveolar sacs at the periphery of the acinus lose volume as the central portions enlarge. Although centriacinar emphysema is often considered to be a diffuse disease process, there is considerable variation in severity from acinus to acinus within the same segment or lobe. In general, however, more of the acini are affected in the upper lung zones than in the lower zones. Extensive centriacinar emphysema is most often found in those with histories of heavy smoking and chronic bronchitis.

In contrast to centriacinar emphysema, panacinar or panlobular emphysema affects the acinus more uniformly with less variability within an individual segment or lobe (see Plate 4-36 ). There is some tendency for the lower zones to be more severely affected. Panacinar emphysema is the characteristic lesion in α ₁ -antitrypsin deficiency, although smokers with α ₁ -antitrypsin deficiency may have centriacinar emphysema as well. Panacinar emphysema to a mild degree is a common finding after the fifth decade of life and may be extensive in elderly nonsmoking patients who have age-related “senile” emphysema. In severe smoking-related chronic obstructive airway disease, both centriacinar and panacinar emphysema are ordinarily found along with chronic bronchitic changes in the airways.

When alveolar wall destruction is restricted to the periphery of the acinus, most often in regions just beneath the visceral pleura, the disorder is designated paraseptal emphysema . This form leads to development of subpleural bullae that may result in episodes of spontaneous pneumothorax in otherwise healthy young adults.

PATHOBIOLOGY

COPD is characterized by chronic inflammation in the peripheral airways and the lung parenchyma (see Plates 4-37 and 4-38 ). The predominant cells are macrophages, CD8+ lymphocytes, and neutrophils. The inflammatory mediators leukotriene B4, tumor necrosis factor-α (TNF-α), and interleukin-8 (IL-8) are increased in the sputum of patients with COPD and may play an important role. An imbalance between proteases and antiproteases is also likely to be important in the pathogenesis of COPD (see Plate 4-38 ). Macrophages and neutrophils release many different proteases that break down connective tissue, such as elastin, in the lung parenchyma. The proteases may induce direct destruction of lung tissue as well as trigger cascades of intracellular events that lead to apoptotic cell death. Moreover, proteases are potent promoters of mucus cell metaplasia and mucus cell secretion, contributing to chronic bronchitis. Neutrophil elastase, proteinase 3, and cathepsins all produce emphysema in laboratory animals. Neutrophil elastase is inhibited by α ₁ antitrypsin and deficiency of this enzyme is the predominant contributor to the emphysema in those with the severe genetic defect. Matrix metalloproteinases (MMPs) from macrophages and neutrophils may also have a key role in inducing emphysema. In the normal state, proteolytic enzymes are counteracted by antiproteases such as α ₁ -antitrypsin and serum leukocyte proteinase inhibitor (SLIPI). By inducing inflammation, smoking increases release of proteases in the terminal airspaces in patients in whom COPD develops. Moreover, smoking may also inactivate antiproteases via MMP inhibition of α ₁ -antitrypsin, which itself is an inhibitor of a protease that counteracts the actions of MMPs. By reducing α ₁ -antitrypsin's inhibition of this protease, known as tissue inhibitor of metalloproteinases (TIMP), the actions of MMPs are enhanced. Smoking also leads to increased reactive oxygen species (ROS), which can promote inflammatory gene transcription by breakdown of the inhibitor of the transcription factor nuclear factor kappa-B (NFκB), known as IN-KB. ROS can also inactivate histone deacetylase (HDAC), leading to increased DNA acetylation and gene transcription. Furthermore, CD8+ cells can promote macrophage production of MMPs through interferon-inducible cytokines, such as inducible protein of 10kD (IP-10), interfection-inducible T-cell alpha chemoattractant (l-TAC), and monokine induced by interferon-gamma (MIG). Thus, an insufficient concentration of antiproteases may result in parenchymal damage.

Oxidative stress may also contribute to the injury characteristic of COPD by oxidation of proteins, cell membranes, and nucleic acids, triggering a cellular stress response that ultimately leads to apoptotic cell death. The inflammation in COPD is not only localized to the lungs but is present on a systemic basis. Patients with COPD have elevated concentrations of C-reactive protein and interleukin-6, even during times of stable symptoms. Weight loss and muscle atrophy in COPD have been associated with increased circulating levels of TNF-α and soluble TNF-α receptors.

The final common pathway of inflammatory cytokines, protease-antiprotease imbalance, and oxidative stress is destruction of alveolar epithelial and capillary endothelial cells by a programmed sequence of cell death, or apoptosis. Because the lung requires replacement of its cellular scaffolding on a continuing basis, any process that leads to an imbalance of cell destruction and cell growth can eventually lead to emphysema. Thus, insufficiency of growth factors is also postulated to contribute to the development of emphysema.

The presence of CD8 cells and airway-associated lymphoid follicles in the lung parenchyma in smokers with COPD has raised the possibility that immunologic processes such as autoimmunity or response to chronic viral infection may also contribute to the pathogenesis of COPD.

α ₁ -ANTITRYPSIN

Serum levels of α ₁ -antitrypsin are either deficient or absent in some patients with early onset of emphysema associated with particular genotypes (see Plate 4-38 ). Most people in the normal population have α ₁ antitrypsin levels in excess of 250 mg/100 mL of serum along with two M genes, designated as Pi-type MM. Several genes are associated with alterations in serum α ₁ -antitrypsin levels, but the most common ones associated with emphysema are the Z and S genes. Individuals who are homozygous ZZ or SS have serum levels of α ₁ -antitrypsin of less than 50 mg/100 mL and develop severe panacinar emphysema at an early age, particularly if they smoke or are exposed to occupational dusts. The MZ and MS heterozygotes have intermediate levels of serum α ₁ -antitrypsin. Although smokers with MZ or MS genotypes may have slightly increased decline in FEV ₁ if they smoke, the risk of developing COPD is not materially increased beyond other smokers.

α ₁ -Antitrypsin deficiency is caused by a single amino acid substitution. The Z mutation is caused by a glutamate to lysine mutation at position 342, and the S mutation is caused by a glutamate to valine mutation at position 264. These mutations lead to misfolding of the protein preventing release from the liver, where it is mainly manufactured. The misfolded protein may be destroyed by proteosomal processes, or if it polymerizes, may be stored in the endoplasmic reticulum and not released into the circulation. Excessive liver storage may lead to inflammatory liver disease and cirrhosis, particularly in affected infants and children.

The precise way that antitrypsin deficiency produces emphysema is unclear. In addition to inhibiting trypsin, α ₁ -antitrypsin effectively inhibits elastase and collagenase, as well as several other enzymes. α ₁ -Antitrypsin is an acute-phase reactant, and the serum levels increase in association with many inflammatory reactions and with estrogen administration in all except homozygotes. It has been proposed, with some supporting experimental evidence, that the structural integrity of lung elastin and collagen depends on this antiprotease, which protects the lung from proteases released from leukocytes. Proteases released by lysed leukocytes in the alveoli may be uninhibited and consequently free to damage the alveolar walls themselves. Alternative theories suggest that the unopposed protease activity may lead to an ongoing immune-mediated inflammatory response or acceleration of natural programmed cell death.

PATHOPHYSIOLOGY

Whether bronchitis or emphysema predominates, by the time a patient with COPD begins to have symptoms, airflow limitation is readily demonstrable as an obstructive ventilatory defect. The most easily measured indexes of obstruction are taken from the volume-time plot of a forced expiratory VC maneuver, classically measured with a spirometer coupled to a rotating drum kymograph. Although volume-measuring spirometers are stable, rugged, and linear instruments, most modern spirometry systems use flow-measuring devices (pneumotachometers) interfaced with a microprocessor that integrates flow over time to produce a time-based record of forced expired volume (see Plate 4-39 ). The FEV ₁ is low both as a percentage of the value predicted for a given gender, age, and height category and as a percentage of the patient's own FVC. Depending on the purpose of the pulmonary function test, an obstructive ventilatory defect is defined either as an FEV1/FVC ratio of less than 70% or less than the 95th percentile for the demographic category.

With COPD, static lung volumes are often abnormal. Plate 4-39 depicts the normal lung volumes and those often found in COPD. The functional residual capacity (FRC) is the lung volume at the end of a quiet exhalation and, in normal subjects, is the volume at which the inward recoil of the lung is equal and opposite to the outward recoil of the relaxed chest wall. An elevated FRC in individuals with COPD results from the loss of the static elastic recoil properties of the lung as well as initiation of inspiration before the static balance volume is reached (so-called “dynamic hyperinflation”). TLC is determined by pressures exerted by the diaphragm and muscles of the chest wall in relation to the static elastic recoil properties of both the chest wall and lung. When TLC is elevated in COPD, a significant degree of emphysema is present, although the TLC can also be elevated during acute episodes of asthma. RV is elevated early in the clinical course of COPD and is a sensitive sign of airflow limitation. Early in the course of the disease, elevation of RV is thought to be caused by closure of airways, but late in the disease, emphysematous bullae may also contribute to the elevation in RV. Because the TLC does not increase as much as the RV increases, the VC (i.e., TLC — RV) decreases with advancing COPD.

The measurement of static lung volumes in COPD is subject to some technical issues (see Plate 2-3 ). Resident gas methods using helium dilution or nitrogen may underestimate the true lung volumes because of incomplete gas mixing or washout in regions with impaired ventilation. Plethysmographic lung volumes that depend on Boyle's law relying on the compressibility of resident gas in the lung are more accurate but are subject to overestimation of the true lung volume if the panting frequency is too rapid to permit equilibration of the mouth and alveolar pressures. Because the difference between the resident gas and plethysmographic measure is caused by regions of lung with little or no ventilation, the difference between the two methods has been called “trapped gas” and used as an indicator of COPD severity (see Section 2 ).

In addition to the easily demonstrable obstructive abnormalities during forced exhalation, there are significant alterations in the pressure-flow relationships during ordinary breathing in COPD. This contrasts with exhalation in normal subjects who can increase expiratory flow during tidal breathing (see Plate 4-39 ). Because of the slow emptying of the lung in COPD, the next breath is initiated before the respiratory system can return to the static FRC. This means that the individual breathes at higher lung volumes to maintain adequate expiratory airflow, a condition referred to as dynamic hyperinflation (see Plate 4-39 ). Although breathing at high lung volumes has the advantage of increasing airflow because of the increased lung elastic recoil, it requires an increase in the work of breathing and a decrease in the efficiency of breathing. Increasing respiratory rate accentuates dynamic hyperinflation and can worsen the sensation of dyspnea. Pursed-lip breathing causes patients to slow their respiratory rate and can relieve dyspnea by diminishing dynamic hyperinflation.

The physiologic hallmark of emphysema is a reduction in lung elastic recoil caused by destruction of alveolar septal elements. This causes the pressurevolume curve of the lung to be shifted upward and to the left, resulting in decreased static recoil pressure at a specific lung volume and an increase in the compliance of the lung (see Plates 4-39 and 4-40 ).

The surface area of the alveolar-capillary membrane is reduced as a consequence of emphysema. This results in decreased transfer of diffusion-limited gases such as carbon monoxide across the alveolar-capillary membrane. This is measured in the pulmonary function laboratory as the DL _CO . The DL _CO correlates roughly with the magnitude of reduction in maximum elastic recoil of the lung as well as the anatomic extent of emphysema assessed by imaging with computed tomography (CT). In chronic bronchitis, the DL _CO may be preserved, and in asthma, the DL _CO tends to be elevated.

With the progression of COPD comes progressive exercise limitation. This is caused by the increased work of breathing as ventilation increases with exercise. With increased respiratory rate, patients develop dynamic hyperinflation, a condition in which the end-expiratory lung volume does not return to the static endexpiratory volume of FRC (see Plate 4-40 ). The hyperinflation that occurs causes an increased work of breathing and exacerbates dyspnea. An indicator of dynamic hyperinflation is the inspiratory capacity (IC), which progressively decreases with increasing ventilation. Measures that reduce dynamic hyperinflation, increasing IC, can improve exercise capacity. These include alterations in breathing pattern, oxygen supplementation, helium inhalation, and use of inhaled bronchodilators, particularly long-acting, and lung volume reduction surgery.

RADIOGRAPHIC APPEARANCE

Emphysema

In evaluating plain radiographs, a range of findings can represent emphysema. These include attenuation of the pulmonary vasculature peripherally, irregular radiolucency of lung fields, flattening or inversion of the diaphragm as seen on both posteroanterior (PA) and lateral projections, and an increase in the retrosternal space on the lateral projection. The latter two findings have correlated best with the severity of emphysema as assessed at subsequent postmortem examination.

High-resolution CT examination of the chest is now considered the best indicator of the extent and distribution of emphysema (see Plate 4-41 ). Qualitative visual assessments can assess the presence of thinwalled bullae and regions of diminished vascularity. Quantitative assessments use the degree of attenuation of x-rays to estimate the air-tissue ratio as a measure of airspace enlargement. Regions of the lung on thin-section CT scans that approach the radiodensity of air (—1000 Hounsfield units [HU]) are considered to be emphysema. For example, the emphysema index is calculated as the percentage of image voxels in the lung regions that have a density <−950 HU). Other methods rely on the statistical distribution of lung densities, quantifying the severity of emphysema by the lung density at the lowest 15th percentile of voxels.

MANAGEMENT

PREVENTIVE MEASURES

TREATMENT OF STABLE CHRONIC OBSTRUCTIVE PULMONARY DISEASE

The goals of treatment of COPD are to prevent progression and complications of the disease, relieve symptoms, improve exercise capacity, improve quality of life, treat exacerbations, and improve survival. In addition to smoking intervention and treatment of hypoxemia with supplemental oxygen, pharmacologic therapy is available for treatment of patients with COPD. See the section on pharmacology ( Plates 5-1 to 5-10 ) for a more detailed description of many of the drugs discussed below.

The current goals of drug therapy are not only to improve lung function, but also to improve quality of life and exercise capacity and to prevent exacerbations. The recommended approach to drug treatment for COPD is to sequentially add agents using the minimum number of agents and the most convenient dosing schedule, starting with the agents having the greatest benefit, best tolerance, and lowest cost (see Plate 4-42 ).

Inhaled bronchodilators, including β-agonists and anticholinergic agents, are the foundation of treatment for patients with COPD. They are given on a regular basis to maintain bronchodilation and on an as-needed basis for relief of symptoms. Both β-agonist and anticholinergic classes are available in short-duration (4-6 hour) and long-duration (12-24 hour) forms. Evidence suggests that long-acting agents are more effective than short-acting agents, but the choice of medication should also account for cost considerations and patient preference. Combination of different classes of bronchodilators is often more effective than increasing the dose of a single agent, and combination inhalers can simplify treatment regimens. Individuals with frequent exacerbations or more severe COPD may benefit from a combination inhaler of corticosteroids and long-acting bronchodilator. Long-acting oral theophylline can also be used as adjunctive therapy. Chronic use of systemic corticosteroids should be reserved for individuals with very frequent or life-threatening exacerbations who cannot tolerate their discontinuation.

Replacement therapy with α ₁ -antitrypsin should be considered for individuals with severe deficiency. Observational studies suggest that individuals with moderate degrees of impairment (FEV ₁ 35%-65% predicted) seem to benefit most in terms of preservation of lung function and improved survival.

Patient education about pharmacotherapy is important to ensure proper use of medications, as well as to enhance adherence. Inhaled agents are administered by metered-dose inhalers or dry powder inhalers or as a nebulized solution. The selection of route of administration is made by cost and convenience of the device because all are similarly effective if used properly. Proper use of inhaled medications is difficult for many patients to learn and retain. Adherence with inhaled medication, particularly when it does not provide immediate symptom relief, is poor. Typically, about half of patients do not take their medication in the dose or quantity prescribed. Reasons for this include a lack of understanding of the role of the medication, failure of the medication to provide meaningful benefit, complexity of the treatment program, and expense of the treatment. Many patients do not want to confide poor adherence to their physician, so it is important for the physician to ascertain this information in a way that does not interfere with the relationship with the patient. If nonadherence is a problem, the treating physician can undertake actions to improve adherence such as simplification of the medication program, education about the benefits of treatment, linking drug use to established habits such as meals or tooth brushing, or prescribing less costly drugs.

TREATMENT OF EXACERBATIONS

COPD exacerbations are characterized by worsening dyspnea, cough, and increased sputum production. There are several formal definitions of a COPD exacerbation, but a useful working definition is that a COPD exacerbation is a worsening of dyspnea, cough, or sputum production that exceeds day-to-day variability and that persists for more than 1 or 2 days. On average, patients with COPD have two to three exacerbations per year, but there is wide variation, and the frequency of exacerbations is only roughly correlated with severity of airflow obstruction. The best predictor of future exacerbations is a history of frequent exacerbations, and these are more common in patients with chronic cough and sputum production. Precipitating events include respiratory and nonrespiratory infections; exposure to respiratory irritants and air pollution; and comorbid conditions such as heart failure, pulmonary embolism, myocardial ischemia, or pneumothorax.

For patients treated at home, increasing the frequency and intensity of inhaled short-acting bronchodilators for several days is effective in mild exacerbations. A nebulizer may be needed for those who have difficulty using inhalers or in those with severe dyspnea. Increasing dyspnea accompanied by a change in the quantity or color of phlegm is usually an indication of bacterial infection and should prompt initiation of antibiotics. A course of corticosteroids, equivalent to 30 to 60 mg of prednisone for 7 to 14 days, will shorten the duration of symptoms for patients with exacerbations managed as outpatients.

For patients admitted to the hospital, intensification of inhaled bronchodilator treatment, systemic corticosteroids, and antibiotics should be administered. Controlled oxygen supplementation should be provided at the lowest level needed to reverse hypoxemia and minimize the induction of hypercapnia. The selection of the oral or intravenous route for antibiotics and corticosteroids is determined by the severity of the illness and the ability of the patient to tolerate oral medication.

Treatment in an intensive care setting should be undertaken for patients with severe life-threatening exacerbations and those who require more constant attention. For patients with respiratory failure, noninvasive mask ventilation has proven to be an effective strategy to avert endotracheal intubation, shorten the duration of illness, and improve outcomes. When noninvasive mask ventilation is not successful in sustaining ventilation or if the patient is too ill to use the mask, endotracheal intubation and mechanical ventilation are needed to treat respiratory failure. The mechanical ventilator should be set to provide a provide a prolonged duration of expiration to minimize dynamic hyperinflation (“intrinsic positive end-expiratory pressure”), which can lead to dyspnea, ventilator dyscoordination, and barotrauma. Care should be taken not to overventilate the patient and cause alkalemia, which may ultimately impede liberation from the ventilator. Survival after an episode of acute respiratory failure for COPD is about 50% at 2 years after discharge, with about 50% of the patients being readmitted to the hospital within 6 months.

TREATMENT COMPLICATIONS

Patients with advanced COPD are prone to developing secondary complications of the disease. The goals of treatment are to restore functional status as quickly and as much as possible and to alleviate distress and discomfort.

Cor Pulmonale

The pulmonary vascular bed normally has an impressive reserve that accommodates large increases in cardiac output with minimal elevations of pulmonary artery pressures (see Plate 4-32 ). In COPD, there is a decrease in the total cross-sectional area of the pulmonary vascular bed caused by anatomic changes in the arteries; constriction of smooth muscle in response to alveolar hypoxia; and, to the extent that emphysema is present, a loss of pulmonary capillaries. Therefore, the pressures that must be generated by the right ventricle are elevated, and dilatation and hypertrophy of the right ventricle result. Overt right ventricular failure often occurs in association with endobronchial infections, which leads to worsening hypoxemia and hypercapnia. Such episodes are more frequent in patients in whom bronchitis is dominant.

Patients with cor pulmonale are cyanotic and have distended neck veins that do not collapse with inspiration, hepatic engorgement with a tender and enlarged liver, and pitting edema of the extremities. The heart may or may not appear enlarged on a PA chest radiograph, but pulmonary vessels are prominent. Physical examination may disclose a palpable right ventricular heave and an audible early diastolic gallop that is accentuated by inspiration. On occasion, there is dilatation of the tricuspid ring with secondary tricuspid insufficiency; this disappears with effective treatment. The electrocardiogram may show changes of right ventricular hypertrophy. Echocardiographic findings may be inconsistent, especially because of difficulty obtaining good-quality views of the right ventricle because of overlying hyperinflation of the lungs. Thus, in patients suspected to have pulmonary hypertension, a right-sided heart catheterization is the most definitive means of making the diagnosis.

Treatment of hypoxemia is the mainstay of prevention and treatment of cor pulmonale. Supplemental oxygen should be prescribed to maintain adequate oxygen saturations regardless of the development of hypercapnia (see Plates 5-12 to 5-14 ). The presence of sleep apnea is common in patients with COPD and pulmonary hypertension. Thus, evaluation with a sleep study is often helpful to determine the need for nocturnal oxygen or continuous positive airway pressure (see Plates 4-165 to 4-166 ). In occasional patients who have severe pulmonary hypertension with minimal COPD, pulmonary thromboembolism should be ruled out. Rarely, pulmonary vasodilators may be used when the magnitude of pulmonary hypertension seems disproportionate to the severity of the COPD and hypoxemia.

SURGICAL TREATMENT

Lung Transplantation (see Plate 5-33 )

In younger patients with advanced disease, lung transplantation should be a treatment consideration (see Plate 5-33 ). Criteria for lung transplantation referral in patients with COPD is an FEV ₁ below 25% predicted, severe hypercapnia, or severe pulmonary hypertension in patients younger than age 60 to 65 years. The traditional recommendation is that patients should be referred for transplantation when their life expectancy is less than 2 years because this is the average waiting time on a transplant recipient list. In recent years, the waiting time has lengthened to closer to 4 years, so this may influence physicians to make earlier referrals. Other comorbid conditions, such as poor nutritional status, obesity, chronic mycobacterial infection, or severe osteoporosis, as well as suboptimal psychosocial support, are considered relative contraindications. Current smoking, recent malignant disease, major organ system failure (particularly renal or chronic hepatitis B or C infections) are considered absolute contraindications. Lung transplantation may be either unilateral or bilateral depending on the availability of donor organs and the preference of the transplant surgeon. Generally, younger patients and those with accompanying bronchiectasis are considered more suitable candidates for bilateral lung transplantation.

In the past, COPD has been the most common indication for lung transplantation, accounting for nearly 40% of all lung transplants and about 50% of single lung transplants. This is accounted for by the high prevalence of COPD as well as the better survival rate for patients with COPD than those with other transplant indications while awaiting donor organs. However, current criteria for prioritization of transplant recipients based on diagnosis rather than waiting time alone are likely to diminish the likelihood that COPD patients will receive donor organs. Early survival for patients with COPD after lung transplant is slightly better than that of other diagnostic groups in the first few years. Overall, 30-day survival is 93%, 3-year survival is 61%, and 5-year survival is 45%.

CAUSE

Causes of bronchiectasis may be categorized as an underlying systemic disease or anatomic abnormality, postinfectious or idiopathic. The most common causes differ by age (children vs. adults) and by country.

Systemic Disease

The most important inherited cause of bronchiectasis is cystic fibrosis (CF). CF is reviewed in Plates 4-45 to 4-47 ; the remainder of this review focuses on non-CF bronchiectasis. Primary ciliary dyskinesia (PCD) is another well-recognized cause of bronchiectasis. PCD is an autosomal recessive, genetically heterogeneous disorder characterized by oto-sino-pulmonary disease caused by abnormal structure and function of cilia. Patients with PCD present with chronic rhinitis, recurrent otitis media and sinusitis, neonatal respiratory distress, chronic cough, and situs inversus (in ∼50%). Nasal nitric oxide measurements are a valuable screening tool, with low concentrations seen almost uniformly in patients with PCD. Evaluation of ciliary ultrastructure from a nasal scrape remains the best method of diagnosis. Most PCD patients (∼90%) have ultrastructural defects of cilia involving the outer dynein arm (ODA), inner dynein arm (IDA), or both. Genetic diagnosis is becoming increasingly possible. Mutations in DHAI1 and DNAH5 (encoding ODA proteins) are found in about 40% of PCD patients with ODA defects.

α ₁ -Antitrypsin disease is increasingly recognized as a cause of bronchiectasis. Although emphysema remains the most common pulmonary feature, 27% of patients in one series had clinically important bronchiectasis.

Immune deficiencies may contribute to bronchiectasis, including IgG subclass deficiencies; hypogammaglobulinemia; or, more rarely, chronic granulomatous disease or other causes of abnormal neutrophil adhesion, respiratory burst, and chemotaxis. HIV/AIDS is also a risk factor for bronchiectasis.

Autoimmune or immune-related diseases such as allergic bronchopulmonary aspergillosis (ABPA), collagen vascular diseases (particularly Sjögren syndrome and rheumatoid arthritis) and inflammatory bowel diseases may be associated with bronchiectasis.

DIAGNOSIS

The diagnosis of bronchiectasis should be considered in individuals presenting with chronic cough and sputum production. Other symptoms may include dyspnea, hemoptysis, and systemic symptoms such as fatigue or malaise. Among adults, bronchiectasis is more common in women than men. Idiopathic bronchiectasis occurs most frequently in middle-aged women who are lifelong nonsmokers. HRCT is the gold standard for diagnosis of bronchiectasis. Plain radiography is insufficiently sensitive, and contrast bronchography no longer plays a role. The extent of disease on HRCT has been correlated with functional change and clinical outcomes.

An underlying cause of bronchiectasis is more frequently identified in children than in adults. In two series from the United Kingdom, among 136 children, the cause of bronchiectasis was identified as an immunodeficiency in 34%, aspiration in 18%, PCD in 16%, and idiopathic in 25%. In two adult series from the United Kingdom, idiopathic bronchiectasis was diagnosed in 25% to 47% of individuals.

Examinations to consider in patients with HRCT-diagnosed bronchiectasis may include a sweat chloride test and CF genetic analysis to evaluate for CF, nasal nitric oxide and nasal scrape for PCD, immunodeficiency evaluation (quantitative immunoglobulins with IgG subclasses, antibody response to vaccines with tetanus, H. influenzae ), barium esophagram for gastroesophageal reflux, α ₁ -antitrypsin levels, sputum culture, and acid-fast baeilli (AFB). In focal bronchiectasis, evaluation for an airway lesion should be considered.

CLINICAL COURSE

The clinical course of non-CF bronchiectasis is highly variable, depending on the underlying cause and management. Some individuals have daily symptoms, frequent exacerbations, and progressive loss of lung function, but others have minimal daily symptoms and relative preservation of lung function. Factors associated with more rapid decline in lung function include colonization with Pseudomonas aeruginosa , more frequent exacerbations, and evidence of systemic inflammation.

MANAGEMENT

There have been few randomized, controlled trials of therapies in individuals with bronchiectasis, partly because of the heterogeneity of the disease. Although the rationale for therapy may be similar in CF and non-CF bronchiectasis, therapies must be tested specifically in this population. For example, because in general, lung function and mortality are less impacted in non-CF bronchiectasis, therapies may be best directed to decreasing exacerbation rates rather than slowing lung function decline. Whereas rhDNase is a mainstay of therapy in CF, it has been demonstrated to have an adverse safety profile in adults with bronchiectasis.

GENETICS

CF is caused by mutations in the CF transmembrane conductance regulator (CFTR), a 230-kb gene on chromosome 7 encoding a chloride channel expressed in epithelial cells in the sweat duct, airway, pancreatic duct, intestine, biliary tree, and vas deferens. More than 1000 mutations in CFTR have been described, although far fewer have been clearly identified as causing disease. These mutations can be grouped into six classes based on their function ( Plate 4-45 ). The level of functional CFTR is important in determining the manifestations of CF, and the broad spectrum of disease related to CFTR dysfunction is increasingly being recognized ( Plate 4-45 ). Attempts to predict the severity of lung disease, the major cause of morbidity and mortality in CF, from the CFTR genotype have been unsuccessful. It is likely that environmental factors and modifier genes play important roles in determining the phenotype of patients with CF.

DIAGNOSIS

Updated guidelines for the diagnosis of CF have recently been published. Although symptoms suggestive of CF include poor weight gain, steatorrhea, rectal prolapse, chronic cough, and recurrent sinusitis, CF is increasingly diagnosed via prenatal or newborn screening. Until the advent of widespread newborn screening for CF, suspicion for CF arose only from the appearance of symptoms or a family history of the disease. But by 2010, newborn screening for CF will be universal throughout the United States, and most individuals will enter the diagnostic algorithm because of a positive newborn screen result. The primary test for establishing the diagnosis of CF remains the sweat chloride test, which is performed by the pilocarpine iontophoresis method. The identification of two CF disease-causing mutations can also establish the diagnosis.

CLINICAL MANIFESTATIONS

Manifestations of CF may include chronic sinusitis, recurrent nasal polyposis, progressive obstructive pulmonary disease, exocrine pancreatic insufficiency, biliary disease, CF-related diabetes, and male infertility. Given the chronic, complex, multisystem nature of the illness, patients with CF should be followed in a specialized CF center, such as those accredited in the United States by the Cystic Fibrosis Foundation.

PULMONARY DISEASE

Lung disease is the primary cause of morbidity and mortality in people with CF. It is characterized by a vicious cycle of endobronchial bacterial infection and a vigorous host neutrophilic inflammatory response, resulting in progressive structural damage (bronchiectasis) and obstructive lung disease (see Plate 4-46 ). The airways of CF patients become infected with a distinctive spectrum of bacterial pathogens, generally acquired in an age-dependent fashion. Common pathogens at an early age include Staphylococcus aureus and Haemophilus influenzae . Later, infection with Pseudomonas aeruginosa becomes increasingly prevalent. At first, P. aeruginosa infection is intermittent and nonmucoid, but it eventually becomes chronic and mucoid in phenotype. Acquisition of P. aeruginosa , particularly mucoid strains, is associated with more rapid clinical deterioration.

Respiratory treatments vary by age and disease severity; guidelines have recently been published. These treatments, although dramatically improving pulmonary outcomes over the past 2 decades, also represent the greatest challenge to patients and families. The inhaled therapies and airway clearance can take more than 1 hour each day and can cause financial hardships. Chronic treatments may include airway clearance techniques; mucolytics such as inhaled rhDNase and hypertonic saline; and in patients chronically infected with P. aeruginosa , oral macrolides and alternate-month inhaled antibiotics.

Individuals with CF intermittently experience episodes of increased cough, increased sputum production, and decline in lung function, often in conjunction with anorexia and fatigue, termed a pulmonary exacerbation . Milder exacerbations are typically treated with oral or inhaled antibiotics coupled with increased airway clearance. Severe exacerbations or those that fail to resolve with outpatient therapy require treatment with intravenous antibiotics, generally in the inpatient setting. In an effort to slow or avoid the decline in lung function associated with chronic Pseudomonas infection, first acquisition of Pseudomonas spp. is treated with an eradication protocol, which may include oral, inhaled, or intravenous antibiotics, often in combination.

Complications include hemoptysis and pneumothoraces. Bilateral lung transplantation is an option for some CF patients with end-stage lung disease.

GASTROINTESTINAL DISEASE

Approximately 20% of infants with CF present acute intestinal obstruction caused by meconium ileus in the neonatal period. Exocrine pancreatic insufficiency occurs in approximately 90% of individuals affected with CF. Patients with two severe CFTR mutations (class 1, 2, or 3) present with pancreatic insufficiency, and those with one or more mild mutations (class 4 or 5) may be pancreatic sufficient. Pancreatic insufficiency places CF patients at risk for fat malabsorption, suboptimal nutrition, and inadequate circulating levels of fat-soluble vitamins. CF patients with pancreatic insufficiency are treated with a high-fat, high-calorie diet and pancreatic enzyme replacement therapy in the form of capsules taken with each meal. Patients with pancreatic sufficiency are at increased risk of acute or chronic pancreatitis.

Some level of liver disease is common in CF patients, with the prevalence increasing with advancing age. Abnormalities may include elevated transaminases, hepatosteatosis, or biliary tract disease. Cholelithiasis is also common. A small number of patients develop frank biliary cirrhosis with portal hypertension. Management of CF liver disease often includes ursodeoxycholic acid.

ENDOCRINE DISEASE

The prevalence of CF-related diabetes also increases with advancing age. The prevalence is 9% at ages 5 to 9 years, increasing to 43% for age older than 30 years. CF-related diabetes is a risk factor for more accelerated decline in lung function and higher mortality. Therefore, routine screening is recommended. Treatment generally involves maintenance of a high-fat, high-calorie diet plus insulin therapy.

Osteopenia is also an increasingly recognized complication of CF. The cause is likely related to poor nutritional status, malabsorption of vitamins K and D, delayed pubertal maturation, steroid exposure, inactivity, and chronic pulmonary inflammation. Routine screening is recommended, and prevention via aggressive nutritional interventions, fat-soluble vitamins, and maximization of pulmonary health is critical.

FERTILITY

At least 98% of men with CF are infertile because of absence or atresia of the vas deferens and absent or dilated seminal vesicles. Men with CF can become fathers with artificial insemination procedures. Female reproduction is normal, and an increasing number of women with CF are becoming mothers.

PROGNOSIS

Survival of patients with CF has made continuous, sustained improvements over the past 50 years, with median survival in the United States improving from 8 years in 1969 to more than 37 years today (see Plate 4-47 ). Female survival has been lower than male, but this “gender gap” appears to be closing. Potential contributors to improved survival include CF center care, aggressive nutritional support, and the introduction of new pulmonary therapies. Major quality improvement initiatives, the widespread uptake of newborn screening, and new therapies aimed at restoring CFTR function and combating chronic inflammation are sure to result in continued improvements in quality of life and survival for individuals with CF.