Fishman's Pulmonary Diseases and Disorders - PART 04 by HD Derma

PART

IV Obstructive Lung Diseases

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SECTION EIGHT

Chronic Obstructive Pulmonary Disease

40 CHAPTER

Pathologic Features of Chronic Obstructive Pulmonary Disease: Diagnostic Criteria and Differential Diagnosis Joanne L. Wright

Andrew Churg

I. HISTORY OF PATHOLOGIC DESCRIPTIONS OF COPD II. LESIONS OF THE LUNG PARENCHYMA IN COPD: EMPHYSEMA Classification of Emphysema Morphology of Emphysema Differential Diagnosis of Emphysema

IV. LESIONS OF THE SMALL AIRWAYS IN COPD Differential Diagnosis V. LESIONS OF THE VESSELS IN COPD VI. SUMMARY

III. LESIONS OF THE LARGE AIRWAYS IN COPD Gross Findings Microscopic Findings Differential Diagnosis

Chronic obstructive pulmonary disease (COPD) is a general name for the chronic airflow obstruction that develops most often as a result of chronic tobacco smoking. The pathology of COPD encompasses a variety of pathologic lesions in the airways, lung parenchyma, and pulmonary vasculature, and these lesions can be correlated, to a greater or lesser degree,

with changes in pulmonary function tests and clinical appearances. In general, although the mechanisms involved are complex, airflow obstruction can be attributed largely to a marked increase in airways resistance secondary to a variable mix of structural abnormalities involving all or many of the compartments of the airway. However, in individual cases, it

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may be difficult to prove associations between physiological abnormalities and pathologic changes. The recently developed Global Initiative on Obstructive Lung Disease (GOLD), classifies patients with COPD purely upon indices of airflow and thus far there is only limited integration with pathologic findings. This chapter presents the pathologic features of COPD and how these findings can be differentiated from other lesions associated with airflow obstruction.

HISTORY OF PATHOLOGIC DESCRIPTIONS OF COPD The word emphysema is derived from Greek and means “to blow into,” hence “air-containing” or “inflated.” Although “voluminous lungs” and lungs “turgid particularly from air” were described respectively by Bonet in 1679, and Morgagni in 1769, the first description of enlarged airspaces in emphysema in the human, together with illustrations, was furnished by Ruysh in 1721, followed by Matthew Baillie in 1807, who not only clearly recognized and illustrated emphysema, but also pointed out its essentially destructive character. Laennec, writing in the early 1800s, made a number of seminal contributions to the basic descriptions of pathologic changes in COPD. He was the first to make a clear-cut distinction between interstitial emphysema and emphysema proper, and related the enlarged airspaces to the clinical syndrome of emphysema. He also recognized that air trapping and increased collateral ventilation were features of emphysematous lungs, and that the peripheral airways were the primary site of obstruction in emphysema. Furthermore, he noted that airspaces enlarged with increasing age, and he distinguished these changes from emphysema. He was the first to describe an association of emphysema with chronic bronchitis and to clearly describe the pathology of bronchiectasis. Little of major importance was added to the gross descriptive morphology of emphysema for almost the next 150 years. The foundation of modern knowledge of the pathologic anatomy of pulmonary emphysema was laid by J. Gough in 1952 when he described centrilobular emphysema and distinguished it from panlobular emphysema. The paper section technique developed by Gough and Wentworth was largely responsible for this advance, as it made examinations of sections of entire inflated lungs possible and simple (Fig. 40-1). A comprehensive microscopic description of emphysema was then provided by McLean, who demonstrated the relationship of destruction to inflammatory alterations of the bronchioles, and also discussed alterations of the vasculature.

LESIONS OF THE LUNG PARENCHYMA IN COPD: EMPHYSEMA A major problem in describing the pathologic features of emphysema has been the lack of a generally accepted and easy to

Figure 40-1 Gough sagittal section. Paper mount. Normal lung. (This section and subsequent sagittal sections courtesy of Dr. S. Moolton.)

apply definition. In 1959, a Ciba Guest Symposium defined emphysema in anatomic terms as “a condition of the lung characterized by increase beyond the normal of airspaces, distal to the terminal bronchiole, either from dilatation or from destruction of their walls.” Subsequent definitions differed in that destruction of respiratory tissue became a requirement: “Emphysema is a condition of the lung characterized by

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Figure 40-2 Anatomic varieties of emphysema. A. Centriacinar (centrilobular). B . Paraseptal (distal acinar). C . Panacinar (panlobular). D . Irregular (scar). The dashed lines mark the edge of the acinus. Only centriacinar and panacinar emphysema are commonly observed in COPD.

abnormal, permanent enlargement of the airspaces distal to the terminal bronchiole, accompanied by destruction of their walls.” This requirement separates emphysema from enlargement of airspaces unaccompanied by destruction, the latter now being termed overinflation. Destruction has been similarly difficult to define in an unambiguous way. A committee of the National Institutes of Health proposed that destruction was present when “there was nonuniformity in the pattern of respiratory airspace enlargement so that the orderly appearance of the acinus and its components is disturbed and may be lost.” They recognized that emphysema was a subset of airspace enlargement defined as “an increase in airspace size as compared with the airspace of normal lungs. The term applies to all varieties of airspace enlargement distal to the terminal bronchioles, whether occurring with or without fibrosis or destruction.” While these definitions, when strictly applied, would eliminate airspace enlargement due to overinflation or failure of septation, they would not eliminate airspace enlargement due to reorganization of the airspaces, such as is found in honeycomb lung.

Classification of Emphysema Not only is emphysema defined in terms of lung structure, it is also classified in similar terms; therefore, several anatomic definitions are important. The part of the lung involved in emphysema is the acinus, which is defined as the unit of lung structure distal to the terminal bronchiole (final generation membranous bronchiole) and that consists of three orders

of respiratory bronchioles: a single order of alveolar ducts, followed by the alveolar sacs, and finally the alveoli. Alveolar ducts are entirely alveolated and characteristically contain smooth muscle around the mouths of their alveoli. While the walls of alveolar sacs are also formed entirely by alveoli, muscle is absent. Alveolar pores of Kohn (also known as vents, stomata, or fenestrae) are normal components of adult alveoli, responsible for collateral ventilation. However, they may also be an initial site of destruction in the development of emphysema, particularly centriacinar emphysema. The acinus is a three-dimensional anatomic structure, but it cannot be easily identified by gross examination. What can be seen instead on the surface of lung slices is the secondary lobule of Miller, defined as the tissue bounded on four sides by interlobular septa or pleura. Lobules vary tremendously in size, but are generally 2 to 4 cm on a side, and contain between three to five acini. The terminal bronchiole and subtending respiratory bronchioles tend to be situated in the center of the lobule. For this reason “centrilobular” emphysema and “panlobular” emphysema are reasonable and widely used approximations for the more accurate “centriacinar” and “panacinar” emphysema (see below) (Fig. 40-2). The ways in which the acini are involved determine the classification of emphysema. There are four recognized patterns (Fig. 40-2). The acinus (and lobule) may be more or less uniformly involved; this is panacinar (panlobular) emphysema. The proximal portion of the acinus (center of the lobule) may be dominantly involved; the best term for this lesion is proximal acinar emphysema, although the usual term

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Figure 40-3 Pathologic subtypes of emphysema. A. Predominantly centriacinar emphysema. Emphysema is more severe in upper lobes. B . Predominant panacinar emphysema. Emphysema is more severe in the lower lobes.

is centrilobular or centriacinar emphysema. Alternately, the proximal portion of the acinus may be normal, and the distal part (alveolar sacs and ducts) may be dominantly involved. This is distal acinar emphysema, more commonly referred to as paraseptal emphysema since the lesion is accentuated along lobular septa where the peripheral parts of the acini lie. Finally, the acinus may be irregularly involved, producing irregular emphysema or paracicatricial emphysema, so called because it is usually associated with obvious scarring.

Morphology of Emphysema Centrilobular Emphysema This destructive lesion of the respiratory bronchioles has a number of characteristic features on gross examination of the lung. In the classical lesion, the enlarged, destroyed respiratory bronchioles coalesce in series and in parallel to produce sharply demarcated emphysematous spaces, separated from the acinar periphery (the lobular septa), by intact alveolar ducts and sacs of normal size. The walls of the emphysematous spaces and adjacent tissue characteristically contain variable amounts of black pigment. The lesions vary qualitatively as well as quantitatively even within the same lung. There is striking irregularity of involvement of lobules, and even within the same lobule. The

lesions are usually more common and become more severe in the upper than in the lower zones of the lung (Fig. 40-3 A, Fig. 40-4A,B). Most affected are the upper lobe, particularly the posterior and apical segments, and the superior segment of the lower lobe. In cases of severe CLE, the destruction proceeds toward the periphery of the lobule, and the distinction between CLE and PLE becomes blurred. In CLE, alveolar pores are abnormal in size and shape, and occasionally contain epithelial debris and macrophages. Although there are numerous pores of variable size in the emphysematous areas, there are also increased numbers of pores in the grossly normal areas, and accentuation of these changes in the center of the lobule. Thus, it appears that in CLE the pores of Kohn are possibly the initial site of destruction. There is increased cellularity in the alveolar walls of cigarette smokers, and when this has been quantified, the parenchyma in severe emphysema has increased numbers of neutrophils, macrophages, eosinophils, and both CD4 and CD8 T lymphocytes. There is also a significant inflammatory cell infiltrate in the airspaces in severe emphysema, with the same cells types increased. Although not readily apparent grossly or on standard histological stains, use of histochemical stains or biochemical analysis demonstrates that collagen is increased in both centrilobular and panlobular emphysema.

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Figure 40-4 A,B. Gross and histologic sections illustrating centriacinar; and (C,D) panacinar emphysema. A. Cut surface from a lung with centriacinar emphysema showing holes in the center of lobules surrounded by relatively normal parenchyma. The severity varies among lobules. B . Microscopic section showing that the airspace enlargement in centriacinar emphysema is most marked adjacent to the abnormal respiratory bronchiole, corresponding to the center of the lobule. Also, some of the alveolar walls of the abnormal airspaces are thickened and fibrotic (H&E × 16). C . Cut surface of a lung slice showing how the entire lobule is uniformly affected in panacinar emphysema. D . Microscopic section demonstrating that in panacinar emphysema, the airspaces adjacent to the lobular septa are enlarged to the same degree as those in the center of the lobule (H&E × 16).

Panlobular Emphysema The recognition of mild panlobular emphysema is very difficult. The normal lung has a very characteristic appearance when seen through a dissecting microscope: The multifaceted alveoli form a contrast to the larger, cylindrical conducting structures that are alveolar ducts and respiratory bronchioles. In panlobular emphysema the distinction between alveolar ducts and alveoli becomes lost as alveoli lose their sharp angles, enlarge, and then lose their contrast in size and shape with the ducts, resulting in simplification of the lung architecture, with formation of small box-like structures. As the process becomes worse, the architectural derangement becomes more obvious, with progressive effacement and loss of the orderly arrangement of the lung until little remains other than the supporting framework of vessels, septa, and bronchi. The

best way to see panlobular emphysema grossly is to examine lung slices immersed in a water or fixative bath and then immediately after removal from the bath. The immersed specimen shows enlarged airspaces and, when the slices are lifted from the bath, panlobular emphysema can be suspected because the lung parenchyma “falls away” from the supporting structures and protrudes slightly above them. In contrast to centrilobular emphysema, panlobular emphysema is usually worse in the lower lobes (Fig. 40-3B). Histological examination is a sensitive method of recognizing panlobular emphysema. The pattern is again one of simplification with diminishing contrast between alveoli and alveolar ducts (Fig. 40-4C,D). Despite the greater extent of tissue destruction, in panlobular emphysema the pores of Kohn are more uniform and inconspicuous than those found in centrilobular emphysema.

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Panlobular emphysema is the characteristic lung lesion seen in α-1-antitrypsin deficiency. Panlobular emphysema may also occur as a consequence of permanent obliteration of airways (obliterative bronchiolitis, constrictive bronchiolitis). Most often, obliteration of airways results in collapse of the distal lung parenchyma and dilatation of the bronchi proximal to the obliterated airways. This is the sequence of events in postinfective bronchiectasis. In some instances, however, the lung parenchyma does not collapse, but remains fully expanded or becomes emphysematous. The parenchymal sequel to bronchial and bronchiolar obliteration depends on the extent of the obliteration and the amount of collateral ventilation between adjacent airspaces distal to unobstructed airways. If collateral ventilation is present, then the units distal to the obliterated airways will remain expanded by virtue of the air reaching them by collateral ventilation, producing overexpansion and destruction of lung parenchyma beyond the obliterated airways. The terms Swyer-James or MacLeod’s syndrome are applied when this process affects most of one lung but spares the other. Distal Acinar Emphysema: Paraseptal Emphysema The original description of distal acinar emphysema is generally credited to Loeschcke, who described collections of subpleural bullae. It was Heard, however, who first noted that the lesions could extend into the substance of the lung, where they lay along the septa, and coined the term “paraseptal” emphysema. Since the distal part of the acinus (alveolar sacs and ducts) is dominantly involved, emphysema is most striking adjacent to the pleura (superficial emphysema or mantel

emphysema), along lobular septa (paraseptal emphysema), at the margins of lobules and acini (periacinar emphysema), and along vessels and airways, which, when cut longitudinally, display a linear pattern. The characteristic morphology is that of multiple contiguous, enlarged airspaces, varying from <0.5 mm to >2 cm in diameter. Paraseptal emphysema is usually limited in extent, and is found most commonly along the anterior and posterior parts of the upper lobe and along the posterior surface of the lower lobe. When extensive, it is usually more severe in the upper half of the lung. Gough has stressed that it is associated with fibrosis of the tissue between the enlarged airspaces, and this is certainly a common finding. Irregular Emphysema Irregular emphysema is logically named, because the acinus is indeed irregularly involved in it. Irregular emphysema is almost invariably adjacent to a scar, giving name to the synonyms scar or paracicatricial emphysema. Most scars within the lung are usually small and the emphysema is limited in extent. The severity of irregular emphysema depends on the extent of damage to lung tissue, and multiple scars through the lung may lead to multiple foci of irregular emphysema.

Differential Diagnosis of Emphysema (Table 40-1) Gas Trapping The lungs of an asthmatic who has succumbed during an attack are usually characterized by gas trapping, and thus

Table 40-1 Differential Diagnosis of Airspace Enlargement Distribution

Enlarged Structure

Centrilobular emphysema

Upper lobes, center of lobule

Alveolar ducts, alveoli

Panlobular emphysema

Lower lobe, uniform in lobule

Alveoli

Paraseptal emphysema

Apical, adjacent to septum

Alveoli

Irregular emphysema

No typical site, adjacent to scars

Alveoli

Aging

Uniform in lung

Alveolar ducts

Compensatory alterations

Uniform in lung

Alveoli

Obstructive alterations

Affected area

Alveoli

Genetic alterations

Uniform in lung

Lack of septuation

Asthma

During acute attack

Alveoli

Honeycomb lung

Variable—often subpleural

Total remodeling

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remain inflated, with focal areas of atelectasis. In a patient with longstanding asthma who has died from other causes, or has had a lung resection, there may still be areas of atelectasis. Focal bronchiectasis can be found also, particularly in the anterior segment of the upper lobe. However, parenchymal destruction is not a feature of asthma, and thus gross, microscopic, and morphometric analyses will all be normal in the chronic asthmatic. Nonemphysematous Airspace Enlargement Although not part of the differential diagnosis of COPD, nonemphysematous airspace enlargement also occurs in infancy. In congenital lobar hyperinflation (emphysema), the lobes are overinflated rather than emphysematous, but in some instances they may be polyalveolar. Some other genetic abnormalities will also give enlarged airspaces, but this is due to failure of septation with a simplified rather than a destroyed alveolar framework. At the other side of the age spectrum, the term senile emphysema was once used to describe the enlarged airspaces found in the aged. On gross examination, lungs round out with increasing age. An analysis of Gough sections showed increases in anteroposterior distance, height, perimeter, and area of the lung up to the age of 59 years. After this age, only the anteroposterior diameter continued to increase significantly, thus â&#x20AC;&#x153;roundingâ&#x20AC;? the lung dimensions. This change is due to an increase in the volume proportion of alveolar duct air, with shallower and flatter alveoli, a process termed ductectasia. There is no evidence of lung destruction; thus, the condition does not fulfil the criteria for emphysema. If a part of the lung collapses or is removed, the remaining lung can expand to fill the increased amount of space available, a process known as compensatory overinflation. The exact way that this happens and the limits of the process are unknown. However, no tissue destruction has occurred and, by definition, this is not emphysema. It is not clear how much larger the overinflated lung can become, or how it expands to reach the new and larger volume. It is generally thought that the possible extent of overinflation is modest and that all the parts of the acinus are equally expanded. Obstructive overinflation can occur in adults, and two mechanisms may be involved. In one, the obstruction in the bronchus may act as a ball valve, so that air enters on inspiration but does not leave on expiration. Alternatively, the bronchus may be completely obstructed and air may be trapped behind channels of collateral ventilation. Whatever the mechanism, the affected part of the lung can expand considerably. Obstructive overinflation differs in a number of ways from compensatory overinflation, although, in both, the lung contains too much air per unit of lung and lung tissue. Honeycomb Lung The airspace enlargement that occurs in cryptogenic fibrosing alveolitis (usual interstitial pneumonia) and other fibrotic lungs diseases could possibly be confused with emphysema. While honeycomb spaces are enlarged airspaces, they are the

Pathologic Features of Chronic Obstructive Pulmonary Disease

result of parenchymal remodeling with formation of new airspaces, rather than destruction of normal airspaces, and thus have thickened and irregular walls with none of the structure of an acinus. They are lined by bronchiolar epithelium, and often contain mucus; the walls have abundant and well collagenized connective tissue, which may also contain impressive amounts of muscle and sometimes fat. There is usually interstitial inflammation in the form of varying degrees of lymphocytic and plasma cell infiltration.

LESIONS OF THE LARGE AIRWAYS IN COPD The majority of studies in this area have focused upon the lesions present when the clinical signs and symptoms of chronic bronchitis are also present.

Gross Findings Gross lesions in the large airways are few and subtle. Bronchial pits are the dilated openings of one or more mucous glands into the epithelium. They are most often found along the margins of the cartilaginous rings and at the bifurcations of the airways. In nonbronchitis the pits can be seen using a hand lens or a dissecting microscope, but in chronic bronchitis, the ducts may be distended with mucus and the mucus may protrude into the lumen of the bronchus and be visible grossly. It is not correct to refer to these as diverticula. First, these are protrusions of normal ducts; and second, they do not extend through all of the muscle coats of the bronchial wall. While enlarged bronchial pits are the most obvious gross lesions in COPD, careful examination of lung specimens will show that the bronchi do not taper progressively as they approach the pleura, and they also display prominent circular ridges, probably due to bands of hypertrophic smooth muscle. Mucus may be present in the airway lumen, particularly in subjects with chronic bronchitis.

Microscopic Findings The intraluminal mucus found in the airways of subjects with COPD contains a mixed population of epithelial cells and acute and chronic inflammatory cells; large numbers of neutrophils can be found during an exacerbation. Detailed microscopic analysis of the large airways in COPD reveals alterations in the entire airway wall (Fig. 40-5). Epithelial changes are mild in degree and are not necessarily consistent from patient to patient. Epithelial sloughing can occur, but in most instances the epithelium is generally intact and shows only mild goblet cell or squamous cell metaplasia, both of which appear to be more marked if the subject has symptoms of chronic bronchitis. The reticular basement membrane thickness is within the normal range. The thickness or area of mucous glands in subjects with COPD in general, or chronic bronchitis in particular, is increased over a population mean, but has a distribution that extensively overlaps that of normals and asthmatics.

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Figure 40-5 Large airway from a subject with chronic bronchitis. The overall wall is thickened with inflammation and fibrosis, and there is prominence of the smooth muscle in addition to the bronchial mucous glands.

Interestingly, there appears to be a decreased percentage of serous acini in these glands, a feature that apparently does not occur in asthma. Thickening of the inner wall (area internal to the muscular layer) appears to be the most consistent component of airway wall thickening in the large airways of subjects with COPD, and appears to be generalized. This increase in thickness can be partially attributed to edema and hyperemia of the bronchi, but is also due to an increase in fibrous tissue or other matrix proteins. In the large airways of subjects with COPD, increases in the thickness of the muscular layer have not been consistently identified. Although some studies have found that the average proportion of muscle in main, lobar, and segmental bronchi was approximately doubled in patients with chronic bronchitis and airflow obstruction, others have found that a substantial number of patients fell within the normal range. Alteration in the amount of cartilage in COPD does not appear to be a consistent finding. While some studies described cartilage atrophy in chronic bronchitis and/or emphysema, or circumferentially arranged cartilage that extended farther distally in nonbronchitis than bronchitis, this was not supported by other reports. However, histological signs of cartilage damage, as judged by loss of cellular or pericellular metachromasia and vacuolated or empty lacunae can be consistently identified. The large airways in COPD show a mild, usually mixed, inflammatory infiltrate. Bronchus-associated lymphoid tissues (BALT) is not consistently found, but its frequency appears to be considerably higher (82 percent) in smokers than nonsmokers (14 percent). Bronchial biopsy analysis consistently shows an increase in CD8 T cells, with eosinophils and neutrophils found during exacerbations. Chronic inflammation can also be found around the bronchial glands, particularly in subjects with chronic bronchitis.

Differential Diagnosis (Table 40-2) Asthma In asthma the large airways are not dilated, but mucus plugs are classically identified in the large airways of subjects with

fatal or near-fatal asthma, and the mucus may be continuous with that present in the ducts of the mucus glands. Visible bronchial pits are not a standard feature of asthma, and although the airway wall may be thickened, this is usually not apparent grossly. In the large airways of subjects with asthma, desquamation of the epithelium is a common feature, and this may be worse in people who have persistent rather than intermittent activity. Sloughing of cohesive epithelial clusters produces the Creola bodies found in cytology specimens. Goblet cell metaplasia can be marked in both asthma and bronchiectasis, but there is a considerable degree of variability, so that this feature cannot be used in isolation to distinguish among the airways of subjects with COPD, asthma, and bronchiectasis. These epithelial cell changes result in an overall thickening of the epithelium in asthma, but not in COPD. In asthma, the reticular basement membrane (lamina reticularis) is characteristically thickened. This alteration occurs early in the course of disease, and remains even when the asthma is mild or well controlled. The airways of asthmatics demonstrate a greater severity of inner wall thickening, with values double those found in patients with COPD. The increase in thickness is due to variable increases in fibrous tissue, inflammatory cells, edema fluid, and vascular prominence. Analysis of the muscular wall in subjects with severe or fatal asthma compared with normals or those with COPD shows a marked increase in amount of muscle, with a lesser increase in asthmatics who died with rather than from their asthma There has also been a suggestion that the increase in muscle mass may occur relatively early during childhood. Neutrophils are the predominant cell present in the mucus of patients with bronchiectasis, while eosinophils and accompanying Charcot Leyden crystals are the hallmark of asthmatic mucus. As noted, the cartilaginous destruction present in polychondritis is severe and associated with chronic inflammation, thus easily distinguishing the two processes. Depending upon the severity of the inflammation in bronchiectasis, there may be significant cartilaginous destruction. Airways from fatal and near-fatal asthma also contain isolated aggregates of lymphoid cells, roughly in the same proportion as that present in COPD. However, in asthma, by contrast to COPD, there is an inflammatory infiltrate consisting of activated eosinophils, and activated CD4 T cells in the submucosa, and both mast cells and neutrophils within the glands. There is little in the literature regarding the inflammatory cell infiltrates present in the airway walls in bronchiectasis. Compared with asthma, there appear to be fewer eosinophils, but a similar population of CD 45 (as opposed to any specific subtype) lymphocytes, with both cell types having a greater density in the inner, as opposed to the outer aspect of the airway. Bronchiectasis In bronchiectasis, there is by definition an abnormal and permanent dilatation of the bronchi, and this is usually present to a much greater degree than is found in COPD, and is often

X √

√

√ X

Diverticula

√

Pits

Check mark indicates that the feature is present; X indicates that the feature is absent.

Relapsing polychondritis

Tracheomegaly

Fibrosis and inflammation Bony nodules

√

Bronchiectasis

Focal

√

Focal

Asthma

Fibrosis and inflammation

Structural Distortion

√

√ √

√

Submucosal Fibrosis

√

Glands

√

Basement Membrane

Focal goblet cell metaplasia

Goblet cell metaplasia

Epithelium

√

Lumenal Mucus

√

Cartilage

√

Muscles

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Tracheobronchiopathia osteoplastica

√

Chronic bronchitis

Dilatation

Pathologic Differential Diagnosis of Large Airway Lesions in COPD

Table 40-2

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accompanied by airway distortion. There is exaggeration of the muscular ridges and the presence of multiple bronchial glandâ&#x20AC;&#x201C;based pits. The large airway walls can be thickened and/or irregularly thinned as a result of inflammation and fibrosis, and there is often inspissated mucus or actual purulent material. Miscellaneous Conditions Tracheobronchomegaly (Mounier-Kuhn syndrome) is characterized by a marked dilatation of the trachea and major bronchi, with diameters 5 to 10 cm above normal values. In this condition there are multiple true diverticula, with outpouchings formed of membranous tracheal tissue between the cartilaginous rings, with atrophy or absence of elastic fibers. Patients with tracheobronchopathia osteoplastica have an obstructive pulmonary function pattern; however, unlike the trachea and large airways in COPD, cartilaginous and bony nodules are present in the subepithelial space (submucosa). Relapsing polychondritis shows variable dynamic expiratory and/or inspiratory obstruction depending on the size and location of the airways involved. In this disease, however, the obstruction is due to impaired airway clearance of inflammatory debris, and an ineffective cough because of dynamic upper airway collapse. The airways are dilated and the walls are thickened because of the extensive fibrosis and chronic inflammation due to the immunological nature of this condition. In particular, the cartilaginous plates show extensive destruction.

LESION OF THE SMALL AIRWAYS IN COPD In the context of COPD, small airways refer to airways with an internal diameter of 2 mm or less. In COPD, intraluminal mucus can be found in the small airways, and there appears to be an overall relationship between the degree to which the airways are occluded by mucus and the FEV1 . Goblet cells are rare in normal small airways, but goblet cell metaplasia is a frequent finding in the airways of patients with COPD. Similar to the large airways, there is alteration of the all of the small airway wall compartments in patients with COPD (Fig. 40-6). These changes result in an overall decrease in the internal bronchiolar diameter and, as assessed by a conformity index, produce significant deformity. Similar results are obtained from three-dimensional reconstructions. Detailed measurements of the airway walls show that the increased wall thickness is due to increases in the epithelium, subepithelial fibrous tissue compartment (submucosa, lamina propria), smooth muscle, and adventitia. Although the adventitia is thickened, there is a loss of alveolar attachments to the airway wall, an important process because it allows early airway collapse on expiration. One of the earliest histological abnormalities that can be detected in cigarette smokers is the presence of macrophages in the lumen of the respiratory bronchioles. However, an inflammatory infiltrate can also be identified within the walls

Figure 40-6 A small airway from a subject with COPD. The lumen contains mucus and inflammatory debris. There is goblet cell metaplasia of the epithelium. The subepithelial (submucosal) layer is increased in thickness due to an increase in fibrous tissue and inflammatory cells.

of both membranous and respiratory bronchioles in subjects with COPD. When examined in conjunction with the GOLD (Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease) stage, the proportion of airways which had measurable neutrophils appear to be increased in GOLD stages 2 to 4, and airways with measurable macrophages show a progressive increase from GOLD stage 0 to 4, while there does not seem to be any alteration in the percentage of airways that contain eosinophils among the GOLD stages. The percentage of airways with CD4, CD8, and B cells also increase with GOLD stage, but when these data are expressed as total accumulated volume, only the B cells and CD8 cells show progressive increases. The presence of lymphoid follicles is markedly increased in GOLD stages 3 and 4.

Differential Diagnosis Asthma Mucous plugs and goblet cell hyperplasia are markedly increased in the small airways of asthmatics and this increase is generally much greater than is seen in COPD. In addition, the basement membrane thickness is approximately 20 percent greater than that found in either normals or patients with COPD. The peripheral airways of asthmatics have an inflammatory infiltrate that features lymphocytes and eosinophils, with many of the inflammatory cells in the adventitial, as opposed to the submucosal compartment. The data regarding the vessels in the submucosa are controversial, with some studies suggesting that they are congested, but not increased in number, in asthmatics compared with COPD, and others demonstrating an increased number of vessels, but a lesser total area in asthma compared with COPD. Although smooth muscle is increased in asthmatics, the increase is not as great as that present in the large airways. Moreover, the distribution of smooth muscle increase in the bronchial tree may be quite different, with some patients displaying a generalized

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increase, while in others the increase is restricted to the larger airways. Overall, the small airways in asthmatic subjects who have died because of their disease have a greater area of subepithelial fibrous tissue, smooth muscle, and adventitial fibrous tissue than do subjects who died with their disease, which in turn have a greater area than do the airways of subjects with COPD. Thus, although the same qualitative changes are present in both asthmatics and COPD, they are more severe in asthmatics and most severe in cases of fatal asthma. Interestingly, there appears to be a loss of alveolar attachments in cases of fatal asthma, although this is less than that present in the airways of patients with COPD. Follicular Bronchiolitis Follicular bronchiolitis is characterized by narrowing of the bronchioles due to adventitial and subepithelial lymphoid follicles, and accompanied by a lymphoplasmacytic inflammatory infiltrate. The condition is classically found in patients with rheumatoid arthritis or those with IgA deficiency. This process can mimic severe COPD small airways disease, but the inflammatory infiltrate is generally magnified compared to COPD, while there is little goblet cell metaplasia in the airway epithelium. Panbronchiolitis The presence of foamy macrophages in the airway wall and lumen and extending down into the alveolar ducts and alveoli is a feature of the condition known as panbronchiolitis, originally described in Japan but now known to occur worldwide. Follicular hyperplasia of the peribronchiolar lymphoid tissue is frequent, and bronchiolectasis is found in the more advanced lesions. Constrictive Bronchiolitis The term constrictive bronchiolitis appears to have been coined by Gosink et al. In constrictive bronchiolitis, the airway lumen is occluded by a progressive thickening of the subepithelial (submucosal) space. Both the membranous and respiratory bronchioles are involved, and show transmural inflammatory cell infiltrates, occasionally with epithelial necrosis. Mucous plugs can also be identified. As the process evolves, the inflammatory infiltrate wanes, and greater amounts of fibrous tissue can be demonstrated both in the peribronchial and subepithelial portions of the airway, acting to narrow or obliterate the airway lumen. Lesions of constrictive bronchiolitis, particularly in the organized phase, may be difficult to demonstrate, and may require elastic stains to outline the obliterated airway. Thus, the lesions in COPD differ from constrictive bronchiolitis only in degree. Mineral dustâ&#x20AC;&#x201C;induced airways disease is a distinctive type of constrictive bronchiolitis, characterized by a stereotypic response of the small airways to high doses of particulate, regardless of the specific mineral dust involved. The lesions consist of fibrosis and thickening of the walls of both the membranous and respiratory bronchioles, sometimes extending down the alveolar ducts, the latter finding providing diagnostic discrimination from tobacco smokeâ&#x20AC;&#x201C;induced airways

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disease, which tends not to involve the alveolar ducts. Pigment deposition is highly variable, and is not a diagnostic feature. Proliferative Bronchiolitis The lesions of proliferative bronchiolitis have been elegantly described and illustrated. Within the lumens of the membranous and respiratory bronchioles are plugs of organizing fibroblastic (granulation) tissue. Occasionally, ulceration of the epithelium can be seen, and early lesions may have fibrin. The granulation tissue is formed of a pale matrix with proliferating spindle cells, accompanied by chronic inflammatory cells. As the lesions age, the granulation tissue usually shrinks and contracts. However, in a certain proportion of cases, the bronchiolar cells proliferate over the granulation tissue, and incorporate it into the subepithelial space, leaving an irregular airway lumen. Although acute bronchiolitis, be it bacterial or viral in nature, is usually easily distinguished from the lesions of COPD by the presence of extensive epithelial damage, healed lesions may show nonspecific airway fibrosis and chronic inflammation, or the residua of proliferative bronchiolitis. Interestingly, latent adenoviral infection has been suggested as a contributor to airflow obstruction in adults by amplifying the inflammatory response in the bronchioles of cigarette smokers. Airway disease complicating other diseases may also need to be distinguished from that of COPD. For example, post-transplant bronchiolitis or airways disease in patients with inflammatory bowel disease (both Crohnâ&#x20AC;&#x2122;s disease and ulcerative colitis) include both proliferative and constrictive bronchiolitis. Inflammatory bowel disease may also have large airway involvement.

LESIONS OF THE VESSELS IN COPD There are no consistent alterations in the large elastic pulmonary arteries of subjects with COPD. Atheromata can be found, but unless there is pulmonary hypertension, the incidence is probably not greater than that found in a carefully matched population. Cigarette smokers, with or without pulmonary hypertension, have an increase in arterial muscle media thickness as well as intimal fibrosis in the muscular arteries, and progressive muscularization of the small arterioles. Increases in intimal thickness with longitudinal muscle formation are a common feature in lungs of patients with COPD (Fig. 40-7). There appears to be a progressive increase in the numbers of smaller muscularized arteries, percent medial thickness, and percent intimal thickness of muscularized arteries from nonsmokers, to smokers without obstruction, to smokers with airflow obstruction. The lesions of primary pulmonary hypertension and hypertension secondary to vascular shunting also include intimal fibrosis and increased muscular media thickness. Intimal fibrosis is often cellular in its early phases, but progresses to concentric laminar fibrosis, which can almost totally obliterate the vessel lumen. These changes are of much greater

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Figure 40-7 A small pulmonary artery from a subject with COPD. These vessels, situated adjacent to the alveolar ducts, are normally poorly muscularized, but in this case, the vessel has a distinct circumferential muscular layer.

severity than those identified secondary to COPD. Vasculitis, fibrinoid necrosis, and plexiform lesions are never found in COPD. Lesions of chronic thromboembolic disease include eccentric intimal thickening, and the occasional formation of webs due to recanalization of the thrombi.

SUMMARY There are a number of pathological alterations of the lung in COPD. These involve almost all of the lung compartments, including the parenchyma, vasculature, and large and small airways. These changes can overlap the pathologic findings present in other diseases associated with airflow obstruction, or other diseases that are manifested in the lung. It is important to be able to make the distinction among these diseases. Although the pathologic alterations roughly correlate to alterations in pulmonary function, it is important to remember that their individual contributions are not well worked out. Thus, it may be difficult on an individual patient basis to proceed from a clinical classification such as the GOLD classification to a mechanistic/pathologic explanation of the airflow obstruction.

SUGGESTED READING Aikawa T, Shimura S, Sasaki H, et al.: Morphometric analysis of intraluminal mucus in airways in chronic obstructive pulmonary disease. Am Rev Respir Dis 140:477–482, 1989. Cardoso WV, Sekhon HS, Hyde DM, et al.: Collagen and elastin in human pulmonary emphysema. Am Rev Respir Dis 147:975–981, 1993. Carroll NG, Mutavdzic S, James AL, et al.: Increased mast cells and neutrophils in submucosal mucous glands and

mucus plugging in patients with asthma. Thorax 57:677– 682, 2002. Ebina M, Yaegashi H, Chiba R, et al.: Hyperreactive site in the airway tree of asthmatic patients revealed by thickening of bronchial muscles. Am Rev Respir Dis 141:1327–1332, 1990. Elliot JG, Jensen CM, Mutavdzic S, et al.: Aggregations of lymphoid cells in the airways of nonsmokers, smokers, and subjects with asthma. Am J Respir Crit Care Med 169:712– 718, 2004. Haraguchi M, Shimura S, Shirato K: Morphologic aspects of airways of patients with pulmonary emphysema followed by bronchial asthma-like attack. Am J Respir Crit Care Med 153:638–643, 1996. Haraguchi M, Shimura S, Shirato K: Morphometric analysis of bronchial cartilage in chronic obstructive pulmonary disease and bronchial asthma. Am J Respir Crit Care Med 159:1005–1013, 1999. Heard BE: A pathological study of emphysema of the lungs with chronic bronchitis. Thorax 13:136–149, 1958. Hogg JC, Chu F, Utokaparch S, et al.: The nature of smallairway obstruction in chronic obstructive pulmonary disease. N Engl J Med 350:2645–2653, 2004. Jeffery P, Wardlaw AJ, Nelson FC, et al.: Bronchial biopsies in asthma. Am Rev Respir Dis 140:1745–1753, 1989. Jeffery PK: Comparison of the structural and inflammatory features of COPD and asthma. Chest 117:251S–260S, 2000. Jeffery PK: Remodeling in asthma and chronic obstructive lung disease. Am J Respir Crit Care Med 164:528–538, 2001. Laurell CB, Eriksson S: The electrophoretica1-globulin pattern of serum in a1-antitrypsin deficiency. Scand J Clin Lab Invest 15:132–140, 1963. Nagai A, Inano H, Matsuba K, et al.: Scanning electron microscopic morphometry of emphysema in humans. Am J Respir Crit Care Med 150:1411–1415, 1994. Niewoehner DE, Kleinerman J, Rice DB: Pathologic changes in the peripheral airways of young cigarette smokers. N Engl J Med 291:755–758, 1974. Pare PD, Wiggs BR, James A, et al.: The comparative mechanics and morphology of airways in asthma and in chronic obstructive pulmonary disease. Am Rev Respir Dis 143:1189–1193, 1991. Pauwels RA, Buist AS, Ma P, et al.: Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: National Heart, Lung, and Blood Institute and World Health Organization Global Initiative for Chronic Obstructive Lung Disease (GOLD): Executive summary. Respir Care 46:798–825, 2001. Retamales I, Elliott WM, Meshi B, et al.: Amplification of inflammation in emphysema and its association with latent adenoviral infection. Am Rev Respir Dis 164:469–473, 2001. Richmond I, Pritchard GE, Ashcroft T, et al.: Bronchus associated lymphoid tissue (BALT) in human lung: Its

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distribution in smokers and non smokers. Thorax 48:1130–1134, 1993. Ryan SF, Vincent TN: Ductectasia: an asymptomatic pulmonary change related to age. Med Thorac 22:181–187, 1965. Saetta M, Turato G, Baraldo S, et al.: Goblet cell hyperplasia and epithelial inflammation in peripheral airways of smokers with both symptoms of chronic bronchitis and chronic airflow limitation. Am J Respir Crit Care Med 161:1016–1021, 2000. Snider GL, Thurlbeck WM, Bengali ZH: The definition of emphysema. Report of a national heart lung and blood

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institute division of lung diseases workshop. Am Rev Respir Dis 132:182–185, 1985. Thurlbeck WM, Wright JL: Thurlbeck’s Chronic Airflow Obstruction, 2nd ed. Hamilton, Ont, BC Dekker, 1998. Wang NS, Ying W-L: Morphogenesis of human bronchial diverticulum. A scanning electron microscopic study. Chest 69:201–204, 1976. Wright JL, Levy RD, Churg A: Pulmonary hypertension in chronic obstructive pulmonary disease: current theories of pathogenesis and their implications for treatment. Thorax 60:605–609, 2005.

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41 Chronic Obstructive Pulmonary Disease: Epidemiology, Pathophysiology, and Pathogenesis Robert M. Senior

Jeffrey J. Atkinson

I. EPIDEMIOLOGY II. RISK FACTORS Environmental Childhood Lower Respiratory Infections III. HOST FACTORS IV. PATHOPHYSIOLOGY Airflow Obstruction Maldistribution of Ventilation and Ventilation-Perfusion Mismatching Hyperinflation Dyspnea Physiological-Pathological Correlations V. PATHOGENETIC PROCESSES Inflammation Proteinase-Antiproteinase Imbalance

For many years, chronic obstructive pulmonary disease (COPD) was defined as “a disease state characterized by the presence of airflow obstruction due to chronic bronchitis or emphysema; the airflow obstruction is generally progressive, may be accompanied by airway hyperreactivity, and may be viewed as partially reversible.” In the past few years a new definition has been presented by the Global Initiative on Obstructive Lung Disease (GOLD) and by a Task Force of the American Thoracic Society (ATS) and the European Respiratory Society (ERS). Both GOLD and ATS/ERS state that “COPD is a disease state characterized by airflow limitation that is not fully reversible. The airflow obstruction is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles and gas.”

Oxidant-Antioxidant Imbalance Apoptosis Mucus Hypersecretion VI. PATHOGENESIS OF EMPHYSEMA General Concepts Lung Elastic Fibers Lung Collagen Turnover Proteinases Proteinase Inhibitors Overall View of the Pathogenesis of Emphysema VII. ALPHA 1-ANTITRYPSIN DEFICIENCY Background Clinical Aspects VIII. CONCLUDING COMMENT

The ATS/ERS definition also states that COPD is both preventable and treatable and that COPD is a systemic disease. A secondary feature of both the GOLD and the ATS/ERS definitions is a scoring system for staging the severity of COPD based upon the post-bronchodilator forced expiratory volume in the first second (FEV1 ) (see Chapter 42).

EPIDEMIOLOGY COPD occurs worldwide, but it is a major health problem principally in societies where cigarette smoking is common and the average life span extends into the sixth decade or

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beyond. Although COPD occurs predominately in smokers, nonsmokers also develop COPD. In a survey of COPD deaths in the United States in 1993, 16.7 percent of individuals who died with COPD were never-smokers (smoked fewer than 100 cigarettes during their lifetime) of whom approximately onethird, an estimated 12,900, had COPD listed as the primary cause of death. A history of asthma was significantly associated with death from COPD in nonsmokers. In undeveloped countries, burning biomass for heating and cooking results in COPD among nonsmokers. COPD has a prevalence of 4 to 10 percent in adults in populations in whom lung function has been measured. The National Health Interview Survey, an annual survey of approximately 40,000 United States households, has yielded an estimate of 10 million adults in the United States with a physician-based diagnosis of COPD. Other estimates, such as that from the Third National Health and Nutrition Examination Survey (NHANES III), that included spirometry along with questionnaires and a physical examination, done between 1988 and 1994, have yielded even more impressive prevalence figures. According to NHANES III, COPD affects 23.6 million adults in the United States, of whom 2.4 million have severe disease. Thus, approximately 10 percent of the United States adult population might be classified as having COPD, and of this group about 10 percent have advanced disease. Impressive as these figures are, they are reasonable considering the estimates for COPD-related physician visits, emergency department visits, hospitalizations, and deaths. Indeed, these prevalence figures may be underestimates since COPD is likely unrecognized in some groups such as elderly persons with low incomes. Irrespective of the precision of the prevalence estimates, it is clear that COPD is a major health burden. The death rate from COPD in the United States has been rising in recent decades in contrast to falling death rates from heart and cerebrovascular diseases over the same interval. COPD is now the fourth most common cause of death in the United States, accounting for approximately 4.5 percent of all deaths. Moreover, COPD is a contributory factor in another 4.3 percent of deaths. Currently, men still have a higher mortality rate from COPD than women (83 vs. 57 per 100,000), but the mortality rate is rising in women and is stable in men. Among women, the death rate from COPD has more than doubled in the past 20 years, and in the year 2000 more women than men died from COPD. The percentage of smokers in the adult population in the United States has dropped over the past several decades from more than 50 percent to about 25 percent. The drop has been most striking among men. Accordingly, morbidity and mortality from COPD may decline in the years ahead, reflecting these favorable trends in smoking practices in recent decades. However, COPD is certain to remain a major health problem in the United States into the foreseeable future since there are an estimated 48 million smokers in the United States and smoking is common in young people. Among high school students 23 percent are current smokers, with a slightly higher incidence for boys (25 percent) than

girls (21 percent), while among middle-school children 10 percent are smokers, equally so among boys and girls. The problem of COPD worldwide is destined to be profound in the future. The World Health Organization reports that 15 billion cigarettes are smoked daily worldwide and predicts that COPD will rank fifth in life-years lost to premature death and disability in 2020.

RISK FACTORS Risk factors for the development of COPD may be broadly divided into those related to environmental exposures and those that are host-based (Table 41-1). Smoking and alpha 1-antitrypsin (Îą1 -AT) deficiency are risk factors for which the data are most compelling, but even for these risk factors much remains to be determined about the specific mechanisms involved. Some factors listed may be a composite of other individual risk factors. A low socioeconomic status, for example, is notable in this regard as it might be linked to COPD through deficient medical care for respiratory infections, occupational exposure to inhaled particulates, and exposure to household allergens. The following sections consider smoking, occupational exposures, childhood lower respiratory infections, airway hyperresponsiveness, and genetic factors other than Îą1 -AT deficiency which is discussed separately later in the chapter.

Environmental Smoking Smoking tobacco accounts for 80 to 90 percent of the risk of developing COPD in the United States. Accelerated deterioration of ventilatory function is common among smokers. However, its magnitude is relatively small in most smokers. In males, the loss of FEV1 in excess of the normal decline

Table 41-1 Risk Factors for COPD Environmental

Host-based

Smoking

Genetic factors

Occupational exposures

Asthma/airway hyperreactivity

Air pollution Childhood respiratory infections Low socioeconomic status

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Figure 41-2 Mean post-bronchodilator FEV1 for participants in the Lung Health Study during 11 years of follow-up in relation to smoking history. Sustained quitters (open circles) and continuous smokers (closed circles). Smokers show progressive deterioration. (From Anthonisen NR, Connett JE, Murray RP: Smoking and lung function of Lung Health Study participants after 11 years. Am J Respir Crit Care Med 166:675–679, 2002, with permission.)

Figure 41-1 Distribution of percent predicted FEV1 in adults with varying pack-years of smoking. Subjects with ‘‘respiratory trouble” before age 16 are excluded. The proportion of smokers with normal expiratory airflow decreases with increasing packyears. Nevertheless, many smokers have a normal FEV1 despite large cigarette-smoking histories. Means, medians, and ± standard deviation of the data for each group are shown in the abscissas. The numbers in parentheses are the numbers of subjects. (From Burrows B, Knudson RJ, Cline M, et al: Quantitative relationships between cigarette smoking and ventilatory function. Am Rev Respir Dis 115:195–205, 1977, with permission.)

with aging is 9 ml per year for each pack-year of smoking; in females, the excess rate of decline is 6 ml. Based on these rates of decline, a man who has smoked one pack daily for 30 years will have an FEV1 that is 270 ml less than it would have been had he not smoked. However, the relationship between amount of smoking and risk of COPD is unpredictable on an individual basis. Many people with a high number of packyears still have a normal or near-normal FEV1 , while some people have a reduced FEV1 with a modest smoking history (Fig. 41-1). Among smokers who have already sustained reductions in FEV1 , the consequences of continued smoking on ventilatory function are much more impressive than when all smokers are lumped together. The Lung Health Study revealed that among middle-aged smokers with an FEV1 between 55 and 90 percent of predicted, differences of about 200 ml in FEV1 developed within 5 years between those who quit and those who did not quit and this difference between smokers and quitters doubled over the next 6 years (Fig. 41-2). Thus, not surprisingly, in smokers who have demonstrated an increased susceptibility to the effects of smoking on ventilatory function, the rate of decline of FEV1 is much larger than that

seen in the average middle-aged smoker who has normal or near-normal ventilatory function. Further evidence of the harmful effects of smoking in susceptible smokers is apparent from the trends in ventilatory function among those who stop smoking. Their rate of decline of FEV1 reverts to that of nonsmokers. Occupation The fact that occupation-related chronic inhalation of particulates and gases carries a risk for COPD has been slow in gaining acceptance. The delay is understandable, since ascertaining the risk of COPD in relation to occupation may be difficult for several reasons. The high prevalence of smoking among workers in certain occupations has been a major confounding factor. Also, workers beginning jobs with a high risk of causing lung disease typically have better lung function than normal (the “healthy worker” phenomenon), obscuring work-related effects among relatively young workers. In addition, among cohorts of workers, those with COPD may drop out, causing an underestimate of risk in follow-up studies confined to those still working. Despite these difficulties, studies from different groups around the world, urban and rural, workforce-based and community-based, clearly implicate occupations producing exposures to dusts, gases, and fumes as risk factors for COPD. The American Thoracic Society states that 15 percent is a reasonable estimate of the occupational contribution to the population burden of COPD. Dusts appear to be most significant. Similar to the experience with tobacco smoke, the presence or absence of chronic cough and sputum does not necessarily imply the presence or absence of airflow obstruction. The risk generally relates to the intensity of exposure, but there is considerable individual variability, pointing to the importance of host factors in determining susceptibility. Apart from the recognized

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risk in occupations involving exposure to organic and inorganic dusts, many less obviously “risky” occupations may carry an increased risk of COPD. A recent analysis of data from NHANES III, in which smoking and other confounders were taken into account, uncovered slightly increased incidences of COPD in many occupations, including construction, plastics manufacturing, and utility work. The impact of an adverse occupation is likely to be particularly important in individuals who have other factors that raise their risk for COPD. An example of this occurrence was found among agricultural workers with α1 -AT deficiency who had never been regular smokers. These individuals showed significantly reduced FEV1 values compared to nonsmoking α1 -AT-deficient individuals not involved in agricultural work. Childhood Lower Respiratory Tract Infections Childhood lower respiratory tract infections (lower respiratory tract infections) are commonly regarded as a risk factor for COPD. Since lung growth and alveolar development continue into early childhood it is plausible that lower respiratory tract infections during childhood might produce permanent damage or impair lung growth and development. However, although correlations have been found between early (up to around age 2) childhood lower respiratory tract infections and reduced lung function later in life, there is not a correlation with airflow obstruction as judged by the FEV1 /forced vital capacity (FVC) ratio. Furthermore, even in the setting of COPD, LRTIs seem to have only a minor lasting effect on the obstruction. In the Lung Health Study COPD exacerbations in smokers were associated with an additional loss of FEV1 of 7 ml per year for those having one exacerbation per year. Among nonsmokers exacerbations had no apparent effect on the FEV1 .

HOST FACTORS Genetic Background Aggregation of COPD in families and concordance of pulmonary function in twin studies have established a role for genetic predisposition to COPD. The occurrence of reduced maximal expiratory airflow among nonsmoking first-degree relatives of individuals with early onset COPD provides further support. Perhaps most compelling is the marked variability in development of COPD among smokers. However, dissecting specific genetic factors that increase the risk of COPD has proven difficult. α1 -AT deficiency illustrates this difficulty. Even among individuals with this clearly identified genetic risk factor, there is wide, unexplained, variability in the occurrence of COPD. Polymorphisms of genes involved in proteaseantiprotease balance, antioxidant function, inflammation, and immune responses have been implicated in COPD. However, none of these polymorphisms could be confirmed in a recent genetic association analysis of families identified through patients who developed severe COPD at an early age (without α1 -AT deficiency). Failure of confirmation may indicate

flaws in previous studies, but differences in COPD phenotypes, ethnic background, or other factors might explain the discrepancies between previous studies and the recent data. A polymorphism in elastin that results in an amino acid substitution and altered elastic fibers has been uncovered in approximately 1 percent of individuals with severe COPD and emphysema. Thus, future studies of the genetic aspects of COPD should extend to extracellular matrix. Two basic approaches are used to identify the genetic determinants of apparently complex genetic disorders such as COPD: candidate gene analysis and positional cloning. Both rely on polymorphisms in the populations studied and careful characterization of the disease phenotype being targeted. Unfortunately, characterization of the COPD phenotype has been variable, involving parameters of airflow obstruction and/or radiographic evidence of emphysema. The advantages of a candidate gene approach are that the selection of genes can be guided by information from mouse models or expression profiling experiments. Since only a limited number of genetic variants are typically tested, associations can be uncovered with relatively small populations. However, the disadvantages are that the small sample size can miss associations due to inadequate power and associations discovered may represent linkage to a polymorphism in a neighboring gene, not the gene of interest. These candidate gene association studies are likely more powerful if performed on a relatively genetically isolated and uniform population, but use of isolated populations decreases the ability to generalize findings to other populations. Some polymorphisms change amino acid sequence of a protein, but polymorphisms in the promoter region are often evaluated, so that confirmation of alteration in protein production or activity is necessary. Since many of these studies attempt to examine multiple polymorphisms in the same sample population, adjustment for multiple statistical testing should be applied. As noted above, candidate genes for COPD have been from categories proposed to be involved in the pathogenesis of COPD, such as proteases-antiproteases, antioxidants, and mediators of inflammation, so this approach will not uncover novel mechanisms. Unlike the candidate gene approach, the positional cloning approach has traditionally been performed in families of affected individuals, using linkage analysis to determine if affected relatives share a region of the genome significantly more often than expected based on random chance. Broad mapping with a genome-wide set of genetic markers is performed on all individuals to evaluate linkage of the phenotype to pieces of chromosomal DNA. The disadvantage of positional cloning is the intensive labor required for the collection, phenotyping, and mapping of a large population of families. The result of linkage analysis is usually identification of a large area on a chromosome rather than a distinct gene. However, unlike the candidate gene approach, linkage analysis can discover unknown or formerly unrecognized genes involved in COPD pathogenesis. Some linkage analysis studies demonstrate that even in the absence of smoking, lung function parameters show heritability, suggesting that some

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of the risk for COPD development may be attributable to genetic control of lung development. In one study a combination of both candidate gene and positional cloning approaches was used. A domain in chromosome 19q that was linked to pre-bronchodilator FEV1 in smokers in the Boston Early-Onset COPD study was evaluated for single nucleotide polymorphisms (SNPs) in and around the transforming growth factor-β1 (TGF-β1) gene. This study then confirmed the candidate gene findings in a second cohort of patients in the National Emphysema Treatment Trial (NETT), which includes not only the initial phenotype of low pre-bronchodilator FEV1 , but also the presence of radiographically confirmed emphysema. These NETT cases were compared to population-based control subjects. It seems likely that combining both approaches of genetic analysis together with better phenotypic characterization of COPD traits will expand knowledge of the genetic factors affecting the risk of developing COPD. Progress in SNP identification and genotyping technology has made genome-wide association studies possible, which may allow the advantages of both the candidate gene and positional cloning approaches to be applied comprehensively to complex diseases like COPD. Airway Hyperresponsiveness Airway hyperresponsiveness (AHR) refers to an acute decline in maximal airflow in response to inhaling potential bronchoconstricting agents such as methacholine or histamine. In COPD, AHR is associated with accelerated decline of FEV1 and therefore is a negative prognostic marker. Intriguingly, however, AHR does not predict whether there will be some bronchodilator reversibility nor does bronchodilator responsiveness have favorable prognostic significance. The pathological features and mechanistic basis for AHR in COPD are not known, but smoking cessation is associated with reduced AHR. AHR leads to consideration of the “Dutch hypothesis,” which ascribes a role of allergy in the risk of developing COPD. What makes this area problematic is whether AHR, which is common in COPD, precedes or follows the development of COPD. An observation that argues against a causal relationship is that smokers typically do not show AHR until their baseline FEV1 is already reduced. Confounding an analysis of the relationship is that smoking is common among asthmatics so that asthmatics are likely to be included in groups regarded as COPD.

PATHOPHYSIOLOGY Many pulmonary function abnormalities occur in COPD, but persistent reduction in maximal forced expiratory flow is the defining physiological feature. Increased airway resistance, increased residual volume, increased residual volume/total lung capacity ratio (RV/TLC), decreased inspiratory capac-

ity, maldistribution of ventilation, and ventilation-perfusion mismatching are also typical features.

Airflow Obstruction Persistent reductions in FEV1 and FEV1 /FVC are the characteristic physiological abnormalities of COPD. Measurement of the FVC at 6 seconds (FEV6 ) may be an adequate and safer equivalent of measuring the FVC in individuals with severe obstruction. The reduced FEV1 is not reversible with inhaled bronchodilators, although improvements up to 15 percent are common. In this respect, COPD differs from asthma in which large improvements in airflow with inhaled bronchodilators are characteristic. Maximal inspiratory flow may be relatively well preserved in the presence of a markedly reduced FEV1 . Such discrepancies between inspiratory and expiratory flow suggest that the reduction in forced expiratory flow in COPD is not due to fixed narrowing or obliteration of airways, but instead that there is airway instability with narrowing during forced exhalation. Airflow during forced exhalation is the result of the balance between the elastic recoil of the lungs promoting flow and the resistance of the airways that limits flow. In normal lungs, as well as in lungs affected by COPD, maximal expiratory flow diminishes as the lungs empty because the lung parenchyma provides progressively less elastic recoil and the cross-sectional area of the airways falls so that resistance to airflow increases. The decrease in flow, coincident with the decrease in lung volume, is readily apparent on the expiratory limb of a flow-volume curve (Fig. 41-3). In the early stages of COPD, the abnormality in airflow is evident only at lung volumes at or below functional residual capacity, appearing as a “scooped out” lower part of the descending limb of the flowvolume curve. In more advanced disease, the entire curve demonstrates decreased expiratory flow. The relative contributions of diminished elastic recoil and increased airway resistance in reducing maximal expiratory airflow can be quantified from flow-pressure curves (Fig. 41-4). With decreased elastic recoil the curve has a normal slope, but it terminates prematurely. In contrast, with increased airway resistance the slope becomes less steep, reflecting the necessity for increased driving pressure for any level of airflow. In theory, therefore, it is possible to distinguish between emphysema (“decreased elastic recoil”) and small airway pathology (“increased airway resistance”) as the cause for the reduced FEV1 . The situation is more complex, however, because most people with COPD have both emphysema and small airway pathology. Moreover, elastic recoil and airway resistance are not necessarily separable. Elastic recoil affects the stiffness of small airways. When elastic recoil is reduced, the curve may be shifted to the right because of increased airway collapsibility. Because flow-pressure data are difficult to collect and interpret and are of little help in patient management, sorting among decreased elastic recoil, airway collapsibility, and increased airway resistance as the mechanism of airflow obstruction in COPD is rarely done in clinical practice. Moreover, other data, such as the diffusing capacity

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Figure 41-3 Maximum expiratory and inspiratory flow-volume (MEFV, MIFV) curves in a normal subject (left), a subject with mild airway obstruction (middle) due to COPD, and a subject with advanced obstruction (right) due to COPD. The FEV1 is indicated on the volume axis by a vertical bar. TLC = total lung capacity; RV = residual volume; FVC = forced vital capacity. Note the development of convexity of flow to the volume axis in mild obstruction, despite preservation of a large peak expiratory flow, a normal FVC, and only a small reduction in FEV1 /FVC ratio. Inspiratory flow is normal. In advanced COPD there is marked decrease of FEV1 , FVC, and maximal expiratory airflow generally. Inspiratory flow is also markedly reduced, but spared relative to expiratory flow. (From Pride NB, Milic-Emili J: Lung mechanics, in Calverley PMA, Pride NB [eds], Chronic Obstructive Pulmonary Disease. London, Chapman & Hall, 1995, pp 135–160, with permission.)

Figure 41-4 Analysis of reduced maximum expiratory flow in COPD from maximum expiratory flow vs. lung recoil pressure curves. With loss of lung recoil pressure–-i.e., ‘‘emphysema” (heavy interrupted line)–-the slope of the flow-pressure curve remains normal, but the curve terminates at lower pressure than normal. With intrinsic airway obstruction–-i.e., ‘‘bronchitis”–-the slope is reduced. Increased airway collapsibility, which may be a result of decreased elastic recoil, causes the curve to be displaced to the right. Commonly in COPD, the flow-pressure curve has premature termination and a decreased slope and is shifted rightward, indicating that decreased elastic recoil, increased airway resistance, and increased airway collapsibility are all involved in causing the reduced maximum expiratory flow. (From Pride NB, Milic-Emili J: Lung mechanics, in Calverley PMA, Pride NB [eds], Chronic Obstructive Pulmonary Disease. London, Chapman & Hall, 1995, pp 135–160, with permission.)

and chest computed tomography may provide estimates of the severity of emphysema. As discussed below, the correlation between FEV1 is better with small airway pathology than with emphysema. Although there is considerable variability in the relationships between the FEV1 and other physiological abnormalities in COPD, certain generalizations may be made. The arterial oxygen tension (PaO2 ) usually remains near normal until the FEV1 is decreased to about half of the predicted level; even a much lower FEV1 may be associated with a normal PaO2 , at least at rest. An elevation of arterial PCO2 (PaCO2 ) is not expected in COPD until the FEV1 is less than about one-fourth of predicted; even then an elevation in arterial carbon dioxide tension (PaCO2 ) may not occur. Pulmonary hypertension due to COPD that is severe enough to cause cor pulmonale and right ventricular failure occurs only in persons who have a marked decrease in FEV1 (one-fourth of predicted or less) and chronic hypoxemia (PaO2 under 55 mmHg), although some elevation of pulmonary artery pressure, particularly with exercise, is common with less advanced COPD.

Maldistribution of Ventilation and Ventilation-Perfusion Mismatching Maldistribution of ventilation and ventilation-perfusion mismatching are characteristic of COPD and reflect the heterogeneous nature of the disease process as it affects the airways and lung parenchyma. Nitrogen washout during breathing of 100 percent oxygen is delayed because of regions that are poorly ventilated, and the profile of the nitrogen washout curve is consistent with many parenchymal compartments

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Figure 41-5 Ventilation-perfusion distributions in three persons with COPD determined by the multiple inert gas elimination technique (MIGET). A. Regions of high ventilation-perfusion characteristic of ‘‘emphysematous,” type A COPD. B . Regions of low ventilation-perfusion characteristic of ‘‘chronic bronchitis,” type B COPD. C . Regions of both high and low ventilation-perfusion characteristic of many people with COPD. In the normal person, not shown, ventilation-perfusion virtually overlaps and peaks at about a ventilation-perfusion ratio of 1. (From Wagner PD, Dantzker DR, Dueck R, et al: Ventfl ation-perfusion inequality in chronic obstructive pulmonary disease. J Clin Invest 59:203–216, 1977, with permission.)

having different washout rates because of regional differences in compliance and airway resistance. Radioisotopic ventilation scanning with 133 xenon reveals regional heterogeneity of ventilation in COPD. The multiple inert gas elimination technique (MIGET), which enables quantification of the ventilation-perfusion profile, has demonstrated different ventilation-perfusion patterns among patients with advanced COPD (Fig. 41-5). In one pattern, so-called type A (“pink puffer”) COPD, there is a substantial amount of ventilation distributed to high ventilation-perfusion regions. In a second pattern, called type B (“blue bloater”) COPD, there is a substantial amount of pulmonary blood flow perfusing low ventilation-perfusion regions. There are important limitations to this simple classification. First, persons with the clinical features of type A or type B (that is, emphysema or chronic bronchitis) do not necessarily have the expected ventilation-perfusion pattern. Of perhaps greater importance, most people with COPD are not easily classified as either type A or type B. They have both high and low ventilation-perfusion regions. MIGET has also revealed that an increased dispersion of ventilation-perfusion values is already present in the early stage of COPD. Ventilation-perfusion mismatching accounts for essentially all of the reduction in PaO2 that occurs in COPD; shunting is minimal. Thus, modest elevations of inspired oxygen are effective in treating hypoxemia due to COPD. If hypoxemia is difficult to correct other problems such as pulmonary emboli or right to left intracardiac or intrapulmonary shunting need to be considered.

Hyperinflation Hyperinflation, defined in various ways (increased functional residual capacity, increased residual volume to total lung ca-

pacity, increased total lung capacity, or decreased inspiratory capacity to total lung capacity) is common in COPD of moderate severity or worse. Hyperinflation might be beneficial as it favors preservation of maximum expiratory airflow because as lung volume increases, elastic recoil pressure increases, airway lumens enlarge, and airway resistance decreases. However, hyperinflation has adverse effects on the mechanics of the thorax, increasing the work of breathing and eliciting dyspnea. Hyperinflation displaces the diaphragm into a flattened position and, thereby, creates a number of adverse effects (Fig. 41-6). First, because the zone of apposition between the diaphragm and the abdominal wall is lost, positive abdominal pressure during inspiration is not transmitted as effectively to the chest wall, hindering rib cage movement and impairing inspiration. Second, because the muscle fibers of the flattened diaphragm are shorter than those of a more normally curved diaphragm, they are less capable than normal of generating inspiratory pressures. Third, the flattened diaphragm must generate greater tension to develop the transpulmonary pressure required to produce tidal breathing. This follows from Laplace’s law, P = 2T/r. As the radius of diaphragm curvature (r) increases with diaphragm flattening, the tension (T) required to develop a transpulmonary pressure (P) to generate tidal breathing must increase. Also, with hyperinflation, the thoracic cage, in general, must operate at a mechanical disadvantage. Because the thoracic cage is distended beyond its normal resting volume, during tidal breathing, the inspiratory muscles must do work to overcome the resistance of the thoracic cage to further inflation instead of gaining the normal assistance from the chest wall recoiling outward toward its resting volume. Typically hyperinflation increases further on exercise because airflow obstruction limits lung emptying during rapid breathing. This additional hyperinflation,

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The mechanisms of dyspnea in COPD are not fully understood. Neural signals relating to abnormalities of chest wall and airway mechanics appear to be important. Specifically, an increased sense of effort relating to the pressures needed from the respiratory muscles relative to their maximum pressure-generating capacity is thought to be one factor in producing dyspnea. Signals of “length-tension inappropriateness” from the respiratory muscles due to hyperinflation constitute another. Also, impulses from airways undergoing abnormal dynamic compression during exhalation have been described. Hypercapnia and hypoxemia play only a small role, except in acute situations. Oxygen administration may decrease breathlessness by reducing ventilation during exertion and through poorly understood direct effects not associated with changes in ventilation.

Physiological-Pathological Correlations Figure 41-6 Detrimental effects of hyperinflation on diaphragmatic function. Hyperinflation causes flattening of the diaphragm, which (1) decreases the zone of apposition between the diaphragm and the abdominal wall, hindering rib cage movement; (2) shortens diaphragmatic muscle fiber length, decreasing the force that can be generated by the diaphragm; (3) increases the radius of curvature of the diaphragm, thereby decreasing transpulmonary pressure (at constant tension); and (4) directs diaphragmatic muscle fibers medially, impairing inflation with diaphragmatic contraction. In addition, hyperinflation prevents the thorax from assisting inspiration during tidal breathing because the resting volume of the thorax is above the volume at which the rib cage recoils outward during inspiration. (From Yusen RD, Lefrak SS, and the Washington University Emphysema Surgery Group: Evaluation of patients with emphysema for lung volume reduction surgery. Semin Thorac Cardiovasc Surg 8:1–12, 1996, with permission.)

designated dynamic hyperinflation, adds to the load on the inspiratory muscles while further reducing their mechanical advantage. The net effect is increased work of breathing, diminished capacity for exercise, and increased dyspnea. Coincident with hyperinflation, the inspiratory capacity (IC) is commonly reduced in COPD. Reduction of the IC has prognostic significance that is independent of FEV1 . In a study of subjects with moderate to very severe COPD, survival was markedly shorter in 286 individuals whose IC/TLC was less than 25 percent compared to 403 individuals whose IC/TLC was greater than 25 percent, even though the two groups had comparable severity of COPD based on percent predicted FEV1 .

Approximately 40 years ago Hogg and colleagues discovered that airways 2 mm or less in internal diameter normally contribute only a minor part of the total airway resistance, but that these airways become the principal sites of increased airway resistance in COPD. Although it is well accepted that the functional obstruction to airflow in COPD is in the small airways, the relative importance of emphysema vs. intrinsic abnormalities of the small airways as the physical basis for the obstruction is still under investigation. Emphysema and small-airway pathology are both present in most persons with COPD so that their relative contributions to obstruction might vary from one patient to another. However, correlations between emphysema severity and airflow obstruction are poor (Fig. 41-7), while a recent analysis found good correlations exist between airway pathology and GOLD classes. Thus, it appears that airflow obstruction in COPD is especially associated with structural abnormalities in the small airways.

Dyspnea People with COPD typically seek medical care because of dyspnea. Dyspnea compromises their activities and quality of life. Dyspnea is seldom a complaint until the FEV1 has fallen below about 60 percent of predicted; however, the correlation between FEV1 and exercise limitation is not strong. Some individuals with COPD are relatively free of dyspnea despite impressively low levels of FEV1 .

Figure 41-7 Emphysema score vs. FEV1 (% predicted). Emphysema graded either by direct examination of lung tissue or by chest computed tomography. There is no correlation between emphysema severity and FEV1 . (From Gelb AF, Hogg JC, Schein M: Contribution of emphysema and small airways in COPD. Chest 109:353–359, 1996, with permission.)

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Luminal occlusion ny mucus and inflammatory exudate

Fibrosis

Disrupted alveolar attachments

Thickening of airway wall

Lymphoid follicles in severe disease

Goblet cells

Inflammatory cell accumulation -macrophage -neutrophil -CD8+, CD4+ T cells

Figure 41-8 Small airway pathology in COPD. Multiple pathological lesions can be found. In some studies, but not all, quantification of these abnormalities correlates with the reduction in FEV1 . (Reproduced with permission from Senior RM, Silverman EK: XXII Chronic Obstructive Pulmonary Disease. 14 Respiratory Medicine. ACP Medicine. Dale DC, Federman DD, eds. WebMD Inc., New York, 2007 [www.acpmedicine.com].)

Small airways in the lungs of individuals with COPD typically show multiple abnormalities that include goblet cell metaplasia, replacement of surfactant-secreting Clara cells with mucus-secreting cells, and infiltration of the walls by inflammatory cells that, in severe disease, may include lymphoid follicles (Fig. 41-8) (see Chapter 40).These changes are accompanied by increased connective tissue and mesenchymal cells in the subepithelial and adventitial compartments of the airway walls. Alveolar tissue surrounding small airways normally provides radial traction on bronchioles at points where alveolar septa attach. Loss of these bronchiolar attachments as a result of proteolytic destruction may contribute to airway distortion, narrowing, and instability.

PATHOGENETIC PROCESSES COPD represents the clinical expression of complex alterations in structure and function of alveolar tissue and small airways. Many processes at the tissue and cellular levels can be implicated, including inflammation, cell proliferation, apoptosis, altered phenotype of lung cells, and remodeling of the extracellular matrix. Numerous mediators, most notably proteinases, oxidants and cytokines, are involved in these processes. Studies in genetically altered mice have proven invaluable in helping to elucidate the pathogenesis of COPD, especially emphysema.

Inflammation As reflected in the definition of COPD, inflammation occupies a central role in current thinking about the pathogenesis of COPD. The inflammation paradigm is that smoking and other types of inhaled irritants lead to recruitment of inflam-

matory cells to the lungs and airways and that products of these recruited cells injure lung tissue and disrupt normal mechanisms of lung repair. Indeed, inflammation is prominent in airways and lung parenchyma in biopsies, surgical specimens, and postmortem material from individuals with COPD. Other indicators of inflammation are increased inflammatory cells in bronchoalveolar lavage fluid (BALF) and sputum and increased volatile products of inflammatory cells in exhaled breath. Inflammatory cells associated with COPD include neutrophils, eosinophils, macrophages, and lymphocytes. Once the inflammatory process is initiated by smoking the process may persist long after smoking has stopped. Unlike nonsmokers, macrophage accumulations are found in respiratory bronchioles in smokers, and BALF from smokers contains many fold increases in macrophages compared to the numbers in BALF from nonsmokers. Besides releasing proteinases that might degrade the extracellular matrix of the lung, alveolar macrophages in COPD make chemotactic factors that recruit other inflammatory cells to the lungs. Likewise, structural cells of the lungs in COPD produce proteinases and chemotactic factors for inflammatory cells. Expression of interleukin-8 (IL-8), macrophage inflammatory protein-1α (MIP-1α), and monocyte chemoattractant protein-1 (MCP-1), for example, are up-regulated in bronchiolar epithelium in COPD. T cells from COPD lungs produce cytokines that stimulate production of matrix metalloproteinases by macrophages. Peptides of elastin are chemotactic for inflammatory cells and, in some experimental models of emphysema the elastin peptides present in the lung are crucial to the inflammatory process, suggesting that destruction of the lung’s extracellular matrix may be a self-perpetuating process. In mice, genetically induced overexpression of cytokines such as IL-13 or γ-interferon by lung cells leads to emphysema that is mediated by proteinases from inflammatory cells. Cellular and humoral immunity may be involved in emphysema pathogenesis. CD4+ and CD8+ T cells and B cells accumulate in alveolar and airway tissue in COPD and form bronchus-associated lymphoid tissue (BALT) in the walls of small airways, and an increasing BALT in small airways correlates with increasing GOLD stage. In mice, exposure of antibodies to endothelial cells elicits alveolar septal cell destruction. Speculation about antigens for immunologically driven emphysema in patients include microbial pathogens, material contained in tobacco smoke, and peptides released from lung extracellular matrix.

Proteinase-Antiproteinase Imbalance Proteinases of several biochemical classes, and requiring different inhibitors, are implicated in the pathogenesis of emphysema. Serine proteinases, especially neutrophil elastase, and several matrix metalloproteinases (MMPs), especially MMP-1 (collagenase), MMP-9 (gelatinase B), MMP-12 (macrophage elastase), and MMP-14 (MT1-MMP, membrane-type 1 MMP), have been the classes and specific proteinases for which there are the most data.

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For many years neutrophils and macrophages were considered to be the exclusive sources of proteinases involved in COPD. Now it is appreciated that other types of inflammatory cells and even structural cells of the lungs may produce proteinases that promote emphysema. Besides degrading matrix proteins, proteinases may exert other effects that relate to the pathogenesis of COPD, such as releasing cell-bound and matrix-bound chemokines, activating growth factors, and inducing expression of mucin genes. However, α1 -AT deficiency is still the only situation of proteinase-antiproteinase imbalance in COPD in which both the proteinase (neutrophil elastase) and its inhibitor (α1 -AT) have been definitively established. It must be emphasized that little is known about proteinases in the pathogenesis of the small-airway pathology of COPD. Virtually all of the information about proteinases in COPD pertains to emphysema. Accordingly, we discuss proteinases below in the context of the pathogenesis of emphysema.

Oxidant-Antioxidant Imbalance

Figure 41-9 Activation of signal pathways by oxidative stress. Ap-1 = activating protein 1; erk = extracellular signal-related kinase; ikk = inhibitor kb kinase; jnk = c-jun n-terminal kinase; nf-b = nuclear factor b; p = phosphate. (From MacNee W: Pulmonary and systemic oxidant/antioxidant imbalance in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2:50–60, 2005, with permission.)

Reactive oxygen species in cigarette smoke or released by inflammatory cells and structural cells of the lungs in response to smoke may lead to lung injury (see Chapter 25). Up to 20 mg of tar may be deposited in a smoker’s lung per cigarette smoked. This tar contains more than 1017 stable, long-lived radicals per gram. The gas phase of tobacco smoke contains 1015 organic radicals per puff of smoke, although in general these small oxygen- and carbon-centered species are more short-lived and reactive than the radicals in the particulate phase. Tobacco smoke appears to “prime” neutrophils and alveolar macrophages to generate elevated amounts of reactive oxygen species, such as hydrogen peroxide, hydroxyl radicals, and superoxide radicals. The lung tissue of smokers also contains significantly more iron than that of nonsmokers, providing a catalyst for the production of hydroxyl radicals from H2 O2 . Additionally, smokers demonstrate increased production of neutrophil myeloperoxidase, which is capable of yielding oxidized halogens such as hypochlorous acid (HOCl). Oxidants can modify and inactivate proteins, protease inhibitors (such as α1 -AT and secretory leukoprotease inhibitor [SLPI]), and histone deacetylase 2 (HDAC2), which is involved in glucocorticoid mediated anti-inflammatory responses. Oxidants can also affect lipids and DNA, and some specific end products, such as 4-hydroxy-2-nonenal (4-HNE) and 8-hydroxy-2′ -deoxyguanosine (8-OHdG), may be markers of COPD. Directly relevant to the inflammatory hypothesis of COPD, oxidants can promote inflammation and proteinase expression via intracellular signaling pathways that involve mitogen-activated protein kinases (MAPK), nuclear factor (NF)-κB, and other pro-inflammatory signaling molecules (Fig. 41-9). Oxidants can induce apoptosis. Oxidants may also facilitate proteinase-mediated extracellular matrix degradation by enhancing matrix molecule susceptibility to proteolytic cleavage, and may participate in nonenzymatic degra-

dation as in the case of the effects of hydroxyl radicals on type I collagen. In experimental animals the combination of cigarette smoke and elastase leads to greater emphysema than either insult alone, suggesting that these insults do not elicit identical responses. A number of antioxidant enzymes protect against oxidative injury. Intracellular oxidant concentrations are controlled by copper- and zinc-dependent superoxide dismutases in the cytoplasm and a manganese-dependent form in mitochondria. H2 O2 is eliminated by catalase and glutathione peroxidase. Additional antioxidants include α-tocopherol and ascorbate, which are enriched in epithelial lining fluid. Gene profiling of airway epithelium in long-time smokers suggests that the glutathione pathways are induced, but the catalase and superoxide dismutases are not. Experimental evidence for the importance of the antioxidant system in protection against cigarette smoke– induced damage is apparent in mice lacking the master antioxidant regulator, nuclear factor E2-related factor (Nγf-2). When these mice are exposed to cigarette smoke they develop emphysema whereas identical mice that have normal Nγf-2 are resistant to the development of emphysema. Interestingly, the underlying mechanisms for emphysema vary between mouse strains. The capacity to mount antioxidant responses appears to influence the capacity to generate antiproteases as Nγf-2– deficient mice develop more severe emphysema in response to intratracheally administered elastase than controls. Thus, it appears that Nγf-2 protects against the development of emphysema not only by regulation of oxidant/antioxidant balance, but also by influencing inflammation and protease/antiprotease balance. Although the antioxidant defense system may be compromised by the oxidative stress imposed by smoking, this has not been proven. In fact, some evidence suggests that

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protective mechanisms are enhanced. The antioxidant capability of alveolar macrophages from smokers is increased and glutathione levels in alveolar lining fluid are elevated. Ascorbate and α-tocopherol levels in smokers are difficult to interpret, with increased levels in macrophages and decreased levels noted in serum and alveolar lining fluid.

Apoptosis An early theory of emphysema development was that alveolar vascular destruction preceded loss of alveolar tissue. Recent data suggest that this speculation may have merit since blockade of vascular endothelial growth factor (VEGF) signaling in alveolar endothelial cells or genetic down-regulation of VEGF production in alveolar epithelium produces apoptosis and noninflammatory emphysema in rodents. The same result can be achieved by instilling the pro-apoptotic protein caspase-3 into the lungs. These experimental studies may actually have relevance to human emphysema as apoptotic cells can be found in emphysematous lungs and smokers’ lungs but not in nonsmokers’ lungs. In vitro, cigarette smoke induces apoptosis of several lung cell types. The mechanisms by which apoptosis leads to emphysema are still not well understood, but in the caspase-3 study mentioned above apoptotic alveolar type II cells degraded elastin. An important feature of experimental models of emphysema due to apoptosis is that there is minimal inflammation. In contrast to the expanding body of information linking emphysema to apoptosis, there is only scant information about apoptosis of the cells of small airways in COPD. Much remains to be learned about apoptosis in the context of COPD.

Mucus Hypersecretion Airway mucus is a normal protective barrier that is constantly replenished and cleared in health (see Chapter 8). Mucin glycoproteins, the main components of mucus, have a core protein rich in serine and threonine, to which carbohydrates and cysteine residues are attached. It is secreted from submucosal glands and airway goblet cells. In COPD there is hyperplasia of goblet cells and hypertrophy of glands with an increase in the ratio of glandular mucus cells to serous cells. The changes in COPD are associated with an alteration of the mucus proteins (MUCs) to favor a predominance of MUC5B over the typical MUC5AC form, and an increase in the MUC2 form, which is uncommon in normal lung mucus. Other alterations in the mucus layer in COPD include greater acidity, less mucin glycosylation, and decreased antimicrobial peptides. Mediators responsible for mucus hypersecretion include proteinases (neutrophil elastase and MMP-9), cytokines (tumor necrosis factor α, TNFα), oxidants, dual oxidase, TNFα-converting enzyme (TACE), and epidermal growth factor receptor (EGFR) ligands. Determining the relationship between chronic cough and sputum in patients with COPD and the natural history of COPD has been elusive. Reports vary from finding weak to

strong correlations between cough and sputum production and COPD progression, COPD exacerbations, and mortality. A relationship between chronic mucus hypersecretion in small airways and adverse outcomes is plausible as histological analysis of small-airway pathology in COPD demonstrated that the extent of small-airway luminal obstruction by mucus correlated with the GOLD stage. However, the correlation with the GOLD stage was stronger for inflammatory cell infiltration into the walls of the small airways than the luminal mucus obstruction.

PATHOGENESIS OF EMPHYSEMA General Concepts The standard definition of emphysema is “a condition of the lung characterized by abnormal, permanent enlargement of airspaces distal to the terminal bronchiole, accompanied by destruction of their walls, and without obvious fibrosis.” Although overt fibrosis may not be a finding, studies since this definition was enunciated indicate increased collagen per unit volume of airspace wall in emphysematous lungs associated with active synthesis of extracellular matrix. Also, emphysematous tissue has been found to exhibit both apoptosis and proliferation of alveolar cells. Accordingly, emphysematous lung tissue should be viewed as undergoing remodeling rather than simply a destructive process. The pathogenesis of emphysema was obscure until 1963 when Laurell and Eriksson reported an association between deficiency of serum α1 -AT and chronic airflow obstruction with emphysema. At approximately the same time Gross and associates described the first reproducible model of emphysema by injecting the plant proteinase papain, a potent elastase, into the lungs of rats via the trachea. Together, these observations led to the proteinase-antiproteinase hypothesis of emphysema which has been the prevailing concept of the pathogenesis of emphysema ever since. According to the proteinase-antiproteinase hypothesis, there is normally a steady or episodic release of proteolytic enzymes into the lung parenchyma, principally from inflammatory cells. Under normal conditions plasma proteinase inhibitors, especially α1 -AT, permeate lung tissue and prevent proteolytic enzymes from digesting structural proteins of the lungs. Proteinase inhibitors synthesized locally in the lungs also contribute to the antiproteinase “shield”. Emphysema results when there is an imbalance between proteinases and antiproteinases in favor of proteinases due to an augmentation of proteinase release in the lungs, a reduction in the antiproteinase defense within the lungs, or a combination of both increased proteinase burden and decreased proteinase inhibitory capacity. It is important to appreciate that proteolytic injury to the extracellular matrix of the lung does not necessarily operate throughout the lungs as a whole. In fact, proteolytic events are tightly controlled and occur at or near the surface of cells. Thus, “imbalance” between proteinases

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Table 41-2 Elastolytic Proteinases that May Affect the Lung Parenchyma

Figure 41-10 Alveolar elastic fiber network. Artist’s sketch of the elastic fibers in the parenchyma of human lung showing how elastic fibers form a helix encircling the alveolar ducts and penetrate into alveolar septae. (From Pierce JA, Ebert RV: Fibrous network of the lung and its change with age. Thorax 20:469–476, 1965.)

and their inhibitors probably should be viewed as operating in microenvironments immediately surrounding cells.

Lung Elastic Fibers The original observations linking proteinases and emphysema led to the concept that destruction of alveolar elastic fibers is a key to emphysema development. Indeed the proteinase-antiproteinase hypothesis of emphysema pathogenesis became, in fact, the “elastase-antielastase hypothesis”. Structurally, the extracellular matrix of the lung is organized into three interdependent cable systems: (1) an axial system that extends from the central airways through the peripheral airways to the alveolar ducts; (2) a parenchymal system that comprises the matrix of the alveolar septae; and (3) a peripheral system that arises from the visceral pleura and extends into the interlobular septae, forming a fibrous sac around the lung. Distal to the respiratory bronchioles, the axial system forms a helix encircling the alveolar ducts, extending into the interstitium of alveolar walls. Elastic fibers, of which elastin is the main component, loop around alveolar ducts, form rings at the mouths of the alveoli, and penetrate as wisps into the alveolar septae, where they are concentrated at bends and junctions (Fig. 41-10). Elastic fibers, which possess rubberlike reversible extensibility, come under tension and provide elastic recoil throughout the respiratory cycle. Unlike elastic fibers, the interstitial collagen fibers in alveolar septa are nondistensible and have high tensile strength. They can be thought of as relaxed ropes that straighten during inspiration and become taut at total lung capacity. Elastin is resistant to many proteinases, most notably the collagenases that cleave interstitial collagens. However, there are a number of enzymes that may come in contact

Proteinase

Cell of Origin

Neutrophil elastase

Neutrophil (Monocyte)

Proteinase 3

Neutrophil (Monocyte)

Cathepsin G

Neutrophil (Monocyte, mast cell)

MMP-9 (Gelatinase B)

Macrophage, neutrophil, eosinophil, fibroblast, epithelial cell

MMP-12 (Macrophage elastase)

Macrophage

Cathepsin L

Macrophage

Cathepsin S

Macrophage

Note: Parentheses denote minor cellular sources.

with the lung that can degrade elastin (Table 41-2). Elastic fibers in the lung normally last a full human life span. There is virtually no elastin synthesis in the normal adult lung, but animal studies indicate that elastin synthesis can be reinitiated in the adult lung. Histological studies of emphysematous lung tissue support the hypothesis that elastic fibers are perturbed in emphysema. There are fragmented elastic fibers in α1 -AT deficiency and poorly formed elastic fibers and clumps of elastin in smokers with centriacinar emphysema. The latter changes appear to be from aberrant synthesis of new elastin and resemble the findings in the lungs in emphysema induced experimentally with elastase. What little is known about lung repair in response to elastolytic proteinases derives from animal research. After an intratracheal injection of human neutrophil elastase into an experimental animal, acute depletion of elastin occurs, followed by a burst of synthesis of extracellular matrix including elastin. Over a few weeks, the elastin content of the lungs returns to normal, although the lungs display emphysema. The elastic fibers, like the elastic fibers in human emphysema, appear disorganized. Thus, even if elastin expression can be reinitiated in the adult human lung, the production of normal elastic fibers is not achieved. This is not surprising as production of elastic fibers entails temporally and physically coordinated expression of the many components of the elastic fiber. One way in which smoking may impair lung elastic

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Figure 41-11 Holes in alveolar walls in early emphysema. Scanning electron micrographs of alveolar walls from surgically resected specimens: lung with mild emphysema (A) and non-emphysematous lung (B ). Holes are more numerous in alveolar walls in the emphysematous lung than in the normal lung. Original magnification Ă&#x2014;250. (From Nagai A, Inano H, Matsuba K, et al: Scanning electron microscopic morphometry of emphysema in humans. Am J Respir Crit Care Med 150:1411â&#x20AC;&#x201C;1415, 1994, with permission.) B

fiber synthesis is by inhibiting lysyl oxidase, the enzyme that catalyzes the first step in the conversion of tropoelastin monomers to the elastin polymer.

Lung Collagen Turnover Although elastases and elastic fiber destruction dominate thinking about the pathogenesis of emphysema, degradation of alveolar wall collagen and aberrant collagen deposition in alveolar tissue may also be involved. Indeed, collagen destruction may be the critical event in some forms of experimental emphysema. Mice genetically engineered to harbor a transgene that leads to expression of human MMP-1 (collagenase) in lung tissue develop enlarged alveoli, bullous lesions, and reduced collagen fibers in alveolar walls and pleura. Depending on the level of transgene activity the lung lesions can start early after birth or later, indicating that the emphysema is post-developmental. Besides showing that collagenase ac-

tivity can lead to emphysema, results with these mice also indicate that proteinases causing emphysema can be from structural cells of the lungs, as there is minimal inflammation in the lungs, and that emphysema can occur without obvious disruption and faulty resynthesis of elastic fibers as the elastic fibers in these lungs look normal. In emphysematous lungs the pores of Kohn are larger and more numerous than in normal lungs (Fig. 41-11). Because interstitial collagens and basement membrane collagens are prominent in alveolar walls, it seems plausible that collagenous structures undergo degradation in the process of increasing the number and size of these interalveolar pores.

Proteinases The high risk of emphysema among smokers with severe Îą1 -AT deficiency is the most compelling evidence linking a

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proteinase, in this case neutrophil elastase, to emphysema. Thus far, gene profiling of emphysematous lung tissue has shown only limited changes in proteinases and proteinase inhibitors compared to control lung tissue. Success in protecting mice from smoke-induced emphysema through knockouts of proteinase genes or by treatment with proteinase inhibitors has reinforced the proteinase-antiproteinase hypothesis. Neutrophil elastase and several MMPs, some released by neutrophils, and others produced by alveolar macrophages and structural cells of the lungs have been the predominant proteinases implicated in emphysema. Neutrophil Elastase Ever since the discoveries of α1 -AT deficiency and neutrophil elastase, this proteinase has been prominent in the consideration of emphysema pathogenesis. Neutrophil elastase is a serine proteinase. Like other serine proteinases it has conserved histidine, asparagine, and serine residues that form a charge relay system that functions by transfer of electrons from the carboxyl group of asparagine to the oxygen of serine. The serine then becomes a powerful nucleophile that is able to attack the carbonyl carbon atom of the peptide bond of the substrate. It is synthesized as a pre-proenzyme in the endoplasmic reticulum, processed by cleavage of the signal peptide (pre-) and removal of a dipeptide (pro-) by cathepsin C. Its synthesis occurs in the bone marrow during a very specific stage in myeloid development and it is stored in azurophil granules as an active packaged protein. It has activity against elastin and other extracellular matrix proteins, as well as many non-matrix substrates. Because neutrophils can concentrate it on their plasma surface, it may function in the extracellular environment despite large excesses of α1 -AT and other inhibitors. Following the early connection of α1 -AT and neutrophil elastase, later evidence implicating neutrophil elastase in the pathogenesis of emphysema has included: (1) increased presence of neutrophil elastase, both free and in complex with α1 -AT, in BALF of people with emphysema; (2) the presence of neutrophil elastase in emphysematous lung tissue; and (3) finding that mice lacking neutrophil elastase (“knockouts”) show significant protection from the development of emphysema in response to chronic inhalation of cigarette smoke. Although neutrophil elastase may be the predominant elastase associated with emphysema, other enzymes in the lung have elastase activity (Table 41-2). Matrix Metalloproteinases (MMPs) For many years neutrophil elastase dominated thinking about proteinases and emphysema. In recent years, however, MMPs have become a focus. MMPs are a family of neutral proteinases that degrade extracellular matrix and modify many other substrates. This enzyme family can be subdivided based on secretion vs. membrane association. Membrane-type MMPs are linked to the cell surface and are more resistant to inhibition by secreted antiproteinases than MMPs in pericellular

spaces. MMPs are secreted as inactive proenzymes, which are activated at the cell membrane surface or within the extracellular space by proteolytic cleavage of the N-terminal domain. Catalytic activity is dependent on coordination of a zinc ion at the active site and is specifically inhibited by members of another gene family, tissue inhibitors of MMPs known as the tissue inhibitor of metalloproteinases (TIMPs) (see below). Although the name implies that MMPs are directed at extracellular matrix, MMPs may exert proteolytic activity against other substrates such as α1 -AT and various cytokines. Accordingly, MMPs may promote the development of emphysema in diverse ways. Individual members of the MMP family can be loosely divided into groups based on their matrix-degrading capacity. As a whole, they are able to cleave all extracellular matrix components at neutral pH. The collagenolytic MMPs have the unique capacity to cleave native triple helical interstitial collagens, but have a restricted substrate specificity and are unable to degrade elastin or basement membrane molecules. In lung tissue exhibiting emphysema, various cell types express MMP-1 (collagenase 1), MMP-2 (gelatinase A), and membrane-type 1 MMP (MT1-MMP; MMP-14). In other types of analyses, MMPs associated with COPD include MMP-8 (collagenase 2) and MMP-9 (gelatinase B) in BALFs and MMP-12 (macrophage elastase) in alveolar macrophages. MMP-8 (neutrophil collagenase) and MMP-9 (gelatinase B) are stored within specific granules in neutrophils from which they are readily released by a variety of stimuli. Alveolar macrophages produce multiple MMPs, including 2, 9, 12, and 14. However, MMPs are scarcely expressed in normal lung tissue. Their production and activity are carefully controlled during normal repair and remodeling processes. With chronic inflammation, regulation of MMPs may go awry, and MMPs may be overexpressed and produced at inappropriate sites. MMP-12 is up-regulated in alveolar macrophages of cigarette smokers. Elimination of MMP-12 by gene targeting protects mice from emphysema induced by cigarette smoke. As already noted, overexpression of MMP-1 in the lungs of transgenic mice leads to enlarged airspaces characteristic of emphysema. In advanced emphysema, alveolar type II cells produce MMP-1 and smoke exposure induces MMP-1 expression by human airway epithelial cells and lung fibroblasts in cell culture. Accordingly, there is considerable evidence implicating both elastolytic and collagenolytic MMPs in the pathogenesis of emphysema. Cysteine Proteinases Human alveolar macrophages can produce multiple cysteine proteinases, including cathepsins L and S which have large active pockets with relatively indiscriminate substrate specificities that include elastin and other matrix components. These enzymes have their maximum activity at acidic pH, but cathepsin S retains about 25 percent of its elastolytic capacity at neutral pH, making it approximately equal to neutrophil

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Table 41-3 Proteinase Inhibitors in the Lung Parenchyma Inhibitor

Cell of Origin

Class of Proteinases Inhibited

α1 -antitrypsin

Hepatocyte (Mononuclear phagocyte)

Serine∗

α2 -macroglobulin

Hepatocyte Lung fibroblast (Macrophage)

Serine, MMP† Cysteine

TIMPs (1,2,3,4)‡

Resident lung cell

MMP

SLPI§

Resident lung cell (Macrophage)

Serine#

Elafin

Large-airway epithelial cell

Serine

Cystatin C

Bronchial epithelial cell (Macrophage)

Cysteine

NOTE: Parentheses denote minor cellular sources. ∗ α -antitrypsin has its greatest affinity for neutrophil elastase 1 † Matrix metalloproteinase ‡ Tissue inhibitors of metalloproteinases § Secretory leukocyte protease inhibitor # SLPI does not inhibit PR3

elastase. Thus, these enzymes have the capacity to cause lung destruction if they are targeted to the cell surface or extracellular space, especially if macrophages can acidify their microenvironment.

Proteinase Inhibitors Considerations of proteinase inhibition in COPD have tended to focus on α1 -AT. However, other inhibitors may serve important antiproteinase functions in lung tissue (Table 41-3). Inhibitors of Serine Proteinases Low-molecular-weight serine proteinase inhibitors are abundant in airway fluid and, hence, are thought to represent the primary defense against proteinase-mediated airway damage. Secretory leukoprotease inhibitor (SLPI) is a 12-kDa protein produced by mucus-secreting and epithelial cells in the airway, as well as type II pneumocytes. SLPI inhibits neutrophil elastase and cathepsin G and many other serine proteinases, but not proteinase 3. Elafin, also produced by airway secretory and epithelial cells, is released as a 12-kDa precursor that is processed to a 6-kDa form that specifically inhibits neutrophil elastase and proteinase 3. These inhibitors are able to inhibit neutrophil elastase bound to substrate, giving them an added dimension that α1 -AT lacks.

Airway mucus contains several other substances that partly inhibit neutrophil elastase, including polyanionic molecules, such as mucins, other glycosaminoglycans, and fatty acids. DNA, released from inflammatory leukocytes, binds to SLPI, greatly enhancing its rate of association with neutrophil elastase. The relative contribution of each of these molecules to proteinase inhibition is unknown.

Tissue Inhibitors of Matrix Metalloproteinases (TIMPs) TIMPs are a family of four proteins that form tight noncovalent bonds with all MMPs. All TIMPs inhibit all MMPs, except TIMP-1 which does not inhibit membrane type (MT)MMPs. Structurally TIMPs have a wedge-shaped N-terminal domain that competes with substrate for the catalytic site; however, the C-terminal domain can bind to specific proMMPs without inhibiting pro-MMP activation. TIMP-2 is secreted complexed to pro-MMP-2 in fibroblasts and interacts with MT1-MMP in the activation of pro-MMP-2. TIMPs are secreted from many cell sources and are abundant in tissues. Cell-specific production and microenvironment localization appear to play an important role in the balance between MMPs and TIMPs. TIMP-3 is more highly glycosylated and interacts with matrix and cellsurface proteoglycans while the other TIMPs are secreted and

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freely diffusible. TIMP-1 is the most highly inducible whereas TIMP-2 expression is more constitutive. Alveolar macrophages secrete TIMP-1 and TIMP-2. Cytokines, such as interferon-γ, inhibit MMP-1 and MMP12 expression in macrophages, with little effect on TIMPs; while TGF-β induces TIMP-1 expression and inhibits MMP production. Thus, MMPs and TIMPs may be coordinately regulated, perhaps limiting tissue injury during normal remodeling associated with inflammation. Alternatively, regulation may become discoordinate, leading to proteolysis of extracellular matrix or fibrosis. In COPD, TIMP-1 is elevated in sputum and tissue homogenates, but may not be in excess of MMPs. Other TIMPs have been less well studied, but TIMP-3 knockout mice have enhanced pulmonary inflammation and impaired lung development that resembles emphysema. A TIMP-2 polymorphism associated with COPD has been uncovered in a Japanese population, but it is unclear if this polymorphism has any effect on TIMP-2 protein expression. Cystatins Cystatins represent families of cysteine proteinase inhibitors, some of which are strictly intracellular, while others such as cystatin C possess a signal peptide and are secreted by a variety of cells. Cystatin C, composed of a single, non-glycosylated,

chain (13 kDa), forms reversible 1:1 complexes with enzymes. It is the most ubiquitous cystatin. It has been found in all human tissues and body fluids, providing protection against tissue destruction by intracellular cathepsin enzymes leaking from cells. It is produced by alveolar macrophages.

Overall View of the Pathogenesis of Emphysema Degradation of lung elastin by elastase activity from inflammatory cells is probably the predominant mechanism for emphysema in most smokers. However, the biology of emphysema is clearly complex and still incompletely understood. It includes inflammatory cell recruitment, proteinaseantiproteinase imbalance, oxidant-antioxidant imbalance, and responses of lung cells to proteinases and oxidants from inflammatory cells and to constituents of tobacco smoke (Fig. 41-12). It may also involve humoral and cellular immunity. Degradation of extracellular matrix components besides elastin, particularly collagens, may be an important feature. In some situations apoptosis of lung cells may precede degradation of extracellular matrix. Senescence of lung cells, a recently identified phenomenon in emphysema, has unclear implications, but suggests that lung repair mechanisms are depressed.

Figure 41-12 Schematic of concepts of the pathogenesis of emphysema due to smoking. Smoke leads to induction and release of chemotactic factors by alveolar macrophages and resident structural cells causing an accumulation of several types of inflammatory cells in the lungs. Smoke-stimulated resident cells and the recruited cells release proteinases and oxidants that damage or degrade extracellular matrix in the walls of alveoli, alveolar ducts, and respiratory bronchioles. Smoke also induces senescence and apoptosis of structural cells (injury to parenchymal cells) which leads to release of products that injure tissue and reduces the capacity of the tissue to repair. Smoke further affects lung homeostasis by inactivating proteinase inhibitors, such as α1 -AT. Peptides released from damaged extracellular matrix, notably from elastin, are chemotactic for inflammatory cells so that degradation of the extracellular matrix leads to a feedback loop that perpetuates inflammation. Not shown is the possibility that cellular and humoral immune processes are also involved.

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ALPHA 1-ANTITRYPSIN DEFICIENCY Background Human plasma contains at least six proteins that function as proteinase inhibitors. Together, they make up about 10 percent of the total plasma protein. At a concentration of 150 to 350 mg/dl, alpha 1-antitrypsin is present in the highest concentration of all of the plasma proteinase inhibitors. α1 AT is a member of a family of serine proteinase inhibitors called serpins. α1 -AT is a glycoprotein of 52 kDa synthesized primarily by the liver. Mononuclear phagocytes are a secondary source. It consists of a single polypeptide chain of 394 amino acids. Carbohydrate side chains account for 12 percent of the molecular mass. The 12.2-kb gene that encodes α1 -AT is on the proteinase inhibitor (PI) locus on chromosome 14. This site is near the gene for α1-antichymotrypsin, the inhibitor for cathepsin G which, like neutrophil elastase, is a proteinase contained in the azurophil granules of neutrophils. The α1 AT gene has seven exons and six introns. Exons four through seven code for the mature protein. Of note, the first two exons and a segment of the third exon are encoded in the transcript expressed in macrophages, but not in hepatocytes. α1 -AT is an acute-phase reactant. Plasma levels rise with trauma, estrogen therapy, use of birth-control pills, and during pregnancy, however the levels do not rise to normal among individuals with severe deficiency. Proteolytic inhibition of neutrophil elastase and other serine proteinases by α1 -AT involves cleavage by the proteinase of the reactive site of α1 -AT between methionine358 and serine359 . The result is an altered, “relaxed” α1 -AT conformation in complex with the proteinase. Formation of the complex renders the proteinase inactive, and because the complex is quite stable, inactivation is essentially permanent. α1 -AT inhibits many serine proteinases and does so at a 1:1 molar basis. However, α1 -AT associates with neutrophil elastase much faster than with trypsin or other serine proteinases. Indeed, the association with neutrophil elastase is so fast in comparison with other serine proteinases that inhibition of neutrophil elastase is almost certainly the primary function of α1 -AT. The capacity of α1 -AT to inhibit neutrophil elastase and other serine proteinases besides trypsin has led some authors to prefer the designations α1 -PI or α1 -antiproteinase, but the name α1 -AT has become a fixture. From the genetic standpoint, α1 -AT is transmitted in a co-dominant fashion. Thus, the gene product from each parent is expressed in the offspring. More than 100 different α1 -AT alleles are known, most of which are SNPs that do not alter expression of the protein or its function and, therefore, have no clinical significance. The nomenclature for α1 -AT polymorphisms uses letters to specify the allelic variants. The original letters were chosen to reflect electrophoretic mobility: F = fast, M = medium, S = slow, and Z = ultraslow. The normal allele, M, exists in more than 95 percent of the US population, with the S and Z alleles being the next most common, having frequencies of

3 percent and 2 percent, respectively. Homozygosity for the Z allele, Pi ZZ, is associated with severe deficiency of α1 -AT (less than 15 percent of normal) and accounts for virtually all of the individuals with severe α1 -AT deficiency. In the United States its incidence is about 1 in 3000 people. It is rare in Asians and infrequent in African Americans. Heterozygosity of the M allele with either the S or Z allele is very common. There are an estimated 15 million MS and 7 million MZ individuals, respectively, in the United States and comparable numbers in Europe. Despite numerous studies, it is still not yet clear whether the Pi MZ phenotype carries an increased risk of COPD. If there is an increased risk it appears to be small or is limited to an as yet undefined subset of MZ individuals. The MS phenotype does not carry an increased risk, but SZ heterozygosity is associated with increased risk. The abnormality in the Z protein is a point mutation in a single nucleotide at codon 342 that results in coding for lysine instead of glutamic acid. This amino acid substitution changes the charge attraction between the amino acids normally present in positions 342 and 290 in α1 -AT and prevents the formation of a fold in the molecule. With this change in tertiary structure, the molecule is susceptible to dimerization with another α1 -AT molecule; the dimerization can result in polymerization of α1 -AT in the endoplasmic reticulum that impedes secretion of the protein from the cell (Fig. 41-13). Inability to secrete α1 -AT from the hepatocyte explains the low levels of the protein in plasma and other body fluids. Polymers may also form in the lung. α1 -AT polymers are chemotactic for inflammatory cells which may help to explain the marked accumulation of inflammatory cells in the lungs of individuals with α1 -AT deficiency. The Z form of α1 -AT has a much slower rate of association with neutrophil elastase than the association rate of normal α1 -AT with neutrophil elastase. Thus, not only do persons with the Pi Z phenotype have a deficiency of α1 -AT protein, but their α1 -AT is less effective than normal α1 -AT as an inhibitor of neutrophil elastase. In contrast to the Z variant, the S variant of α1 -AT, which involves a single nucleotide substitution of glutamic acid264 with valine, does not accumulate in the liver. This protein is less stable, presumably owing to loss of a salt bridge between the glutamic acid in position 264 and the lysine in position 387, and it polymerizes more slowly than the Z protein. Quantification of serum α1 -AT concentration is done routinely by immunoassay. To confirm an immunoassay showing severe deficiency phenotyping is done in specialized laboratories by isoelectric focusing in the pH range of 4.0 to 5.0 (Fig. 41-14). Typing with molecular probes may be performed to definitively identify α1 -AT genotypes, but there is seldom an indication for this procedure to be performed in clinical practice.

Clinical Aspects Alpha 1-antitrypsin deficiency may be suspected in adults as a result of respiratory symptoms, evidence of liver disease, or

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Figure 41-13 Globular cytoplasmic inclusions in hepatocytes in Pi Z α1 -AT deficiency. A. Periodic acid–Schiff stain after diastase digestion (×1250). B . Electron micrograph showing dilated cisterns of endoplasmic reticulum containing α1 -AT in a hepatocyte. These correspond to the globular inclusions in panel A (×25,000).

rare clinical manifestations such as panniculitis. In practice, however, most (about 80 percent) patients are discovered because of chronic respiratory symptoms and most of the rest are detected from screening for α1 -AT deficiency prompted by finding the deficiency in a family member. Liver disease is the mode of presentation in only a small percentage of adults with α1 -AT deficiency. Because of its infrequency in the practice of most physicians, the diagnosis of α1 -AT deficiency may not be suspected for a number of years after the onset of chronic respiratory symptoms, and often the patient has been seen by several physicians before the diagnosis is established.

Figure 41-14 Patterns of Pi M, Pi Z, and Pi MZ α1 -AT on isoelectric focus. By this analysis, α1 -AT has microheterogeneity and thus appears as multiple bands. Pi M and Pi Z have distinctly different band patterns, while Pi MZ has a pattern that combines the patterns of both Pi M and Pi Z. (Courtesy of John A. Pierce, M.D.)

Lung Disease In the classic situation, the patient with Z type α1 -AT deficiency presents with the typical symptoms of COPD, especially shortness of breath, but is atypical on the basis of being rather young, often around age 40. The patient has hyperinflation, an increased total lung capacity, a decreased diffusing capacity, and radiographic changes consistent with emphysema that include hyperlucent lower lung fields reflecting the pathology (Fig. 41-15). This classic patient reports a mild smoking history relative to the severity of his/her COPD and may describe other family members with chronic respiratory symptoms. In fact, however, there are many exceptions to this classic picture of α1 -AT deficiency. Wheezing, cough and sputum mimicking asthma, or chronic bronchitis that is poorly responsive to standard therapy may be the predominate symptoms. Evidence of emphysema may be minimal relative to the severity of the airflow obstruction. Finally, no other family members may have chronic respiratory symptoms, including siblings or other close relatives, even some who also have severe deficiency.

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Figure 41-15 Lung pathology of Pi Ztype α1 -AT deficiency. Panacinar emphysema that is worst in the lung base. Papermounted whole lung section.

Because the presentation of α1 -AT deficiency can deviate so much from the classic presentation, some experts in this field advise that everyone diagnosed with COPD be screened for α1 -AT deficiency by the routine immunoassay. Other indications for screening include asthma that is not fully reversible despite aggressive therapy, recurrent bronchitis with or without bronchiectasis, a family history of the deficiency, and chronic liver disease without apparent risk factors. It is estimated that there are approximately 100,000 Pi Z individuals in the United States, of whom only around 10,000 are known, in part because they have few or no symptoms that lead to medical attention or, as noted above, clinicians do not think of the diagnosis. Smoking is highly deleterious and hastens the development of COPD in most people with the deficiency. The typical Pi Z individual who smokes has respiratory symptoms by age

40, about 15 years earlier than equally deficient individuals who have never smoked. However, some Pi Z individuals reach advanced age with minimal respiratory symptoms. Liver Disease α1 -AT deficiency can present as liver dysfunction in infancy in various forms ranging from asymptomatic jaundice to frank liver failure. In most instances the clinical manifestations are mild and resolve. However, α1 -AT deficiency represents one of the main indications for liver transplantation in children. In adults, liver abnormalities may be limited to tests of liver function. Clinical manifestations seldom present before middle age. However, among Pi Z individuals who live beyond age 60, liver abnormalities are common and may overshadow respiratory symptoms. Indeed, among those individuals who

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have not smoked and for other unexplained reasons avoid significant pulmonary function deterioration, hepatic cirrhosis and associated complications is the predominant terminal illness. In such individuals there is also a high incidence of hepatic cell carcinoma. Alpha 1-antitrypsin deficiency is a paradoxical situation in which there is a severe systemic deficiency of α1 -AT despite substantial production of α1 -AT by the liver. The distinction between what is happening in the liver and what is happening systemically is clinically important. Infusions of α1 -AT, or other techniques under investigation for boosting systemic α1 -AT levels, can compensate for a severe systemic α1 -AT deficiency and so help protect the lung, but these approaches do not correct or ameliorate problems associated with the accumulation of abnormal α1 -AT in liver cells. At present, liver transplantation is the only treatment for the liver defect.

CONCLUDING COMMENT Better understanding of COPD is imperative. This potentially disabling and fatal disease is already epidemic in many countries and appears destined to become epidemic worldwide in coming decades given trends of smoking prevalence.

SUGGESTED READING American Thoracic Society Statement: Occupational contribution to the burden of airway disease. Am J Respir Crit Care Med 167:787–797, 2003. American Thoracic Society/European Respiratory Society Statement: Standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med 168:818–900, 2003. Anthonisen NR, Connett JE, Murray RP: Smoking and lung function of Lung Health Study participants after 11 years. Am J Respir Crit Care Med 166:675–679, 2002. Aoshiba K, Yokohori N, Nagai A: Alveolar wall apoptosis causes lung destruction and emphysematous changes. Am J Respir Cell Mol Biol 28:555–562, 2003. Barnes PJ, Shapiro SD, Pauwels RA: Chronic obstructive pulmonary disease: Molecular and cellular mechanisms. Eur Respir J 22:672–688, 2003. Casanova C, Cote C, de Torres JP, et al: Inspiratory-to-total lung capacity ratio predicts mortality in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 171:591–597, 2005. Celedon JC, Lange C, Raby BA, et al: The transforming growth factor-β1 (TGFβ1) gene is associated with chronic obstructive pulmonary disease (COPD). Hum Mol Genet 13:1649–1656, 2004.

Celli BR, MacNee W, and ATS/ERS Task Force: Standards for the diagnosis and treatment of patients with COPD: A summary of the ATS/ERS position paper. Eur Respir J 23:932–946, 2004. DeMeo DL, Carey VJ, Chapman HA, et al: Familial aggregation of FEF25–75 and FEF25–75 /FVC in families with severe, early onset COPD. Thorax 59:396–400, 2004. DeMeo DL, Silverman EK: α1-Antitrypsin deficiency. 2: Genetic aspects of α1-antitrypsin deficiency: Phenotypes and genetic modifiers of emphysema risk. Thorax 59:259–264, 2004. Foronjy RF, Okada Y, Cole R, et al: Progressive adult-onset emphysema in transgenic mice expressing human MMP-1 in the lung. Am J Physiol-Lung Cell Mol Physiol 284:L727– 737, 2003. Fuke S, Betsuyaku T, Nasuhara Y, et al: Chemokines in bronchiolar epithelium in the development of chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 31:405– 412, 2004. Grumelli S, Corry DB, Song LZ, et al: An immune basis for lung parenchymal destruction in chronic obstructive pulmonary disease and emphysema. PLoS Med 1:75–83, 2004. Hersh CP, DeMeo DL, Lange C, et al: Attempted replication of reported chronic obstructive pulmonary disease candidate gene associations. Am J Respir Cell Mol Biol 33:71–78, 2005. Hogg JC: Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. Lancet 364:709–721, 2004. Hogg JC, Chu F, Utokaparch S, et al: The nature of smallairway obstruction in chronic obstructive pulmonary disease. N Engl J Med 350:2645–2653, 2004. Imai K, Dalal SS, Chen ES, et al: Human collagenase (matrix metalloproteinase-1) expression in the lungs of patients with emphysema. Am J Respir Crit Care Med 163:786–791, 2001. MacNee W: Pulmonary and systemic oxidant/antioxidant imbalance in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2:50–60, 2005. Mahadeva R, Atkinson C, Li Z, et al: Polymers of Z α1antitrypsin co-localize with neutrophils in emphysematous alveoli and are chemotactic in vivo. Am J Pathol 166:377–386, 2005. Mannino DM: Epidemiology and global impact of chronic obstructive pulmonary disease. Semin Respir Crit Care Med 26:204–210, 2005. Needham M, Stockley RA: α1-Antitrypsin deficiency. 3: Clinical manifestations and natural history. Thorax 59:441– 445, 2004. Owen CA: Proteinases and oxidants as targets in the treatment of chronic obstructive pulmonary disease. Proc Am Thorac Soc 2:373–385, 2005. Rangasamy T, Cho CY, Thimmulappa RK, et al: Genetic ablation of Nγf2 enhances susceptibility to cigarette

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smoke-induced emphysema in mice. J Clin Invest 114:1248–1259, 2004. Shao MX, Nakanaga T, Nadel JA: Cigarette smoke induces MUC5AC mucin overproduction via tumor necrosis factor-alpha-converting enzyme in human airway ep-

ithelial (NCI-H292) cells. Am J Physiol Lung Cell Mol Physiol. 287:L420–L4207, 2004. Yokohori N, Aoshiba K, Nagai A: Increased levels of cell death and proliferation in alveolar wall cells in patients with pulmonary emphysema. Chest 125:626–632, 2004.

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42 Chronic Obstructive Pulmonary Disease: Clinical Course and Management Robert A. Wise

I. OVERVIEW OF COPD II. NATURAL HISTORY OF COPD III. DIAGNOSIS OF COPD IV. PROGNOSIS OF COPD V. TREATMENT OF STABLE COPD Education Prevention of COPD Progression and Complications Exercise and Rehabilitation Nutritional Support Sleep Disorders in COPD Air Travel Long-Term Oxygen Therapy Treatment of Anemia Drug Therapy

In past decades, the treatment of COPD has been approached by many physicians and patients alike with a nihilistic attitude, assuming that the disease was progressive, incurable, and untreatable. More recently, as our understanding of the clinical epidemiology and value of therapy of COPD has improved, this attitude has changed. Physicians have come to approach COPD in the same way as other chronic diseases, such as diabetes, rheumatoid arthritis, and coronary artery disease. With modern comprehensive treatment, the diagnosis of COPD is compatible with prolonged survival, good quality of life, and independent functional status for many who have this illness. The purpose of this chapter is to summarize the current understanding of the course of COPD and best approaches to treatment.

VI. TREATMENT OF COMPLICATIONS Treatment of COPD Exacerbations Pneumoth orax Cor Pulmonale Supraventricular Arrhythmias Hypercapnia VII. ADVANCED TREATMENTS Lung Volume Reduction Surgery Lung Transplantation Chronic Ventilator Support VIII. CONCLUSIONS

OVERVIEW OF COPD Chronic obstructive pulmonary disease (COPD) is a disorder that is characterized by slow emptying of the lung during a forced expiration. In practice, this is measured as the FEV1 /FVC ratio, and the arbitrary definition of airflow obstruction is generally taken to be an FEV1 /FVC ratio lower than 0.70. Because the rate of emptying of the lung falls with advancing age, many elderly individuals demonstrate airflow obstruction even in the absence of a clinical diagnosis of COPD. Several disorders cause chronic airflow obstruction: long-standing asthma, cystic fibrosis, bronchiectasis, bronchiolitis obliterans, lymphangioleiomyomatosis,

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panbronchiolitis, silicosis, Sj¨ogren’s syndrome, and diffuse interstitial processes such as eosinophilic granuloma and sarcoidosis. The diagnosis of COPD is usually limited to individuals who have chronic airflow obstruction associated with tobacco smoke or some other noxious inhalant, and it is usually not difficult to distinguish it from other causes of chronic airflow obstruction. The most commonly associated clinical disorders associated with COPD are emphysema and chronic bronchitis. Emphysema is defined anatomically by airspace enlargement due to disappearance of alveolar septae (see Chapter 40). This leads to the characteristic loss of elastic recoil, which, in turn, causes slowing of airflow from the lungs, hyperinflation, and air-trapping (see Chapter 41). Chronic bronchitis is characterized by chronic cough and sputum production, which is present in about one out of three people with early COPD. Chronic cough and sputum production in cigarette smokers is often, but not always, associated with chronic airflow obstruction. When chronic mucus hypersecretion is associated with airflow obstruction, it is often called chronic obstructive bronchitis. The anatomic correlates of chronic bronchitis are mucus gland hyperplasia and goblet cell metaplasia in large and medium-size airways. Patients with COPD also have small and medium-size airway involvement with inflammation, narrowing, tortuosity, and fibrosis that contributes to the airflow limitation. Some patients with a long-standing history of asthma develop airflow obstruction that is not completely reversible, episodes of cough and wheeze, and chronic sputum production. These individuals are often classified as having chronic asthmatic bronchitis and tend to have a somewhat better prognosis for survival than those with typical tobacco-related COPD. Physicians have a tendency to classify women as having asthma and men as having COPD despite similar medical histories.

NATURAL HISTORY OF COPD COPD results from an increase in the rate of decline in lung function over time. Normal nonsmoking adults lose FEV1 at a rate of 30 ml/y, thought to be the consequence of the aging-related loss of elastic recoil of the lung. Persons who develop COPD may start in early adulthood with lower levels of lung function and also have increased rates of decline. Studies of patients with COPD show an average annual decline in FEV1 of 45 to 69 ml/y (Fig. 42-1 A). This leads to the insidious loss of ventilatory reserve capacity that often is asymptomatic and unrecognized by patients and physicians alike. Chronic bronchitis may be dismissed as an innocent “smoker’s cough” because patients fail to understand that it is abnormal to produce daily sputum. As ventilatory reserve decreases, people with mild COPD tend to limit strenuous activities, so breathlessness with activities of daily living is not ordinarily an early symptom of the disease. When the ventilatory reserve decreases to the extent that mild exertion such as climbing stairs, bed making, or carrying groceries is

Figure 42-1 A. The natural history of COPD is presented for three hypothetical individuals. Pulmonary function is plotted as the percent of predicted lung function for a young adult who has attained maximal lung growth. Those who do not smoke, or are not susceptible to cigarette smoke typically lose about 25 percent of their young adult lung function throughout life. Individuals are susceptible to the adverse effects of smoking because of increased decline of lung function, or low lung function in young adult life. Although the abnormality of lung function is detectable for many years, symptoms do not develop until there is loss of approximately 50 percent of lung function (upper dashed line), which occurs in middle age or later. If the disease progresses, it may lead to substantial disability within a decade of the onset of symptoms (lower dashed line). B . The natural history of COPD is displayed for a hypothetical continuing smoker, and an individual who quit smoking at age 45. The axes are identical to those in (A). If an individual ceases smoking in the asymptomatic phase of COPD, the rate of decline of lung function reverts toward normal. In this example, the detection of abnormal lung function and cessation of smoking has a substantial effect of delaying the onset of respiratory symptoms. This plot is modified from the work of Fletcher and Peto and is commonly referred to as Fletcher curves. (From Fletcher C, Peto R. The natural history of chronic airflow obstruction. Br Med J 1:1645–1648, 1977.)

limited, patients tend to seek medical advice. In some cases, the first clinical presentation of disease is an acute episode of bronchospasm, dyspnea, or even respiratory failure in association with a respiratory infection or exposure to respiratory irritants. Thus, the onset of COPD may appear precipitous

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even though it is the cumulative result of decades of progression. People who discontinue smoking with mild to moderate degrees of airflow obstruction cease the rapid decline in FEV1 , and have better survival (Fig. 42-1B). The improvement in survival depends largely upon the stage of disease. Persons who quit smoking with earlier disease have better outcomes compared with those who continue to smoke or those who quit smoking later in the disease. Once the disease is advanced, the inflammatory response persists and the rate of decline of lung function tends to progress. Because there are many years of asymptomatic decline in lung function, it is possible to diagnose COPD with forced expiratory spirometry before the disease is apparent and implement aggressive smoking intervention programs. There is no consensus whether it is necessary to screen for COPD among all cigarette smokers. Opponents of using spirometry for case-finding argue that the finding of a normal test would not alter physician behavior because all smokers should be encouraged to quit. It has also been argued that a normal spirometry test might provide a false sense of complacency for active smokers. Moreover, current evidence does not support the idea that drug treatment of asymptomatic individuals provides any benefit. Those who support the use of spirometry for COPD case-finding argue that early detection and aggressive smoking intervention have been proved to halt disease progression, and the finding of abnormal spirometry may encourage patients and health care professionals to be more aggressive with smoking cessation. With the progression of COPD comes progressive exercise limitation. This is due to 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 end-expiratory volume of functional residual capacity (FRC). The hyperinflation that occurs causes increased work of breathing and exacerbates dyspnea. An indicator of dynamic hyperinflation is the inspiratory capacity (IC), which progressively falls 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. As COPD progresses, ventilation-perfusion inhomogeneity causes an increase in the alveolar-arterial oxygen difference. Eventually, alveolar hypoxemia leads to pulmonary hypertension, which becomes manifest as cor pulmonale. The alveolar hypoxemia may be compounded by alveolar hypoventilation—manifest by arterial hypercapnia. Physical findings indicative of cor pulmonale are venous engorgement, edema, and physical findings of pulmonary hypertension and right ventricular failure. Chest imaging shows central enlargement of the pulmonary arteries. Once cor pulmonale is clinically apparent, survival is markedly reduced in proportion to the elevation of pulmonary artery pressure. Chronic respiratory failure is defined by chronic hypoxemia (sea-level

Chronic Obstructive Pulmonary Disease: Clinical Course and Management

resting PaO2 ≤ 60 mmHg or 8 kPa) with or without attendant hypercapnia (PaCO2 > 45 mmHg). Patients with advanced COPD may restrict their activities to a bed-and-chair lifestyle because of severe exercise incapacitation. This limitation can lead to social isolation, depression, and skeletal muscle deconditioning which, in turn, further restrict activity and impair quality of life. Protein and calorie malnutrition occurs as the consequence of impaired nutritional intake caused by dyspnea. Malnutrition is augmented by increased metabolic demands caused by increased basal oxygen consumption, inefficient skeletal muscle oxygen utilization, and cachexia-producing cytokines such as tumor necrosis factor alpha.

DIAGNOSIS OF COPD Physical examination and chest imaging are insensitive methods for diagnosis of COPD. Physical findings of hyperinflated lungs such as low-lying diaphragms, decreased breath sounds, and hyperresonant chest percussion are highly specific for COPD, but usually only in advanced disease. One study has suggested that a distance between the thyroid cartilage and the sternal notch less than 4 cm in a smoker older than age 45 is highly indicative of the presence of COPD. Clubbing of the fingers is not common in COPD and, if present, suggests another diagnosis such as bronchiectasis, asbestosis, or lung cancer. High-resolution computed tomography (HRCT) of the lung, analyzed by quantitative measures of lung density, is a promising technique for early detection of emphysema, but the role of HRCT in early detection and monitoring of COPD is not established at present. α1 -Antitrypsin deficiency is an uncommon, but not rare, condition associated with premature emphysema. Testing for α1 -antitrypsin deficiency is indicated in those most likely to have the disorder (see Chapter 41 and Table 42-1). Although controversial, some experts advocate that all patients with COPD should be tested for α1 -antitrypsin deficiency. HIV/AIDS is also associated with premature emphysema, and screening for HIV should be performed for persons with emphysema and HIV risk factors such as intravenous drug use or high-risk sexual activity. The diagnosis of COPD, classification of its severity, and progression of the disease can be monitored with spirometry, a simple, noninvasive, and inexpensive test. The FEV1 /FVC ratio, reflecting the rate of emptying of the lung, is used to define the presence of an obstructive ventilatory defect, commonly defined as a ratio less than 0.70. Once airflow obstruction is established, the severity of the disease is classified by the reduction of FEV1 compared with a healthy reference population. Table 42-2 shows the widely used GOLD classification of COPD severity based on the FEV1 . Lung volume measurements, by plethysmography, helium dilution, nitrogen washout, or single-breath methods typically show hyperinflation (elevated TLC) and air trapping (elevated residual

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Table 42-1 Conditions suggesting alpha-1 anti-trypsin deficiency Early-onset emphysema (age under 45 years) Emphysema in a nonsmoker Emphysema predominantly in lung bases (pan-acinar) Necrotizing panniculitis (Weber-Christian disease) c-ANCA positive vasculitis (e.g., Wegener’s granulomatosis) Family history of early onset emphysema or non-smoking–related emphysema Bronchiectasis without other etiology

volume [RV]), and thus are useful to exclude restrictive lung diseases. The carbon monoxide diffusing capacity (DCO ) is an indicator of emphysema and is roughly inversely correlated with the anatomic extent of emphysema in patients who have an FEV1 greater than 1.0 L.

and physicians are poor prognosticators of survival in COPD. In part, this is because the disease is one of widely varying rates of progression, and, in part because death is often due to susceptibility to intercurrent illness and other smokingrelated illness such as lung cancer rather than progressive respiratory failure. Several factors have been identified that predict poor survival in COPD. These include low FEV1 , active smoking status, hypoxemia, poor nutrition, the presence of cor pulmonale, resting tachycardia, low exercise capacity, severe dyspnea, poor health-related quality of life, anemia, frequent exacerbations, co-morbid illnesses, and low carbon monoxide diffusing capacity. Patients with an FEV1 less than 35 percent predicted have about 10 percent mortality per year. If a patient reports that they are unable to walk 100 meters without stopping because of breathlessness, the 5-year survival is only 30 percent. A multidimensional prognostic index that takes into account several indicators of COPD prognosis is the BODE index (body mass index [BMI], obstructive ventilatory defect severity, dyspnea severity, and exercise capacity). See Table 42-3 for calculation of the BODE prognostic score. The components are derived from measures of the body mass index (weight in kg/height m2 ), FEV1 percent predicted, and the modified Medical Research Council dyspnea score (Table 42-4). A BODE score greater than 7 is associated with a 30 percent 2-year mortality; whereas a score of 5 to 6 is associated with 15 percent 2-year mortality. If the BODE score is less than 5, the 2-year mortality is less than 10 percent.

PROGNOSIS OF COPD After COPD becomes clinically apparent, the median survival is about 10 years. The prognosis may vary widely, however,

Table 42-2

TREATMENT OF STABLE COPD 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.

Classification of COPD Severity Stage

Characteristics

I Mild COPD∗

FEV1 80% predicted

II Moderate COPD∗

FEV1 50%–79% predicted

III Severe COPD∗

FEV1 30% to 49% predicted

IV Very Severe COPD∗

FEV1 <30% predicted or <50% predicted with room air PaO2 <60 mm Hg (8.0 kPa)

∗ Postbronchodilator FEV /FVC 0.70. 1 Adapted from the 2006 GOLD COPD guidelines, www.goldcopd.com; Celli BR, MacNee W: ATS/ERS Task Force. Standards for the diagnosis and treatment of patients with COPD: A summary of the ATS/ERS position paper. Eur Respir J 23:934; 2004.

Education The diagnosis of COPD can be a life-changing event for people, so understanding the nature and prognosis of the disease is an important and underemphasized aspect of care. There is a wide divergence of understanding of the implications of having COPD, and many patients do not understand that COPD comprises both the diagnoses of emphysema and chronic bronchitis. Table 42-5 lists topics that should be discussed with COPD patients. It is neither possible nor effective to cover all of these topics in a single session, so several sessions with repetition and expansion of the educational messages is necessary. Supplemental written materials or referral to a health educator is also necessary for many patients. Local and national volunteer health organizations provide useful educational materials and group educational sessions. Special counseling is needed for patients with α1 -antitrypsin

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Chronic Obstructive Pulmonary Disease: Clinical Course and Management

Table 42-3 Calculation of the BODE Index∗ Points on the BODE Index Variable

FEV1 (% predicted)

≥65

50–64

36–49

≤35

Distance walked in 6 min (meters)

≥350

250–349

150–249

≤149

MMRC dyspnea scale

0–1

Body-mass index (kg/M2 )

> 21

≥21

∗ The BODE index is calculated as the sum of points from each row. Adapted from: Celli BR, Cote CG, Marin JM, et al: The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med 350:1005–1012; 2004.

deficiency and their family members to determine whether genetic testing is necessary or desired. In patients with advanced disease, discussions about end-of-life planning and advance directives regarding life support are often welcomed by patients and initiate discussions between the patient and family. Patients should be encouraged to discuss information that they obtain from newspapers or the Internet, as some may be instructive, but others are incorrect. Physicians should

Table 42-5 Patient Education Topics for Office Management of COPD Risk factors for COPD Smoking cessation advice and instruction Reduction of noxious environmental exposures

Table 42-4

Immunization for influenza and pneumococcus

Modified Medical Research Council Dyspnea Scale (MMRC Scale)

Nature and prognosis of COPD

Grade

Description

Indications, dose, benefits, and adverse effects of medications

Not troubled with breathlessness except with strenuous exercise

Proper inhaler and nebulizer use

Troubled by shortness of breath when hurrying on the level or walking up a slight hill

Strategies to improve adherence with prescribed treatment

Walks slower than people of the same age on the level because of breathlessness or has to stop for breath when walking at own pace on the level

Stops for breath after walking about 100 yards or after a few minutes on the level

Too breathless to leave the house or breathless when dressing or undressing

Pacing, arm support, and other strategies to minimize dyspnea Importance of regular exercise and social interaction Options for pulmonary rehabilitation programs Recognition and early treatment of exacerbations Indications for and proper use of supplemental oxygen

Adapted from: Mahler DA, Wells CK: Evaluation of clinical methods for rating dyspnea. Chest 93:580–586; 1988.

Options for surgical management if indicated Advanced directives for end-of-life care

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be prepared to deal with patients’ sense of guilt, as many view COPD as a self-induced disease. Caregivers need to address the reality that COPD is often stigmatized by patients, their families, and other health care providers. The physician should let the patient understand that nicotine dependence is a strong physical addiction and difficulty quitting smoking is not a measure of moral weakness or lack of will. The general message provided should be realistic, but positive. Current treatments for COPD can usually improve quality of life, restore activity levels, maintain social interactions, and reduce the frequency of complications.

Prevention of COPD Progression and Complications Presently, there are no proven treatments that prevent the progression of COPD in patients who continue to smoke cigarettes. Smoking cessation, however, does prevent the excessive decline in lung function and should be a primary goal for physicians caring for COPD patients. Patients with mild or moderate COPD may not know that they have underlying lung disease that can be halted by smoking cessation, or may adopt a fatalistic attitude that it is too late for help. Even severely impaired patients who are dyspneic at rest or use continuous oxygen may continue to smoke cigarettes or relapse after quitting. A smoking history should be obtained at each patient encounter because many patients fail to volunteer the extent of their smoking or report a smoking relapse following cessation. In patients who do smoke, achieving cessation should be a primary and persistent goal of treatment. Approaches to smoking cessation are given in detail in Chapter 43. For patients who do smoke, a direct, unambiguous, and personalized smoking cessation message should be given by the physician. The message should emphasize the harm of continued smoking, the benefits of cessation in terms of activities that are meaningful for the individual, and the understanding that smoking cessation is a realistic and achievable goal. Assistance with pharmacologic adjuncts such as nicotine replacement therapy, varenicline, or bupropion and referral to smoking cessation groups should be offered. Follow-up of smoking status and repeated smoking cessation messages should be performed at each encounter. Exposure to respiratory irritants should be avoided in the workplace as well as the home. Although heavy occupational dust exposure rarely is the primary cause of COPD, exposure to dusty occupational jobs in smokers can increase the lung function deterioration from smoking and increase symptoms of cough and sputum. Respiratory protective equipment should be worn by COPD patients exposed to heavy dust concentrations. There is no level of FEV1 that absolutely prohibits the use of respiratory protective equipment, but patients with COPD often experience untoward breathlessness with these masks because of the increased dead space and increased inspiratory resistance. Thus, many COPD patients need to change their work environment if they cannot tolerate protective devices. If COPD is complicated by allergy

or overlaps with allergic asthma, environmental control measures should be instituted to the extent that these strategies are helpful. Smoking of marijuana and cocaine may cause airway irritation, and although there is no convincing evidence that they contribute to progression of COPD, their use ought to be discouraged. Pneumococcal vaccination is recommended, although the evidence of its particular efficacy in COPD is lacking. Annual influenza immunization can prevent or attenuate this potentially fatal infection. The killed vaccine is preferred, as coldattenuated live influenza vaccines have not been approved for use in older patients and those with underlying lung disease. For individuals who are not immunized, prophylaxis with amantadine or rimantadine during an influenza epidemic can often prevent infection with influenza A, although recent reports have shown increasingly resistant strains of influenza and side-effects may limit usefulness. During influenza epidemics, the use of neuraminidase inhibitors such as zanamivir and oseltamivir can minimize severity of infection if taken within 48 hours of onset of illness and are useful against both influenza A and B, and may limit the spread of infection. Replacement therapy with α1 -antitrypsin should be considered for those individuals with severe deficiency. Observational studies suggest that individuals with moderate degrees of impairment (FEV1 35 to 65 percent predicted) appear to benefit most in terms of preservation of lung function and improved survival. The human plasma-derived preparation of α1 -antitrypsin is administered intravenously in a dose of 60 mg/kg weekly. Although the replacement treatment is derived from pooled human plasma, the risk of viral transmission is low and immunization for hepatitis B is not required prior to initiating therapy. Monitoring of immunoreactive serum levels of α1 -antitrypsin does not accurately reflect the enzymatic activity in the blood or alveolar lining fluid and is not necessary to adjust treatment dose. Alternative dosage schedules, use of recombinant preparations, specific protease inhibitors, or aerosolized preparations may be available in the future.

Exercise and Rehabilitation Regular prudent self-directed exercise is recommended for all individuals with COPD to prevent the muscle deconditioning that often accompanies the disorder. Individuals should be encouraged to perform at least 20 to 30 minutes of constant low-intensity aerobic exercise such as walking at least three times per week. Even the most severely impaired patients with COPD can usually attain an exercise regimen of 30 minutes of walking at 1 mph (i.e., one-half mile in 30 minutes). It is important to instruct patients that they should exercise to a level of dyspnea that is tolerable for the entire exercise period. Patients should understand that dyspnea, by itself, is not injurious to the heart or lungs, but patients should pace themselves to avoid severe dyspnea that disrupts activity, can lead to panic reactions, and is distressing to onlookers. Patients who demonstrate desaturation with exertion may be prescribed supplemental oxygen for exercise. Some may

735 Chapter 42

benefit in terms of exercise capacity and training effect even if they do not have demonstrable oxygen desaturation. Many patients, particularly those with marked hyperinflation, find that they can ambulate better with the use of a rolling walker that supports the arms, improving the mechanical advantage of the accessory muscles in the neck. Formal rehabilitation programs offer a comprehensive approach to exercise training, patient education, nutritional counseling, group support, and psychological support that cannot be efficiently provided in the physician’s office. Rehabilitation programs are established as an effective component of COPD management and should be offered to patients who have substantial limitation in daily activities. A detailed discussion of rehabilitation is provided in Chapter 44.

Nutritional Support In patients with very severe COPD (FEV1 less than 35 percent predicted) about half show protein-calorie malnutrition. Reasons for this include increased resting metabolic demands, inadequate caloric intake due to dyspnea and anorexia, and possibly elaboration of cachexia-associated inflammatory cytokines such as TNF-α, IL-1, and IL-6. Patients with a BMI of less than 90 percent of normal have increased mortality and decreased exercise capacity. Muscle wasting and loss of bone mass may be present even in patients who have normal BMI. Although clinical trials of nutritional supplementation have been disappointing, it is prudent to monitor body weight in COPD patients and encourage caloric supplementation as needed since those patients who do gain weight show improved survival. High-fat diets have the theoretical advantage of offering higher caloric content with lower CO2 production than high carbohydrate diets, but there is no convincing evidence that this strategy is clinically superior to a well-balanced diet. For patients with less advanced disease, a balanced diet with avoidance of overweight or underweight is a rational goal. In particular, patients with mild to moderate disease who quit smoking tend to gain excessive weight which might adversely affects lung function.

Sleep Disorders in COPD Sleep disturbances, including insomnia and daytime hypersomnolence, are common symptoms in patients with COPD, and are often overlooked because of the focus on breathlessness and exercise intolerance. The causes for sleep symptoms are multifactorial and include anxiety/panic disorder, depression, resting hypoxemia, nocturnal bronchospasm, sleep apnea, and nocturnal oxygen desaturation. Patients with COPD often relate insomnia to a fear of suffocation or death during sleep, a situation that may respond to repeated reassurance, cognitive therapy, or small doses of anxiolytics or antidepressants. Patients with resting hypoxemia treated with low-flow nasal oxygen often report improved sleep quality. Nocturnal bronchospasm, more common among those with an asthmatic component to their disease, may respond to longer-acting bronchodilators, or rearrangement of the dos-

Chronic Obstructive Pulmonary Disease: Clinical Course and Management

ing schedule to provide nocturnal coverage. In some cases, treatment for gastroesophageal reflux by elevation of the head of the bed and prescription of acid suppressant drugs can help. Sleep apnea syndrome, probably not more common in COPD patients than the general community, has particularly severe complications in COPD. Patients with COPD and sleep apnea, the so-called “overlap syndrome” are prone to develop pulmonary hypertension and daytime hypercapnia. Accordingly, symptoms of sleep apnea such as snoring, intermittent nocturnal breathing, and daytime hypersomnolence should be sought in patients with COPD. If present, then formal sleep studies and treatment with continuous positive airway pressure (CPAP) are indicated. Nocturnal oxygen desaturation (NOD) is common during rapid eye movement sleep in patients with COPD. The causes are not entirely understood, but contributing factors include hypoventilation, ventilationperfusion mismatch, respiratory muscle dysfunction, and increases in upper airway resistance. NOD is thought to be associated with poorer sleep quality and pulmonary hypertension. It is controversial whether NOD is associated with poorer survival. However, small studies have shown inconclusive results about the utility of treating nocturnal oxygen desaturation. Current guidelines do not recommend that all patients with COPD have nocturnal oxygen monitoring, nor do they recommend treatment with supplemental oxygen or nocturnal ventilation if NOD is found. Many physicians, though, will prescribe these diagnostic studies and treatments for selected symptomatic patients, and most insurance companies will provide reimbursement for such treatment. Patients who have resting room air daytime hypoxemia should be prescribed nocturnal oxygen at the same flow rate as used during the day, and it is usually not necessary to monitor nocturnal oxygen saturation in such patients.

Air Travel Patients with COPD should not avoid air travel, but must be aware of the medical and regulatory issues that are involved. Modern airplanes are pressurized to an equivalent altitude of approximately 5000 to 8000 feet, but may, on occasion, pressurize to an equivalent altitude of 10,000 feet without providing emergency oxygen. Many patients with COPD who do not use sea-level oxygen can tolerate short flights without supplemental oxygen. As flight distance becomes longer, the flying altitude becomes higher and the cabin pressure becomes lower, so transcontinental or transoceanic flights should prompt medical advice. The general rule of thumb used by the commercial airline industry is that patients who can ambulate 50 meters without stopping are safe for air travel. A more conservative approach is to estimate the PaO2 during air travel by performing a high altitude simulation test. High altitude simulation can be performed by administering 15 percent oxygen via a face mask or by using 100 percent nitrogen in a 40 percent Venturi mask. If the oxygen saturation falls below 86 percent or 50 mmHg, then supplemental oxygen is recommended. Formulas are available to estimate

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Obstructive Lung Diseases

Figure 42-2 Estimated PaO2 at altitude based on resting sea level arterial oxygen tension. Isopleths are drawn for the range of cabin pressures that occur on commercial aircraft. The dashed line is drawn at 54 mmHg, which indicates a threshold for prescribing supplemental oxygen for air travel. The nomogram is derived from the data of Gong et al. (Gong H Jr, Tashkin DP, Lee EY, et al: Hypoxia-altitude simulation test. Evaluation of patients with chronic airway obstruction. Am Rev Respir Dis 130:980–986, 1984.)

altitude hypoxemia from sea-level room air blood gases. Figure 42-2 provides a nomogram for estimating altitude PaO2 from sea-level room-air arterial oxygen tensions. If estimated altitude PaO2 is used, it is prudent to prescribe oxygen for estimated altitude PaO2 of 54 mmHg or lower. Patients who use oxygen supplementation at sea level should increase their resting oxygen prescription by a flow rate of 2 L/min. For patients with COPD who travel by air frequently, low-cost finger pulse-oximeters that are marketed to airplane pilots can be used to adjust their oxygen flow. Airlines have inconsistent policies with respect to providing supplemental oxygen for travelers, so it is important to check with the airline service desk prior to booking travel. In the past, it was required that airlines provide compressed oxygen tanks for travelers. Recently the United States Federal Aviation Administration has promulgated regulations that permit some approved portable oxygen concentrators to be carried on board by passengers as personal luggage with a physician’s statement of need.

Long-Term Oxygen Therapy In addition to smoking intervention in early COPD, treatment of resting daytime hypoxemia with oxygen is a treatment that prolongs survival. The two strongest indications for prescription of long-term oxygen therapy are: (1) resting room-air PaO2 ≤ 55 mmHg or oxygen saturation ≤ 88 percent while a person is in usual state of health; and (2) resting room-air PaO2 56 to 60 mmHg or oxygen saturation 88 to 89 percent with supporting evidence of chronic hypoxemia such as polycythemia, pulmonary hypertension, cor pulmonale, or psychological impairment. Oxygen is usually administered by nasal cannula, with the flow rate adjusted to maintain a resting saturation greater than 90 percent. The usual starting flow rate is 2 L/min, although some patients with severe hypercap-

nia require lower flows. A few patients, particularly those with concomitant interstitial pulmonary disease or cardiac disorders, require higher flow rates. The most convenient and cost-effective oxygen source at home is usually a concentrator device that uses a molecular sieve to extract oxygen from room air. For ambulation, small compressed air cylinders or liquid oxygen reservoirs that can be carried provide patients with the ability to leave their homes. Conserving devices such as reservoirs or demand valves permit portable ambulatory oxygen tanks to last up to 10 hours at flow rates of 2 L/min. Compressed oxygen cylinders or liquid oxygen reservoirs should be provided to patients who use electrically driven oxygen concentrators for emergency use in the event of a power failure. Ideally, oxygen should be used constantly 24 hours per day. At least 18 hours of oxygen per day, however, has been show to have substantial benefit over 12 hours per day. If continuous oxygen supplementation is prescribed following an exacerbation of COPD, it is recommended to check arterial oxygen levels in 6 months, as many patients will no longer require oxygen. Nasal drying or congestion is a common symptom for those who use continuous oxygen. This may be alleviated to some extent by alternating the nasal cannula from one nostril to the other or placing it in the mouth for periods. Copious watery nasal secretions often respond well to ipratropium nasal spray, and dry, crusted nasal mucosa is treated with hourly instillations of saline nasal spray. Other nasal disorders that are aggravated by oxygen, such as allergic rhinitis or vasomotor rhinitis, should be considered and treated with appropriate therapy such as intranasal corticosteroids or cromolyn. Smoking or exposure to any open flame, of course, is prohibited by the danger of fire and airway burns in those who use oxygen. This is a surprisingly common cause of burns in the United States, with estimates that up to 50 percent of patients on oxygen continue to smoke to some extent. Accordingly, it is safer to counsel patients to discontinue oxygen while smoking or cooking over an open flame if they insist on doing these imprudent activities. Patients at particular risk are those who live alone, have cognitive impairment, and do not have functioning smoke detectors. Transtracheal oxygen administered via a percutaneous catheter is useful for patients who need high oxygen concentrations or in whom use of a nasal cannula is not tolerated because of local nasal adverse effects or cosmetic preference. Transtracheal oxygen has the advantage of decreasing effective dead space ventilation and permitting lower flow rates to provide high oxygen concentrations. However, the catheter and insertion site require meticulous care to prevent complications such as local infection or mucus concretions. On occasion, the catheter insertion site may lead to a pneumothorax or pneumomediastinum. High flow rates with humidified oxygen via transtracheal catheters may augment ventilation and reduce hyperinflation. Ambulatory oxygen, although not shown to improve survival, may be provided for patients who desaturate with exertion. Some, but not all, patients show improved exercise

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Chronic Obstructive Pulmonary Disease: Clinical Course and Management

capacity and reduced breathlessness. There is a growing body of evidence that suggests that oxygen supplementation may also benefit COPD patients who do not have exercise desaturation by reduction in minute ventilation and diminution of dynamic hyperinflation. Because it permits greater exercise intensity, oxygen supplementation is also a useful adjunct for aerobic conditioning during pulmonary rehabilitation.

Treatment of Anemia Anemia, usually mild, is present in about 10 percent of patients with severe COPD, similar to other chronic inflammatory diseases, and is a poor prognostic indicator. Although there is no evidence that COPD, per se, causes anemia, patients with COPD have a lower erythropoietic response to hypoxia than healthy people at altitude. For patients who are anemic and breathless, restoration of normal hemoglobin content reduces resting minute ventilation and work of breathing, which presumably improves exercise capacity. Thus, pending definitive clinical trials, it is prudent to test for anemia and treat it appropriately in patients who are markedly symptomatic.

Drug Therapy Over the past several decades, the evidence base for use of drug therapy in COPD has expanded, and provides an objective and generally optimistic picture that such treatment is effective. Bronchodilators and anti-inflammatory agents are used in COPD to reverse bronchoconstriction and improve airflow limitation. The goals of drug therapy are not only to improve lung function, but also to improve quality of life, exercise capacity, and prevent exacerbations. No drug treatment is known to diminish the decline in pulmonary function with continued smoking, or substantially reduce mortality, but large and long-term clinical trials needed to definitively determine this have not yet been done for newer agents. Recent evidence however suggests that a combination of inhaled steroids and long-acting bronchodilators may improve survival as well as reduce exacerbations. Proposed future drug treatments that might alter progression of COPD are under active investigation, including inhibitors of cytokines, proteases, and oxidative stress. There is a poor correlation between the effect of bronchodilating drugs on lung function and symptom relief, so monitoring of treatment requires attention to patient-centered outcomes as well as lung function. Small amounts of bronchodilation can cause considerable improvement in functional capacity through decrease in dynamic exercise hyperinflation; and reduction in days of exacerbation can make considerable improvement in patientsâ&#x20AC;&#x2122; quality of life. The usual 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. One approach to step-up therapy is provided in Figure 42-3. Inhaled bronchodilators are the foundation

Figure 42-3 Step-care approach to treatment of COPD. Treatments are sequentially added to maximize functional status and minimize symptoms. Patients with greater impairment receive more advanced treatments. At each phase of treatment, assessment of lung function, symptoms, and functional status are used to evaluate need for additional treatments. If patients are stable for 6 to 12 months, consideration should be given to trial reductions of treatment.

of treatment for COPD. They are given on a regular basis to maintain bronchodilation and on an as-needed basis for relief of symptoms. Most breathless patients benefit from regular use of a maintenance bronchodilator. Both beta-agonist and anticholinergic classes are available in short duration (4- to 6-hour) and long-duration (12- to 24-hour) forms (Tables 42-6 and 42-7). The choice of bronchodilator class and duration of effect depends upon the preference of the patient and the cost of the preparation. 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. Patients with advanced COPD often use a combination of bronchodilators, including longacting maintenance anticholinergics and beta agonists as well as symptomatic use of shorter-acting bronchodilators. Individuals with frequent exacerbations often benefit from a combination inhaler of corticosteroids and long-acting bronchodilator. Long-acting oral preparations of theophylline are useful adjuncts in cases in which inhaled medication is too expensive or not acceptable for the patient. Chronic use of systemic corticosteroids should be reserved for individuals with very frequent or life-threatening exacerbations who cannot tolerate their discontinuation. Response to treatment is judged by symptomatic improvement, functional status,

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Table 42-6 β-Sympathomimetic Agonists Drug Name

Onset of Inhalation Peak Duration of Action (min) Effect (min) Effect (h) Dosage Form

Metaproterenol 1–5

30–60

2–5

Metered-dose inhaler, 650 µg/puff Nebulized solution, 5%, or premixed 0.4%–0.6% ampules

Terbutaline

1–5

—

2–5

Oral tablets 2.5 or 5.0 mg Injection, 1 mg/ml

Pirbuterol

30–60

4–5

Metered-dose inhaler, 200 µg/puff

Albuterol

5–15

60–90

3–6

Metered-dose inhaler, 90 µg/puff Nebulized solution 0.5% or premixed 0.083% ampules

—

6–12

Oral tablets 4.0 to 8.0 mg, rapid and slow-release forms

10–20

180

Metered-dose inhaler, 25 µg/puff

Levalbuterol Salmeterol

Dry powder inhaler, 50 µg/dose Formoterol

2–10

120

Dry powder inhaler, 12 µg/dose

frequency of exacerbations, and spirometry. If patients are doing well for 6 to 12 months on a stable treatment regimen, then it is reasonable to see if a trial withdrawal of one of the drug components can be tolerated. Inhaled agents are administered by metered dose inhaler (MDI), dry powder inhaler (DPI), 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. Many patients find that it is diffi-

cult to coordinate an MDI, and addition of a spacer device is helpful. There are many forms of DPI, some more intuitive to use than others, so specific instruction and demonstration is required by most patients. Nebulizers are easier for patients to coordinate, but each treatment takes longer to complete, and they require additional effort to maintain cleanliness. Although nebulized medications are more expensive overall, the cost of the medication is often covered by insurance, so many patients prefer nebulizers for financial considerations.

Table 42-7 Anticholinergic Bronchodilators Generic Name

Onset of Action (min)

Inhalation Peak Effect (min)

Duration of Effect (h)

Dosage Form

Ipratropium

6–8

HFA or CFC metered-dose inhaler 17–18 µg/puff Nebulized solution 0.02% (500 µg in 2.5-ml vial)

Tiotropium

120

>24

Dry powder inhaler 18 µg/dose

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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. For example, a physician could inquire, “It is often difficult for patients to remember to take all of their medications. Has this been a problem for you?” or “Are you able to afford all your medication?” or “Do you think that your medicines are working for you?” 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. Proper use of MDIs is difficult for many patients to learn and retain. Repeated review and training of patients in MDI use is an important component of treatment of COPD and asthma. The inhaler should be held about 4 cm from the mouth to minimize deposition of larger droplets in the mouth. The patient should exhale to functional residual capacity and take a slow inhalation to TLC over about 5 seconds. The slow inhalation diminishes impaction of particles in the mouth and larynx. At the initiation of inspiration the patient should actuate the MDI one time. After full inspiration, the patient should hold the breath for about 10 seconds to permit deposition of particles in the distal airspaces. If the patient finds that hoarseness or mouth irritation occurs with inhaler use, this can often be corrected by use of a spacer, slowing the rate of inspiration, and rinsing the mouth after each inhaler use. Although waiting a period of time between inhalations or between different MDIs is sometimes recommended for optimal effect, the benefit is small compared with the inconvenience and risk of worsening adherence. Therefore, it is usually appropriate to permit the patient to take additional inhalations as soon as he or she has rested a few seconds. If the patient has difficulty coordinating the actuation of the MDI with inspiration, a spacer device or holding chamber can be used. This device is placed directly in the mouth and the MDI can be actuated prior to inspiration. In some circumstances, it is necessary for patients to use a breath-actuated MDI or nebulizer to achieve optimal benefit from inhalational medication. Dry powder inhalers usually require less coordination than MDIs, but there are many different devices, some rather complicated to use. Therefore, each device requires individual instruction and review of technique. (For a compendium of patient instructions, see http://www.ginasthma.com/OtherResources.asp. Ipratropium bromide is an inhaled anticholinergic drug that causes 4 to 8 hours of bronchodilation through inhibition of vagal stimulation of the airways. Although it is more expensive than beta agonists, it is often used as first-line ther-

Chronic Obstructive Pulmonary Disease: Clinical Course and Management

apy. The dosage is started at two MDI inhalations three times daily, and can be increased to six inhalations four times daily. Adverse effects are minimal, even with relatively high doses, so the maximum dose is limited by cost and convenience. Local side effects include mouth irritation and cough, which can be diminished by good inhaler technique or use of a spacer. Supraventricular tachyarrhythmias may occur more frequently in patients using ipratropium but are rare. Urinary retention or acute narrow-angle glaucoma are potential but exceedingly rare complications of inhaled ipratropium. Although ipratropium provides sustained benefit in patients with moderate disease, it does not inhibit progression of the disease if smoking is continued. Tiotropium is an anticholinergic bronchodilator that has the benefit of once-daily dosing, and is more effective than usual doses of ipratropium in bronchodilation, quality of life, and reducing exacerbations. Exercise capacity is improved by reduction in dynamic hyperinflation. Tolerance does not develop with prolonged use. First morning spirometry is improved after long-term use of tiotropium, but it is not yet known whether this reflects sustained improvement in lung function, or it is residual bronchodilation due to the very long duration of action. It is inhaled once daily from a capsule inserted into a dry powder inhaler. Tiotropium is most useful in patients with moderately symptomatic disease who find frequent use of bronchodilators inconvenient or those who have nocturnal or early morning symptoms. Because of the slower onset of bronchodilation, some individuals do not recognize the efficacy of this drug, and use additional short-acting agents for symptomatic use. Proper instruction is needed in use of the inhaler, but the dry powder inhaler does not require as much coordination as a metered dose inhaler. Some patients with mild disease prefer to use once-daily tiotropium rather than as-needed short-acting bronchodilators as initial therapy, which is a reasonable treatment approach. Short-acting β-adrenergic agonists are used at dosages comparable to those used in asthma. Selective beta2 agonists should be administered by the inhaled route and oral forms reserved for the occasional person who cannot or refuses to take inhaled drugs. Oral beta agonists, although longeracting, tend to have more side effects such as tremor, tachycardia, and hypokalemia. Albuterol is the most widely prescribed selective beta2 - adrenergic bronchodilator and is available in MDI formulations with either CFC or HFA propellants. The typical dose is two inhalations every 4 to 6 hours as an asneeded or regular agent. Pirbuterol has similar pharmacologic properties, but is supplied in a breath-actuated MDI that is easier for discoordinated patients to use effectively without a spacer. Long-acting inhaled beta agonists such as salmeterol or formoterol are useful because of the long duration of action and documented benefit on quality of life and exercise tolerance. Monotherapy with a long-acting beta agonist is discouraged in treating patients with asthma, but has been used effectively in patients with COPD. Both salmeterol and formoterol are available in dry powder inhaler formulations.

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Formoterol has a quicker onset of action and is sometimes used for intermittent symptom relief, but does not permit as frequent re-dosing as short-acting agents. Increasing doses beyond the recommended dose adds little to the bronchodilator effect, but does increase the risk of adverse effects such as hypokalemia, tremor, and tachycardia. Therefore, it is usually advised that patients started on long-acting beta agonists also be provided with a short-acting bronchodilator for as-needed treatment of symptoms. Combination inhaler therapy with a beta agonist and a short-acting anticholinergic provides better bronchodilation than either agent alone and the simplified treatment regimen may improve adherence. Combinations of inhaled corticosteroids and long-acting bronchodilators provide more bronchodilation than either alone in patients with chronic bronchitis and airflow obstruction. Theophylline is taken as a long-acting oral preparation once or twice daily. Although it is possible to monitor blood levels, because the drug is protein bound there is a poor correlation between efficacy or adverse effects and serum levels. Theophylline is a bronchodilator; it improves arterial oxygenation and exercise tolerance. If typical side effects such as nausea, vomiting, tremor, or tachyarrhythmias occur, the dose should be adjusted irrespective of serum levels. Prescriptions for theophylline for COPD have diminished in recent years because of the availability of long-acting inhaled agents, but it is still an effective second-line drug for patients who show benefit or prefer inexpensive oral medications. Theophylline has other putative pharmacologic actions that might be beneficial for the COPD patient: improvement in diaphragm contractility, prevention of respiratory muscle fatigue, increased ventilatory drive, potentiation of catecholamine function, prevention of microvascular permeability, increased mucociliary clearance, prevention of late-phase antigen responses, inhibition of mast cell histamine release, and suppression of leukocyte activation. Recent evidence has suggested that the anti-inflammatory effect of theophylline is mediated by augmentation of steroid effects through activation of histone deacetylase (HDAC), an effect that is of particular importance in COPD patients who have lower HDAC activity. Newer agents that are more specific inhibitors of phosphodiesterase-4 have been developed but are not yet marketed in the United States, and hold the promise of similar efficacy as theophylline with lower toxicity. Oral corticosteroids are effective for treatment of COPD exacerbations. About 10 to 20 percent of chronic symptomatic patients show substantial short-term improvement in pulmonary function, but it is not possible to identify these patients based on clinical characteristics alone. Because of the well-defined long-term adverse effects of systemic corticosteroids, and the ill-defined long-term benefits, most patients should not be maintained on long-term oral or systemic corticosteroids. Patients with COPD who are on chronic corticosteroids can most often taper the dose at the equivalent of 5 mg of prednisone per week, and exclusively reserve their use for exacerbations. Long-term low doses of oral corticosteroids are occasionally needed by patients who cannot afford

or tolerate inhaled agents, and who suffer frequent exacerbations. Patients on long-term systemic steroids should receive prophylaxis for osteoporosis with calcium and vitamin D or bisphosphonates, and should be instructed about the need for stress-dose steroids for acute illnesses. Inhaled corticosteroids do not effectively alter the progression of COPD in those who continue to smoke.Inhaled corticosteroids are most useful in patients who have an overlap between asthma and COPD and those with more advanced disease who have frequent exacerbations. Inhaled corticosteroids can reduce the frequency of exacerbations, improve airways reactivity, and slow the decline in quality of life. In patients with chronic bronchitis and obstructive lung disease, inhaled corticosteroids improve pulmonary function, and the results are additive to those achieved with long-acting bronchodilators. The efficacy of inhaled corticosteroids cannot be predicted based on the response to oral corticosteroids, so it is not necessary to conduct an oral steroid trial prior to initiating this treatment. Combined corticosteroid and long-acting bronchodilator inhalers are available in the United States and throughout the rest of the world and can simplify the treatment regimen. Inhaled corticosteroids, although poorly absorbed, probably do contribute to steroid side effects such as cataracts, capillary fragility, and osteoporosis in susceptible individuals. In most cases, the risk is low compared to the benefit of treatment, but it is prudent to prescribe the lowest effective dose. In patients who are at risk for osteoporosis (i.e., older age, cigarette smoking, low exercise) as most patients with COPD are, it is prudent to recommend prophylactic treatment such as calcium supplements and vitamin D. In those with established osteoporosis, bisphosphonates are advised. Monitoring for osteoporosis with DEXA bone scans is guided by the overall clinical situation and is not required for all patients using inhaled corticosteroids. Mucolytic agents to control mucus hypersecretion with the use of expectorants and physical means such as highfrequency chest wall oscillation is not of proven benefit in improving lung function, although symptoms are sometimes improved. N-acetyl cysteine a mucolytic with antioxidant properties does not prevent exacerbations, nor does it alter the decline in FEV1 .

TREATMENT OF COMPLICATIONS Patients with advanced COPD are prone to develop secondary complications of the disease. The goal of treatment is to restore functional status as quickly and as much as possible and to alleviate distress and discomfort.

Treatment of COPD 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

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dyspnea, cough, or sputum production that exceeds day-today variability and persists for more than a day or two. 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 past history of frequent exacerbations, and these are more common in patients with chronic cough and sputum production. Only half of COPD exacerbations come to the attention of treating physicians, and many of these eventually resolve without specific treatment. Precipitating events include respiratory and nonrespiratory infections, exposure to respiratory irritants and air pollution, or co-morbid conditions such as heart failure, pulmonary embolism, myocardial ischemia, or pneumothorax. The management of these exacerbations depends upon the severity. Indications for hospital evaluation or hospitalization are listed in Table 42-8. Arterial blood gas studies and chest radiographs are useful for evaluating etiology and severity of acutely ill patients. Spirometry during the acute exacerbation is usually not helpful in predicting the severity or duration of the exacerbation. In selected patients with frequent or life-threatening exacerbations, monitoring of FEV1 with inexpensive home spirometers may facilitate early recognition of exacerbations and communication with health care providers. For patients treated at home, increasing the frequency and intensity of inhaled short-acting bronchodilators for several days is effective in mild exacerbations. A handheld inhaler and spacer are usually effective, but a nebulizer may be needed for those who cannot coordinate well or who have 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. The choice of antibiotic is determined by severity of the underlying disease, resistance patterns of likely pathogens, and likelihood of treatment failure (Table 42-9). 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 are 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. Evaluation for the cause of the exacerbation does not have to be extensive if it responds to initial treatment and conforms to the patientâ&#x20AC;&#x2122;s usual exacerbation pattern. Sputum culture for resistant bacterial strains, a chest radiograph for exclusion of pneumonia and pneumothorax, and an electrocardiogram for exclusion of myocardial ischemia and arrhythmia are useful tests in all hospitalized patients. Echocardiography for assessment of ventricular function, and Doppler venous flow studies, radionuclide, or computed tomographic lung imag-

Chronic Obstructive Pulmonary Disease: Clinical Course and Management

Table 42-8 COPD Indications for Hospitalization Indications for Hospital Assessment or Admission for COPD Exacerbation Sudden onset of new or severe symptoms (e.g., dyspnea) Inability to sleep or eat because of dyspnea Severe or very severe underlying COPD Onset of new physical findings (e.g., edema, cyanosis, change in mental status) Failure to respond to initial medical treatment Associated comorbidities (e.g., cardiac, renal, hepatic failure, or diabetes) Diagnostic uncertainty (e.g., suspected pneumonia or pulmonary embolism) Unusual presenting symptoms Older age or frailty Inadequate home or social support History of poor adherence with treatment Indications for ICU Admission for COPD Exacerbation Severe dyspnea unresponsive to initial treatment Change in mental status (e.g., confusion, lethargy, coma) Persistent or worsening hypoxemia, hypercapnia, or respiratory acidosis Need for sedation or narcotic pain control Table modified from 2004 GOLD COPD guidelines (www.goldcopd.com) and 2004 ATS/ERS Standards for treatment of COPD.

ing for evaluation of pulmonary thromboembolism need to be performed only in selected cases. Selection of antibiotics for hospitalized patients should be based on local bacterial antibiotic sensitivities, and guided by culture results. Usually a 2-week course of steroids is sufficient for hospitalized patients. Treatment in an intensive care setting should be undertaken for patients with severe life-threatening exacerbations or those who require more constant attention (Table 42-8). For patients with respiratory failure, noninvasive mask ventilation has proved to be an effective strategy to avert

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Table 42-9 Risk Stratification for COPD Exacerbation and Suggested Antibiotic Treatment First-Choice Alternatives for Treatment Failure

Basic Clinical State

Symptoms and Risk Factors

Acute tracheobronchitis

Cough and sputum without other pulmonary disease

Usually viral

If symptoms persist for >10–14 days, then macrolide or tetracycline

Chronic bronchitis without risk factors (simple)

Increased cough and sputum, sputum purulence and increased dyspnea

Haemophilus influenzae, Haemophilus spp., Moraxella catarrhalis, Streptococcus pneumoniae

Second-generation macrolide, ketolide, fluoroquinolone, secondor third-generation cephalosporin, β-lactam + β-lactamase inhibitor, doxycycline, trimethoprim/sulfamethoxazole, amoxicillin

Chronic bronchitis with risk factors (complicated)

As in group I plus one of the following: FEV1 <50% predicted, >4 exacerbations/year, cardiac disease, home oxygen use, chronic oral steroid use, or antibiotic use in past 3 months

As in group I plus Klebsiella + other gram-negatives. Increased probability of β-lactam resistance

Fluoroquinolone, β-lactam +β-lactamase inhibitor

III

Chronic suppurative bronchitis

As in group II with constant purulent sputum or bronchiectasis. FEV1 < 35% predicted, or multiple risk factors (e.g., frequent exacerbations and FEV1 <50%)

As in group II plus Pseudomonas aeruginosa and multiresistant Enterobacteriaceae

Tailor treatment based on pathogen and sensitivities. For Pseudomonas spp., ciprofloxacin is preferred. Hospitalized patients may need intravenous antibiotics.

Group

Probable Pathogens

Adapted from: Balter MS, La Forge J, Low DE, et al: Canadian guidelines for the management of acute exacerbations of chronic bronchitis. Can Respir J 10:3B–32B; 2003.

endotracheal intubation, shorten duration of illness, and improve outcomes. Institution of mask ventilation requires specialized skills of trained respiratory therapists. Attention needs to be paid to selecting and fitting a comfortable wellsealed mask, and providing a ventilator that minimizes the patient’s work of breathing and triggering effort. When noninvasive mask ventilation is not successful in sustaining ventilation, or 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 minute ventilation that does not overventilate the patient and cause alkalemia, which may ultimately impede liberation from the ventilator. The inspiratory flow rates and inspiratory to expiratory time ratios should be adjusted to provide a prolonged duration of expiration to minimize dy-

namic hyperinflation (auto-PEEP), which can lead to dyspnea, discoordination, and barotrauma. Weaning and liberation from mechanical ventilation can be hindered by anxiety, oversedation, mucus secretions, intravascular volume overload, myocardial ischemia, or respiratory muscle deconditioning. Survival after an episode of acute respiratory failure for COPD is about 50 percent at 2 years after discharge, with about half of the patients being re-admitted to the hospital within 6 months.

Pneumothorax COPD is thought to be the most common cause for secondary spontaneous pneumothorax. A pneumothorax can either cause an acute symptomatic exacerbation of COPD

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from rupture of a bleb, or may occur during the course of an exacerbation as a consequence of hyperinflation or mechanical ventilation. Because this is a life-threatening but quickly treatable cause for worsening respiratory failure in COPD, it should always be considered in the differential diagnosis for worsening dyspnea in COPD. The physical examination can be misleading because diminished breath sounds are a component of the underlying disease. Imaging studies are usually diagnostic, but at times it can be difficult to distinguish a pneumothorax from an overdistended bulla. If the patientâ&#x20AC;&#x2122;s clinical situation can tolerate it, imaging with inspiratory and expiratory views, or chest computed tomograms can be helpful. In the intensive care unit, upright and supine views sometimes show mobility of the pleural air. Urgent treatment for the patient in extremis is performed by aspirating the pleural space at the second intercostal space anteriorly in the mid-clavicular line. Definitive emergency treatment is placement of a thoracostomy tube, which should be done with care to avoid laceration of a bulla and creation of a broncho-pleural fistula. In patients with advanced COPD, recurrence of a pneumothorax can be life threatening, so definitive pleural sclerosis with surgical or medical thoracoscopy should be strongly considered. Whether one adopts a surgical or medical approach to pleural sclerosis depends upon the clinical situation and preference of the treating physicians.

Cor Pulmonale Pulmonary hypertension and consequent right ventricular failure, cor pulmonale, are usually the consequence of chronic alveolar hypoxia, with secondary contributions from destruction of the alveolar capillary bed, lung hyperinflation, and increased blood viscosity. Diagnosis of pulmonary hypertension and right ventricular failure can be difficult, as physical findings of venous engorgement, and right ventricular hypertrophy and dilatation are late signs. Peripheral edema is poorly correlated with resting right atrial pressure and may reflect fluid retention from activation of the renin-angiotensin-aldosterone system. Functional imaging studies including echocardiography or radionuclide ventriculography are more probative for evaluation of right ventricular function. Doppler echocardiographic measures of pulmonary artery systolic pressure are often inaccurate and may overdiagnose pulmonary hypertension, but a normal value is reassuring that pulmonary hypertension is not present. Once cor pulmonale is present, survival is diminished. If the pulmonary artery pressure exceeds 45 mmHg, the average 2-year survival is less than 2 years. The primary treatment of cor pulmonale consists of continuous oxygen to overcome hypoxemia and diuretics to control peripheral edema. Digitalis is useful for rate control of atrial fibrillation. Calcium channel blockers and other vasodilators can dilate the pulmonary circulation, but they worsen hypoxemia and their benefit is not established. Phlebotomy increases exercise capacity when the hematocrit exceeds 55 percent, but persistent erythrocytosis suggests in-

Chronic Obstructive Pulmonary Disease: Clinical Course and Management

adequate oxygen supplementation or another cause. Anticoagulation, which is considered beneficial in severe pulmonary vascular hypertension of other causes, is of uncertain benefit in patients with pulmonary hypertension caused by COPD.

Supraventricular Arrhythmias Supraventricular tachyarrhythmias are common in patients with COPD, as a consequence of right atrial enlargement, increased endogenous adrenergic tone, hypoxemia, and drug treatmentâ&#x20AC;&#x201D;specifically theophylline and anticholinergic bronchodilators. Treatment is similar to that in nonpulmonary patients; however, the presence of COPD should not prevent evaluation for treatable causes of arrhythmias such as pulmonary embolism, hyperthyroidism, or valvular heart disease, which may be difficult to diagnose in COPD patients.

Hypercapnia Chronic hypercapnia secondary to alveolar hypoventilation can be considered an adaptive response to obstructive lung disease by decreasing the work of breathing, preventing respiratory muscle fatigue, and allowing a diminished sensation of dyspnea. The adverse effect of chronic hypercapnia is the development of alveolar hypoxia and consequent pulmonary hypertension. Accordingly, the approach to chronic hypercapnia is the use of supplemental oxygen in controlled concentrations. In patients who are very sensitive to oxygen, it is preferable to provide oxygen in controlled concentrations with Venturi masks rather than nasal cannulae. Nocturnal ventilation has been effective in reducing daytime hypercapnia in patients with neuromuscular disease and kyphoscoliosis. Short-term trials have shown divergent effects of nocturnal ventilation in patients with COPD. A 2year controlled long-term trial of nocturnal ventilation in hypercapnic patients with COPD has shown modest improvement in symptoms and quality of life, and a trend toward reduced hospitalization, but only small improvements in daytime hypercapnia. Thus, based on our current state of knowledge, long-term nocturnal ventilation ought to be reserved for selected symptomatic patients with frequent hospitalizations who can tolerate the treatment.

ADVANCED TREATMENTS For patients who have far-advanced disease evidenced either by severe breathlessness or short life expectancy, more aggressive treatments should be considered. Undertaking these treatments requires thoughtful consideration by patients and their families, and frank discussion of the risks and benefits by the medical caregivers.

Lung Volume Reduction Surgery Lung volume reduction surgery (LVRS) is a surgical procedure that involves stapled resection of 20 to 30 percent of

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the lung bilaterally, usually from the apices. The procedure is equally safe and effective done by median sternotomy or video-assisted thoracoscopy (VATS). The theory behind this procedure is that the remaining lung expands to fill the thorax, thereby increasing its elastic recoil pressure, which improves expiratory airflow. The reduction of lung volume permits the diaphragm to attain a more normal, domed configuration, which improves its mechanical efficiency. Moreover, the preferential removal of unventilated bullae reduces residual volume, permitting an increase in the vital capacity. While some patients show substantial physiological and symptomatic improvement following LVRS, many do not. An algorithm for selection of patients for LVRS, based on distribution of emphysema and functional measures, is presented in Figure 42-4. Generally, LVRS should not be done on patients with an FEV1 less than 20 percent predicted and either diffusing capacity less than 20 percent predicted or diffuse homogeneous emphysema on HRCT, because these patients have high surgical mortality. The group of patients who fare best with LVRS are those who have emphysema predominantly in the upper lung zones and low exercise capacity despite pulmonary rehabilitation. These patients have improved survival after LVRS and show improved functional status and quality of life. Conversely, patients without upper lobe predominance (i.e., lower lobe emphysema or homogeneous emphysema) and who have adequate exercise capacity after rehabilitation, have worse outcomes after LVRS. In selected cases, resection of a pulmonary nodule may be accompanied by LVRS as an

attempt to improve postoperative functional status. Although LVRS was originally proposed as a temporizing measure while patients were awaiting lung transplantation, most LVRS candidates are not suitable candidates for lung transplantation. However, prior LVRS does not alter the outcome of subsequent lung transplantation. Surgical resection of a single large bulla is rarely indicated for treatment of COPD. Isolated giant bullae are usually the result of an expanding congenital cyst. The generally accepted indication for resection of a single large bulla is that it occupies more than one-third of the hemithorax and causes compression of normal lung. Some believe that a preserved carbon monoxide diffusing capacity is an indicator of those most likely to improve following a bullectomy. Preliminary studies with nonsurgical approaches to lung volume reduction using bronchoscopically implantable one-way valves to cause lobar atelectasis are currently being evaluated for safety and efficacy. This or other nonsurgical methods may ultimately provide an alternative approach for patients who are not otherwise surgical LVRS candidates.

Lung Transplantation In younger patients with advanced disease, lung transplantation should be a treatment consideration. Criteria for lung transplantation referral in patients with COPD are an FEV1 below 25 percent predicted, severe hypercapnia, or severe pulmonary hypertension in patients under the age of 60 years.

Figure 42-4 Decision tree for selection of candidates for lung volume reduction surgery based on distribution of emphysema on high-resolution computed tomogram and functional impairments.

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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 co-morbid conditions such as poor nutritional status, chronic mycobacterial infection, severe osteoporosis, or 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 upon the availability of donor organs and preference of the transplant surgeon. Generally, younger patients and those with accompanying bronchiectasis are considered better candidates for bilateral lung transplantation. COPD is the most common indication for lung transplantation, accounting for nearly 40 percent of all lung transplants and about half of single lung transplants. This is accounted for by the high prevalence of COPD as well as the better survival for COPD than other transplant indications while awaiting donor organs. However, newly promulgated 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 following lung transplant is slightly better than other diagnostic groups in the first few years. Overall, 30-day survival is 93 percent; 3year survival is 61 percent; and 5-year survival is 45 percent. Evidence suggests that COPD transplant recipients do not have better survival than comparable wait-listed candidates, so the rationale for lung transplantation in COPD, in contrast to other diseases, is the demonstrable improvement in functional capacity and quality of life.

Chronic Obstructive Pulmonary Disease: Clinical Course and Management

tilation is judged by noninvasive measures of oxygenation and patient comfort. Narcotics in small doses are administered for relief of dyspnea. Diagnostic studies and invasive testing are performed less frequently than in critical care units. Although the care in long-term ventilator units is complex and expensive, the quality of life experienced by patients in chronic ventilator units is similar to that of patients confined to a bed and chair existence by other chronic maladies. The survival of COPD patients on long-term mechanical ventilation is less than those on such treatment for neuromuscular diseases, in part, because of their older age and co-morbidities.

CONCLUSIONS COPD develops insidiously. However, the disease can be easily detected with simple spirometric testing before symptoms occur, and cessation of smoking can slow or even halt the disease progression and prolong survival. Once the disease is symptomatic, a coordinated, comprehensive, and individualized approach to treatment, both pharmacologic and nonpharmacologic, can increase functional status, prevent complications, and improve the quality of life. Exacerbations of COPD can range from those that are nuisances to those that are life threatening, but treatment can shorten the duration of illness and improve outcomes. In advanced disease, treatments including surgical approaches are directed toward relief of symptoms and prolongation of survival. Thus, although there is certainly need for improvement in our treatment of symptomatic COPD, current treatments are effective and a nihilistic attitude is not warranted.

ACKNOWLEDGMENTS Chronic Ventilator Support Some patients remain on long-term ventilator support following an episode of acute respiratory failure. Most often these patients are treated in a long-term ventilator unit, but some can be managed at home with adequate support. In some cases, the goal of long-term ventilator support is to provide rehabilitation via respiratory care, nutrition, and exercise to eventually be liberated from the ventilator entirely or for substantial portions of the day. In other cases, the goal of care is to provide comfort and support for terminal care without attempts at rehabilitation. Whatever the goal, a coordinated team of physicians, respiratory therapists, physical therapists, nutritionists, social workers, psychologists, and nurses are needed to undertake the care of these patients. The treatment of long-term ventilator patients differs from the treatment of acute respiratory failure in the intensive care unit. Ventilators are less sophisticated in terms of modes of ventilation and monitoring, but more portable. Ventilation is often performed with an uncuffed tracheostomy with an air leak to avoid complications at the cuff site. Sufficiency of ven-

Disclosure of financial conflicts: During the preceding 5 years, Dr. Wise has received fees for consultation or support of research from the following companies: Astra-Zeneca, Boehringer-Ingleheim, Emphasys, Forest, GlaxoSmithKline, Millenium, Otsuka, Pfizer, Sanofi-Aventis, Spiration. Financial conflicts of interest are managed by the Johns Hopkins University School of Medicine.

SUGGESTED READING Agency for Healthcare Research and Quality. A Clinical Practice Guideline for Treating Tobacco Use and Dependence: A US Public Health Service Report. JAMA 283:3244â&#x20AC;&#x201C;3254, 2000. American Thoracic Society/European Respiratory Society Statement: Standards for the Diagnosis and Management of Individuals with Alpha-1 Antitrypsin Deficiency. Am J Respir Crit Care Med 168:818â&#x20AC;&#x201C;900, 2003.

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Anthonisen NR, Connett JE, Kiley JP, et al: Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study. JAMA 272:1497–1505, 1994. Anthonisen NR, Skeans MA, Wise RA, et al: The effects of a smoking cessation intervention on 14.5-year mortality: A randomized clinical trial. Ann Intern Med 142:233–239, 2005. Appleton S, Poole P, Smith B, et al: Long-acting beta2-agonists for chronic obstructive pulmonary disease patients with poorly reversible airflow limitation. Cochrane Database Syst Rev 3:CD001104, 2003. Barr RG, Bourbeau J, Camargo CA, et al: Inhaled tiotropium for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2:CD002876, 2005. Calverley PM, Anderson JA, Celli B, et al: Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 356:775–789, 2007. Celli BR, MacNee W, ATS/ERS Task Force: Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 23: 932–946, 2004. http://www.ersnet.org/ers/viewer COPD/ mainFrame/default.aspx Celli BR, Cote CG, Marin JM, et al: The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med 350:1005–1012, 2004. Crockett AJ, Cranston JM, Moss JR, et al: Domiciliary oxygen for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 4:CD001744, 2000. Ferreira I, Brooks D, Lacasse Y, et al: Nutritional intervention in COPD: A systematic overview. Chest 119:353–363, 2001. Fishman A, Martinez F, Naunheim K, et al: A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med 348:2059– 2073, 2003. Johnson AO: Chronic obstructive pulmonary disease: fitness to fly with COPD. Thorax 58:729–732, 2003. McCrory DC, Brown CD: Anti-cholinergic bronchodilators versus beta2-sympathomimetic agents for acute exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev 4:CD003900, 2002. Medical Research Council Working Party: Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema: Report of the Medical Research Council Working Party. Lancet 1:681, 1981. Naeije R: Pulmonary hypertension and right heart failure in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2:20–22, 2005. Nannini L, Lasserson TJ, Poole P: Combined corticosteroid

and long acting beta-agonist in one inhaler for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 4:CD003794, 2003. Update in: Cochrane Database Syst Rev 3:CD003794, 2004. Niewoehner DE, Erbland ML, Deupree RH, et al: Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. N Engl J Med 340:1941–1947, 1999. Nocturnal oxygen therapy trial group: Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: A clinical trial. Ann Intern Med 93:391, 1980. Pauwels RA, Buist AS, Calverley PM, et al: Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med 163:1256–1276, 2001. 2004. Update at: http://www.goldcopd.com Ram FS, Jones PW, Castro AA, et al: Oral theophylline for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 4:CD003902, 2002. Ram FS, Lightowler JV, Wedzicha JA: Non-invasive positive pressure ventilation for treatment of respiratory failure due to exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev 1:CD004104,2003. Update in: Cochrane Database Syst Rev 1:CD004104, 2004. Ram FS, Sestini P: Regular inhaled short acting beta2 agonists for the management of stable chronic obstructive pulmonary disease: Cochrane systematic review and metaanalysis. Thorax 58:580–584, 2003. Scanlon PD, Connett JE, Waller LA, et al: Smoking cessation and lung function in mild-to-moderate chronic obstructive pulmonary disease. The Lung Health Study. Am J Respir Crit Care Med 161:381–390, 2000. Sin DD, McAlister FA, Man SF, et al: Contemporary management of chronic obstructive pulmonary disease: Scientific review. JAMA 290:2301–2312, 2003. Singh JM, Palda VA, Stanbrook MB, et al: Corticosteroid therapy for patients with acute exacerbations of chronic obstructive pulmonary disease: A systematic review. Arch Intern Med 162:2527–2536, 2002. Sutherland ER, Cherniack RM: Management of chronic obstructive pulmonary disease. N Engl J Med 350:2689–2697, 2004. Weitzenblum E, Chaouat A: Sleep and chronic obstructive pulmonary disease. Sleep Med Rev 8:281–294, 2004. Wise RA, Enright PL, Connett JE, et al: Effect of weight gain on pulmonary function after smoking cessation in the Lung Health Study. Am J Respir Crit Care Med 157:866–872, 1998.

43 Cigarette Smoking and Disease Stephen I. Rennard Lisa M. Hepp

David M. Daughton

V. CHRONIC OBSTRUCTIVE PULMONARY DISEASE

IX. SMOKING CESSATION Background Behavioral Approaches Pharmacologic Treatment Practical Aspects of Intervention Health Benefits of Smoking Cessation Risks of Smoking Cessation

VI. MALIGNANCY

X. HARM REDUCTION

VII. CARDIOVASCULAR DISEASE

XI. SMOKING PREVENTION

VIII. OTHER ADVERSE HEALTH EFFECTS OF SMOKING

XII. CONCLUSION

I. NICOTINE ADDICTION II. SOCIAL AND CULTURAL ASPECTS OF SMOKING III. MASTER SETTLEMENT AGREEMENT IV. SMOKING AS A PUBLIC HEALTH PROBLEM

Native Americans discovered the use of the tobacco plant, Nicotiana tabacum, during antiquity. By the time Columbus arrived in America, tobacco use was widespread throughout the western hemisphere and was well integrated into Native American cultures. Production of tobacco and its trade represented a major economic activity in the pre-Columbian Americas. Early European explorers learned of the tobacco plant from Native Americans, and by the mid-seventeenth century tobacco was widely used in Europe. The most important, but not the only, active psychopharmaceutical drug contained in the leaves of the tobacco plant is nicotine. It is likely that this alkaloid, which represents a major metabolic product of the tobacco plant, evolved as a protection against insect predators, as nicotine is a potent insect neurotoxin. Interestingly, nicotine has been exploited in this regard as a commercial insecticide. Nicotine is a potent euphoriant. On a molar basis, nicotine is more active than such euphoria-inducing drugs as cocaine, amphetamine, or morphine. Nicotine also has a number of other effects on the central nervous system (CNS). For example, nicotine can improve task performance and attention time by measurable degrees in nonhabituated individuals and may have beneficial effects on cognition. Nicotine can also ameliorate anxiety and depression and induce a

sense of well-being while causing a state of arousal. In addition, nicotine can attenuate pain. Unfortunately, nicotine is also highly addictive.

NICOTINE ADDICTION Nicotine exerts its biologic effects on “nicotinic” receptors, a subset of cholinergic receptors whose endogenous ligand is acetylcholine. Nicotinic receptors are homo- or heteropentamers that bind two ligand molecules and form an ion channel. In humans, 17 genes code for distinct component chains, resulting in a very large number of potential pentamers, although only a relative few are believed to have a biologic role. The (alpha4)3 (beta2)2 receptor is believed to be most important in the addicting effects of nicotine, while the (alpha7)5 , for example, is believed to mediate some of the cognitive effects of nicotine. In contrast, the muscarinic receptors, the other major class of cholinergic receptors, are single-chain G-protein–coupled receptors. Support of the addictive potential of nicotine includes the well-described withdrawal syndrome (Table 43-1), evidence that nicotine withdrawal is associated with

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Table 43-1 Nicotine Withdrawal Symptoms (DSM-IV) Dysphoric or depressed mood Insomnia Irritability, frustration or anger Anxiety Difficulty concentrating Restlessness Decreased heart rate Increased appetite or weight gain

drug-seeking behavior, and the general dose escalation observed early in the habitual use of nicotine in most individuals. Current concepts suggest that both the psychoactive effects of nicotine and its addiction potential depend on its pharmacokinetics. As with many other addicting drugs, the CNS effects of nicotine depend on both the absolute level of the drug and the rate of drug level increase at the receptors in the brain. Smoking is a particularly effective means of delivering nicotine to induce psychoactive effects. When the drug is inhaled into the lungs its lipid solubility allows it to be rapidly absorbed across the alveolar surface into the pulmonary capillary blood. This results in a very rapid increase in nicotine levels in arterial circulation. Consequently, at the level of receptors in the brain, nicotine concentration rises very rapidly following inhalation of a cigarette. This type of pharmacodynamics maximizes not only the psychoactive potential of nicotine, but is also important in its addictive potential. Alternative forms for delivering nicotine, which do not achieve such rapid rises in blood levels, are associated with less psychoactive effect and less addictive potential. These pharmacodynamic principles are important in the use of nicotine replacement as an aid to smoking cessation, as they underlie the basis for nicotine vaccines and provide part of the rationale for partial nicotine agonist therapy (see below). Nicotine addiction is primarily a pediatric problem. That is, most individuals who become addicted to nicotine become addicted prior to adulthood. In the United States, the peak incidence for developing a regular nicotine habit is in adolescence. Individuals who do not acquire a nicotine habit prior to age 20 are exceedingly unlikely to do so as adults. The demographics of smoking initiation were well known to the tobacco industry. Marketing campaigns designed to promote the image of specific brands of cigarettes were carefully designed and were exceedingly effective in leading to logo recognition among children as young as kindergartners and

contributed to brand selection among American adolescents. The susceptibility of children to these campaigns was a major driver in leading to the current ban on tobacco advertising in media likely to be seen by children. Most children who begin to smoke do so on an occasional basis. Within a few years, however, a regular habit may develop. Most often this habit is characterized by smoking only a few cigarettes daily. The number of cigarettes smoked, however, generally increases for the first 8 to 10 years. Important variations on this pattern exist, suggesting biologic differences among smokers. Some smokers achieve a “mature addiction” very rapidly. In contrast, as many as 15 percent of smokers, termed “chippers,” may continue to smoke episodically and may not be fully addicted. Once a smoker achieves a mature addiction, however, cigarette consumption typically remains very constant. Interestingly, the smoker appears to be adjusting nicotine intake. If supplemental nicotine is administered, smokers often reduce their nicotine consumption. Alternatively, if smoking is restricted (e.g., by decreasing the number of cigarettes available), smokers alter their smoking strategy (e.g., by smoking each cigarette more deeply) in order to maintain a relatively constant nicotine intake. While the pathogenetic mechanisms underlying withdrawal symptoms are incompletely understood, it is generally believed that some withdrawal symptoms are related to decreases in nicotine blood levels below certain thresholds. Some smokers experience nicotine withdrawal at night when sleep interferes with nicotine intake. The concept that nicotine replacement can help ameliorate withdrawal symptoms by maintaining nicotine blood levels is also an important concept underlying nicotine replacement as an aid to smoking cessation (see below). Smoking is a perfect example of a gene-environment interaction. Twin studies have established a genetic basis for both smoking initiation and smoking persistence. It is likely that many genes affect smoking behavior, and several candidate genes have been suggested. Among these is CYP2A6, the enzyme that normally metabolizes about 70 percent of nicotine into cotinine. Individuals with a null mutation in CYP2A6 are less likely to become smokers, presumably because they “overdose” when they smoke. If they do smoke, they smoke fewer cigarettes and smoke them less intensely and, as might be expected, are at less risk for smoking-related disease. Nicotine, through its action on the (alpha4)3 (beta2)2 receptors located on the neurons in the mesolimbic system, is believed to modulate release of the neurotransmitter dopamine. Interestingly, other drugs of addiction, including opiates, alcohol, and amphetamines, also modulate dopamine release. Further supporting a key role of dopamine in mediating the addiction to nicotine is the observation that the dopamine antagonist haloperidol increases smoking behavior while the dopamine agonist bromocriptine decreases smoking. Consistent with this, several candidate genes for smoking behavior have been suggested in the pathways of dopamine signaling and metabolism.

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SOCIAL AND CULTURAL ASPECTS OF SMOKING Social factors also play a vital role in smoking. The experience a child has with the initial attempts at smoking appears to be important, as is an individual’s attitude toward smoking (i.e., the “image” of the smoker, peer pressure, parental cigarette use, and availability). Social attitudes can account for very low smoking prevalence in some groups. These observations support attempts to place restrictions on smoking in public places and other efforts to “de-normalize” smoking. Nicotine, moreover, is not the only psychoactive compound in cigarettes. While less well studied, monoamine oxidase inhibitors are present, and these may have either direct effects or interact with other psychoactive drugs. Thus, while it is clear that nicotine is a highly addicting psychoactive substance, smoking is highly complex. This complexity suggests that various smokers may smoke for different reasons; some may be relatively casual smokers, while others may be hard core. Understanding the nature of the addiction is likely to become more important as cessation techniques become more sophisticated. As in ancient America, the use of tobacco products has become well integrated into modern cultures worldwide. Tobacco is a multi–billion dollar industry. In some regions, tobacco is a crucial cash crop in an agricultural economy. In addition, the manufacture, distribution, marketing, and sale of tobacco products employ many individuals worldwide. Taxation on tobacco products has become an important means for the support of many governments. Thus, any changes in tobacco usage are likely to have economic impacts well beyond any health effects. The use of tobacco not only has an economic role, but a cultural one as well. In some societies, e.g., certain Native American tribes, tobacco usage has religious significance. In other groups, tobacco usage is associated with a strong cultural image. Often this image may have been created through direct efforts of the tobacco industry to market their product. In this regard, advertising messages promoting the image of the cigarette smoker as rugged, independent, and masculine or as sophisticated, independent, and feminine have been developed. While these images of cigarette smoking have their origins in advertising campaigns, the effectiveness of such marketing programs cannot be underestimated. The portrayal of these images in media such as film may help promote smoking. Whatever the reasons, cigarettes clearly have a cultural significance. The social and economic impact of tobacco usage, therefore, must be considered when attempting to deal with smoking as a public health problem.

MASTER SETTLEMENT AGREEMENT In an effort to combat the public health ramifications of tobacco usage, the Master Settlement Agreement was signed

Cigarette Smoking and Disease

into effect in 1998. It served as a measure to recuperate what states had lost through Medicaid expenditures due to smoking-related illnesses and as a measure to fine the tobacco industry for deceitful actions. Four major United States tobacco companies awarded 46 states $206 billion dollars to be paid over 25 years and to be utilized as the states saw fit. Four states had previously settled separately. Unfortunately, since its inception, many states have failed to use the funding for tobacco control causes, instead using it to fill budget deficits or support other state programs. Among many other actions, the agreement also prohibited advertisements targeted at youth and permitted access to tobacco industry documents.

SMOKING AS A PUBLIC HEALTH PROBLEM Cigarette smoking is a major public health problem. In fact, it can be considered the major public health problem. The number of deaths attributed to cigarette smoking in the United States has been estimated to be in excess of 400,000 annually. This vastly exceeds deaths attributed to other specific causes. The health burden attributable to smoking parallels smoking prevalence. As a result, smoking-induced disease is becoming more common in the developing world, where smoking prevalence has been increasing. In the United States, where comprehensive tobacco control programs have reduced smoking prevalence, the burden of tobacco-related disease has begun to decrease. Smoking can cause disease through a myriad of effects. Cigarette smoke contains in excess of 6000 compounds. Detailed toxicity studies have been done on relatively few of these inhaled toxins. Some are present in the tobacco plant; others, including much of the carcinogenic nitrosamines, are generated during the processing of the tobacco leaf, and many more toxins are generated during the pyrolysis of the processed tobacco. While the mechanisms of toxicity are legion, tobacco smoke contains compounds that can disrupt DNA, causing both mutations and altering gene expression, bind to and disrupt proteins, and alter cellular lipids. Obviously, such a diverse group of toxins interacts with many biochemical and cellular pathways. It is not surprising, therefore, that individuals whose biochemistry may differ considerably will be heterogeneous in their response to cigarette smoke. Recognizing that there appears to be a wide range of poorly understood inter-individual susceptibilities, tobacco smoke is associated with an increased mortality from atherosclerotic vascular disease, cancer, chronic obstructive pulmonary disease and is associated with a number of other adverse health effects as well (Table 43-2).

CHRONIC OBSTRUCTIVE PULMONARY DISEASE Cigarette smoking is the major risk factor associated with the development of chronic obstructive pulmonary disease

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Table 43-2 Diseases Associated with Cigarette Smoking Cardiovascular Atherosclerotic vascular disease Coronary artery disease Carotid vascular disease Mesenteric, renal, iliac Abdominal aortic aneurysm Peripheral vascular disease Thromboangiitis obliterans (Berger’s) Deep venous thrombosis Pulmonary embolus Cardiac disease Angina pectoris Coronary artery spasm Arrythmia Malignancy Respiratory tract Lung cancer Squamous cell Adenocarcinoma Large cell Small cell Laryngeal cancer Oral cancer Other tissues Esophagus Pancreas Bladder Uterine cervix Kidney Anus Penis Stomach Liver Leukemia Lung disease COPD Emphysema Chronic bronchitis Asthma Other lung diseases Idiopathic pulmonary fibrosis Histiocytosis X Respiratory bronchiolitis Goodpasture’s syndrome Sleep apnea Pneumothorax Gastrointestinal disease Peptic ulcer disease Gastric Duodenal Gastroesophageal reflux

Chronic pancreatitis Chron’s disease Colonic adenomas Dermatologic disease Skin wrinkling Psoriasis Reproductive disease Ovarian failure Pregnancy related Prematurity Premature rupture of membranes Spontaneous abortion Decreased sperm quality Fetal effects Low birth weight Impaired lung growth Sudden infant death syndrome Febrile seizures Reduced intelligence Behavioral disorders Atopic disease/asthma Effects on children of parental smoking Asthma Rhinitis Otitis Pneumonia Increased risk to smoke Rheumatologic disease Osteoporosis Rheumatoid arthritis Psychiatric Depression Schizophrenia Oral disease Periodontal disease Loss of taste Loss of olfaction Infectious disease Tuberculosis Pneumococcal infection Meningococcal infection Endocrine disease Altered hormonal secretion Graves’ disease Antidiuresis Goiter Renal Glomerulonephritis Benign prostatic hypertrophy Cataracts

Most of the associations of cigarette smoking and disease are based on epidemiologic studies. While in some cases there is clear evidence of an etiologic role of cigarette smoking, in other cases this relationship is not clear. Cigarette smoking, for example, may be associated with something else that is, in fact, etiologically related to a specific disease. In some cases, for example, depression, cigarette smoking may be therapeutic; thus, the association may not be that the smoking causes the disease, but rather the disease causes the smoking.

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(COPD) (see Chapter 41). Approximately 80 percent of patients with clinically significant COPD are or have been smokers. The number of individuals with COPD in the United States is estimated to be as high as 23 million, of whom as many as 10 percent have severe disease. Evidence supporting the relationship between smoking and COPD includes a dose-response effect; that is, heavy smokers are at greater risk of developing COPD. Low doses are also likely hazardous, as symptoms of bronchitis and increased risk for COPD have been associated with passive smoke exposure. On average, expiratory airflow in cigarette smokers decreases twice as fast in smokers (40 ml/y) than nonsmokers (20 ml/y). Although only a minority of smokers, perhaps 15 percent, who lose lung function faster than the average, are commonly diagnosed with COPD, it is likely that as many as 50 percent of smokers will have at least moderate disease and, upon careful questioning, will have evidence of functional compromise. In addition, COPD is a major risk factor for acute cardiac events with even minor decrements in lung function being associated with increased cardiac risk. Current understanding of the mechanisms by which cigarette smoke leads to the development of COPD is presented in Chapter 41. A number of interacting mechanisms appear to be involved. Emphysema likely develops from lung damage, which can be a result of direct injury from oxidants in cigarette smoke, and the action of oxidants released by inflammatory cells recruited into the lung as a result of smoke exposure. Smoke-generated oxidants may also disrupt the anti-protease protective mechanisms of the lung, creating a milieu more susceptible to protease-induced damage. When damage induced by smoking is not balanced by appropriate repair mechanisms, emphysema may result. In this context, cigarette smoke may disrupt repair processes. Chronic bronchitis appears to result from similar mechanisms in the airway. Inflammation induced by cigarette smoke appears capable of stimulating both acute production of secretions and inducing long-term anatomic changes in the airway. Changes such as goblet cell metaplasia may predispose to a hypersecretory state. Others, such as peribronchial fibrosis, may result in airflow obstruction. The development of autoimmune processes has been suggested to contribute to disease that persists after smoking cessation. The heterogeneity of clinical COPD likely results from varied host responses to the many pathogenetic pathways initiated by cigarette smoke.

MALIGNANCY The association of smoking with the development of lung cancer is also well established. The risk for developing lung cancer is increased about 20-fold in smokers compared to nonsmokers. Furthermore, smoking is the major risk factor associated with lung cancer. The attributable risk for the development of lung cancer is estimated to be 79 percent in women and 90 percent in men. In further support of the association of

Cigarette Smoking and Disease

cigarette smoking and lung cancer, as with COPD, epidemiologic evidence supports a dose dependency. Specifically, lung cancer risk increases with amount smoked and, most importantly, with the duration of smoking. The increased risk of lung cancer among passive smokers again is suggestive that even low-dose exposures to cigarette smoke carry significant risk. A direct etiologic role of cigarette smoke in the development of lung cancer is also supported by considerable evidence. The current model of carcinogenesis is a multistage process in which cigarette smoke plays a role at several stages. Both tumor initiators and tumor promoters are present in cigarette smoke. Although many substances in cigarette smoke likely contribute to carcinogenesis, polycyclic aromatic hydrocarbons and nitrosamines have attracted considerable attention. These toxins can lead to acquired somatic cell mutations and persistently altered cellular function. As a result, smokers frequently have epithelial cell abnormalities, which progress from mild metaplastic changes through severe dysplasia and, it is believed, finally to cancer. These lesions are also often widespread raising the possibility that the development of lung cancer in the smoker may be a multi-focal process. These epithelial cell alterations may also contribute to the pathogenesis of other diseases, such as COPD. Interestingly, the development of cancer may depend on host factors. Some potential carcinogens, for example, must be activated in the lung by mixed function oxidases. These enzymes are themselves under genetic control. It has been suggested that varying capacity to induce such enzymes could contribute to varying cancer risk. Cigarette smoking is associated with several other nonmalignant lung diseases besides COPD (Table 43-2). Nearly all patients with pulmonary histiocytosis X are smokers, suggesting cigarette smoke may have a pathogenetic role in this illness. Similarly, a large number of individuals with spontaneous pneumothorax are smokers. As a result, it has been thought that cigarette smokeâ&#x20AC;&#x201C;induced damage may contribute to the development of this condition. Malignancies of both the upper respiratory tract and outside the respiratory tract are also associated with cigarette smoking. Cigarette smoking is a major cause of oral and laryngeal cancer. Cigarette smoking, moreover, has been associated with a number of other malignancies (Table 43-2). The mechanism by which cigarette smoking contributes to the development of these various malignancies is not fully established. Cigarette smokeâ&#x20AC;&#x201C;derived carcinogens are concentrated in the urine and, as a result, the urinary tract, particularly the bladder, is exposed to high concentrations of these toxins.

CARDIOVASCULAR DISEASE Cigarette smoking is also a major risk factor for the development of cardiovascular disease. In this regard, the impact

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of cigarette smoking is of a similar magnitude to that of the other two major risk factors: hypertension and hypercholesterolemia. As with other smoking-related diseases, the cardiovascular risks correlate with the intensity of smoking. Finally, smoking can contribute to cardiovascular disease by contributing to both the chronic development of atherosclerosis and acute cardiac events. As with COPD and cancer, the epidemiological associations of cigarette smoking and cardiovascular disease are supported by considerable clinical and experimental evidence. In this regard, cigarette smoking can contribute to the development of atherosclerosis through a variety of mechanisms. For example, endothelial injury is associated with the development of atherosclerosis. Cigarette smoking can cause endothelial injury through direct toxicities. In addition, cigarette smoking is associated with tachycardia. Persistent tachycardia is thought to also cause endothelial injury and thus contribute to the development of atherosclerosis. Cigarette smoke per se is not associated with hypertension, but it is associated with hyperlipidemias. In particular, cigarette smoking appears to contribute to increased levels of oxidized low-density lipoproteins, which are believed to be particularly atherogenic. Smokers also have increased levels of circulating neutrophils, which may contribute to atherogenesis through injury of the vascular wall. Finally, smoking exerts effects on blood coagulability. Specifically, fibrinogen levels are increased, and platelet activation may be present. Activation of coagulation can result in release of cytokines, which is believed to contribute to atherogenesis. Microvascular disease is associated with cigarette smoking. It is the major risk factor associated with thromboangiitis obliterans. Smoking is also associated with an accelerated development of microvascular disease when there is concurrent diabetes mellitus. Abdominal aortic aneurysm is highly associated with a history of smoking. Cigarette smoke can also contribute to acute cardiac events. While smoking does not increase blood pressure chronically, acute smoking is associated with a transient increase in blood pressure. Combined with tachycardia, therefore, smoking is associated with acutely increased myocardial oxygen requirements. This may be one mechanism by which smoking contributes to acute myocardial ischemia. Cigarette smokers also have increased levels of blood carbon monoxide (CO). This impairs oxygen delivery. Increased CO levels, in addition, may also contribute to the increased red cell mass of smokers, which together with increased fibrinogen levels contributes to increased blood viscosity. These factors in turn contribute to the hypercoagulable state associated with smoking and lead to an increased predisposition for the development of acute thrombosis. Finally, cigarette smoking is associated with acute release of catecholamines and the development of coronary vasospasm. Through such mechanisms, cigarette smoking could contribute not only to acute ischemic events, but also to acute arrhythmias.

OTHER ADVERSE HEALTH EFFECTS OF SMOKING There are also considerable data associating cigarette smoking with a variety of other diseases (Table 43-2). Adverse effects of smoking during pregnancy, for example, are well recognized. Smoking is associated with a twofold increase in premature deliveries. Smoking also has a dose-dependent association with abruptio placenta, placenta previa and premature rupture of placental membranes. Smoking during pregnancy is associated with increased spontaneous abortion. On average, babies of smokers weigh less than those of nonsmokers. With regard to pulmonary disease, infants whose mothers smoked during pregnancy are more likely to develop both sudden infant death syndrome (SIDS) and asthma than are infants whose mothers did not smoke during pregnancy. Smoking is also related to reduced fertility in women, where it is associated with both secondary amenorrhea and irregular menstrual cycles. In men, cigarette smoking has been associated with impaired sexual functioning. Some studies of sperm quality have shown slight impairments in smokers, but an association with infertility has not been demonstrated. Sexual activity appears to be relatively normal in smokers. Impotence may be increased in smokers, but is generally associated with the development of significant pelvic atherosclerotic vascular disease. Considerable epidemiologic and experimental data support an association of smoking with the development of peptic ulcer disease. In this context, smoking has been associated with increased gastric acid output, increased duodenal gastric reflux, and has been suggested to decrease gastric blood flow. Smoking may also decrease the effect of antiulcer medications. Finally, smoking appears to potentiate the development of peptic ulcer disease in individuals taking nonsteroidal anti-inflammatory drugs and individuals colonized with Helicobacter pylori. Cigarette smoking is also associated with a number of other diseases (Table 43-2). While the mechanisms by which cigarette smoke can exert these varying effects are not fully understood, currently available data do make some general suggestions. For example, osteoporosis is increased in smokers, particularly in older women. While the mechanism is not fully understood, mineral content is reduced in older smoking women, an effect that may be dependent on reduced circulating hormones and earlier menopause associated with smoking. Smoking is also associated with a number of inflammatory and destructive diseases such as skin wrinkling, psoriasis, chronic pancreatitis, and glomerulonephritis. It is interesting to note the mechanistic overlap among smoking-related diseases. Activation of inflammatory processes, for example, appears to play an important role in the development of COPD and atherosclerosis, and may also play a role in the development of ulcers, skin wrinkling, pancreatitis, gingivitis, and so on. The destruction of the connective tissue macromolecular framework, particularly elastin,

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is believed to play an important role in the development of pulmonary emphysema. Similar processes may also take part in the development of skin wrinkling and gum disease. Moreover, the release of cytokines driving cell accumulation and proliferation is believed to play an important role in the development of chronic bronchitis and atherosclerosis, but may also play an important role in the development of neoplasia. Finally, cigarette smoking appears to alter the release of regulatory molecules. This could account for a myriad of consequences smoking has on endocrine disease, altered immunity, and the CNS. In support of this “systemic concept” of cigarette smoking are important epidemiologic associations. Thus, while most smokers have an accelerated decline in lung function, only a small percentage are routinely diagnosed with clinically significant COPD. This observation has been interpreted as suggesting that the effects of smoking are not clinically important with regard to lung function in the majority of smokers. Refuting this concept, however, are epidemiologic data associating an increase in mortality primarily from cardiac disease that may occur with even very modest declines in FEV1 . The important point is that the presence of a smoking-related effect, even if not symptomatically important, clearly defines an increased risk group.

SMOKING CESSATION Background Since Dr. Luther Terry released the first Surgeon General’s report on smoking and health in 1964, the prevalence of adult smokers in the United States has dropped from 40 percent to close to 20 percent. Antismoking awareness has increased worldwide to the extent that smoking bans have become commonplace in public buildings, workplaces, and public transportation. In 1984, Surgeon General C. Everett Koop proclaimed that the United States’ number one health goal was to achieve a “smoke free society by the year 2000.” Unfortunately, this goal was not achieved, yet the overall incidence of smokers in the adult population in the United States continues to decrease. A more realistic goal of adult smoking reduction to 12 percent in the United States was put into place through Healthy People 2010. Whether this goal will be obtained remains to be determined; however, it still highlights the importance of a smoke-free society. The greatest reductions in smoking have been in states with the most comprehensive tobacco control programs, supporting the effectiveness of currently available interventions. Comprehensive tobacco control programs, including bans on advertising, restriction of sales to minors, and increased price for cigarettes, also appear to be having an effect in reducing smoking initiation and prevalence among high school students. Nevertheless, smoking remains a highly prevalent disorder. Since more than three-fourths of smokers wish to quit, there is need for effective smoking cessation interventions.

Cigarette Smoking and Disease

Behavioral Approaches Behavioral interventions for smoking cessation should be recognized as part of all patient-physician interactions. For example, not inquiring and intervening about smoking is also a message. Current concepts suggest that not addressing smoking, when it would have been relevant, sends three messages: (1) the physician does not care if the patient smokes; (2) the physician does not have an effective intervention to offer; and/or (3) the physician does not think the patient will be able to quit. All of these “non-messages” have negative effects, particularly as smokers gradually make the decision to quit. A sense of empowerment and control over the behavior is vital to making and succeeding in a quit attempt. Inadvertently eroding a patient’s sense of mastery is an unanticipated adverse consequence of not asking about smoking. In addition, many patients are unaware of the potential available therapies; appropriate information can increase motivation to engage in quit attempts. A wide spectrum of behavioral techniques has been used to treat cigarette addiction. These include some that are effective, such as individual and group counseling, and many that are not effective, such as education, aversive conditioning, psychotherapy, transcendental meditation, sensory deprivation, hypnosis, and desensitization. Unfortunately, these latter, some of which have been assessed in detail, have tended to isolate smoking cessation interventions from mainstream medical practice. Smoking Behavioral Intervention Models Several models have been proposed to both understand and enhance the quitting process. Stages of Smoking Cessation

Prochaska and DiClemente described the smoking cessation process as involving five stages: precontemplation, contemplation, preparation, action, and maintenance. These stages are viewed as a continuum, with smokers progressing sequentially through each stage. In the precontemplation stage, smokers are not interested in quitting smoking and will likely be nonresponsive to direct intervention. Smokers in the contemplation stage are considering quitting smoking and may be receptive to a physician’s advice about the risks and benefits of quitting. In the preparation stage, smokers are actively preparing to quit. The action stage encompasses both initial abstinence and the 6-month postcessation period. The maintenance period commences after the 6-month abstinence period. It is rare for a smoker to progress successfully through these stages in the initial quit attempt. The cycle will likely be repeated several times before smoking cessation is ultimately achieved. National Cancer Institute’s Model for Smoking Intervention

The National Cancer Institute’s (NCI) recommended model for smoking intervention is based, in part, on five NCIsupported trials involving more than 30,000 patients and was

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later expanded by the Public Health Service. This approach, popularly referred to as “the five As,” emphasizes the role of medical professionals to ask patients about their smoking status, assess their willingness to make a quit attempt, advise smokers to stop, assist them in their stop smoking efforts, and arrange for follow-up visits to support the patient’s efforts. This approach utilizes brief intervention techniques and emphasizes the role of physicians as facilitators in the quitting process. Simple advice has been assessed in a number of studies, and a meta-analysis suggests a small but significant benefit of these limited interventions. Physician advice is effective both in the outpatient and hospital setting and may also be effective when given by letter or telephone. Group Counseling Group counseling programs for smoking cessation are offered by several commercial and voluntary health organizations. These programs are similar in content and typically include lectures, group interactions, exercises on self-recognition of one’s habit, some form of tapering method leading to a quit day, development of coping skills, and suggestions for relapse prevention. Group counseling programs sponsored by voluntary health organizations, such as the American Lung Association, are generally the best cost value for smokers. However, these programs are generally limited to large metropolitan areas and are offered on a sporadic basis. One-year success rates associated with group counseling programs are typically in the 15 to 35 percent range. Gradual Reduction vs. Abrupt Abstinence Gradual reduction or tapering intuitively appears to offer smokers the least abrasive way to stop smoking, and may be effective for some. However, gradually cutting down can be stressful when smokers attempt to reduce their cigarette use below their critical blood nicotine threshold. At this stage, smokers may begin to experience tobacco withdrawal symptoms. Rather than suffer prolonged discomfort, many taperers will gradually return to their customary cigarette levels and will not succeed in quitting. One of the negative consequences of tapering is that this method can strongly reinforce the smoker’s belief of the underlying need for cigarettes. Abrupt abstinence is often stressful and can lead to tobacco withdrawal symptoms. However, within a few weeks of total abstinence, complete abstainers experience less frequent cigarette cravings than taperers and are less prone to relapse. Cigarette tapering is often a component of many group programs in which gradual cigarette reduction is used as a preparatory stage leading toward a target quit day. In this circumstance, the tapering approach may prove beneficial to some smokers. Educational Techniques For years, cigarette smoking was viewed as largely a social or psychological habit. As such, the ability to quit was viewed as a measure of personal motivation and psychological willpower. Motivation to stop smoking, combined with sufficient psychological resources, was seen as a driving force behind suc-

cessful cigarette abstinence. Thus, if smokers could be educated about the health risks of cigarette smoking, they could theoretically become sufficiently motivated and psychologically empowered to quit. Unfortunately, anticipated benefits of the smoking cessation value of educational awareness messages were overly optimistic and simplistic. Over 80 percent of current smokers indicate they would like but are unable to quit. Educational programs to aid smoking cessation have produced disappointing results, with high long-term failure rates. Nevertheless, education about smoking is still regarded as a useful activity. Other Modes The goal of hypnosis in smoking cessation is to enable the smoker to achieve an altered state of consciousness to enhance the ability to quit. Controlled trials of hypnosis have generally been unable to document long-term smoking cessation efficacy. Aversive conditioning is based on the premise that smoking is a learned response that can be extinguished by creating an association between smoking and a negative sensation. Impressive quit rates are generally not seen unless these techniques are combined with other methods, such as individual or group counseling programs. Acupuncture has been advocated, but controlled trials with “sham” acupuncture have not demonstrated an effect.

Pharmacologic Treatment Two classes of agents, nicotine replacement and bupropion, are approved to aid smoking cessation. In addition, two other agents, clonidine and nortriptyline, are supported by guidelines for “off-label” use as secondary agents. In addition, several other agents are under active investigation and have shown promise. Nicotine Replacement Therapies A wide variety of nicotine replacement formulations have been developed, including tablets, polacrilex (gum), transdermal systems, nasal spray, a variety of inhalers, and nicotine toothpicks. Five formulations are currently approved as aids for smoking cessation in the United States, and three are available over the counter. In clinical trials, all have demonstrated about twofold increases in quit rates above placebo. Nicotine Polacrilex

Nicotine polacrilex gum was the first nicotine replacement therapy to gain Food and Drug Administration approval. It is now commercially available over the counter in 2- and 4-mg forms. In nicotine polacrilex, nicotine is bound to a resin that contains a buffering agent to improve delivery of nicotine through the buccal mucosa. The rate of chewing can influence the rate of nicotine release, and the pH in the mouth can influence absorption as acid foods or drinks convert nicotine base to salt, which, because of its charge, does not cross the buccal mucosa. Ad libitum use of 2-mg nicotine polacrilex is associated with blood nicotine levels less than 40 percent

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of customary smoking. At this level of nicotine replacement, many smokers may still experience discomforting tobacco withdrawal symptoms. A fixed dosage regimen of nicotine gum can produce higher blood nicotine levels than ad libitum use. Although effective in clinical trials, less successful results have been observed with nicotine gum in general practice and unsupervised settings. This may be due, in part, to the difficulty associated with using this pharmaceutical agent. Nicotine Polacrilex Lozenge

A nicotine polacrilex lozenge is also approved as an aid for smoking cessation, and is available over the counter. Chewing is not required, but acid food and/or beverages impair absorption. While the potential to develop addiction to nicotine polacrilex is believed to be low, many smokers who have quit continue to use these formulations chronically. This suggests that the pharmacokinetics of nicotine delivery by nicotine polacrilex, which is substantially slower than that of a cigarette, is insufficient to induce addiction, but may be sufficient to sustain it.

Cigarette Smoking and Disease

2-week period are unlikely to achieve abstinence. For this reason, simultaneous nicotine patch wearing and smoking should be discouraged. Nicotine Inhaler

The nicotine inhaler is a plastic nicotine-containing cartridge that fits on a mouthpiece. Nicotine is released when air is inhaled through the device, which is similar in size to a cigarette. The nicotine is not effectively delivered to the lungs as the particle size is too large. Rather, it is deposited and absorbed through the buccal mucosa, which results in pharmacokinetics that resembles nicotine polacrilex. Blood levels depend on the frequency of inhalations but can be about one-third of conventional smoking. It may cause irritation of the throat and mouth and may precipitate bronchospasm in individuals with reactive airways. Nicotine Nasal Spray

The nasal spray delivers nicotine to the nasal mucosa through which it is absorbed. It has the most rapid pharmacokinetics of the currently available nicotine replacement formulations. Nasal irritation is very common, particularly when initiating therapy.

Transdermal Nicotine

The primary advantage of transdermal patch delivery systems are ease of use and controlled drug delivery. Several formulations are available over the counter. In general, they achieve nicotine blood levels roughly 40 to 50 percent of that achieved by customary smoking of about 30 cigarettes daily. Transdermal nicotine systems have been repeatedly found to reduce tobacco withdrawal symptoms and significantly enhance smoking cessation rates. Unlike nicotine polacrilex, transdermal nicotine systems have consistently improved quit rates in primary care settings. This difference is likely due to the ease of patch use in this setting. The recommended use period for patches varies according to product, but a minimum of 4 weeks of therapy is probably required to help achieve longterm abstinence. Patches are most commonly worn at night, which provides a level of nicotine when a smoker awakes. Often this is a time when the individual is at risk to relapse since the low nicotine levels are associated both with withdrawal and increased effect of the smoked cigarette. On the other hand, delivery of nicotine at night may disturb sleep, particularly through vivid dreams. Spontaneous long-term use of the patch has not been observed, suggesting that the very slow kinetics of nicotine delivery with this system is insufficient to sustain addiction effectively. In addition, perhaps due to the partial replacement of nicotine, most smokers on patches still experience some tobacco withdrawal symptoms during the first few days of quitting. While these symptoms will likely be less severe compared to quitting cold turkey, some patients will be tempted to smoke and wear patches. Early concerns about increased cardiac risk among individuals who smoked while wearing the patch have not been substantiated. In fact, reduced smoking may decrease cardiac events. However, individuals who continue to smoke and use patches after the

Combination Therapy

Although not approved by drug regulatory agencies, various combinations of nicotine replacement may have utility for selected individuals who need higher doses. In addition, combination of a transdermal system with an ad libitum modality (e.g., nasal spray) can increase the control of nicotine levels and may result in increased quit rates. Bupropion Bupropion is approved as an antidepressant, and several studies have demonstrated its efficacy as an aid in smoking cessation. It is believed to act by potentiating dopaminergic and noradrenergic signaling. The formulations for depression and smoking cessation have different trade names, which has clinical relevance. First, an appropriate diagnosis is often required for reimbursement. Second, care is needed not to prescribe bupropion under one name to an individual already taking it under its other name, as overdosage can result. In clinical trials, bupropion approximately doubled quit rates compared with placebo. Subjects with a history of depression, however, appeared to benefit from bupropion but did not with nicotine replacement, suggesting that bupropion may be a superior initial choice in such individuals. Combination of nicotine replacement with bupropion has been assessed and appears more effective than either agent alone. The currently recommended dose is 150 mg daily for 3 days followed by 150 mg twice daily. The quit date should be after a week of therapy so that blood levels are established. The drug is generally well tolerated, although dry mouth and insomnia may occur. In combination with nicotine replacement, an increase in blood pressure may also occur. A reduction in seizure threshold makes the drug contraindicated

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among those predisposed to seizures, or with anorexia nervosa or bulimia. As the 150-mg once-daily dose was nearly as effective as the 150 mg twice daily, many practitioners use the lower dose routinely. The appropriate duration of therapy is not established. Clinical trials that formed the basis for approval treated for 7 weeks. However, with prolonged therapy, there is an increase in secondary quits, and therapy for 1 year resulted in more quits than therapy for 7 weeks.

Nicotine Vaccines Nicotine vaccines are also under investigation. Antibodies can be made to nicotine, if it is presented bound to an appropriate carrier. The antibodies then bind nicotine reversibly. By slowing the delivery of nicotine to the brain, the vaccine would distort the pharmacokinetics of a cigarette. These investigational agents may have utility for long-term relapse prevention or for prevention of smoking initiation.

Off-Label Agents

Practical Aspects of Intervention

Clonidine

Clonidine is an α-adrenergic agonist active in the central nervous system that is used to treat hypertension. A number of clinical trials have evaluated its efficacy in smoking cessation and have generally shown a trend toward benefit, although individual trials have generally not been statistically significant. Its use is supported by a meta-analysis, and the DHHS guidelines suggest it can be used by experienced practitioners comfortable with the drug. Nortriptyline

Nortriptyline is a tricyclic antidepressant that has been evaluated for efficacy in smoking cessation in several studies. Both individual studies and a meta-analysis support its benefit as an aid to smoking cessation, and it is also recommended as a possible second-line agent for practitioners comfortable with its use by the DHHS guidelines. A number of other agents approved for other uses have also been assessed for smoking cessation. None are currently recommended off-label by established guidelines, although several are under investigation. These include topimirate, an antiseizure medication that has shown promise for combined alcohol and tobacco addiction, and selegiline, an agent used as an adjunct in the treatment of Parkinson’s disease that has also shown promise in smoking cessation. Several other agents, including selective serotonin reuptake inhibitors (SSRIs) antidepressants, opiate antagonists, and amphetamines have been demonstrated to be without benefit. Anxiolytics have generally been without benefit, but buspirone remains controversial as studies have been mixed. Investigational Drugs Several drugs are under active investigation for smoking cessation. Varenicline is an (alpha4)3 (beta2)2 receptor partial agonist that has looked promising in phase 2 and 3 clinical trials. As a partial agonist, it has the potential to mitigate some of the nicotine withdrawal syndrome. Also, as a partial agonist, it may function as an inhibitor and block some nicotine effects, and thus may prevent full relapse if a smoker “slips.” Rimonabant is a CB1 receptor antagonist. It appears to attenuate a wide variety of cravings and has shown promise in clinical trials for smoking and for obesity. The potential to treat smoking and control the weight gain that is often associated would be a great boon.

Pragmatic Approaches to Smoking Cessation There is no single “best” approach for smoking cessation. In the past, 95 percent of all successful quitters stopped smoking on their own without any outside intervention. This should no longer be regarded as the treatment of choice, however. Approximately 25 percent of smokers who spontaneously quit, stop smoking without developing tobacco withdrawal symptoms. Many other self quitters, however, do develop tobacco withdrawal symptoms, but the discomfort is not sufficiently powerful to overwhelm their desire to quit. The two critical factors required for successful abstinence are that smokers must have a reason for quitting and the ability to quit. Reason for Quitting

Educational activities related to smoking risks are such that almost any smoker can enumerate a number of reasons for quitting smoking. There are exceptions, however, and the impact of specific reasons can vary greatly from person to person. Appropriate education, therefore, is still vital to smoking cessation. The more important issue is whether the reasons for quitting are sufficient to lead to a quit attempt. Often the motivation to make a quit attempt is driven as much by the sense of control as empowerment to succeed. This leads directly to the second factor. Ability to Quit

Many smokers take a defeatist approach to smoking cessation that leads to a self-restoring pattern of continued smoking. The availability of effective support and, more importantly, of effective pharmacologic interventions should be known to the smoker, as this will encourage quit attempts. Evaluation Process In the evaluation process, patients are assessed regarding their motivation or reason to quit and their ability to stop smoking. For patients who indicate they are not currently interested in quitting, the goal is simple: Provide them with a reason for quitting. For some, this may be information about health risks. For others, it may be information about effective interventions. The second component of the evaluation process assesses the smoker’s ability to quit. A simple, easyto-use measure, the Fagerstrom test for nicotine dependence (Table 43-3), can provide a brief assessment of the patient’s nicotine dependence. The most important question is time to first cigarette, and smokers who smoke within 30 minutes of awakening are usually heavily addicted to nicotine. These

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Table 43-3 Items and Scoring for Fagerstrom Test for Nicotine Dependence

Cigarette Smoking and Disease

Preparing Smokers for Quitting By anticipating the problems smokers will likely encounter, clinicians can help guide patients through the pitfalls that await them. Tobacco Withdrawal Period

Questions

Answers

Points

1. How soon after you wake up do you smoke your first cigarette?

Within 5 minutes 6–30 minutes 31–60 minutes After 60 minutes

3 2 1 0

2. Do you find it difficult to refrain from smoking in places where it is forbidden (e.g., in church, at the library, at the mates?)

Yes No

1 0

3. Which cigarette would you hate most to give up?

The first one in the morning All others

4. How many cigarettes do you smoke per day?

10 or less 11–20 21–30 31 or more

0 1 2 3

5. Do you smoke more frequently during the first hours after waking than during the rest of the day?

Yes No

1 0

6. Do you smoke if you are so ill that you are in bed most of the day

Yes No

1 0

Reprinted with permission from K.O. Fagerstrom. National Cancer Institute. Clearing the Air: Quit smoking today. Washington, DC: National Institute of Health, 2003. NIH publication 03-1647.

The first 3 days of abstinence are usually the most difficult. Tobacco withdrawal symptoms (Table 43-1) generally peak during the first 72 hours, and then gradually subside over a 3- to 4-week period. These symptoms can include restlessness, anxiety, difficulty concentrating, irritability, frustration, depression, and almost unrelenting craving for cigarettes. Common suggestions to help smokers cope with these early withdrawal symptoms in addition to nicotine replacement therapy can include: (1) Be active. Increased activity may curtail some of the drive to smoke. (2) Use deep breathing exercises. The simplest breathing exercise involves nothing more than extended breath holding followed by slow exhalation through pursed lips. (3) Avoid high-risk situations for smoking during the first 3 weeks of quitting. (4) Use plenty of cinnamon gum or chewable candies. (5) Combat strong urges to smoke: the urge to smoke will go away whether one smokes or not. Cravings

Of all the symptoms associated with nicotine withdrawal, cravings to smoke are the most persistent. Unlike the other symptoms, cravings can also recur long after abstinence is achieved. During the second and third week of abstinence, the craving waves usually occur less frequently, but can sometimes catch smokers off-guard because of their unexpected intensity. The decrease in frequency is greater than the decrease in intensity, and cravings can be precipitated months and years after abstinence if precipitated by specific cues. In this context, cravings recapitulate, in some ways, the grief response. Relapse is commonly associated with concurrent alcohol consumption. It is likely that alcohol, and the associated situations in which it is consumed, serves both as a cue leading to craving and decreases the inhibitions that may prevent smoking. Ex-smokers should be aware of these moments of hazard. Depression

patients and those with Fagerstrom scores greater than or equal to 7 comprise a group of individuals likely to benefit from nicotine replacement therapy. In contrast, patients with low Fagerstrom scores who are able to cope with smoke-free environments for an extended time period (greater than 4 hours) without developing discomforting withdrawal symptoms, may not require nicotine replacement therapy. For these individuals, bupropion may be a better choice for pharmacologic support. Current guidelines suggest that all individuals who are making a serious quit attempt should be given the best chance for success. Thus, in general, pharmacotherapy should be recommended for all individuals who have no contraindications. As noted below, this approach is probably both the most effective and the most cost effective.

At some time during the first three months of abstinence, some smokers may experience depression. For many this depression is mild and transient. For a small minority of smokers, quitting smoking may produce a clinical depression that may require antidepressant therapy, counseling, or return to smoking. Weight Gain

One of the most disheartening components of quitting smoking is weight gain. Rapid weight gain is common during the first 6 to 8 weeks of cigarette abstinence. This is followed by a more gradual increase in weight to roughly 4 kg at 6 months. Average weight gain at 10 years following cessation is 4.4 kg and 5.0 kg for males and females, respectively. The health risks associated with postcessation weight gain are unknown

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but are likely surpassed by the health benefits of stopping smoking. Additional resources are now available to clinicians to help prepare smokers for quitting. Toll-free tobacco quit lines are currently provided by many countries, including the United States and Canada. Research has found that telephone counseling is an effective smoking intervention. Thus, clinicians should encourage every smoker who wishes to quit to utilize the National Quit Line (1-800-Quit Now). Additional support can be found via the internet using smokefree.gov. Using this approach, a smoker can choose to talk with a telephone specialist with either internet instant messaging or telephone support. Both methods are designed to provide smokers with a personalized quit plan.

Health Benefits of Smoking Cessation Data on the health benefits of smoking cessation largely come from studies of former smokers. In many cases, these are individuals who may have quit smoking because of the development of disease; therefore, they represent a highly selected group. Other data are derived from interventional studies. Many times, however, such interventional studies include smoking cessation efforts together with many other interventions. Finally, such studies are generally designed to assess the intervention. In general, such interventions will only be partially successful at achieving smoking cessation, and the control group is likely to also have some quitters. As a result, the effect of the intervention cannot be equated with the effect of cessation. Nevertheless, smoking cessation is clearly associated with health benefits. All-cause mortality is significantly decreased among former smokers. The decrease in mortality rates, moreover, is observed among all age groups and in both men and women. Thus, there is little doubt that all smokers, regardless of age or gender, are likely to benefit from cessation. Most of the reduction in mortality is due to decreased mortality from cardiovascular events. Smoking cessation is associated with a very rapid reduction in acute myocardial events. It is also associated with a more gradual reduction in complications of atherosclerotic vascular disease. These effects are consistent with the concept that smoking contributes to cardiovascular disease by several mechanisms. The rapid reduction in acute events may be due to removing the acute stresses smoking places on the heart. The longer-term gradual effects may be associated with alteration of the atherosclerotic disease process. Smoking cessation is also associated with significantly improved risk of both respiratory tract and nonrespiratory malignancies. The risk for the development of lung cancer appears to decrease gradually following cessation, although it will never reach that of a nonsmoker. Smoking cessation is associated with improvement in lung function in subjects with relatively mild impairment. Improvements can be observed in the first 6 months to 1 year following cessation in FEV1 , an observation initially made in several smaller trials and subsequently confirmed in the Lung

Health Study. This large study (nearly 6000 individuals) assigned individuals to three groups, no special intervention, and a smoking cessation intervention with or without the addition of the bronchodilator ipratropium. Among the individuals who successfully quit in the intervention program, there was a significant improvement in FEV1 in the first year following cessation that was dramatically different than the continued decline observed in the continuing smokers in the same treatment group. Follow-up evaluation of this group has demonstrated continued benefits for at least 11 years, and a reduction in mortality. While not assessed in the Lung Health Study, smaller studies have also demonstrated that smoking cessation is associated with improvement in measures of small airways function including closing volume, closing capacity, and the slope phase III of the nitrogen washout curve. While more limited, several studies also suggest that smoking cessation may be associated with partial improvement in the impaired diffusion capacity of a lung for carbon monoxide (DlCO ) associated with smoking. This physiological effect may have a correlate in the cellular changes associated with smoking cessation. Smokers have markedly increased numbers of alveolar macrophages recoverable by bronchoalveolar lavage. Following cessation in normal smokers, the numbers of recoverable alveolar macrophages decreases significantly towards normal. Among individuals with more severe COPD, however, cessation may not be associated with a reduction in inflammation. Cross sectional studies have demonstrated similar inflammation among current and ex-smokers. Other prospective studies suggest persistent inflammation following cessation. How these studies relate to the improved clinical status of COPD patients following cessation remains to be delineated. Smoking cessation is associated with an improvement in nonspecific respiratory symptoms. Individuals with cough, sputum production, dyspnea, and wheeze have all reported improvement in symptoms in long-term follow-up studies, with symptoms often improving in the first few months. Smoking is the major risk factor for respiratory bronchiolitis, and smoking cessation is usually associated with a dramatic improvement in this condition. It seems reasonable to suggest that clinically recognizable respiratory bronchiolitis represents one end of a spectrum, and the physiologic and cellular changes noted above in asymptomatic individuals represent a more common result of similar pathogenetic mechanisms. Histiocytosis X occurs almost exclusively in smokers. Smoking cessation is generally regarded as an important therapeutic goal for such individuals. There are cases of complete roentgenographic resolution of the changes of histiocytosis X with cessation. While the pathogenetic mechanisms underlying histiocytosis X are unknown, such case reports suggest that at least part of the anatomic abnormalities associated with this condition are reversible with cessation of smoking. The effect of smoking cessation on other diseases associated with smoking is, unfortunately, somewhat limited. Former smokers have a reduced incidence of peptic ulcer disease and a more rapid rate of ulcer healing than do current

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smokers. Similarly, women who are former smokers seem to have ovarian function that more closely resembles never smokers than smokers. These observations are consistent with a benefit of smoking cessation.

Risks of Smoking Cessation Smoking cessation may be associated with some hazards in selected cases. Nicotine and other components of cigarette smoke may have a significant antidepressant effect, and many endogenously depressed individuals may have empirically found smoking helped alleviate their symptoms. Depression is a well-recognized manifestation of the nicotine withdrawal syndrome. At times, this depression can be of major clinical importance. Exacerbations of colitis have also been associated with acute smoking cessation. These potential adverse effects should not minimize the importance of smoking cessation, but the clinician should be prepared to address them when necessary. Anecdotal reports have suggested that asthma may worsen following cessation. Anti-inflammatory action of toxins contained in smoke such as NO or CO has been suggested to account for such an effect. Smoking as a Chronic Relapsing Disease With current therapeutic interventions, only a minority of smokers will achieve permanent abstinence. This has led to the concept that smoking should be regarded as a chronic relapsing disease. The goal, therefore, is to induce remissions that are as robust as possible. When relapse occurs, re-induction at the earliest possible time is appropriate.

HARM REDUCTION A more controversial approach for smokers who are unwilling or unable to quit at all is that the health consequences may be partially addressed by reducing the exposure to smokederived toxins. This approach, termed â&#x20AC;&#x153;harm reduction,â&#x20AC;? has been the subject of an Institute of Medicine report. Three general categories of harm reduction are theoretically possible: (1) administration of agents to counteract the effects of cigarette smoking; (2) smoking reduction; and (3) development of a less toxic cigarette. Since cigarette smoking is thought to cause its effects through pathogenetic mechanisms that are at least partially defined, it is appealing to use such mechanisms as targets for therapeutic intervention. In this regard, antioxidants to ameliorate the oxidant-induced injury caused by cigarette smoke and protease inhibitors to bolster the antiprotease defenses are both potential therapies. While conceptually appealing, no data exist to suggest that any such approach is of benefit in continuing smokers. Pharmacologic support may facilitate reduction in smoking. The observation that most smokers maintain a relatively constant nicotine intake creates the possibility that nicotine replacement can help sustain smoking reduction.

Cigarette Smoking and Disease

Smoking reduction has also been achieved with several formulations of nicotine replacement, and there is some evidence for physiological benefit. Short-term smoking reduction, facilitated with the use of nicotine polacrilex gum, was associated with improvements in lower respiratory tract inflammation assessed by bronchoscopy and bronchoalveolar lavage in a group of heavy smokers. In patients with cardiac disease who reduced smoking, measurable improvements in cardiac function were associated with improved oxygen delivery to the heart due to reduced carbon monoxide. Bupropion has also been associated with reduction in smoking, suggesting that several pharmacologic approaches may be possible to quantitatively reduce smoking. Reducing the delivery of cigarette smoke toxins while still providing the smoker with a satisfactory cigarette has been an important commercial goal. This was a major motivation in the development of filtered cigarettes and of low-tar, low-nicotine cigarettes. Unfortunately, these approaches do not reduce, and may actually increase, exposure to smokederived toxins. As most smokers maintain constant nicotine intake, many smokers compensate for altered smoke composition by simply smoking more or changing the way in which each cigarette is smoked. By causing an altered smoking strategy, filtered and low-yield cigarettes may actually deliver more toxins. Many of the cigarette-derived toxins are generated as a result of pyrolysis. As a result, tobacco products that do not burn have the promise to yield fewer toxins. There has been much interest in oral tobacco products in this regard. Moist snuff, which has low nitrosamine content due to its processing, has been widely used for several decades in Sweden. It has been associated with a measurable decrease in a number of tobacco-related diseases among Swedish men. Several cigarette-like devices have been developed with similar goals. Some burn small amounts of processed tobacco together with a carbon heat source in order to have a taste that more closely resembles a cigarette. Others electrically heat the tobacco. These products appear to deliver fewer toxins in standardized smoking regimes. Limited data are available on physiological effects but, in one study, a reduction in lower respiratory tract inflammation and in airway metaplasia was observed among heavy smokers who switched to a harm reduction product. Whether such products are associated with health benefits, however, remains to be determined. Harm reduction strategies may have unforeseen problems. Reduced risk products or smoking reduction strategies may encourage smokers to continue and thus discourage quit attempts. Available data, however, suggest the opposite. Smokers who switch to harm reduction products or who reduce with pharmacologic support appear to have an increased rate of subsequent quits. It may be that the sense of mastery that comes with the reduction effort helps make smokes able to quit. There are other potential hazards. Reduced risk products, for example, might be particularly appealing for individuals beginning smoking both because they may be easier to smoke and they are not perceived as having significant risks. Finally, if use of reduced-risk products erodes the social

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climate that discourages smoking, such products could increase use of conventional cigarettes.

SMOKING PREVENTION As noted above, smoking initiation is generally a pediatric problem. Precisely why some children begin smoking is not fully understood. More than two-thirds of children experiment with cigarettes, but only half will eventually smoke regularly. A number of factors are believed to contribute, including the child’s social environment and attitude toward smoking, which appears to be based, in large part, on the smoking behavior of parents, friends, and peer group role models. The reasons for initiating smoking, however, are not entirely environmental, as twin studies suggest a genetic basis for smoking as well. Interventions aimed at altering the social milieu are of some benefit. Participation in sporting activities is associated with lower rates of smoking initiation, as is control of affective disorders. Attitudes toward smoking appear to be important factors leading to smoking initiation, which may depend, at least in part, on advertising and marketing programs; hence the effectiveness of bans on advertising. A second approach to limiting smoking initiation is to restrict the sale of tobacco products to minors. Many states have legal restrictions on such sales. In many cases, however, these laws are not enforced. Active enforcement, however, can lead to a decrease in both experimental smoking and regular cigarette use among younger smokers. For such measures to be effective, they must be uniformly enforced in the community, and vending machines must be made inaccessible to minors. Another approach to restrict tobacco usage by minors is taxation. It has been suggested that increasing tobacco taxes will decrease use, and that this effect will be particularly prominent among less addicted smokers. Because adolescents may have less disposable income, the effect may be even greater. While such an approach is appealing, the magnitude of price changes required is unclear. Measures aimed at restricting tobacco sales to minors may lead simply to a deferral of smoking initiation. Thus, if measures are effective at delaying smoking initiation among children, it may be that parallel measures will also be required to affect smoking initiation among older adolescents and young adults. Currently available data suggest that smoking behavior among high school students has begun to decrease. There does not appear to be a corresponding increase in smoking among older individuals. These changes are associated with comprehensive tobacco control programs, which therefore seem to have measurable benefits.

CONCLUSION Cigarette smoking is a complex social and medical issue. The physician has a particularly important role in curbing

smoking. Not only must the physician participate in efforts to reduce smoking as a citizen, but as a protector of public health and a possessor of specific expertise in health care matters, the physician must take an active role in health promotion. Such a role includes discouraging smoking initiation among younger patients, encouraging and assisting smoking patients to quit, and participating in social efforts designed to reduce smoking at various levels. A number of policy statements have been prepared regarding smoking and the role of the physician. By implementing these recommendations, it is hoped that cigarette smoking, the number one preventable cause of death in the developed world, eventually can be eradicated.

SUGGESTED READING Anderson GP, Bozinovski S: Acquired somatic mutations in the molecular pathogenesis of COPD. Trends Pharmacol Sci 24:71–76, 2003. Anthonisen NR, Connett JE, et al: Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. JAMA 272:1497– 1505, 1994. Benowitz NL: Pharmacokinetic considerations in understanding nicotine dependence. Ciba Found Symp 152:186– 200, 1990. Botvin GJ, Goldberg CJ, et al: Smoking behavior of adolescents exposed to cigarette advertising. Public Health Reports 108:217–224, 1993. Coe JW, Brooks PR, et al: Varenicline: An alpha4beta2 nicotinic receptor partial agonist for smoking cessation. J Med Chem 48:3474–3477, 2005. Despres JP, Golay A, et al: Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 353:2121–2134, 2005. Fiore MC: US public health service clinical practice guideline: Treating tobacco use and dependence. Respir Care 45:1200–1262, 2000. Gilpin EA, Lee L, et al: Smoking initiation rates in adults and minors: United States, 1944–1988. Am J Epidemiol 140:535–543, 1994. Hatsukami DK, Rennard S, et al: Safety and immunogenicity of a nicotine conjugate vaccine in current smokers. Clin Pharmacol Ther 78:456–467, 2005. Hughes JR, Stead LF, et al: Antidepressants for smoking cessation. Cochrane Database Syst Rev 4:CD000031, 2004. Hughes JR, Stead LF, et al: Anxiolytics and antidepressants for smoking cessation. Cochrane Database Syst Rev 2, 2000. Jason LA: Active enforcement of cigarette control laws in the prevention of cigarette sales to minors. JAMA 266:3159– 3161, 1991. Joseph AM, Norma SM, et al: The safety of transdermal nicotine as an aid to smoking cessation in patients with cardiac disease. N Engl J Med 335:1792–1798, 1996.

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Munafo M, Clark T, et al: The genetic basis for smoking behavior: A systematic review and meta-analysis. Nicotine Tob Res 6:583–597, 2004. Prochaska JO, DiClemente CC: Stages of change in the modification of problem behaviors. Prog Behav Modification 28:183–218, 1992. RJ Reynolds Company: New Cigarette Prototypes that Heat Instead of Burn Tobacco. Winston-Salem, NC, RJ Reynolds Tobacco Co, 1988. Rennard S: Defective repair in COPD: The American hypothesis, in Pauwels RA, Postma DS (eds), Long-Term Intervention in Chronic Obstructive Pulmonary Disease. New York, Marcel Dekker, 2004, pp 165–200. Sin DD, Wu L, et al: The relationship between reduced lung function and cardiovascular mortality: A populationbased study and a systematic review of the literature. Chest 127:1952–1959, 2005. Stratton K, Shetty P, Wallace R, et al: (eds.), Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction. Washington, DC, National Academy Press, 2001. Tapper AR, McKinney SL, et al: Nicotine activation of alpha4* receptors: Sufficient for reward, tolerance, and sensitization. Science 306:1029–1032, 2004.

Cigarette Smoking and Disease

The Health Consequences of Smoking: A Report of the Surgeon General. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health. Washington, DC, 1984. The Health Consequences of Smoking: A Report of the Surgeon General. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health. Washington, DC, 1990. The Health Consequences of Smoking: A Report of the Surgeon General. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health. Washington, DC, 2004. Von Essen S, West W, et al: Complete resolution of radiographic changes of histiocytosis X after smoking cessation. Chest 98:765–767, 1990. Willemse BW, ten Hacken NH, et al: Effect of 1-year smoking cessation on airway inflammation in COPD and asymptomatic smokers. Eur Respir J 26:835–845, 2005.

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44 Rehabilitation in Chronic Obstructive Pulmonary Disease and Other Respiratory Disorders Andrew L. Ries

I. DEFINITION II. PATIENT SELECTION III. PATIENT EVALUATION Interview Medical Evaluation Diagnostic Testing Psych osocial Assessment Goals IV. PROGRAM CONTENT Education Respiratory and Chest Physiotherapy Techniques Bronchial Hygiene Breathing Retraining Techniques Oxygen Exercise

Rehabilitation for patients with chronic lung diseases is well established as a means of enhancing standard pharmacologic and other therapies in controlling and alleviating symptoms and optimizing functional capacity. The primary goal of any rehabilitation program is to restore the patient to the highest possible level of independent function. This goal is accomplished by helping patients and significant others learn more about the underlying disease, treatment options, and coping strategies. Patients are encouraged to participate actively in providing their own health care, become more independent in daily activities, and be less dependent on health professionals and expensive medical resources. Rather than addressing solely reversal of the disease process, rehabilitation focuses on improving disability from disease.

Exercise Prescription Blood-Gas Changes Other Types of Exercise Psych osocial Support V. BENEFITS OF PULMONARY REHABILITATION VI. PULMONARY REHABILITATION AND LUNG SURGERY Lung Transplantation Pretransplant Rehabilitation Posttransplant Rehabilitation Lung Volume Reduction Surgery Rehabilitation after Lung Resection VII. SUMMARY AND FUTURE OF PULMONARY REHABILITATION

Historically, pulmonary rehabilitation strategies were developed and have been used primarily for patients with chronic obstructive pulmonary disease (COPD). However, pulmonary rehabilitation has also been applied successfully to patients with other chronic lung conditions, including interstitial diseases, cystic fibrosis, bronchiectasis, and thoracic cage abnormalities. It has been used successfully in the evaluation and preparation of patients for surgery, such as lung transplantation and volume reduction lung surgery, and in maximizing recovery after surgery. Pulmonary rehabilitation has been used to facilitate patient recovery from acute processes such as acute lung injury, or exacerbations of chronic lung disease requiring mechanical ventilation or acute hospital care. Pulmonary rehabilitation is appropriate for any

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patient with stable lung disease who is disabled by respiratory symptoms. Even patients with advanced disease may benefit if they are selected appropriately and realistic goals are set. This chapter defines pulmonary rehabilitation and outlines issues related to patient selection and evaluation. Key components of a pulmonary rehabilitation program are described and results of rehabilitation programs reviewed. Finally, the role of rehabilitation prior to and following lung surgery is reviewed.

Table 44-1 Patient Selection Criteria for Pulmonary Rehabilitation Symptomatic chronic lung disease Stable on standard therapy Functional limitation from disease Relationship with primary care provider

DEFINITION In 1999, the American Thoracic Society adopted the following definition: Pulmonary rehabilitation is a multidisciplinary program of care for patients with chronic respiratory impairment that is individually tailored and designed to optimize physical and social performance and autonomy.

This definition focuses on three important features of successful rehabilitation. First, the program is multidisciplinary. Pulmonary rehabilitation programs utilize expertise from various health care disciplines that is integrated into a comprehensive, cohesive program tailored to the needs of each patient. Second, the program is tailored to the individual. Patients with disabling lung disease require individual assessment of needs, individual attention, and a program designed to meet realistic individual goals. Third, the program addresses both physical and social function. To be successful, pulmonary rehabilitation must address the social and emotional problems as well as seek to optimize medical therapy to improve lung function. The interdisciplinary team of health care professionals in pulmonary rehabilitation may include physicians, nurses, respiratory and physical therapists, psychologists, exercise specialists, and others with appropriate expertise. The specific team make up depends upon the resources and expertise available, but it usually includes at least one full-time staff member. Responsibilities of team members generally cross disciplines. Within this general framework, successful pulmonary rehabilitation programs have been established in both outpatient and inpatient settings and with different formats. A key to success is a dedicated, enthusiastic staff that is familiar with respiratory problems and can relate well to pulmonary patients and motivate them.

Motivated to be actively involved in and take responsibility for own health care No other interfering or unstable medical conditions No arbitrary lung function or age criteria

improve their health status. Patients with mild chronic disease may not perceive their symptoms to be severe enough to warrant a comprehensive care program. On the other hand, patients with severe disease who are bed bound may be too limited to benefit greatly. Criteria based on arbitrary lung function parameters or age alone should not be used in selecting patients. Pulmonary function is not a good predictor of symptoms, function, or improvement after rehabilitation. In general, selection should be based upon a personâ&#x20AC;&#x2122;s disability and functional limitation from respiratory symptoms, potential for improvement, and motivation to participate actively in a comprehensive selfcare program. Also, pulmonary rehabilitation is not a primary mode of therapy. Patients should be stabilized on standard medical therapy and should not have other disabling or unstable conditions that might limit their ability to participate fully in the program and to concentrate on the necessary tasks. The ideal patient for pulmonary rehabilitation, then, is one with functional limitation from moderate to severe lung disease who is stable on standard therapy, not distracted or limited by other serious or unstable medical conditions, willing and able to learn about his or her disease, and motivated to devote the time and effort necessary to benefit from a comprehensive care program.

PATIENT EVALUATION PATIENT SELECTION Any patient with symptomatic chronic lung disease is a candidate for pulmonary rehabilitation (Table 44-1). Appropriate patients are aware of disability from their disease and are motivated to participate actively in their own care in order to

The initial step is screening patients to ensure appropriate selection and to set realistic individual and program goals. The evaluation process includes the following components: interview, medical evaluation, psychosocial assessment, diagnostic testing, and goal setting (Table 44-2).

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Table 44-2 Components of a Comprehensive Pulmonary Rehabilitation Program Patient evaluation Interview Medical evaluation Diagnostic testing Pulmonary function Exercise Arterial blood gases/oximetry Psychosocial assessment Goal setting Program content Education Respiratory and chest physiotherapy instruction Exercise Psychosocial support

Interview The screening interview is an important first step. It serves to introduce the patient to the program, review the medical history, and identify psychosocial problems and needs. Family members and significant others should be included. Communication with the primary care physician is important to establish the vital link for the rehabilitation staff to clarify medical questions prior to the program and facilitate subsequent recommendations. Care and attention in this initial evaluation helps in setting goals compatible with everyone’s expectations as well as appropriate programmatic objectives.

Medical Evaluation Reviewing medical history helps to identify the patient’s lung disease and assess its severity. Other medical problems that might preclude or delay participation may be identified. Available laboratory data should be reviewed, including pulmonary function and exercise tests, rest and exercise arterial blood gas measurements, chest radiographs, electrocardiogram, and pertinent blood tests. Program staff can then determine the need for any additional information or action before the program begins.

Diagnostic Testing Planning an appropriate rehabilitation program requires accurate, current information. The complexity of the testing procedures performed depends upon individual patient and program goals as well as the facilities and expertise available. Pulmonary function testing is used to characterize lung disease and quantify impairment. Spirometry and lung volume measurements are most useful. Other tests (e.g., diffus-

ing capacity, maximal respiratory pressures to assess muscle strength) can be added as needed. Exercise testing helps to assess the patient’s exercise tolerance and to evaluate changes in arterial blood gases (e.g., hypoxemia or hypercapnia) with exercise. This may also uncover coexisting diseases (e.g., heart disease). The exercise test is also used to establish a safe and appropriate prescription for subsequent training. Maximal exercise of patients with chronic lung disease is limited largely by their breathing reserve. Simple pulmonary function tests such as spirometry can be used to estimate a patient’s capacity for sustained breathing (maximal ventilation) during exercise. The forced expiratory volume in 1 s (FEV1 ) is most useful in this regard. However, lung function only provides an estimate of an individual patient’s maximum work capacity. Exercise tolerance depends also on the patient’s perception and tolerance of the subjective symptom of breathlessness. Therefore, it is important to exercise patients to assess their physical function and symptom tolerance. Exercise evaluation for rehabilitation is most easily performed with the type of activity planned for training (e.g., treadmill for a walking training program). Variables measured or monitored during testing should include workload, heart rate, electrocardiogram, arterial oxygenation, and symptoms (e.g., breathlessness). Other measures, such as ventilation or expired gas analysis to calculate oxygen up˙ 2 ) and related variables may be obtained dependtake (VO ing on the interest and expertise of the program staff and laboratory. Measurement of arterial blood gases at rest and during exercise is important because of the frequent but unpredictable occurrence of exercise-induced hypoxemia. Arterial blood gas sampling during exercise makes testing more complex. The noninvasive estimate of arterial oxygen saturation by cutaneous (e.g., pulse) oximetry is useful for continuous monitoring, but it has limited accuracy (95 percent confidence limits, ±4 to 5 percent).

Psychosocial Assessment Successful rehabilitation requires attention not only to the patient’s physical problems but also to psychological, emotional, and social issues. Patients with chronic illnesses experience psychosocial difficulties as they struggle to deal with symptoms they may not fully understand. Neuropsychological impairment is common in patients with chronic lung diseases and cannot be accounted for solely on the basis of age, depression, or organic disease. Commonly, such patients become depressed, frightened, anxious, and more dependent on others to care for their needs. Progressive dyspnea is a frightening symptom and may lead to a vicious “fear-dyspnea” cycle: With progressive disease, less exertion results in more dyspnea, which produces more fear and anxiety, which, in turn, lead to more dyspnea. Ultimately, the patient avoids any physical activity associated with both of these unpleasant symptoms.

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In addressing these problems, the initial evaluation should assess the patient’s psychological state and pay attention to “psychosocial clues” that may be apparent during the screening interview (e.g., level of family and social support, the patient’s living arrangement, activities of daily living, hobbies, and employment potential). Important clues in initial interviews may be evident in nonverbal communication, such as facial expression, physical appearance, handshake, and “body space.” Cognitive impairment that may limit the patient’s ability to participate fully in the rehabilitation program may be identified. Family members and significant others may provide valuable insight and should be included in the screening process and program whenever possible.

Goals After a patient’s medical, physiologic, and psychosocial state have been evaluated, specific goals should be set that are compatible with his or her disease, needs, and expectations. Goals should be realistic in light of the objectives of the program. Family members and significant others should be included in this process so that everyone understands what can and cannot be achieved.

PROGRAM CONTENT Comprehensive pulmonary rehabilitation programs typically include several key components: education, instruction in respiratory and chest physiotherapy, psychosocial support, and exercise training (Table 44-2). Often, the various components are provided simultaneously; for example, during an exercise session, a patient may learn and practice breathing techniques for symptom control while being encouraged and supported by staff or other patients.

Education Successful pulmonary rehabilitation depends upon an understanding of lung disease and active involvement by patients and important others in providing social support. Education is an integral component; even patients with severe disease can gain a better understanding of their disease and learn specific means to deal with problems. Instruction can be provided individually or in small groups, but it should be adapted to different learning abilities. Topics discussed commonly include normal lung function, chronic lung disease, medications, nutrition, travel, stress reduction and relaxation, reasons to call the physician, and planning a daily schedule. Individual instruction and coaching may be provided on the use of respiratory therapy equipment and supplemental oxygen, breathing techniques, bronchial drainage, chest percussion, energy-saving techniques, and self-care tips. The general philosophy is to encourage patients to assume responsibility for their own care and become partners with their physician in providing the care.

Despite the importance of education, it is unlikely that increased patient knowledge alone will lead to improved health status. It is more difficult to change patient attitudes and behaviors. Patients require specific, individualized treatment strategies, instruction, and reinforcement. Thus, education is a necessary but not sufficient component of pulmonary rehabilitation.

Respiratory and Chest Physiotherapy Techniques Patients with chronic lung disease use, abuse, and are confused about respiratory and chest physiotherapy techniques. In pulmonary rehabilitation, each patient’s needs for respiratory care techniques should be assessed and instruction provided in proper use. These techniques may include chest physiotherapy to control secretions; breathing retraining techniques to relieve and control dyspnea and improve ventilatory function; and proper use and care of respiratory equipment, including nebulizers, metered dose inhalers, and supplemental oxygen.

Bronchial Hygiene Patients with chronic lung diseases frequently have abnormal lung clearance mechanisms that increase problems with retained secretions and infection. Therefore, rehabilitation programs teach a variety of chest physiotherapy techniques for secretion control (e.g., coughing, postural drainage, chest vibration and percussion). These are important for patients who experience excess mucus production during exacerbations as well as for those with chronic sputum production. The use of mucolytic agents to reduce viscosity of secretions is of questionable benefit.

Breathing Retraining Techniques Pulmonary rehabilitation typically includes instruction in breathing techniques, such as diaphragmatic and pursed lips breathing—techniques aimed at helping patients relieve and control breathlessness, improve their ventilatory pattern (i.e., slower respiratory rate and increased tidal volume), prevent dynamic airway compression, improve respiratory synchrony of the abdominal and thoracic musculature, and improve gas exchange. Review of studies evaluating these techniques indicates that improvement in symptoms (e.g., dyspnea) is a more consistent finding than are measurable changes in physiological parameters. The diaphragmatic breathing technique is a maneuver in which the patient consciously coordinates abdominal wall expansion with inspiration and slows expiration through pursed lips. The primary effect is to slow respiratory rate and increase tidal volume. Pursed-lips breathing is commonly taught to pulmonary patients, particularly those with COPD. This technique was observed by Laennec as early as 1830 and was advocated as a physical exercise for pulmonary patients in the early part of the twentieth century. As a maneuver assumed

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naturally by many patients with respiratory disease, pursedlips breathing is characterized by tensing the lips and narrowing the mouth opening during expiration. The aim is to slow expiration and maintain positive airway pressure in order to “stent the airways open” and prevent collapse.

Oxygen When chronic oxygen therapy is required, available delivery methods should be reviewed to help select the best system for the patient’s needs. Supplemental oxygen is beneficial for patients with severe resting hypoxemia. Long-term continuous oxygen therapy has been clearly shown to improve survival and reduce mortality and morbidity in hypoxemic patients with COPD. The benefits of supplemental oxygen for nonhypoxemic patients or those with intermittent hypoxemia (e.g., during exercise or sleep) are less clearly defined. Although continuous oxygen therapy is feasible and safe, maintaining patients on supplemental oxygen presents several challenges. Handling equipment is particularly difficult for physically disabled and frail patients. Therefore, it is important to assess each person’s oxygen needs and provide appropriate instruction. Several new developments have improved the efficiency of gas delivery systems and patient compliance with continuous oxygen therapy. Liquid oxygen provides more gas with less weight than tanks of compressed gas, particularly in portable systems. Oxygen conserving devices may increase the efficiency of delivery, reducing flow requirements and prolonging the life span of portable gas sources. Transtracheal oxygen delivery may help to improve compliance and avoid problems with nasal catheters; however, patients must be instructed carefully in caring for the catheter.

Exercise Exercise is important in pulmonary rehabilitation. Considerable evidence supports favorable responses to exercise training in patients with chronic lung diseases. Benefits are both physiological and psychological. Patients may increase their maximum capacity and endurance for physical activity, even though objective measures of lung function do not usually change. Patients may also benefit from learning to perform physical tasks more efficiently. Exercise training provides an ideal opportunity for patients to learn their capacity for physical work and use and practice methods for controlling dyspnea (e.g., breathing and relaxation techniques). Of all the components in a comprehensive pulmonary rehabilitation program, exercise is probably the most costly and laborintensive, considering the personnel, equipment, and expertise required. Principles of exercise for patients with lung disease differ from those based on normals or other patient populations because of differences in the limitations to exercise and the problems encountered in training. Many approaches have been used to train the person with chronic lung disease. To be successful, the program should be tailored to the individual’s physical abilities, in-

terests, resources, and environment. For general application, techniques should be simple and inexpensive. As in normals and other patients, benefits are largely specific to the muscles and tasks involved in training. Patients tend to do best with activities and exercises for which they are trained. Walking programs are particularly useful. They have the added benefit of encouraging patients to expand social horizons. In inclement weather, many can walk indoors (e.g., at shopping malls). Other types of exercise (e.g., cycling, swimming) are also effective. Patients should be encouraged to incorporate regular exercise into daily activities they enjoy (e.g., golf, gardening). Since many persons with chronic lung disease have limited exercise tolerance, emphasis during training should be placed on increasing endurance. Changes in endurance with rehabilitation are often greater than changes in maximal exercise tolerance and allow patients to become more functional within their physical limits. Increase in maximum exercise is also possible as patients gain experience and confidence.

Exercise Prescription Selecting a training target based upon a predetermined per˙ 2 ) is a wellcentage of predicted maximal heart rate or (VO established practice for normals or patients without underlying pulmonary disease. However, in patients with chronic lung diseases, the best method of choosing an appropriate training prescription is less clearly defined. Exercise tolerance in pulmonary patients is typically limited by maximal achievable ventilation and breathlessness. Such patients frequently do not reach their limits of cardiac or peripheral muscle performance. Much controversy exists regarding the appropriate training intensity target for patients with chronic lung disease. Use of a target heart rate has been advocated by some, although it is recognized that such a target may not be reliable for patients with more severe disease. Many patients with lung disease can be trained at a high percentage of maximal exercise tolerance, with work levels approaching or even exceeding the maximal level reached on the initial exercise test. In a study of 52 patients with moderate to severe COPD, patients were able to perform endurance exercise testing at an average workload of 95 percent of their baseline maximum. After 8 weeks of training, these patients were training at 86 percent of the baseline maximum. In fact, many patients with severe COPD were exercising at levels exceeding their baseline maximum. In another study that examined 59 patients with moderate to severe COPD who trained at levels near their ventilatory limits, a mean peak exercise ventilation of 100 percent of measured maximal voluntary ventilation was achieved after 12 days of training and at 3 months of follow-up. These findings suggest that even patients with advanced disease can be trained successfully at or near maximal exercise levels. Based on the findings noted previously, some pulmonary rehabilitation programs define exercise targets and progression during training more by symptom tolerance than heart rate, work level, or other physiological measurements.

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Ratings of perceived symptoms (e.g., breathlessness) help teach patients to exercise to “target” levels of breathing discomfort. A typical approach is to begin training at a level that the patient can sustain with reasonable comfort for several minutes and then to increase the time or exercise level according to symptom tolerance. Patients are encouraged to exercise daily and increase exercise duration up to 15 to 30 minutes of continuous activity. This graduated program helps patients to achieve a goal of improved tolerance for tasks of daily living, which often require a period of sustained activity.

inspiratory resistive loading, and inspiratory threshold loading have been shown to improve function of the respiratory muscles in both normals and patients. In normals, respiratory muscle function does not limit exercise tolerance; therefore, specific respiratory muscle training is unlikely to be of clinical benefit. In patients with COPD, the patient group most extensively studied, improvement in general exercise performance from ventilatory muscle training alone has not been demonstrated consistently. Thus, the role of respiratory muscle training as a routine component of pulmonary rehabilitation has not been clearly established.

Blood-Gas Changes A major problem in planning a safe exercise program for patients with lung disease is the potential for worsening of hypoxemia with exercise. Patients who are not hypoxemic at rest may develop changes in arterial oxygenation that cannot be predicted reliably from resting measurements of pulmonary function or gas exchange. Normal individuals do not become hypoxemic with exercise. In patients with obstructive lung disease, Pao2 changes unpredictably during exercise. In patients with mild COPD, Pao2 typically does not change with exercise; in fact, it may even improve. However, in patients with moderate to severe COPD, Pao2 may increase, decrease, or remain the same. Patients with interstitial lung disease commonly develop worsening oxygenation with exercise. Based on these observations, it is important to evaluate a patient’s oxygenation status both at rest and during exercise. Such testing is also used to prescribe oxygen therapy at rest and with physical activity. With the availability of convenient, portable systems for ambulatory oxygen delivery, hypoxemia is not a contraindication to safe exercise training.

Other Types of Exercise Exercise programs for pulmonary patients typically emphasize lower extremity training (e.g., walking or cycling). Since exercise conditioning is largely specific to the muscles and tasks involved in training other forms of exercise may be particularly valuable for persons with chronic lung diseases. Upper Extremity Training Many patients with chronic lung disease report disabling dyspnea with daily activities involving the upper extremities (e.g., lifting, grooming) at much lower work levels than with the lower extremities. Upper extremity exercise is accompanied by a higher ventilatory demand for a given level of work than is lower extremity exercise. Given the aforementioned muscle specificity of training, upper extremity exercises may be important in helping pulmonary patients cope better with common daily activities. Ventilatory Muscle Training The potential role of ventilatory muscle fatigue as a cause of respiratory failure and ventilatory limitation in patients with chronic lung disease has stimulated attempts to train the ventilatory muscles. Techniques of isocapnic hyperventilation,

Psychosocial Support An essential component of pulmonary rehabilitation is psychosocial support, the goal of which is to help patients combat progressive feelings of hopelessness and an inability to cope with chronic, progressive disease. Depression is common in patients with chronic pulmonary disorders, as are anxiety (especially anxiety over dyspnea), denial, anger, and isolation. Patients become sedentary and dependent upon family members, friends, and medical services to provide for their needs. Excessive concern over other physical problems and psychosomatic complaints arise. Sexual dysfunction and fear are common and represent often unspoken consequences of chronic lung disease. Patients may also demonstrate cognitive and neuropsychological dysfunction, possibly related to or exacerbated by the effects of hypoxemia on the brain. Psychosocial support is provided best by a warm and enthusiastic staff who can communicate effectively with patients and devote the time and effort necessary to understand and motivate them. Family members and significant others should be included in activities so that they can understand the disease and help the patient cope. Support groups are also effective. Patients with severe psychological disorders may benefit from individual counseling and therapy. Psychotropic drugs should generally be reserved for patients with more severe psychological dysfunction.

BENEFITS OF PULMONARY REHABILITATION A growing body of evidence supports the expected results and benefits of pulmonary rehabilitation in the management of patients with chronic lung disease (Table 44-3). Evidencebased guidelines, published by a joint effort of the American College of Chest Physicians (ACCP) and the American Association of Cardiovascular and Pulmonary Rehabilitation (AACVPR), summarized clinical trials in pulmonary rehabilitation. The rehabilitation components included lower extremity training, upper extremity training, ventilatory muscle training, and psychosocial/behavioral interventions. Outcomes evaluated included dyspnea, quality of life, health care utilization, and survival. Based on this review, the Panel rated the highest level of supportive evidence regarding

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Table 44-3 Results of Pulmonary Rehabilitation Decreases in Medical resource utilization (e.g., hospitalizations, emergency room visits) Respiratory symptoms (e.g., breathlessness) Psychological symptoms (e.g., depression, fear) Increases in Quality of life Physical activity Exercise tolerance (endurance or maximal level of activities of daily living) Knowledge Independence Return to work possible No change in lung function Possible prolonged survival

documented improvements in lower extremity exercise training and in dyspnea after pulmonary rehabilitation. Other positive recommendations included the inclusion of upper extremity exercise training and the improvements in quality of life and health care utilization after pulmonary rehabilitation. Two meta-analyses evaluated the effects of respiratory rehabilitation on exercise capacity and health-related quality of life. In a review of 14 randomized controlled trials employing systemic exercise as the primary intervention for at least 4 weeks for COPD patients, Lacasse and coworkers found significant improvements for dyspnea and mastery as two important aspects of health-related quality of life, and for maximal and functional exercise capacity. However, functional exercise capacity demonstrated heterogeneity that could not be explained by the sensitivity analyses performed. Cambach and coworkers reviewed 18 controlled studies evaluating the long-term effects of pulmonary rehabilitation on patients with asthma and COPD. Significant improvements were found for exercise tolerance (6-minute walk) and in dyspnea, fatigue, emotion and mastery measures of health-related quality of life. The authors noted heterogeneous results in improvements in maximal exercise capacity. Several published randomized trials demonstrate important and significant benefits of pulmonary rehabilitation for patients with COPD, including improvements in exercise performance, symptoms, and quality of life. In a clinical trial of rehabilitation versus an education program in 119 patients with COPD, Ries and coworkers reported a highly significant improvement in exercise endurance after rehabilitation that was maintained up to 18 months later. This

was associated with a significant decrease in perceived symptoms of breathlessness and muscle fatigue during exercise as well as improvement in maximum exercise tolerance, breathlessness with daily activities, and self-efficacy for walking. A follow-up trial of maintenance versus routine care after pulmonary rehabilitation was conducted in 164 patients with chronic lung disease. Similar to previous studies, both groups demonstrated decline in benefits over the first year of followup, although they remained above pre-rehabilitation levels. In comparison to 81 routine care patients, the 83 patients receiving maintenance care of weekly telephone contacts and monthly reinforcement sessions after pulmonary rehabilitation sustained improvement in maximum exercise tolerance at 1-year follow-up. However, a decline in measures of dyspnea, depression, self-efficacy, quality of life, and health care utilization were also observed in both groups. At 2-year follow-up, with both groups receiving routine care, there was a progressive decline in exercise tolerance and other measures of symptoms and morbidity. In another randomized trial, Berry and colleagues demonstrated the added benefit of a longer-term exercise (18 months) compared to short-term training (3 months) in 140 patients with COPD. Patients in the long-term training group maintained greater improvements in measures of physical function and self-reported disability. In a randomized controlled trial of 79 older adults with COPD, Emery and coworkers investigated physiological, psychological, and cognitive outcomes of a 10-week pulmonary rehabilitation program. Significant improvements were observed at program completion among 29 patients receiving exercise training, education, and stress management in measures of cardiopulmonary endurance, anxiety, illness-related physical and emotional impairment, and verbal fluency. These changes were not observed among patients receiving a combined intervention of education and stress management or patients with no intervention at all, suggesting that education without exercise may have limited value for the physical and psychological functioning. Benefits and cost savings associated with pulmonary rehabilitation have been demonstrated not only in highly specialized centers, but also in community-based settings. A collaborative study of 647 patients in 10 centers in California reported significant improvements in dyspnea and quality of life with substantial reduction in health care utilization over 18 months of follow-up (Fig. 44-1).

PULMONARY REHABILITATION AND LUNG SURGERY Pulmonary rehabilitation has been applied primarily in the medical management of patients with stable, chronic pulmonary disease. In recent years, surgical options for patients with severe, disabling lung disease have been used more frequently. Lung surgery in these patients represents new challenges and may further compromise already reduced lung

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Table 44-4 Goals of Pulmonary Rehabilitation in Lung Transplantation Pretransplant Maintain and increase mobility and exercise tolerance Monitor disease progression Prevent complications Provide education about Underlying disease Transplantation procedures Self-care and self-assessment Provide psychosocial support during waiting period for patients and families Figure 44-1 Changes in health care utilization over 18 months after pulmonary rehabilitation in a collaborative study of 647 patients in 10 centers in California. Results are presented as mean ± SE. (From California Pulmonary Rehabfl itation Collaborative Group: Effects of pulmonary rehabfl itation on dyspnea, quality of life and health care costs in California. J Cardiopulmonary Rehabfl 24:52–62, 2004., with permission).

function. Pulmonary rehabilitation has been found to be a valuable adjunct in preparing the patient for surgery or in postsurgery recovery.

Lung Transplantation Pulmonary rehabilitation is recommended and used commonly in both the preoperative and postoperative phases of lung transplantation programs. Although the general strategies of rehabilitation may be similar, the individual and program goals and specific program components differ.

Pretransplant Rehabilitation Patients with advanced lung disease who are candidates for lung transplantation are usually evaluated by the transplant team and then referred for pulmonary rehabilitation after their transplant candidacy is approved. Rehabilitation staff evaluate the patient to assess needs and plan an appropriate program that can be maintained throughout a waiting period, which may last months to years. Since these patients have advanced disease with limited life expectancy, the goals in the preoperative period differ from those that typically apply to rehabilitation in chronic lung disease (Table 44-4). The overall goals of pretransplant pulmonary rehabilitation are to maintain function, monitor disease progression, prevent complications, provide education about the underlying lung disease and lung transplantation, and offer psychosocial support for patients and families in coping with the stresses of waiting for a potentially life-saving procedure. The exercise training program may be similar to that provided to other chronic lung disease patients, with the exception that

Posttransplant Improve physical work tolerance Monitor clinical status and assess symptoms and oxygenation Prevent complications Reinforce self-care and self-assessment Encourage compliance with medical regimen Provide psychosocial support for adaptation to new demands and expectations

patients with primary pulmonary vascular diseases do not typically participate in exercise or other physical activities because of the increased risk of sudden death. Although patients may have some initial improvement in exercise tolerance or endurance as they begin rehabilitation, the primary goal for these patients is to maintain mobility and exercise capacity. Exercise sessions also provide an excellent means to monitor disease progression and to detect, at an earlier stage, problems that commonly occur (e.g., increased breathlessness or reduced arterial oxygenation with exercise). The goals of education in the pretransplant period are to teach patients about their underlying lung disease, the transplant procedure itself, and expectations following transplantation. Patients can also be taught techniques for self-care and self-assessment that will be useful before and after surgery. The psychosocial stresses of waiting for transplantation are considerable. Many patients feel as though their lives are “on hold.” Some may have moved away from family and social support networks to live close to the transplant center. Providing support for patients and families during this time, whether through formal group support sessions or informal contact with supportive staff and other patients, helps patients cope better with these problems.

Posttransplant Rehabilitation After lung transplantation, patients must learn to cope with a new level of function, new expectations, and a new set of

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problems. Rehabilitation for patients in this phase can facilitate physical reconditioning, help implement self-care and assessment techniques, and facilitate coping with the psychosocial adaptations to a new life-style. Goals of exercise training after rehabilitation are improved physical work tolerance and continued assessment of symptoms and oxygenation as early warning signs of complications, including rejection and infection. Educational goals are focused on self-care and assessment and the importance of compliance with a new medical regimen. Psychosocial support can assist with adaptation to a new set of stresses related to additional demands and expectations from both patients for themselves and significant others. Patients who are used to being sick, disabled, and cared for by others may now be expected to be well, independent, return to work, and provide support for others.

have resectable disease and are operative candidates. Following resection, these patients with already limited lung function have to learn to adapt to a new, lower level of function. Similar changes may be observed in patients who undergo radiation therapy. Patients in a stable phase of their treatment or in remission may be appropriate candidates for pulmonary rehabilitation. Improvement in health status, physical and psychological symptoms, exercise tolerance, and quality of life—as well as reduced health care burdens— are potential benefits. These patients’ survival may be as limited by their underlying lung disease as by their treated malignancy.

Lung Volume Reduction Surgery

Pulmonary rehabilitation has been well established as a means of improving functional status and reducing the disability and economic burden of the growing number of patients with chronic lung diseases. In adopting a broad rehabilitation medicine perspective, such programs provide interdisciplinary expertise directed toward the needs of the individual disabled patient. Much of the experience in pulmonary rehabilitation has been in patients with COPD. However, it is clear that similar benefits can result for patients with other disabling pulmonary conditions. Pulmonary rehabilitation may also play an important role in the preoperative evaluation, preparation, and postoperative recovery of patients undergoing surgical procedures, including lung transplantation, lung volume reduction surgery, and lung resection.

Recently, there has been a resurgence of interest in lung volume reduction surgery (LVRS) in the treatment of patients with severe emphysema. Pulmonary rehabilitation has been recommended as an important modality in the evaluation for and preparation of patients for this procedure as well as in the postoperative recovery phase. Since these patients have severe, disabling chronic lung disease, they are typically good candidates for pulmonary rehabilitation. Enrolling patients in rehabilitation prior to surgery has the advantage of optimizing their functional status, improving physical and psychological symptoms, helping them learn more about their disease and alternative treatment options, and improving their skills for coping and actively co-managing their disease. Patients can then make an informed decision about surgical treatment based upon their optimal level of baseline function. After surgery, similar to the post-transplant period, rehabilitation helps patients to adapt to new levels of function and to reassess symptoms and oxygenation needs. The National Emphysema Treatment Trial (NETT), a multicenter, randomized clinical trial of medical therapy versus medical therapy plus LVRS, evaluated the benefits and risks of LVRS in patients with severe bilateral emphysema. All patients enrolled in the NETT completed 6 to 10 weeks of pulmonary rehabilitation prior to randomization into medical therapy or medical therapy plus LVRS and participated in a maintenance program of additional rehabilitation after randomization. Results from the prerandomization phase demonstrated significant improvements in exercise tolerance, symptoms and quality of life following pulmonary rehabilitation.

Rehabilitation after Lung Resection Patients who undergo pulmonary resection frequently experience a significant increase in symptoms and reduced functional status. This is particularly true for patients with underlying chronic lung disease. Most commonly, surgery is used to treat patients with thoracic neoplasms who are deemed to

SUMMARY AND FUTURE OF PULMONARY REHABILITATION

SUGGESTED READING ACCP-AACVPR Pulmonary Rehabilitation Guidelines Panel: Pulmonary rehabilitation: Joint ACCP/AACVPR evidence based guidelines. Chest 112:1363–1396, 1997. American Association of Cardiovascular and Pulmonary Rehabilitation: Guidelines for Pulmonary Rehabilitation Programs, 2nd ed. Champaign, IL, Human Kinetics, 1998. American Association of Cardiovascular and Pulmonary Rehabilitation: Guidelines for Pulmonary Rehabilitation Programs, 3rd ed. Champaign, IL, Human Kinetics, 2004. American Thoracic Society: Pulmonary rehabilitation: 1999. Am J Respir Crit Care Med 159:1666–1682, 1999. American Thoracic Society: Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis 152:S78– S121, 1995. Berry MJ, Rejeski WJ, Adair NE, et al: A randomized, controlled trial comparing long-term and short-term exercise in patients with chronic obstructive pulmonary disease. J Cardiopulmonary Rehabil 23:60–68, 2003.

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Breslin E: Breathing retraining in chronic bbstructive pulmonary disease. J Cardiopulmonary Rehabil 15:25–33, 1995. California Pulmonary Rehabilitation Collaborative Group: Effects of pulmonary rehabilitation on dyspnea, quality of life and health care costs in California. J Cardiopulmonary Rehabil 24:52–62, 2004. Cambach W, Wagenaar RC, Koelman TW, et al: The long-term effects of pulmonary rehabilitation in patients with asthma and chronic obstructive disease: A research synthesis. Arch Phys Med Rehabil 80:103–111, 1999. Crouch R, MacIntyre NR: Pulmonary rehabilitation of the patient with nonobstructive lung disease. Respir Care Clin NA 4:59–67, 1998. Emery CF, Hauck ER, Schein RL, et al: Psychological and cognitive outcomes of a randomized trial of exercise among patients with chronic obstructive pulmonary disease. Health Psychol 17:232–240, 1998. Lacasse Y, Wong E, Guyatt GH, et al: Meta-analysis of respiratory rehabilitation in chronic obstructive pulmonary disease. Lancet 348:1115–1119, 1996. National Emphysema Treatment Trial Research Group: A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med 348:2059–2073, 2003. Palmer SM, Tapson VF: Pulmonary rehabilitation in the surgical patient: Lung transplantation and lung vol-

ume reduction surgery. Respir Care Clin NA 4:71–83, 1998. Ries AL: Pulmonary rehabilitation and lung volume reduction surgery, in Fessler HE, Reilly JJ Jr, Sugarbaker DJ (eds), Lung Volume Reduction Surgery for Emphysema. New York, Marcel Dekker, 2004, pp 123–148. Ries AL: Pulmonary rehabilitation in patients with thoracic neoplasm, in Aisner J, Arriagada R., Green MR, et al (eds), Comprehensive Textbook of Thoracic Oncology. Baltimore, Williams & Wilkins, 1996, pp 1019–1029. Ries AL, Bullock PJ, Larsen CA, et al: Shortness of Breath: A Guide to Better Living and Breathing, 6th ed. St. Louis, Mosby, 2001. Ries AL, Kaplan RM, Limberg TM, et al: Effects of pulmonary rehabilitation on physiologic and psychosocial outcomes in patients with chronic obstructive pulmonary disease. Ann Intern Med 122:823–832, 1995. Ries AL, Kaplan RM, Myers R, et al: Maintenance after pulmonary rehabilitation in chronic lung disease: A randomized trial. Am J Respir Crit Care Med 167:880–888, 2003. Ries AL, Make BJ, Lee SM, et al: The effects of pulmonary rehabilitation in the National Emphysema Treatment Trial. Chest 128:3799–3809, 2005. Ries AL, Squier HC: The team concept in pulmonary rehabilitation, in Fishman A (ed), Pulmonary Rehabilitation. New York, Marcel Dekker, 1996, pp 55–65.

SECTION NINE

Asthma

45 CHAPTER

The Biology of Asthma Sameer K. Mathur

William W. Busse

I. MODELS OF MECHANISMS OF ASTHMA PATHOGENESIS Late-Phase Asthmatic Response Respiratory Viruses in Asthma II. CELLS IN ASTHMA Mast Cells and Basophils Eosinophils Neutrophils T Cells Macrophage and Dendritic Cells Airway Smooth Muscle Cells Epithelial and Goblet Cells III. MOLECULAR MEDIATORS Cytokines

Asthma is characterized by intermittent airflow obstruction, airway inflammation, and bronchial hyperresponsiveness. This disorder affects an estimated 5 to 10 percent of the population, and as such is a major health care issue in most Western countries. A precise definition of asthma remains elusive, partly because the cause of this disease has yet to be found. Moreover, it is entirely possible that asthma is not a distinct disease, with a discrete etiology, but rather a “syndrome” with a variety of phenotypes in which various precipitating factors result in similar clinical, physiological, and pathological manifestations. This view of asthma likely explains its varied patterns and presentations, while explaining the common

Chemokines IgE Leukotrienes Prostanoids Nitric Oxide Granule Proteins IV. ROLE OF ADHESION MOLECULES IN INFLAMMATION Selectins Integrins Ig Gene Superfamily Members Mechanisms of Cellular Migration V. AIRWAY INFLAMMATION IN ASTHMA VI. CONCLUSION

development of intermittent airflow obstruction, airway inflammation, bronchial hyperresponsiveness, and response to treatment. Twenty years ago, the focus for the study and treatment of asthma had emphasized the mechanisms of acute bronchospasm with the treatment directed toward control of airway smooth muscle tone. With the exception of “severe asthma,” the consideration of airway inflammation as an essential component of the disease had been largely neglected. However, with the use of fiberoptic bronchoscopy and biopsy, airway inflammation was found as an underlying feature of asthma and shifted therapeutic emphasis toward

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anti-inflammatory medications. This has led to the current belief that bronchoconstriction, airway hyperresponsiveness, and airway inflammation are not mutually exclusive. Rather, acute and chronic inflammation, including airway edema, mucus secretion, and altered bronchial smooth muscle function are important, if not central, to the airflow obstruction and overall reactivity of the airways in asthma. Furthermore, it has been recognized that, although asthma covers a wide spectrum of clinical severity, inflammatory changes may be seen even in the airways of asymptomatic asthmatics. This chapter details our understanding of the mechanisms underlying acute and chronic inflammation in asthma. It focuses on the cellular components of the asthmatic inflammatory response and elucidates how the properties of these cells, and the mediators they produce, contribute to the pathophysiology of asthma.

MODELS OF MECHANISMS OF ASTHMA PATHOGENESIS The bronchoconstriction and airway inflammation of asthma can be elicited by allergens, respiratory infections, and occupational exposures. Two models have been particularly instructive in the efforts to further understand the pathogenesis of asthma in these settings. They are the late-phase asthmatic response to antigen and the airway changes seen with viral respiratory infections.

Late-Phase Asthmatic Response Inhalation of antigen can elicit responses to provide insight to allergic airway inflammation. This model for an asthmatic response results in a distinct pattern of airway limitation (Fig. 45-1). In the acute-phase response (APR), inhalation of allergen causes an immediate fall in lung function. This airway response is characterized by wheezing, coughing, and/or shortness of breath. The APR usually resolves within 1 hour and may be followed by a late-phase response (LPR), beginning about 4 to 6 hours after allergen challenge. The LPR often persists for 24 to 48 hours. An isolated LPR is rare and is found primarily in occupational asthma. Late asthmatic reactions share a number of features with chronic asthma: increased airway responsiveness, decreased responsiveness to bronchodilator therapy, and bronchial inflammation. In asthma patients who exhibit the dual-phase features of an APR followed by the LPR, the LPR is not only more prolonged but also more intense. This is true even though the original apparent stimulus (allergen exposure) for bronchoconstriction has been removed. The LPR is associated with the recruitment of inflammatory cells into the airway. Many have used bronchoscopy and bronchoalveolar lavage (BAL) to examine the cellular and mediator composition of the airways both before and after allergen challenge. In the past, airway eosinophilia appeared to exhibit the most significant correlation with LPR. However, recent studies with improved detection for basophils indi-

Figure 45-1 Acute and late phases of asthmatic responses (time in hours). (Based on data from Lemanske RF Jr, Kaliner MA: Late phase allergic reactions, in Middleton E Jr, Reed CE, Ellis EF, et al (eds), Allergy: Principles and Practice, vol 1. St. Louis, Mosby–Year Book, 1993, pp 320–361, with permission.)

cate that basophil levels correlate more strongly to the LPR in all forms of allergic inflammation, including airway, nasal, and skin (upon skin prick with allergen). Furthermore, in contrast to the BAL fluid from the APR with increased levels of histamine, tryptase, and PGD2 (prostaglandin D2 ) reflecting mast cell activation, the BAL fluid from a LPR contains histamine and tryptase while lacking PGD2 , which is consistent with products from basophil activation. Basophils have also been shown to release Th2 cytokines such as IL-4, IL-5, and IL-13. Thus, although several inflammatory cells including T cells and eosinophils accumulate during the LPR, it is currently thought the basophil is of central importance in mediating the LPR.

Respiratory Viruses and Asthma Viral respiratory infections increase asthma symptoms in many patients, particularly children. The viruses most typically associated with asthma in epidemiologic studies are respiratory syncytial virus (RSV) and rhinoviruses (RVs). Infection with “cold viruses” normally occurs in the upper airway and entails viral entry into a minority of bronchial epithelial cells. It has been difficult to determine the extent to which

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actual viral infection and replication occur in the lower airway or whether viruses adversely affect asthma by indirect means. Experimental infection of subjects with respiratory viruses provides a useful model to establish the mechanisms in the pathogenesis of asthma. Airway hyperresponsiveness to inhaled histamine may be increased in normal subjects as well as in allergic rhinitis and asthma patients during acute infection with RV, which can persist as long as 4 weeks after virus inoculation. Furthermore, bronchoscopy has shown a prominent acute neutrophilic response to RV infection in normal and allergic subjects. In a subsequent investigation of allergic patients who underwent segmental bronchoscopy and antigen bronchoprovocation 1 month before, during, and 1 month after RV infection, the viral infection also potentiated eosinophilic airway inflammation. Thus, the results of several studies suggest that viral respiratory infections not only increase airway hyperresponsiveness, but also change the pattern of allergic airway response, including the factors responsible for, or contributing to, the neutrophilic and eosinophilic inflammatory responses. RVs stimulate the production of several mediators from respiratory epithelial cells and mononuclear cells, including IL-8, GM-CSF (granulocyte-monocyte colony stimulating factor), INF-γ (interferon-γ), and RANTES (regulated upon activation, normal T cell expressed). These cytokines and chemokines are important for the recruitment and activation of neutrophils and eosinophils. Thus, viral respiratory infection may modulate the airway environment or the interaction of components of airway inflammation, including cells and mediators, to promote allergic inflammation.

CELLS IN ASTHMA The inflammatory response in the asthmatic airway is the manifestation of complex interactions between multiple cell types, both resident and recruited, and their molecular mediators. It is characterized by varying degrees of mononuclear cell and eosinophil infiltration, epithelial desquamation, mucus hypersecretion (and airway plugging), smooth muscle hyperplasia, and airway remodeling with subepithelial fibrosis. The presence or recruitment of inflammatory cells into the airway provides the basis for these changes. Each cell type exerts effector and regulatory functions in the pathogenesis of asthma as detailed in this section.

Mast Cells and Basophils Mast cells are granulocytes generated from a nonmyeloid lineage derived from CD34+ hematopoietic stem cells. Mast cells enter the peripheral circulation in an immature form and differentiate upon localization to a tissue compartment typically adjacent to an epithelial surface such as the skin, lung, and gastrointestinal tract. The differentiation requires IL-3 and the ligand for the c-kit receptor on mast cells, SCF (stem cell factor).

The Biology of Asthma

Two types of mast cells are found in humans. The cell subtypes are distinguished primarily by their tissue location and biochemical characteristics: mucosal mast cells (atypical) and connective-tissue mast cells (typical). MCt refers to mast cells containing the neutral protease tryptase alone, while MCtc denotes mast cells containing chymase in addition to tryptase and the other neutral proteases, carboxypeptidase and cathepsin G–like proteins. In the normal human lung, alveoli-associated mast cells are almost exclusively of the MCt type, which also predominate in the subepithelium of the bronchi and bronchioles. In vitro studies indicate that one role for tryptase in asthma pathogenesis includes the increase of airway smooth muscle responsiveness to histamine. Mast cells are notable for expression of the high-affinity IgE receptor, FcεRI. IgE molecules are constitutively bound to these receptors on the surface of mast cells. Upon encountering an allergen, the antigen-specific IgE molecules are bound with allergen and the subsequent cross-linking of FcεRI receptors activates mast cells. There is the immediate release of preformed mediators including histamine and tryptase. In some mast cells, TNF-α (tumor necrosis factor-α and VEGF (vascular endothelial growth factor) may also be among the preformed mediators. This is followed by the synthesis of leukotrienes (primarily LTC4 ), prostaglandins (primarily PGD2 ), and cytokines, which all contribute to the inflammatory milieu as discussed below. Basophils are also derived from CD34+ hematopoietic stem cells via the myeloid lineage; however, in contrast to mast cells, these cells are typically found in the peripheral circulation. Basophils share some common features with mast cells in the expression of FcεRI and tryptase; however, both are expressed at much lower levels than the mast cells. In addition, basophils are also capable of an immediate release of histamine upon activation. It is currently thought that mast cell activation is involved in immediate allergic inflammation, whereas basophils are involved in the late-phase response.

Eosinophils Eosinophils are granulocytes derived from CD34+ hematopoietic stem cells. The cytokines IL-3, IL-5, and GMCSF are involved in the stimulation of eosinophil production, growth, and maturation. IL-5 is particularly important in the development and terminal differentiation of eosinophils. Upon exposure to allergen, eosinophils are actively recruited into the airway predominantly by chemokines such as eotaxins. The migration of eosinophils to the airway is dependent on extravasation of peripheral blood eosinophils. This process is highly regulated and occurs via interaction between adhesion molecules on the endothelium (e.g., VCAM-1) and eosinophils (e.g., VLA-4). The activation of these integrins and subsequent recruitment of eosinophils to the airway is the result of cytokine and chemokine signaling, including IL-5, GM-CSF, eotaxin, and RANTES. Eosinophils have a variety of cell surface receptors, including low-affinity IgE receptors (in contrast to the highaffinity mast cell IgE receptors), cytokine receptors such as the IL-5 receptor (IL-5R), which is thought to be specific for

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eosinophils, and receptors for immunoglobulins and complement. Some of these molecules function in the primordial role of eosinophils in host defense against parasitic infectious agents. They are also likely, however, to be important in allergic diseases and asthma. Upon entry into the airway, eosinophils are able to release numerous mediators including granule proteins, leukotrienes (primarily LTC4 ), prostaglandins, and cytokines. Eosinophils contain primary and secondary granules. The primary granules contain Charcot-Leyden crystal protein. The secondary granules contain four principal cationic proteins: MBP (major basic protein) in the dense core, along with the matrix proteins ECP (eosinophil cationic protein), EDN (eosinophil-derived neurotoxin), and EPO (eosinophil peroxidase). Peripheral blood eosinophilia is a prominent feature of asthma. Autopsy samples from the airways of asthma patients, even those who died of non-asthma causes, and biopsies from asthmatics, even with mild disease, also contain eosinophilic inflammatory cell infiltrates. Similarly, eosinophil numbers are increased in the BAL and tissue after segmental antigen challenge. Immunohistochemical studies have also demonstrated eosinophils and their granule products in the asthmatic airway, and elevated levels of ECP have been found in the BAL and sputum of asthmatics. These observations and several lines of evidence speak to the importance of the eosinophil in the asthmatic process. Among the most compelling are the positive correlation between the levels of blood and airway eosinophilia and the severity of asthma and the subsequent drop in eosinophilia upon effective treatment with corticosteroids. The specificity of IL-5 for promotion of eosinophil activity led to studies in mice to antagonize IL-5 for the depletion of eosinophils, which resulted in differential effects on airway hyperresponsiveness depending on the mouse strain. The subsequent use of a humanized anti–IL-5 monoclonal antibody in clinical trials succeeded in significantly reducing peripheral blood eosinophil counts with only modest effects (approximately 50 percent reduction) on airway tissue eosinophil counts; however, there was no evidence for improved control of asthma. The lack of efficacy in asthma control has been attributed to deficiencies in experimental design. However, further study of the anti–IL-5 treatment has revealed significant reduction in measures of airway remodeling. Therefore, the role of eosinophils may be in the development of the chronic changes associated with asthma. Recently, two different models of eosinophil deficient mice were created and found to have conflicting results regarding the development of airway hyperresponsiveness upon allergen sensitization and challenge. Thus, the role of eosinophils in acute exacerbations of asthma remains unclear.

Neutrophils Neutrophils are derived for the CD34+ hematopoietic stem cells. Neutrophils are characterized by a multilobed nucleus and are normally found in the bloodstream and tissues. Neutrophils are terminally differentiated cells that are no-

table morphologically for their granules, whose synthesis and assembly occur only during early stages of neutrophil development. Primary (azurophilic) and secondary (specific) granules contain various antimicrobial enzymes, neutral proteases, and acid hydrolases. Neutrophils, in contrast to eosinophils, are natural residents of the lung, particularly the lung parenchyma. Airway neutrophilia can be observed in response to viral infections, during nocturnal exacerbations of asthma, and in the BAL fluid of allergic asthmatics 4 hours, but not 24 hours, after inhaled allergen challenge. Neutrophils contain or synthesize a number of molecules with the potential to damage airway tissue and, perhaps more importantly, to act as chemotactic factors or mediators for other inflammatory cells.

T Cells T cells are thought to be a prominent source of cytokines in the asthmatic inflammatory response. In asthma, an increase in activated T cells is observed in the airway. Furthermore, increased numbers of activated BAL T cells have been correlated with increased bronchial responsiveness and numbers of eosinophils. These observations suggest that T cells may play a critical role is the pathogenesis of asthma by regulating or orchestrating the inflammatory response. The study of T cells and their relationship to inflammation led to the discovery of “helper” CD4+ T cell subsets called T helper-1 (Th1) and T helper-2 (Th2) cells. These subsets are distinguishable on the basis of their patterns of cytokine production. In addition, a Th0 has been defined which are na¨ıve T cells that have not encountered antigen. Th1 cells are noted for the secretion of IL-12 and IFN-γ , whereas Th2 cells secrete IL-4, IL-5, and IL-13. It follows that Th2 cells, by virtue of their associated cytokines, can specifically enhance allergic inflammation with promotion of IgE synthesis and eosinophil activation and accumulation. It has been proposed that allergic inflammation represents the predominant activation of Th2 cells and release of their proinflammatory cytokines. In accord with this notion, cells in the BAL fluid from patients with asthma have shown increased mRNA expression for both IL-4 and IL-5. This and other observations suggest that Th2 cells and their associated cytokines play a major role in orchestrating the inflammatory response in the asthmatic airway, in particular its IgE production (IL-4, IL-13), eosinophilia (IL-5), mucus secretion (IL-13), and airway hyperresponsiveness (IL-13). Although in vitro experiments indicate that Th1 and Th2 cells inhibit the activity of the other, the analyses of animal models of airway inflammation and BAL fluid from human asthma subjects suggests that both Th1 and Th2 cells and their respective cytokines are present, although Th2 does appear to predominate. Given the role of IFN-γ in increasing the expression of adhesion molecules and antigen presentation molecules, it is likely that a coordinated Th1 and Th2 response coexists in asthmatic airway inflammation. Recently, another subset of CD4+ T cells has been identified: the T regulatory cell. T regulatory cells are characterized by high levels of CD25 cell surface expression, expression of

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the FOXP3 transcription factor, and secretion of IL-10 and TGF-β. These cells are noted to have an immunosuppressive function for both Th1 and Th2 cells and are thought to be important in generating and maintaining tolerance to antigen. Furthermore, glucocorticoids or cytokines such as IL-6 are thought to increase or decrease, respectively, the activity of T regulatory cells. Thus, T regulatory cells may represent another critical component in the regulation of airway inflammation.

The Biology of Asthma

tional findings of airway smooth muscle cell proliferation and hypertrophy along with subepithelial fibrosis are observed. These changes are thought to be a consequence, in part, of smooth muscle effector functions triggered by inflammatory mediator signaling. Some of the airway smooth muscle immunoregulatory and effector functions are mediated by the secretion of cytokines, chemokines, and extracellular matrix components, including GM-CSF, TGF-β, RANTES, eotaxin, IL-8, MCP-1 (monocyte chemotactic protein-1), fibronectin, collagen, and laminin.

Macrophage and Dendritic Cells Macrophage and dendritic cells are phagocytic cells capable of presenting antigen to T cells. Alveolar macrophages are present in abundance within the airway of normal and asthmatic patients and are known to play a critical role in the clearing of microbes from the airway. There are also suggestions that alveolar macrophages can suppress allergic inflammation in the airway by the secretion of Th1 cytokines, including IL-12, IL-18, and IFN-γ . In a rat model, the airway hyperresponsiveness of one strain could be suppressed with the adoptive transfer alveolar macrophage from another non-hyperresponsive strain. This supports a role for alveolar macrophage to modulate airway responses in asthma. In contrast to the alveolar macrophage, dendritic cells can play either a proinflammatory or tolerogenic role in allergic inflammation. These functions correspond with two distinct subsets of dendritic cells, myeloid and plasmacytoid, respectively. The dendritic cells are present in the lung in an immature form, either adjacent to epithelial cells or in the interstitium. These immature dendritic cells encounter antigen and migrate to a local lymph node, where they mature, characterized by increased expression of MHC class II molecules and B7 costimulatory molecules. The plasmacytoid dendritic cells can then induce tolerance, possibly by inducing T regulatory cells or by providing inhibitory costimulatory signaling via PDL-1 (programmed death ligand-1). In contrast, myeloid dendritic cells are thought to be important both for the initial sensitization with allergen as well as for enhancing the inflammation upon repeat exposure to allergen. Interestingly, repeated exposure to antigen may bypass the requirement for dendritic cells to migrate to a lymph node. In mice, it has been observed that following repeat antigen challenge, the myeloid dendritic cell population increases in numbers significantly within the airway in a mature form. This suggests that these cells may be maturing and interacting with the influx of T cells (predominantly Th2) within the airway itself rather than migrating to a lymph node.

Airway Smooth Muscle Cells Bronchospasm remains an important component of asthma, particularly acute asthma. Despite this long-standing recognition, the details of airway smooth muscle function, both in normal and asthmatic persons, are still under investigation. It is recognized that the airway smooth muscle contraction is a component of airway hyperresponsiveness. Relaxation of this smooth muscle contraction has been the predominant target of beta-agonist therapy for asthma. However, addi-

Epithelial Cells and Goblet Cells Airway epithelium functions as much more than a simple anatomic barrier. These cells actively regulate fluid and ion transport in the airway as well as mucus production. One of the most important activities of the airway epithelium is mucociliary clearance of secretions in conjunction with foreign particles. In addition, epithelial cells also participate in inflammation with the release of several molecular mediators, including cytokines, chemokines, and lipid mediators. Furthermore, epithelial cells are capable of producing endothelins, which are a family of three related peptides with potent bronchoconstrictor activity. Some of the stimuli for endothelin secretion include IL-1, IL-6, IL-8, TNF-α, TGF-β and LPS (lipopolysaccharide). Endothelin secretion is inhibited by IFN-γ and glucocorticoid treatment. Goblet cells are a component of the bronchial epithelium and comprise up to 25 percent of the epithelial surface. The primary function of goblet cells is to secrete mucin into the airway, which along with other proteins and lipids, produces a thin layer of lubrication in the airway (mucus). The epithelial cells and submucosal glands assist in the production of mucus components. The mucus traps particulate matter and debris within the airway and, in conjunction with the mucociliary clearance apparatus, is able to clear these products from the airway. In asthma, goblet cell hyperplasia and increased mucus production are typically observed. The increased numbers of goblet cells are derived from the proliferation and differentiation of epithelial cells. In asthma, several cytokine signaling pathways, including IL-9 and IL-13, induce goblet cell hyperplasia and increased secretion of mucin into the airway. The clinical sequelae are mucus plugging and obstruction.

MOLECULAR MEDIATORS The above-mentioned cells are able to coordinate and regulate the inflammatory process with the synthesis and secretion of several different classes of molecular mediators. These mediators have a variety of functions as discussed below.

Cytokines Cytokines are small-molecular-weight glycosylated signaling molecules secreted by a number of different cell types with

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autocrine, paracrine, or endocrine signaling activities. The over 30 cytokines identified thus far are categorized as interleukins, interferons, and growth factors. Cytokine secretion is usually a brief, self-limited event. It may, however, require new mRNA and protein synthesis, which takes place over a matter of hours rather than seconds or minutes. A variety of cytokines have been implicated in the regulation of airway inflammation and thus in the pathogenesis of asthma (Table 45-1). Support for cytokine involvement in inflammation was obtained by the detection of these mediators in the airways of patients with asthma, particularly in bronchoalveolar lavage fluid after allergen challenge and in situ hybridization of retrieved cells or biopsy materials. The overall effect of the complex cytokine network in the airway depends on a number of factors, including the relative abundance of the various cytokines, their ability to recruit and perpetuate the actions of inflammatory cells such as eosinophils and lymphocytes, and their ability to amplify inflammation by interacting with structural cells such as fibroblasts, endothelial cells, and epithelial cells. There is no question, however, that cytokines are key mediators in the pathogenesis of the chronic inflammation characteristic of asthma. The recognition that cytokines may have key immunoregulatory activities in the pathogenesis of asthma has led to the development of specific therapeutics to inhibit their function. Currently, humanized monoclonal antibodies, antiIL-5 and anti-TNF-α, have been used for the treatment of asthma. Neither has yet emerged as the “magic bullet” for the treatment of asthma, although each, in preliminary studies, has been shown to have some clinical efficacy, anti-IL-5 for the prevention of airway modeling and anti–TNF-α or improvement in lung function.

Chemokines The chemokines are small-molecular-weight proteins, 8-12 kD, that are classified in four categories based on the organization of specific cysteine residues in their protein sequence: C, CC, CXC, CX3C. The predominant function of chemokines is the recruitment or chemotaxis of inflammatory cells. Some chemokines also have additional signaling function. There are corresponding families of chemokine receptors for each class of chemokines. Notably, there is considerable overlap and redundancy in the chemokines and their target receptors. Since the localization of inflammatory cells into the airway is dependent to a large extent on chemotaxis via chemokine signaling, the chemokine receptors have become an attractive target for asthma therapy. There are currently chemokine receptor inhibitors for CCR5 as well as others in development as potential therapy for asthma.

IgE Allergic inflammation plays a prominent role in the pathogenesis of asthma. The initial association of IgE with asthma was based on several epidemiological studies. With the in-

creased understanding of the role of mast cell mediators in the pathogenesis of asthma, the importance of IgE in triggering mast cell activation and the resulting airway inflammation was underscored. This relationship between IgE levels and asthma led to the development of a humanized monoclonal antibody directed to IgE for asthma therapy. This antibody (omalizumab, Xolair) has been shown to be effective in the treatment of severe asthma, specifically allowing a significant reduction in dosage of corticosteroids.

Leukotrienes The leukotrienes are a family of lipid compounds generated from the metabolism of arachidonic acid via the lipoxygenase pathway (Fig. 45-2). These compounds are typically not preformed; rather, they are rapidly synthesized within minutes following activation of the source cell. LTC4 , LTD4 , and LTE4 are potent bronchoconstrictors that are produced by several cell types, including eosinophils and mast cells. The leukotrienes are also able to increase mucus secretion in the airway and facilitate a plasma leak generating edema in the airway. The use of leukotriene receptor antagonists (e.g., montelukast, Singulair) is currently recommended as a second-line agent in the treatment of asthma (behind inhaled corticosteroids).

Prostanoids The prostanoids are a family of lipid compounds generated from the metabolism of arachidonic acid via the cyclooxygenase pathway (Fig. 45-2). Most of the prostanoids, i.e., PGD2 , PGF2 , and TxA2 , are potent bronchoconstrictors and can be produced by several cell types including eosinophils and mast cells. However, another prostanoid, PGE2 , has bronchodilatory and anti-inflammatory activity. The use of nonsteroidal anti-inflammatory medications to inhibit cyclooxygenase activity has not been shown to have an appreciable effect on airway inflammation. It has been observed that PGD2 is the predominant prostanoid involved in asthma. Therefore, specific PGD2 receptor antagonists are currently being developed to ameliorate some of the bronchoconstriction in asthma.

Nitric Oxide The role of nitric oxide (NO) in the pathogenesis of asthma is unclear. NO is continually synthesized at low levels in the airways of normal subjects. Cell sources of NO in the respiratory tract include airway epithelial cells, smooth muscle cells, sensory nerves, endothelial cells, and macrophages. At low levels, NO is a bronchodilator and vasodilator that antagonizes endothelin and has protective effects in the airway. Higher levels of NO are found in asthma, secondary to increased inducible NO synthase expression. Higher levels of NO production may be detrimental to airway epithelium. This may be mediated by the ability of NO to react with superoxide anion in inflamed tissue to produce biologic oxidants that could contribute to ongoing tissue damage and chronic asthmatic inflammation. The production of NO is thought to reflect the level or severity

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Table 45-1 Cytokines Cytokine

Primary Source(s)

Primary Target(s)

Effects or Function

bFGF (basic fibroblast growth factor)

Endothelial cells

Fibroblasts

Proliferation of fibroblasts and extracellular matrix formation

G-CSF (granulocyte colony stimulating factor

Monocytes, fibroblasts, epithelial cells

Neutrophils

Proliferation and differentiation

GM-CSF (granulocyte-monocyte colony stimulating factor)

Macrophage, T cells

Eosinophils, neutrophils, macrophage

Proliferation, differentiation, activation, prolonged cell survival, and enhanced cytokine production Degranulation (eosinophils)

IFN-α (interferon)

Monocytes, macrophage

Virus-infected cells

Inhibition of viral replication

IFN-β

Monocytes, macrophage

Virus-infected cells

Inhibition of viral replication

IFN-γ

Th1 cells, CD8+ T cells, natural killer cells

Macrophage

Differentiation, activation, and expression of Fcγ receptor, MHC molecules, and cytokines Shift in cytokine profile to Th1 phenotype and expression of IL-2 receptor Increased cytotoxicity

CD4+ T cells

CD8+ T cells IL-1

Monocytes, macrophage

Th2 cells CD8+ T cells B cells

Production of cytokines Production of cytokines and increased cell cytotoxicity Proliferation, differentiation, and Ig production Proliferation, differentiation, production of cytokines

IL-2

CD4+ T cells

T cells

IL-3

T-cells

Hematopoietic stem cells

Proliferation and differentiation

IL-4

Th2 cells

B cells

Proliferation, activation, and production of MHC class II, IL-6, TNF, and CD23; class switching to IgE; enhanced production of IgE, IgG1, and IgG4; diminished production of IgM, IgG2, and IgG3 Inhibition of differentiation and IFN-γ production Differentiation Differentiation Inhibition of proliferation

Th1 cells Th2 cells CD8+ T-cells Natural killer cells IL-5

T cells

Eosinophils

Proliferation, chemoattraction, adhesion, activation, and degranulation (Continued)

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Table 45-1 (Continued) Cytokine

Primary Source(s)

Primary Target(s)

Effects or Function

IL-6

Monocytes, macrophage

B cells Monocytes, macrophage

Maturation to plasma cells, class switching to IgA Production of IL-1 and TNF-α

IL-7

Bone marrow stromal cells

Pre-B cells T cells

Proliferation Proliferation

IL-8

Macrophage

Neutrophils

Chemoattraction and inhibition of adhesion

IL-9

Th2 cells

B cells

Enhanced response to IL-4

IL-10

T cells

Monocytes Macrophage

Differentiation to macrophage Inhibition of MHC class II and adhesion molecule expression; inhibition of IFN-γ , TNF-α, and IL-4

IL-11

Bone marrow stromal cells

B cells

Similar to IL-6

IL-12

Monocytes, macrophage

Natural killer cells Th0 cells

Activation Proliferation and production of IL-2 Production of IFN-γ and TNF-α Inhibition of IL-4, IL-5 and IL-10 expression

Th1 cells Th2 cells IL-13

Th2 cells

B cells Monocytes

Similar to IL-4 Enhanced expression of MHC class II molecules and integrins; inhibition of IL-1 and TNF expression

IL-14

Activated T cells

Activated B cells

Proliferation of B cells and suppression of Ig secretion

IL-15

Monocytes, macrophage

T cells, natural killer cells

Proliferation and increased cytotoxicity; expression of ICAM-3

IL-16

CD8+ T cells

CD4+ T cells

Proliferation, chemoattraction

IL-17

CD4+ T cells

Proliferation and expression of autocrine factors

IL-18

Macrophage

Activated B cells

Similar to IL-12

IL-19

T cells, B cells, Monocytes

IL-20

T-cells

Increased expression of IL-4 and IL-13 Keratinocytes

Proliferation

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The Biology of Asthma

Table 45-1 (Continued) Cytokine

Primary Source(s)

Primary Target(s)

Effects or Function

IL-21

CD4+ T cells

IL-22

Th1 cells, NK cells

Hepatocytes

Increased expression of acute phase reactants

IL-23

Macrophage, dendritic cells

T cells, NK cells

IL-24

Monocytes, T cells

IL-25

CD4+ T cells

T cells, epithelial cells

Increased expression of Th2 cytokines

IL-26

Th1 cells, NK cells

IL-27

Antigen presenting cell

Na¨ıve CD4 + T cells

Proliferation

IL-28

Mononuclear cells

Antiviral activity

IL-29

Mononuclear cells

Antiviral activity

M-CSF (macrophage colony stimulating factor)

Monocytes, fibroblasts, epithelial cells

Hematopoietic stem cells

Differentiation of monocytes

PDGF (platelet derived growth factor)

Platelets, monocytes, macrophage

Fibroblasts, smooth muscle

Proliferation and chemoattractant for fibroblasts; active in wound healing, atherogenesis, and airway remodeling

SCF (stem cell factor)

Bone marrow stromal cells, fibroblasts

Mast cells

Chemoattraction, induction of histamine release, differentiation and proliferation

TGF-β (transforming growth factor)

Platelets, mononuclear cells

T cells B cells NK cells Fibroblasts Macrophage

Inhibits proliferation Ig class switch for IgA Inhibits cytotoxicity Proliferation and fibrosis Chemotaxis

TNF-α (tumor necrosis factor)

Monocytes, macrophage, granulocytes

T cells

Proliferation, increased cytokine expression Increased phagocytosis, increased MHC class I and II expression, increased adhesion molecule expression

Neutrophils, endothelial cells, epithelial cells

source: Busse WW, Lemanske RF. Advances in immunology: Asthma. N Engl J Med 344:350–362, 2001.

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derived neurotoxin (EDN), as the name implies, damages myelinated neurons. Eosinophil peroxidase (EPO) differs from neutrophil and monocyte myeloperoxidases (MPOs); it decreases LTC4 and LTD4 degradation and causes histamine release from mast cells. Neutrophil release of MPO and neutrophil elastase enhances their host defense function and is potentially injurious to normal tissues, including airway epithelium. The primary granules contain MPO and lysozyme as well as hydrolases and proteinases, which are important in tissue penetration by neutrophils. Secondary granules contain lysozyme and collagenases, which can also potentially damage airway tissue. Thus, the neutrophil granule proteins are considered toxic to the airway epithelium and tissue.

Figure 45-2 Pathways in the formation of prostaglandins, thromboxanes, and leukotrienes.

of airway inflammation. Thus, exhaled NO measurement has been utilized successfully as a tool to reflect the extent of airway inflammation as a measure of asthma control.

Granule Proteins The granulocytes (mast cells, basophils, eosinophils, and neutrophils) are capable of releasing granule proteins, each of which has been proposed to play a role in the pathogenesis of asthma. Insights into the kinetics and importance of mast cell mediators have been obtained from measurements of the levels of BAL histamine and tryptase. These studies have demonstrated that mast cell activation is an early event, with elevated BAL histamine and tryptase levels being seen 12 minutes after endobronchial antigen challenge and the levels of tryptase returning to normal by 48 hours. The levels of histamine remain elevated after 48 hours, raising the possibility that nonâ&#x20AC;&#x201C;mast cells (e.g., basophils) are activated and produce the histamine at these later points. Furthermore, the BAL of allergic asthmatic subjects had only moderately elevated levels of tryptase at baseline but higher concentrations of tryptase following antigen challenge. Histamine is capable of inducing bronchoconstriction, increasing vascular permeability to cause edema, and increasing mucus secretion. The role of tryptase is not well established, although there are data to suggest that tryptase can activate inflammatory cells such as eosinophils, mast cells, and epithelial cells by cleaving a family of protease activated receptors (PAR) on their cell surfaces. Major basic protein (MBP) is the principal protein constituent of eosinophil granules. It is toxic for epithelial tissues, induces airway hyperresponsiveness, and causes histamine release from basophils. Eosinophil cationic protein (ECP) is more cytotoxic to the epithelium than MBP and damages target cells by membrane pore formation. Eosinophil

ROLE OF ADHESION MOLECULES IN INFLAMMATION The recruitment of cells from the circulation and their activation in the airways, in part, involves cell-cell and cellextracellular matrix communication, a process that is facilitated and regulated by adhesion molecules and cytokines. Adhesion molecules are cell surface proteins that have been grouped according to structural and functional similarities. Several categories have been identified, including the selectins, integrins, and members of the immunoglobulin (Ig) gene superfamily. These molecules interact with complementary binding sites (ligands) on respective cells, allowing them to adhere to epithelial or endothelial surfaces and, in some cases, enter the pulmonary interstitium.

Selectins Three members of the selectin group have been identified: endothelial (E)-selectin, platelet (P)-selectin, and leukocyte (L)-selectin. Both E- and P-selectin are found on endothelial cells, while L-selectin is located only on leukocytes, including lymphocytes, eosinophils, monocytes, basophils, and neutrophils. L-selectin can also be shed from leukocytes and, like P-selectin, may be found in a circulating soluble form, in which it is potentially available to participate in inflammatory reactions.

Integrins Integrins are found on the surfaces of leukocytes but not endothelial cells. They are classified according to the composition of their various subunits, including several different alpha and beta chains. One line of evidence for the importance of integrins in human disease is the finding that partial or total absence of a Î˛2 -integrin subunit leads to a crucial defect of neutrophil recruitment to sites of inflammation and recurrent, potentially life-threatening bacterial infections in patients with leukocyte adhesion deficiency syndromes. Some integrin interactions that are

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important in leukocyte–endothelial cell adhesion and signaling include very late antigen-4 (VLA-4) with lymphocyte function–associated antigen–1 (LFA-1), also known as CD11a/CD18, which also serves as a ligand for intercellular adhesion molecule–1 (ICAM-1) and ICAM-2. Not surprisingly, integrins have also been implicated in tissue repair, platelet aggregation, and tumor invasion, in addition to their other, more general roles in leukocyte binding and recruitment. Integrins are the primary mediators of cell-extracellular matrix adhesion. In asthma, integrins are also important for transendothelial migration of inflammatory cells into the airways.

Ig Gene Superfamily Members Endothelial proteins of the immunoglobulin gene superfamily share functional as well as structural similarities with immunoglobulin domains. ICAM-1, ICAM-2, vascular cell adhesion molecule–1 (VCAM-1), platelet–endothelial cell adhesion molecule–1 (PECAM-1), and mucosal addressin cell adhesion molecule–1 (MadCAM-1) are all active in later steps of leukocyte–endothelial cell adhesion. These interactions are not final random events, but represent a coordinated effort of cells, cell surface molecules, and cytokines.

Mechanisms of Cellular Migration There are three major interrelated steps in leukocyte recruitment from the circulation into tissues. They are categorized as adhesion, diapedesis, and chemotaxis (Fig. 45-3). Although the specific molecules and cytokines associated with these processes may vary, depending on the particular cells involved, the following general steps for leukocyte– endothelial cell and extracellular matrix interaction are thought to occur. As leukocytes move through capillary vessels, they initially contact the endothelial cell walls in a random fashion. In vascular beds in the region of inflammation, endothelial cells are “activated,” with increased expression of adhesion molecules, such as E-selectin, on their cell surfaces. During flow through vessels with activated endothelial cells, leukocytes begin to “roll” along the endothelial cell lu-

The Biology of Asthma

minal surfaces as a consequence of the interactions of adhesion molecules on leukocyte and endothelial cell surfaces. As leukocytes travel near sites of inflammation, locally produced cytokines up-regulate expression of cell surface proteins, including those active in cell adhesion and migration. These activated leukocytes then participate in “firm adhesion,” much of which is mediated through interactions of leukocyte integrins (VLA-4, CD11a/CD18) and endothelial cell surface Ig gene superfamily members (ICAM-1, VCAM-1). The next step is transmigration of leukocytes across endothelial cells and between endothelial cells into the surrounding tissues, i.e., diapedesis. Since there are cell-type specific differences in the expression of adhesion molecules, the pattern of adhesion molecule expression on the endothelium can confer selectivity in recruitment of specific leukocytes. For example, endothelial cell VCAM-1 binds mononuclear leukocytes and eosinophils, but not neutrophils. In contrast, both neutrophil and eosinophil migration across endothelial cells is enhanced by binding to ICAM-1. Various inflammatory mediators, including cytokines and chemokines, induce an increased expression of adhesion molecules and ligands that aid in the preferential recruitment of particular cell types into the tissues. The consequence of these interactions is the recruitment of inflammatory cells into target tissues such as the airway and, frequently, a complete or partial activation of these cells during their transit.

AIRWAY INFLAMMATION IN ASTHMA Thus far, a description of cells, the mediators they release, and the mechanism for their recruitment into tissue have been presented, but how do they cooperate to generate asthma? It is likely that each of these components plays a role in the pathophysiology of an asthma exacerbation. However, given the heterogeneity in clinical and physiological features of asthma from patient to patient and from trigger to trigger, it is likely that the relative contributions of each cell type and/or mediator can vary. Furthermore, it is clear that multiple cells types are able to express similar sets of molecular mediators; thus, it

Figure 45-3 Mechanism of leukocyte vascular adhesion and migration into tissues and airways. Leukocytes ‘‘roll” along endothelial cell layer and then selectively adhere firmly to endothelium near inflammatory sites. The adhering leukocytes then migrate into subendothelial tissue. Cell surface molecules (selectins, integrins, Ig superfamily members) facilitate the process. (Based on data of Carlos TM, Harlan JM: Leukocyte-endothelial adhesion molecules. Blood 84:2068–2101, 1994, with permission.)

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Figure 45-4 A. Distribution of cells in airway, lung parenchyma, and pulmonary lymph nodes. B. Introduction of antigen induces changes in the airway including: antigen interaction with alveolar macrophage, dendritic cells, mast cells, and B cells; goblet cell hyperplasia; basement membrane thickening; smooth muscle hyperplasia; recruitment of eosinophils, basophils, and neutrophils from the circulation into the lung parenchyma and airway facilitated by adhesion molecule interactions; antigen presentation to T cells in pulmonary lymph nodes; and, recruitment of activated T cells from lymph nodes into the lung parenchyma. AM, alveolar macrophage; GC, goblet cell; Epi, epithelial cell; BM, basement membrane; DC, dendritic cell; MC, mast cell; SM, smooth muscle cell; BV, blood vessel; End, endothelial cell; EOS, eosinophil; Neut, neutrophil; Bas, basophil; Ad, adhesion molecule; LN, lymph node; BC, B cell; TC, T cell; Ag, antigen.

is possible that different patterns of cell activation can result in the same effector responses. In a quiescent state, the cells involved in the pathogenesis of asthma are resident in the airway tissue, peripheral circulation, or local lymph nodes (Fig. 45-4A). Following exposure to an asthma trigger, the inflammatory cascade is initiated resulting in cell activation, cell recruitment, cell hyperplasia, and release of mediators (Fig. 45-4B), which collectively yield the hallmark findings of asthma: airway obstruction, mucus secretion, and hyperresponsiveness.

CONCLUSION Recent cellular and molecular advances have yielded a wealth of information regarding the biology of asthma. There is an extensive cadre of cell and molecular “players” involved in asthma. It is clear that allergic inflammation is the result of a complex interaction of numerous signaling and effector events. The orchestration of this inflammatory response comprises the participation of airway cells, mast cells, and lym-

phocytes; the generation of proinflammatory cytokines; the recruitment and activation of eosinophils and neutrophils; and the development of factors in the lung that sustain these events to cause persistent airway obstruction and injury. Many questions remain to be answered, including the genetic factors at work in the initiation and regulation of this process and an individual’s susceptibility to this process. What is clear is the importance of airway inflammation to altered airway physiology in asthma and the relevance of this component of asthma as a principal therapeutic target. As further research begins to unravel more details regarding the inflammatory response, specific targets will be identified for the development of novel therapies to safely abrogate the inflammatory process and possibly cure asthma.

SUGGESTED READING Adamko DJ, Odemuyiwa SO, Vethanayagam D, et al: The rise of the phoenix: The expanding role of the eosinophil in health and disease. Allergy 60:13–22, 2005.

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Bates CA, Silkoff PE: Exhaled nitric oxide in asthma: From bench to bedside. J Allergy Clin Immunol 111:256–262, 2003. Bochner BS, Schleimer RF: Mast cells, basophils, and eosinophils: Distinct but overlapping pathways for recruitment. Immunol Rev 179:5–15, 2001. Busse WW, Lemanske RF: Advances in immunology: Asthma. N Engl J Med 344:350–362, 2001. Carlos TM, Harlan JM: Leukocyte-endothelial adhesion molecules. Blood 84:2068–2101, 1994. Friedlander SF, Busse WW: The role of rhinovirus in asthma exacerbations. J Allergy Clin Immunol 116:267–273, 2005. Goetzl EJ, An SZ, Smith WL: Specificity of expression and effects of eicosanoid mediators in normal physiology and human diseases. FASEB J 9:1051–1058, 1995. Kanaoka Y, Boyce AA: Cysteinyl leukotrienes and their receptors: Cellular distribution and function in immune and inflammatory responses. J Immunol 173:1503–1510, 2004. Lambrecht BN: Dendritic cells and the regulation of the allergic immune response. Allergy 60:271–282, 2005.

The Biology of Asthma

Lazaar AL, Panettieri RA: Airway smooth muscle: A modulator of airway remodeling in asthma. J Allergy Clin Immunol 116:488–495, 2005. Lemanske RF Jr, Kaliner MA: Late phase allergic reactions, in Middleton E Jr, Reed CE, Ellis EF, et al (eds), Allergy: Principles and Practice, vol 1. St. Louis, Mosby–Year Book, 1993, pp 320–361. Lloyd C: Chemokines in allergic lung inflammation. Immunology 105:144–154, 2002. Peters-Golden M: The alveolar macrophage the forgotten cell in asthma. Am J Respir Cell Mol Biol 31:3–7, 2004. Platts-Mills TAE: The role of immunoglobulin E in allergy and asthma. Am J Respir Crit Care Med 164:S1–S5, 2001. Rogers DF: The airway goblet cell. Int J Biochem Cell Biol 35:1–6, 2003. Sampson AP: The role of eosinophils and neutrophils in inflammation. Clin Exp Allergy 30:22–27, 2000. Umetsu DT, Akbari O, DeKruyff RH: Regulatory T cells control the development of allergic disease and asthma. J Allergy Clin Immunol 112:480–487, 2003. Williams CMM, Galli SJ: The diverse potential effector and immunoregulatory roles of mast cells in allergic disease. J Allergy Clin Immunol 105:847–859, 2000.

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46 Asthma: Epidemiology Andrea J. Apter Scott T. Weiss

I. DEFINITIONS AND PREVALENCE II. HOSPITALIZATIONS AND EMERGENCY DEPARTMENT VISITS III. TRENDS IN ASTHMA MORTALITY IV. INTERMEDIATE PHENOTYPES Airway Responsiveness Allergy Relationship of Airway Responsiveness and Allergy to Asthma V. GENETIC SUSCEPTIBILITY AND GENE-ENVIRONMENT INTERACTIONS

Asthma is a clinical syndrome that affects 20 million Americans and accounts for 12.7 million medical visits yearly. Onethird of those afflicted with asthma are children under the age of 18 years. It is estimated that roughly half of these children received their diagnosis prior to the age of 6 years. As a result, the origins of asthma are believed to have a clear genetic component that is often manifest in early childhood. The clinical course of this illness is influenced greatly by exposures, including respiratory viruses, indoor allergens, maternal tobacco smoke, and other physical and social aspects of the environment. Thus, this clinical disease has important consequences in childhood and may have important consequences for adult obstructive lung disease. Asthma is an extremely common clinical problem and the most common cause of hospitalization for children in the United States. The estimated annual direct and indirect cost of asthma care is rising dramatically and totaled approximately $16 billion in 2001 in the United States according to the National Heart Lung and Blood Institute (NHLBI). In 2002 14.7 million school days were missed due to childhood asthma, while adults missed 11.8 million work days in the same year. The paradox of this illness is that despite important strides in understanding etiologic environmental factors

VI. ENVIRONMENTAL RISK FACTORS Perinatal Factors Indoor and Outdoor Allergens Smoking and Environmental Tobacco Smoke Other Pollutants Race/Ethnicity and Socioeconomic Status Obesity Respiratory Illnesses VII. PROGNOSIS VIII. IMPLICATIONS OF CURRENT TRENDS IN PREVALENCE, HOSPITALIZATIONS, AND MORTALITY

and mechanisms of airway inflammation characteristic of the syndrome, its prevalence and morbidity remain unacceptably high. Although asthma morbidity and mortality rates have been steady over the last few years, the rates are dramatically higher than past 25 years ago and continue to be very significant, particularly for urban minority groups, low-income populations, and children. The purpose of this chapter is to describe trends in asthma epidemiology, specifically prevalence, hospitalization, and mortality. In so doing, we examine potential reasons for these trends, and the recent research on the interactions of genes and environment. We also examine the relationship of the intermediate phenotypes of airway hyperresponsiveness and allergy to the asthma syndrome and consider a variety of risk factors for asthma occurrence. We conclude with a review of asthma natural history and the implications of the current trends.

DEFINITIONS AND PREVALENCE The NHLBI defined asthma in 2002 as:

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a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. The chronic inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night and in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment.

Because asthma is a clinical syndrome, there is no gold standard for its diagnosis. As such, physicians employ nonstandardized algorithms for making the diagnosis, such as a history of wheezing or a parental history of asthma in conjunction with a favorable response to a bronchodilator to identify the asthmatic patient. Frequently, age, gender, and other patient characteristics such as smoking status or response to allergen may influence a physician’s diagnosis. Rarely are tests of airway responsiveness systematically used to investigate symptomatic patients in the clinical setting. In general, epidemiologic surveys have tended to rely on historical or questionnaire sources to identify patients with asthma. Asthma cases have been identified, either by physicians or surveys of population groups in whom the definition of who is asthmatic has been left to the patients themselves, surrogates, or the report of the diagnosis having been made by the patient’s physician. Clearly, each of these methods of identifying asthma patients has inherent weaknesses. One must, therefore, assume that some bias in the reporting of cases is present and that the biases in each method of gathering data are different. The National Health Interview Survey (NHIS) is an annual random population household interview survey that provides information on asthma prevalence in the United States. Its data demonstrate an almost doubling of asthma prevalence over the last quarter century, from 3.2 per 100 population in 1981 to 5.5 percent per 100 in 1996 (Fig. 46-1). In 1997 the NHIS questions and methodology were modified,

limiting comparisons of prevalence before and after 1997. Instead of asking whether the respondent or a family member had had asthma over the past 12 months the newer version asks, “Has a doctor or other health professional ever told you that you had asthma?” (lifetime prevalence). Information about adults can no longer be obtained from a family member or proxy. If the response is affirmative, an “attack” question is asked, “During the past 12 months have you had an episode of asthma or asthma attack?” Beginning in 2001, if the lifetime prevalence response was positive, a point prevalence or “Current” measure was added asking, “Do you still have asthma?” The data from the “Current” question, is most comparable with previous data, but not exactly the same. It indicates no rise in asthma prevalence over 2001 through 2003. The prevalence in children under 18 years is higher than adults, for example, in 2003, 8.5 per 100 compared with 6.4 (Fig. 46-1). There is a difference in prevalence by racial/ethnic groups. Until 1997 racial groups were classified as black or white with black population having slightly higher 12-month prevalence. In 2003, with an expanded racial and ethnic classification, the current prevalence was 9.2 for black nonHispanics, 5.5 for Hispanics, and 6.9 per 100 for white nonHispanics. It is noteworthy that the rate for Puerto Ricans was 14 per 100. The current data show a significant modification of prevalence by gender, in that males tend to predominate in this younger age group, whereas gender ratios equalize in the pubertal years, and females predominate throughout the rest of the adult life. For example, the current prevalence for males between 5 and 14 years in 2003 was 10.8 per 100 compared with 8.1 for females, but in adults 18 years and older female prevalence is about twice that for males. Thus, age and gender play an important role in modifying disease prevalence. There does not appear to be substantial regional variation in prevalence rates.

Child and Adult Asthma Prevalence United States, 1980-2002 Child Prevalence (%)

Adult

Lifetime

Current 12-Month

6 4 2

Attack

0 1

8 19

83 85 87 89 91 93 95 97 99 01 19 19 19 19 19 19 19 19 19 20

Year

Figure 46-1 National asthma prevalence figures from the National Health Interview Survey (NHIS). This survey was redesigned in 1997. The previous measure of asthma prevalence was a 12-month period prevalence estimate; proxy responses were accepted and no doctor diagnosis was required. This measure was replaced by two others in 1997, both of which required a medical diagnosis of asthma, and proxy reporting was eliminated. One new measure was lifetime prevalence; the second measured the occurrence of an asthma episode or attack in the past 12 months (a period prevalence). In 2001, a point prevalence measure was added to assess current asthma prevalence. If the respondent answered ‘‘yes” to the lifetime question, a second question asked, ‘‘Do you still have asthma?” As can be seen in this graph, children have higher asthma prevalence than adults on all four measures.

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Asthma* Hospital Discharge Rates# by Race: United States, 1980-2002

Rate per 10,000

45 40

Black

35 30 25 20

Other

15 10 5

White

19 81 19 83 19 85 19 87 19 89 19 91 19 93 19 95 19 97 19 99 20 01

0 Year

HOSPITALIZATIONS AND EMERGENCY DEPARTMENT VISITS Data from the National Hospitalization Discharge Survey suggest that hospitalization and emergency department (ED) visit rates for asthma have been reasonably stable from 1980 to 2002 even during a period of rising prevalence (Fig. 46-2). With respect to age, ED visits and hospitalizations are highest among children and particularly among children 0 to 4 years of age, in whom there were 59 hospitalizations and 162 per 10,000 ED visits in 2002. Females are hospitalized and make ED visits more frequently than males. What is particularly striking are racial/ethnic disparities in ED visits and hospitalizations. In 2002, the hospitalization rate for blacks was more than three times that for whites and the ED visit rate was almost five times higher than for whites. These differences are proportionally larger than the milder increase in prevalence in blacks over whites (Fig. 46-3). It is important to note that race data are frequently missing in reviewed records. Since 2000, race data have been absent from about 25 percent of hospital records.

TRENDS IN ASTHMA MORTALITY Asthma mortality rates in the United States are quite low. Figure 46-4 describes the trends in asthma mortality in the United States between 1979 and 2001. There is an overall decline in deaths since 1998, although 11 percent of that decline can be attributed to the new coding. However, the downward trend in countrywide asthma mortality belies pockets of very high prevalence, morbidity, and mortality in inner-city minority populations. These mortality rates do not represent a public health concern in an absolute sense, as the number of deaths is still very low. However, the rates do represent a clear public health

Figure 46-2 Asthma hospital discharge rates per 10,000 population from 1980 to 2002 for three racial groups; black, white, and ‘‘ other.” During this period, asthma hospital discharge rates have been consistently higher for blacks than whites. Since the late 1980s, asthma prevalence has also been higher for blacks than whites, but not sufficiently higher to explain the higher hospitalization rates. The rates for the ‘‘ other” group (other than black or white) are more variable because of the relatively smaller size of the population. Source: National Hospital Discharge Survey, National Center for Health Statistics, Centers for Disease Control. *, first-listed diagnosis; #, age adjusted to 2000 US population.

concern because almost all asthma deaths are preventable, and certain urban and minority areas have extremely high mortality rates, suggesting inadequate care practices.

INTERMEDIATE PHENOTYPES There are two intermediate phenotypes that contribute to the asthmatic syndrome: airway responsiveness and allergy. Both have a genetic component, and both are influenced by environmental factors. We will discuss these phenotypes and their interrelationship to each other and to asthma.

Airway Responsiveness Airway responsiveness is measured by quantitating the decline in lung function caused by using increasing doses of a bronchoconstrictive stimulus, such as histamine or methacholine. When the patient’s FEV1 decreases by 20 percent from its initial value, or after a maximum stimulus dose has been administered, the test is terminated. The dose at which this drop occurs is called the provocative dose (PD20 ). Individuals that manifest a PD20 at a low dose of stimulus are said to have increased airway responsiveness and are hyperresponsive to the inhaled agent. Cross-sectional population-based surveys of children and adults conducted in many different countries and using a variety of techniques for measuring airway responsiveness have shown that the prevalence of airway hyperresponsiveness is roughly 20 percent in the general population. The prevalence of increased airway responsiveness exceeds the prevalence of asthma by from two- to fivefold. These studies have also demonstrated that airway responsiveness is log normally distributed in the general population. An example of this is given in Fig. 46-5. In this population-based study of the distribution of histamine airway responsiveness, symptomatic or asthmatic subjects

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Figure 46-3 Asthma emergency department visits (top) and hospitalizations (bottom) per 10,000 populations, 2002. Hospitalizations are three times more frequent and emergency department visits almost five times more frequent among blacks. Hospitalizations are more frequent in children than adults. Source: National Hospital Ambulatory Medical Care Survey, National Center for Health Statistics, Centers for Disease Control. *, age adjusted to 2000 population.

appear at the more responsive end of the distribution, but there is considerable overlap with asymptomatic subjects. Other population-based studies have confirmed that a large number of asymptomatic subjects manifest increased airway hyperresponsiveness to this agent. It has now been well demonstrated in studies of both children and adults that airway hyperresponsiveness antedates and predicts the development of asthma. Increased airway responsiveness carries at least twice the risk for the development of asthma in children and young adults. But increased airway responsiveness is a necessary, but not a sufficient condition for the development of asthma. In all likelihood, subjects who are genetically predisposed have increased airway responsiveness. They then encounter environmental stimuli that generate airway inflammation. The inflammation then moves them in the direction of greater responsiveness and the development of respiratory symptoms. This theoretical paradigm is graphically depicted in Fig. 46-6. A variety of mechanical factors influence airway responsiveness. First, and most important, is the level of lung

function. Individuals with lower levels of lung function are more likely to have increased airway responsiveness. In part, this is simply a mathematical phenomenon. Since airway responsiveness is expressed as a percent change from baseline, baseline value will obviously be important in determining the level at which an individual would be considered responsive (i.e., have a PD20 ). This can be best understood with a simple mathematical example. A man with a 5-L FEV1 would be required to drop his pre-challenge level of lung function by 1 L to achieve a PD20 for FEV1 . In contrast, a man with a 500-ml FEV1 will only need to drop his FEV1 by 100 ml to achieve a comparable PD20 for FEV1 . Other factors, such as the central deposition and distribution of the inhaled aerosol, the fact that airflow is inversely proportional to the fourth power of the airway radius, and baseline bronchomotor tone all contribute to the relationship of lung function to airway responsiveness. For this reason, airway responsiveness is likely to be increased at the extremes of age (i.e., in children and older adults) and reduced in young adults between the ages of 15 and 45 years.

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Asthma Mortality Rates* by Race, United States: 1979-2001 50 Black

Other

30 20

White

0 19

Rate per million

ICD-10

ICD-9

Year

Figure 46-4 Asthma mortality trends. Since1998, both the overall number of deaths and the rate have clearly declined. However, a new mortality coding scheme was implemented in 1999. About 11 percent of the decline in asthma deaths can be attributed to the new coding scheme. This graph shows the difference in mortality rates by race. The green line is the mortality rate for blacks, the red line is for whites, and the yellow line represents all other races combined. Clearly, asthma mortality rates rose for each of these three racial groups during the period before 1995. Source: Underlying Cause of death: National Center for Health Statistics. *, age-adjusted to 2000 population.

Figure 46-5 The log-transformed distribution of histamine airway responsiveness from a random population of subjects in the Netherlands. Note that symptomatic subjects are more common in the responsive end of the distribution. (From Rijcken B, Schouten JP, Weiss ST, et al: The distribution of bronchial responsiveness to histamine in symptomatic and in asymptomatic subjects. Am Rev Respir Dis 140:615â&#x20AC;&#x201C;623, 1989, with permission.)

Figure 46-6 The effect of environmental exposures on the population distribution of airway responsiveness acting to move people in a more responsive direction. (Reprinted from Brown RW, Weiss ST (eds): Seminars in Respiratory Infections, vol. 6, The Influence of Lower Respiratory Illness on Childhood Asthma: Defining Risk and Susceptibility. Seminar Respir Infect 6:225â&#x20AC;&#x201C;234, with permission.)

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Allergy Allergy refers to immediate (Type 1) hypersensitivity to environmental antigens. It is characterized by wheal and flare reactions to skin testing with common environmental antigens, usually with appropriate clinical history. Atopy is the demonstration of allergy and familial aggregation of this trait. The pathophysiology of the allergic response has been explained by a conceptualization sometimes called the TH1TH2 paradigm of CD4+ T helper cells. This model, summarized in Fig. 46-7, is also the basis for much recent clinical research seeking to understand the development of asthma. Antigen presenting cells (APCs) display peptide antigens, either allergen or infectious, on their cell surfaces for recognition by na¨ıve T cells (TH0). TH0 differentiate into TH1 or TH2 cells, depending on the nature of the antigen, the characteristics of the APC, local concentration of cytokines, and other factors not fully understood. TH1 cells secrete IFN-γ, while TH2 cells secrete IL-4 and IL-5. For example, activation of APC by microbial products results in production of IL-12 and TH0 cells differentiate into TH1 cells. The presence of IL-4 results in differentiation of TH0 cells into TH2 cells. TH2 cells promote allergic inflammation through the production of cytokines including IL-4, IL-5, and IL-13. IL-4 and IL-13 induce B lymphocytes to differentiate into IgEproducing plasma cells. IL-5 secreted by TH2 cells results in eosinophilopoiesis and resistance to apoptosis. In addition to IFN-γ, TH1 cells produce tumor necrosis factor-β (TNF-β) and IL-2. A TH1 response results in activation of macrophages

Figure 46-7 The TH1-TH2 paradigm. The figure depicts the developing immune system and the cytokines elaborated by mature CD4+ T lymphocytes in both Th1 and Th 2 cells. It also shows the central role of T-regulatory cells in controlling Th 1 and Th 2 clinical expression.

and natural killer cells and production of IgG1, which plays a role in complement binding and opsonization.TH1 and TH2 cells cross-regulate each other. That is, IFN-γ inhibits TH2 proliferation and IL-4 inhibits IFN-γ–induced macrophage activation. T-regulatory cells are recently characterized cells that inhibit TH1 and TH2 cells. TH1 and TH2 cells also interact with cells of the innate immune system. The relationship of acute inflammation to chronic irreversible processes in targeted cells like smooth muscle, in airway remodeling, is another area of expanding interest to researchers. Recent research suggests the TH1-TH2 paradigm is more complex than as described above. In mouse models of asthma, TH1 and TH2 cells have been observed to synergistically promote inflammation and airway hyperresponsiveness. In a birth cohort of 172 children, Heaton et al found allergic diseases and asthma associated with IL-4, IL-5, IgE production, and eosinophilia; but they also found IFN-γ production associated with airway hyperreactivity and skin-test reactivity. Additionally, the investigators found that cytokine patterns among the children were heterogeneous. Clinical Markers of Allergy A variety of clinical allergy markers have been utilized in epidemiologic studies of asthma based on the TH1-TH2 paradigm. Specific and total IgE, measured by skin or serologic testing, assess sensitization as well as exposure to environmental antigens and frequently are used to determine the prevalence of allergic responsiveness. Skin test reactivity depends on at least three separate factors: (1) an intact immune system; (2) the presence of IgE-sensitized mast cells that release mediators when exposed to antigen; (3) and skin that can respond to histamine with the development of an inflammatory response, including erythema and induration. Although these manifestations of an allergic response depend on prior exposure to environmental antigen, they do not measure or take into account the level of exposure in the environment. Total serum IgE, although used in epidemiologic studies, has relatively limited value in the diagnoses of atopic diseases, with the exception allergic bronchopulmonary aspergillosis (see Chapter 49). Although total and specific IgE levels correlate with each other and with skin test results, no level of total IgE avoids misclassifying a significant proportion of those with and without allergic diseases. The limitations in clinical information imposed by these tests limit their utility when they are used epidemiologic studies. Total and specific IgE measurements appear to be comparable in males and females. Both increase with age and peak at approximately age 15 years. After this time, there is a progressive decline, although the decline in skin test reactivity exceeds the reduction in total serum IgE, perhaps related to local factors in the skin. Clinical Implications of the TH1-TH2 Paradigm As indicated, processes that lead to the development of a hypothesized TH2-dominant phenotype in early life are

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complex and the subject of ongoing research. It is believed that IgE responses to inhalant allergens are commonly set in early childhood. It is also believed that sensitization, i.e., production of IgE directed at environmental antigens, is not only a function of genetic susceptibility, dose, timing, and duration of allergen exposure, but also may reflect exposure to other environmental antigens, particularly microbial or viral organisms. One hypothesis of the development of atopic disease, the “hygiene hypothesis,” states that the development of TH1 responses are dependent upon early exposure to infection. Since newborns are thought to have TH2-dominant immune responses, the development of TH1 responsiveness depends upon exposure to infection. That is, respiratory or gastrointestinal infections may stimulate macrophages to produce interferon-α and IL-12 that stimulate NK cells to produce IFN-γ, which would inhibit the development of a TH2-type response. The Tucson Epidemiologic Study, a birth cohort of 1246 subjects, noted that children who had a nonwheezing lower respiratory tract illness before 9 months of age had lower total IgE levels at 9 months and 6 years of age when compared with children who had no lower respiratory illnesses before 9 months of age. These children were also less likely to be atopic than those who had no lower respiratory tract illnesses. These investigators also found that children exposed to more siblings at home or to day care in the first 6 months of life, presumably exposed to more infections, were protected from the development of asthma between ages 6 and 13 years. Interestingly, investigators from Norway using a birth cohort of 2540 children followed until age 10 did not find a protective effect of early respiratory infections and the subsequent development of asthma or day care attendance. This research confirms the complexity of environmental influences on the immune system. The TH1-TH2 paradigm will need further exploration of its explanatory ability in asthma.

Relationship of Airway Responsiveness and Allergy to Asthma Atopy and increased airway responsiveness are separate but related factors, both of which contribute to the development of the asthma phenotype. Over 80 percent of childhood asthmatics are atopic and there are many studies of exposure to allergen in sensitive individuals associated with bronchospasm. Thus, exposure and sensitization are linked to airway responsiveness. But individuals may have airway hyperresponsiveness without atopic manifestations. The introduction of omalizumab, a recombinant, humanized anti-IgE antibody, is helping to elucidate the relationship of airway responsiveness and allergy. Omalizumab lowers total serum IgE and reduces eosinophils in sputum. In some studies it has allowed reduction of corticosteroid therapy, but in others it has failed to show reduce airway hyperresponsiveness, supporting the notion that airway hyperreactivity and allergy have other separate influences. Current research explores the relationship between exposure to allergen and the subsequent development of

Asthma: Epidemiology

asthma. A birth cohort design has been used to examine this relationship. Preventing loss of participants to follow-up makes these studies difficult to conduct. It is also difficult to measure exposure to allergen, that is, to quantify inhalation by subjects, while accounting for intermittent and varying exposure over time and place. Furthermore, there is an imperfect correlation among skin test reactivity, total serum IgE level, and peripheral blood eosinophil count, such that no single phenotypic marker completely defines the atopic state. Nevertheless, in studies of children with atopic parents, exposure is associated with the development of asthma. Sensitization, a reflection of exposure and genetics, has also been associated with the development of asthma. It is likely that where no relationship is found between exposure and the development of asthma, genetic influences are not present, i.e., the majority of the studied families are not atopic. The Tucson Respiratory Study showed that patterns of wheezing and lung function tend to be established by age 6. Increased sensitization and higher levels of indoor allergens (exposure) may be important risk factors that have changed in the past 30 years, potentially accounting for some of the increased prevalence of asthma. Buildings with synthetic wallto-wall carpeting, higher humidity, cloth-upholstered furniture, and bed-reduced ventilation have higher levels of house dust mites and other indoor allergens. Evidence from Scandinavian studies suggests that thermally tighter homes have been associated with higher indoor allergen levels. Other risk factors, notably maternal cigarette smoking, childhood respiratory infection, and the effects of poverty, likely contribute to the development of asthma. Such research demonstrates that environmental-gene interactions contribute to the development of asthma.

GENETIC SUSCEPTIBILITY AND GENE-ENVIRONMENT INTERACTIONS Geneticists describe asthma as a complex disease, a disease in which many genes influence the development and phenotype of asthma, each having only a small influence. Since the human genome project was completed in 2000, remarkable advances have been made in identifying asthma genes. There are two main types of genetic studies; linkage studies and association studies. In an association study, candidate genes are examined to determine a statistical association between polymorphism in the gene and asthma phenotypes; either cases and controls or trios can be used. These studies focus on known pathophysiology. Linkage studies start with families with wellcharacterized phenotypes such as asthma. Genes within families are examined for linkage, the sharing of genes markers that may be located near or at the disease gene. Association studies are then used to follow up and “fine map” the linkage peak. These studies focus on novel genes. To date five genes: ADAM 33, DPP10, PDH11, GPRA, and HLA-G, have been identified by linkage and fine

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mapping. Fifteen other genes: IL1R, IL4, IL4RA, IL13, LTC4S, CTLA4, SCYA11, ADRB2, CD14, SPINK5, NOS1, STAT6, HLA-DRB, FCER1B, TGFB1, have been replicated in four or more genetic association studies. This is more than what has been found for many other complex traits.

ENVIRONMENTAL RISK FACTORS Below we present some of the most important environmental risk factors for the development or exacerbation of asthma not discussed earlier.

Perinatal Factors Prematurity carries an increased risk for the development of asthma. Prematurity also is associated with bronchopulmonary dysplasia, a disease characterized by increased airway responsiveness and asthma symptoms. Some investigators have found that low birth weight independent of prematurity has been associated with asthma risk. Note that blacks have higher rates of prematurity than whites; thus, prematurity may contribute to racial differences in asthma prevalence and morbidity. Young maternal age (i.e., less than 20 years) has not been shown to have a consistent independent association with the development of asthma. Despite much research, there is no conclusive evidence that breastfeeding influences atopic sensitization or the development of asthma.

Indoor and Outdoor Allergens Indoor allergen sources include animals (cats, dogs, rodents); insects (mites, cockroaches); and fungi. Allergens from pets, particularly cats, are well-known precipitants of asthma exacerbations. There has been some recent investigation as to whether exposure to pets would be useful in preventing asthma, but most data indicate an increased risk of the development of asthma in homes of atopic families with pet exposure (i.e., a genetic-environmental interaction). It is noteworthy that animal allergens, particularly cat allergen, can be found in settled dust and in circulating air in homes, school classrooms, and other buildings that never housed a cat. House dust mites are ubiquitous in all but very dry climates and sensitization to mite body and fecal allergens is associated with asthma. Mites infest fabrics, including mattresses, bedding, floor coverings, and upholstered furniture. The use of wall-to-wall carpets has increased exposure to mites. Covering mattresses and pillows with vapor-permeable fine weave materials, washing bedding in hot (greater than 130â&#x2014;Ś F) water, vacuuming weekly, and removing carpets, especially from the bedroom, reduce mite levels. Whether reducing exposure results in improvement in asthma outcome has been difficult to ascertain. Horak and coworkers randomly assigned 696 infants to receive miteimpermeable mattress encasings and their parents education about reduction of mite exposure. The control families re-

ceived educational information in which avoidance of mite exposure was not presented. The investigators were unable to show a protective effect against the development of asthma. In contrast, a recent small study showed efficacy in prevention of asthma exacerbations. Adherence to the demanding protocols for control of mite exposure is difficult and whether control of exposure without other simultaneous interventions like control of environmental tobacco smoke (ETS) or pet exposure is not yet established. Sensitization to cockroach has been shown to be associated with the development of asthma and asthma morbidity. Although the presence of this allergen is not limited to low-income homes, it has not been studied in more affluent settings. Removal of this allergen is difficult and more research is needed to evaluate the impact on asthma of allergen removal. Although home and school dampness and the presence of fungi have been associated with reports of respiratory symptoms, it has not been determined whether mold allergens or mold-derived irritants or other factors are involved. Some recent studies have employed multifaceted environmental interventions making assessment of individual factors impossible. None have been conclusively successful. Day care establishments may be sources of indoor allergens, including pets, insects, fungi. They also may be sources of gram-negative bacterial endotoxin and lipopolysaccharides, which induce TH1 activity and have been hypothesized to be protective against the development of allergy and asthma. However, longitudinal studies have not consistently supported this notion. A recent study found that day care exposure was associated with increased risk of wheeze in the first 6 years of life in children with a maternal history of asthma. Day care and presumably endotoxin exposure were not protective in this study. Outdoor allergens include trees, grass, and weed pollen constituents. Susceptible individuals may have increased asthma symptoms at times of pollination. For example, in the Northeast and Midwest grass pollinates in May and June and ragweed in late August and September. Pollens most closely linked to exacerbations of asthma in at-risk individuals are trees such as birch, oak and Western red cedar; grasses; and ragweed.

Smoking and Environmental Tobacco Smoke Maternal cigarette smoking is a major risk factor for the development of asthma in the first year of life. The risk of developing asthma is roughly twofold in infants born to nonatopic mothers who smoke but increases to almost fourfold in infants of allergic parents with mothers who smoke. The predominant effect of maternal cigarette smoking is due to in utero exposure with decreased lung function at birth. A large population-based birth cohort study from Finland by Jaakkola and Gissler shows that infants of mothers who smoke carry increased risk of developing asthma through the first 7 years of life and only a small fraction of the effect during the first 7 years is mediated by fetal growth. It

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is also clear that maternal cigarette smoke exposure is associated with a greater occurrence of lower respiratory tract infections. ETS exacerbates asthma in children of all ages. Wilson and coworkers evaluated a cotinine-feedback behavioral intervention administered to caregivers which successfully reduced ETS exposure and health care utilization by children with asthma at one year follow-up. In adults, cigarette smoking is associated with the development of airway hyperreactivity. Whether this hyperreactivity represents asthma or COPD can be difficult to determine. Cigarette smoking in asthma produce a synergistic and accelerated decline in lung function. Additionally, the response to corticosteroid therapy used for asthma is reduced in active smokers.

Other Pollutants Outdoor pollutants implicated in the development or exacerbations of asthma include ozone, sulfur dioxide, particulate matte, and components of motor vehicle exhaust. Measuring exposure to potential pollutants is difficult and correlating exposure with symptoms and exacerbations of disease is very expensive. Most monitoring of pollutants is from fixed external stations. Sometimes proxy measures of pollutant exposure, such as traffic counts, are used. Although potentially more accurate, monitoring of personal exposures is particularly difficult and expensive. Assessing which of the many possible simultaneous outdoor inhalants affects asthma morbidity is also a formidable task. Conclusions drawn from such data may be indirect. An example is the observation that asthma morbidity is highest among low-income individuals who tend to live in less desirable areas, which are frequently those with high traffic volumes and pollution. There has been much interest in indoor environmental pollutants, such as nitrogen dioxide, sulfur dioxide, volatile organic compounds, and particulate matter, and their possible association with asthma, particularly in inner city homes. As with studies of outdoor pollution difficulties in measurement over time, controlling for other exposures such as allergens, infectious agents, and social determinants of health, while linking exposures to symptoms and physical findings makes research challenging.

Race/Ethnicity and Socioeconomic Status Asthma prevalence and especially morbidity and mortality are higher in blacks than whites. Whether these racial differences in asthma prevalence, hospitalization, and mortality are solely due to inadequate treatment and access to medical care remains unclear, but there is indisputable evidence of unequal treatment of minority and low income groups by health professionals. Additionally, environmental factors that are the products of poverty, such as urban crowding, exposure to tobacco smoke or other pollutants or allergens contribute to these findings. In one recent paper, maternal exposure to community violence was related to asthma morbidity of children, even controlling for socioeconomic status,

Asthma: Epidemiology

housing deterioration, and negative life events such as the death of a family member. There is much current debate about the relative importance of social and genetic effects and/or gene-environment interactions that might account for the health disparity seen in asthma and other diseases. In most studies race and ethnicity are not well-defined and socioeconomic factors tend to be inseparably linked to ethnicity and race. Perceptions of a personsâ&#x20AC;&#x2122; race influence social experiences including those with the health system. In a recent survey, black and Hispanic women were more likely to report a doctorâ&#x20AC;&#x2122;s diagnosis of asthma and less likely to report a diagnosis of hayfever or eczema. However, these women had higher mean total IgE levels and were more likely to be sensitized to aeroallergens. The investigators concluded that these findings could represent either under-diagnosis by medical personnel (e.g., fewer referrals to an allergist or other specialist) or under-reporting of symptoms by patients. They also concluded that it was unlikely that genetics alone could explain the differences in sensitization and that these differences more likely were related to differences in housing and community environmental exposures. There are many ethnic groups within the United States for whom there is no information on asthma morbidity and access to care. It was noted earlier that minority status is missing from 25 percent of surveys of the National Hospital Discharge Survey. This survey finds Puerto Rican ethnic groups have very high morbidity from asthma, while recent studies have not shown the same effect in Mexican groups. Social effects might account for this difference among Hispanic groups. Non-Puerto Rican Hispanics are more likely to be illegal residents, making it less likely that these persons will seek medical care and, less likely that they will be counted in health statistics. As our cultural and ethnic diversity increases, communication between patient and health care provider becomes more complicated and miscommunication more likely. Miscommunication may result in mistrust of the medical advice, or refusal of treatment and poor adherence and thus contribute to health disparities. Supporting this argument we found patients beliefs in the risks over the benefits of inhaled steroids to be associated with lower adherence. In focus groups, blacks with moderate or severe asthma reported their adherence was influenced by reliance on their own assessment of asthma control over that of the health provider. They expressed concern about adverse effects of inhaled steroid therapy and several had misperceptions of their risks. Such misperceptions can be addressed in the patient-provider encounter. Adherence was also adversely affected by the cost of the medication or its copay and insurersâ&#x20AC;&#x2122; approval policies and restricted formularies.

Obesity Obesity has reached epidemic proportions in the United States and has been related to asthma in cross-sectional and longitudinal studies. A number of mechanisms for this

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relationship have been proposed. A mechanical effect is postulated to be the result of decreased tidal volume and decreased functional residual capacity leading to reduced ability of the smooth muscles to stretch and thus respond to changes in respiration with exercise. Obesity enhances gastroesophageal reflux, a condition associated with asthma. Immune effects also have been postulated. For example, certain inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and IL-6 are expressed by adipocytes. TNF expression is increased in asthma exacerbations and may have a role in amplifying the inflammatory response of asthma. IL6 stimulates a Th1 response which may contribute to the inflammation of severe asthma. Leptin, a product of adipocytes, is a member of the IL-6 cytokine family. Whether or not leptin plays a role in asthma is unknown. Because asthma in adults is more common in women and because estrogen is increased in obesity, estrogen has been hypothesized to play a role in a link between asthma and obesity but no such role has been demonstrated. Since asthma and obesity are both complex diseases, it is possible that some genetic susceptibilities are shared (pleiotropy). There is some evidence for this in that there are regions of the human genome important for both asthma and obesity, such as chromosome 6p, which contains the gene for TNF. Alternatively, it is possible that obesity is related to asthma as an epiphenomenon; that is, that there are shared lifestyle or social exposures, for example, physical exercise or diet, that influence both obesity and asthma. Obesity is more prevalent in the same socioeconomic groups in which asthma is more prevalent. No randomized interventional studies have been completed showing that weight reduction ameliorates asthma.. Clearly, more research is needed.

risk of developing asthma. Most children who wheezed only during the first 2 years of life had lower levels of lung function when evaluated at age 2 and 6 years. In contrast, children who wheezed early in life and who were still wheezing at age 6 years had normal lung function, but statistically elevated serum total IgE levels when studied during the first year of life. When restudied at age 6 years, they had elevated IgE, but lung function had deteriorated and was below that of individuals who had never wheezed. This has led to the hypothesis that there are two wheezing syndromes associated with lower respiratory tract infection in young children. One occurs in children with small airway caliber who lack bronchial hyperresponsiveness, and have excellent prognosis. The other syndrome, which represents early-onset asthma, is associated with increased prevalence of allergic markers, bronchial hyperreactivity, and a significant decrease in lung function over the first 6 years of life. RSV bronchiolitis is most prominently associated with the development of asthma in patients with a concomitant family history of atopy and/or asthma. Viral respiratory illnesses trigger asthmatic exacerbations. A number of studies have demonstrated a close temporal relationship, at the individual and population level, between virus infection and asthma exacerbations. These studies have also demonstrated that: (1) in contrast to viral, bacterial infections are not associated with asthmatic exacerbations; (2) viruses precipitate a high percentage of severe (versus mild) asthmatic exacerbations; and (3) viral infections can induce nonspecific increases in airway responsiveness and airway obstruction in children.

PROGNOSIS Respiratory Illness There is a prominent association between lower respiratory tract viral infections and wheezing illnesses in infancy and increased risk of chronic childhood asthma. Respiratory syncytial virus (RSV) has drawn particular attention, since it is the major cause of bronchiolitis in children and RSV infection is associated with IgE production, airway inflammation, and increased airway responsiveness. Severe RSV bronchiolitis in infancy is associated with the development of chronic wheezing in later life. Respiratory tract infections by rhinoviruses, parainfluenza viruses, influenza virus, and human metapneumovirus during infancy are all associated with childhood wheezing. It is hypothesized that susceptibility to asthma associated with viral infection in early life results from the interaction of developmental, genetic, and environmental factors. Developmentally, infancy is a time of pulmonary alveolarization and a time when the immune system has not reached full maturity. It has also been observed that most children who wheezed before 2 years of age had few if any respiratory symptoms when studied 3 to 5 years later. Atopic status and bronchial hyperreactivity may be important genetically determined characteristics that influence whether RSV or other respiratory viral infections increase the

The prognosis of asthma in early childhood has been clarified substantially by data from the Tucson Epidemiologic Study. These investigators followed a cohort of children through the first 6 years of life. They characterized four groups of children: “persistent wheezers,” who wheezed both before and after the age of 3 years; “transient early wheezers,” who wheezed before the age of 3 years and then stopped; “transient late wheezers,” who wheezed after age 3 years but not before; and “never wheezers.” Fully 40 percent of all children in the Tucson Epidemiologic cohort wheezed in the first year of life. Significant predictors of persistent wheezing, and hence children at greatest risk for developing chronic asthma, were young maternal age, IgE level at 9 months, parents with asthma, maternal cigarette smoke exposure in utero, abnormal lung function at birth, and male gender. It is likely that early-life wheezing is predominantly a mechanical factor and less due to severe and chronic airway inflammation. It also seems unlikely that allergen exposure predominates as a factor in early childhood. The characteristics of older children who wheeze are atopy, female gender, and active and passive cigarette smoking. By preadolescence, atopy and environmental allergen exposure are important risk factors for wheezing in children.

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In roughly half of all childhood asthmatics, symptoms decrease or disappear by late adolescence and early adulthood. Characteristics that suggest a good prognosis include male gender, precipitation of attacks by viral respiratory illness, and children with airway parenchymal desynapsis (i.e., large lungs but small airways). These children are predominantly male, and, although often atopic, still are likely to outgrow their asthma. In a longitudinal study of children initially 5 to 9 years of age followed over a 13-year period, the effect of asthma on lung growth was different for boys than girls. Boys with asthma had larger growth in vital capacity than boys without asthma and tended to have mild disease. This was associated with fewer hospitalizations for asthma, despite somewhat greater prevalence than in girls. Asthmatic girls, however, had persistent reductions in FEV1 and were more likely to be hospitalized for asthma, despite an initially reduced prevalence relative to the boys. These data are consistent with asthma being milder in boys in that the boys are more likely to “outgrow” their asthma. Existing data suggest that atopy per se is not a risk factor for asthma persistence. In older adults, airway responsiveness predicts the development of asthma and antedates and predicts accelerated decline in lung function. Active cigarette smoking further increases the risk of asthma in older adults. Several studies suggest that asthma in adults with or without active cigarette smoking is associated with the development of fixed airflow obstruction. The severity of adult asthma is clearly predicted by the severity of childhood asthma, and the persistence of symptoms in childhood and early adulthood is associated with reduced lung function and more severe disease in later adult life.

IMPLICATIONS OF CURRENT TRENDS IN PREVALENCE, MORBIDITY, HOSPITALIZATIONS, AND MORTALITY Although prevalence, morbidity, and hospitalizations have remained stable recently, these absolute levels remain unacceptably high, particularly for certain minority groups and low-income populations. Risk factors such as obesity, prematurity, young maternal age, and cigarette smoking are all associated with these same patient groups, speaking to social and health care disparities. There are many vulnerable groups for which no data on asthma prevalence and morbidity yet exist. Certainly, genetic differences exist from patient to patient. These differences must be better characterized. Understanding the influence of gene-gene and gene-environment interactions is crucial. Gene-environmental interactions must be carefully studied for all exposures, and particularly for the exposure of socioeconomic status and cultural groups.

ACKNOWLEDGMENTS We gratefully acknowledge the Air Pollution and Respiratory Health Branch, National Center for Environmental Health,

Asthma: Epidemiology

CDC, for production of Figs. 48-1, 48-2, and 48-4. We particularly would like to thank Jeanne Moorman, MS, for her help with the figures and review of relevant parts of the chapter, and Anyana Banerjee for helping to guide us to relevant data. We also would like to thank Lara Akinbami, MD, National Center for Health Statistics, for her assistance and for the National Center for Health Statistics for production of Fig. 48-3. We greatly acknowledge the careful review and suggestions of Arnold I Levinson, MD.

SUGGESTED READING Apter AJ, Boston R, George M, et al: Modifiable barriers to adherence to inhaled steroids among adults with asthma: It’s not just black and white. J Allergy Clin Immunol 111:1219– 1226, 2003. Apter AJ, Eggleston P: Controlling the environment of asthmatic children: Benefits and limitations. In: L’Enfant C, Szefler S, Pedersen S (eds), Childhood Asthma: Breaking Down Barriers. New York, Marcel Dekker, 2005, pp 187– 212. Brown RW, Weiss ST (eds): Seminars in Respiratory Infections, vol. 6, The Influence of Lower Respiratory Illness on Childhood Asthma: Defining Risk and Susceptibility, St. Louis, Elsevier, 1991, pp 225–234. Brussee JE, Smit HA, van Strien RT, et al: Allergen exposure in infancy and the development of sensitization, wheeze, and asthma at 4 years. J Allergy Clin Immunol 115:946–952, 2005. Celedon JC, Litonjua AA, Ryan L, et al: Exposure to cat allergen, maternal history of asthma, and wheezing in first 5 years of life. Lancet 360:781–782, 2002. Celedon JC, Wright RJ, Litonjua AA, et al: Day care attendance in early life, maternal history of asthma, and asthma at the age of 6 years. Am J Respir Crit Care Med 167:1239–1243, 2003. Djukanovic R, Wilson SJ, Kraft M, et al: Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma. Am J Respir Crit Care Med 170:583–593, 2004. Expert Panel Report: Guidelines for the diagnosis and management of asthma. Update on selected topics—2002. J Allergy Clin Immunol 110:S141–S218, 2002. George M, Freedman TG, Norfleet AL, et al: Qualitative research enhanced understanding of patients’ beliefs: Results of focus groups with low-income urban African American adults with asthma. J Allergy Clin Immunol 111:967–973, 2003. Heaton T, Rowe J, Turner S, et al: An immunoepidemiological approach to asthma: identification of in-vitro T-cell response patterns associated with different wheezing phenotypes in children. Lancet 365:142–149, 2005. Hoffjan S, Nicolae D, Ober C: Association studies for asthma and atopic diseases: A comprehensive review of the literature. Respir Res 4:14, 2003.

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Horak F Jr, Matthews S, Ihorst G, et al: Effect of miteimpermeable mattress encasings and an educational package on the development of allergies in a multinational randomized, controlled birth-cohort study: 24 months results of the Study of Prevention of Allergy in Children in Europe. Clin Exp Allergy 34:1220–1225, 2004. Gern JE, Rosenthal LA, Sorkness RL, et al: Effects of viral respiratory infections on lung development and childhood asthma. J Allergy Clin Immunol 115:668–674; quiz 75, 2005. Institute of Medicine: Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care: Institute of Medicine. Washington DC, The National Academies Press, 2003. Jaakkola JJ, Gissler M: Maternal smoking in pregnancy, fetal development, and childhood asthma. Am J Public Health 94:136–140, 2004. Lau S, Illi S, Platts-Mills TA, et al: Longitudinal study on the relationship between cat allergen and endotoxin exposure, sensitization, cat-specific IgG and development of asthma in childhood: Report of the German Multicentre Allergy Study (MAS 90). Allergy 60:766–773, 2005. Litonjua AA, Celedon JC, Hausmann J, et al: Variation in total and specific IgE: Effects of ethnicity and socioeconomic status. J Allergy Clin Immunol 115:751–757, 2005. Morgan WJ, Stern DA, Sherrill DL, et al: Outcome of asthma and wheezing in the first six years of life: Follow-up through adolescence. Am J Respir Crit Care Med 172:1253– 1258, 2005. Nafstad P, Brunekreef B, Skrondal A, et al: Early respiratory infections, asthma, and allergy: 10-year follow-

up of the Oslo Birth Cohort. Pediatrics 116:e255–262, 2005. National Center for Health Statistics: National Center for Health Statistics, 2005. Accessed 10/2/2005, 2005, at http://www.cdc.gov/nchs Peden DB: The epidemiology and genetics of asthma risk associated with air pollution. J Allergy Clin Immunol 115:213– 219; quiz 20, 2005. Raby BA, Celedon JC, Litonjua AA, et al: Low-normal gestational age as a predictor of asthma at 6 years of age. Pediatrics 114:e327–332, 2004. Rijcken B, Schouten JP, Weiss ST, et al: The distribution of bronchial responsiveness to histamine in symptomatic and in asymptomatic subjects. Am Rev Respir Dis 140:615–623, 1989. Taussig LM, Wright AL, Holberg CJ, et al: Tucson Children’s Respiratory Study: 1980 to present. J Allergy Clin Immunol 111:661–675; quiz 76, 2003. van den Bemt L, van Knapen L, de Vries MP, et al: Clinical effectiveness of a mite allergen-impermeable bed-covering system in asthmatic mite-sensitive patients. J Allergy Clin Immunol 114:858–862, 2004. Weiss ST: Obesity: insight into the origins of asthma. Nat Immunol 6:537–539, 2005. Wilson SR, Yamada EG, Sudhakar R, et al: A controlled trial of an environmental tobacco smoke reduction intervention in low-income children with asthma. Chest 120:1709– 1722, 2001. Wright RJ, Mitchell H, Visness CM, et al: Community violence and asthma morbidity: The inner-city asthma study. Am J Public Health 94:625–632, 2004.

47 Aspirin- and Exercise-Induced Asthma Gregory P. Geba

I. ASPIRIN-INDUCED ASTHMA Clinical Presentation Genetics Cross-Reactivity Pathogenesis Diagnosis Treatment

Asthma is well known to be triggered by specific immune factors such as aeroallergen exposures. There are, however, several important nonallergic triggers for the development of asthmatic bronchial obstruction. Two of the most important are aspirin and related nonsteroidal anti-inflammatory drugs (NSAIDs), and exercise. Both of these can provoke airway responses in individuals with established symptomatic aeroallergen-induced asthma or, in some instances, seem to occur in isolation. These two nonspecific triggers may also share pathophysiological mechanisms, including mast cell and leukotriene mediation and appear to be, in part, related to vascular responses that may mediate the airway narrowing.

ASPIRIN-INDUCED ASTHMA The first report of aspirin-induced asthma (AIA) was made by Hirschberg in 1902. Six decades later, the association between aspirin sensitivity, asthma, and nasal polyps was documented in a classic paper by Samter and Beer. In 1928, the clinical importance of sensitivity to aspirin was highlighted by van Leewen, who challenged 100 asthmatics with aspirin, provoking bronchoconstriction in 16. Several others have made similar observations, documenting a prevalence of aspirin sensitivity in asthmatics that ranges from 5 percent to as high as 30 percent, depending on the characteristics of the asthmatics studied (severity increases risk) and the criteria applied to make the diagnosis.

II. EXERCISE AND ASTHMA Clinical Presentation Pathophysiology Genetics Differential Diagnosis Physiological Documentation Treatment

Aspirin was the first drug recognized to be capable of precipitating asthma. With the development of other analgesic and NSAIDs after 1950, these related agents were also implicated in exacerbations of asthma. In a study of 781 asthmatics observed over a period of 2 years, drugs were found to provoke asthmatic airway responses in 10.5 percent of the patients. Reactions to NSAIDs were thought to be responsible for 77 percent of the exacerbations, with aspirin accounting for two-thirds of the reactions to NSAIDs, or nearly 50 percent of all instances of drug-induced asthma. Thus, although aspirin is the most common drug to induce asthma and the most common NSAID to cause asthma, other NSAIDs are responsible for an important number of attacks of asthma.

Clinical Presentation Reactions to aspirin can take two distinct forms: cutaneous, leading to urticaria and angioedema, and respiratory, resulting in rhinoconjunctivitis and bronchospasm. In the former, a subpopulation of patients with established urticaria experienced cutaneous flares of hives with or without angioedema after ingesting NSAIDs. Almost all of these patients were able to ingest the same NSAIDs before the development of urticaria, suggesting that the NSAIDs interact with an underlying urticarial process but do not directly and independently cause the hives. Therefore, avoiding the ingestion of NSAIDs does not eliminate the urticarial syndromes experienced by these patients. In contrast, a small subgroup of patients experienced hives exclusively after exposure to these

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drugs, without an antecedent history of underlying chronic urticaria. It is postulated, although, not proven, that such patients manifest immunoglobulin E (IgE)-mediated immune responses to some NSAID-related antigen. NSAID avoidance therefore is an effective treatment for urticaria in these patients. In general, the upper (nasal) and lower (asthma) respiratory manifestations of aspirin sensitivity are generally temporally linked, although sometimes upper respiratory symptoms, typically rhinitis, precede the development of lower respiratory asthmatic reactions to these agents. AIA can occur upon a background of established asthma or can appear de novo without previous symptoms of asthma. This observation has led to the use of more accurate descriptors for this condition such as: aspirin-intolerant asthma or aspirinexacerbated respiratory disease (AERD); the latter is used to account for the full spectrum of respiratory symptoms that can be provoked by aspirin. Clinically, patients often first present with what appears to be an upper respiratory tract illness of viral origin leading to persistent inflammation of the nasal mucosa and paranasal sinuses, which becomes chronic. Chronic nasal inflammation is characterized by impressive mucosal eosinophilic infiltration which frequently leads to the development of nasal polyps. These patients usually cannot be distinguished from asthmatics with sinusitis and nasal polyps until the relationship is established between the ingestion of aspirin or related

compounds and exacerbation of asthma. Although nasal polyps were originally described by Samter as part of the classic triad, it is becoming increasingly evident that polyps are often absent. In contrast, almost all cases present with sinusitis. Opacification of one or more sinuses on plain radiographs can be seen in some 90 percent of these patients; an even higher prevalence of sinus disease may be detected by computed tomography (CT) sinus scans that typically show mucosal thickening and, sometimes, air-fluid levels. Many patients with AIA are not atopic; aeroallergen skin testing is positive in 30 to 60 percent of these patients, but skin tests are negative. For many, IgE levels are in the normal range. The search for NSAID-specific IgEs is often unsuccessful. Furthermore, after acute challenge with aspirin, patients with AIA do not develop blood eosinophilia and fail to produce detectable increases in blood histamine or in complement activity; such increments occur following acute aeroallergen challenge of atopic asthmatics, suggesting that atopic mechanisms are not primarily responsible for the development of this syndrome. The typical reaction after aspirin ingestion by patients with AIA is the slow development (within 30 min to 4 h, mean 50 min) of nasal congestion with profuse rhinorrhea, cutaneous flushing of the head and neck, mild conjunctivitis, and bronchial obstruction, usually manifested as wheezing. A typical reaction provoked by an oral challenge under laboratory conditions is illustrated in Fig. 47-1. In severe

Figure 47-1 Typical reaction to aspirin in AIA. The timeline illustrates the kinetics of respiratory compromise and naso-ocular symptoms after graded aspirin or placebo challenge. IPPB = intermittent positive-pressure ventilation with Î˛-adrenergic agonist bronchodilator. (Based on data of Stevenson DD, Simon RA: Aspirin sensitivity: Respiratory and cutaneous manifestations, in Middleton E Jr, et al (eds), Allergy: Principles and Practice. St. Louis, CV Mosby, 1993, pp 1747â&#x20AC;&#x201C;1767.)

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reactions, headache, nausea, and vomiting and acute hypercarbic respiratory failure can occur, culminating in death. Life-threatening responses with faster kinetics have also been reported after systemically administered NSAIDs, such as ketorolac. Combined cutaneous and respiratory reactions (i.e., true urticarial eruptions in association with asthma) occur in less than 3 percent of cases.

Genetics In contrast to classic atopic asthma, which patients usually develop before the age of 20, AIA typically occurs in individuals in the fourth decade of life. Thus, AIA appears to be an acquired disease. In general, these patients do not have a prior history of exposure and potential sensitization to NSAIDs. Familial predisposition is also rare; in one study a positive family history was noted in only 2 of 500 patients. Men and women are affected equally. Despite the lack of familial association, one study did show an increase in the expression of HLA-DQw2 in one group of such patients. A later study in European patients showed increased expression of HLA-DPB1∗ 0301 (odds ratios [OR]: 4.4 and 5.3) and decreased expression of DPB1∗ 0401 (OR: 0.42 and 0.49) in AIA versus normals and nonaspirin-sensitive asthmatics, respectively. Korean investigators confirmed a higher risk of AIA in patients carrying HLA-DPB1∗ 0301, whereas individuals who carried HLA-DRB1∗ 1302 and/or DQB1∗ 0609 exhibited a higher risk of aspirin-induced urticaria. Other studies have implicated up-regulation of the expression of leukotriene C4 (LTC4 ) synthase which was found to be increased in blood eosinophils of patients with AIA. In Europeans, single nucleotide polymorphism (SNP) resulting from an A-444C transversion seemed to be associated with increased expression of the LTC4 synthase and a higher relative risk of AIA (2.62; 95 percent CI: 1.38, 4.98). More recently, the same group showed a functional and gender association of the G-765C polymorphism in the cyclooxygenase-2 (COX-2) promoter region in AIA patients with severe disease. Another group in Japan found a functional promoter polymorphism for the TBX21 gene, the human analog for the T-bet gene in mice; absence of this gene had previously been shown to result in airway eosinophilia and hyperresponsiveness. The polymorphism –1993T-C SNP was in linkage disequilibrium with a synonymous coding 390A-G SNP in exon 1, and was significantly associated with AIA. Others have observed increased transcription or polymorphisms in the 5-lipoxygenase activating protein (ALOX5AP) gene in AIA. New insight may result from the recent observation of selective expression in AIA patients of cysteinyl leukotriene type 2 receptor, but not type 1 receptor, expressed by infiltrating inflammatory cells of the upper airway; this expression was not observed in aspirinsensitive patients with chronic allergic rhinitis or in normals. Taken together, although much more remains to be discovered, AIA may be a disease with multiple genetic associations, a disease that depends on gene-environment interaction for its expression. A genetic predisposition in individuals who are also exposed to certain environmental factors ap-

Aspirin- and Exercise-Induced Asthma

pears to be required to produce the full manifestations of the disease.

Cross-Reactivity Cross-reactivity of aspirin with other NSAIDs was first recognized in 1967 by Vanselow and Smith. This report was followed by others of reactions to structurally unrelated NSAIDs, which suggested that these reactions were not atopic. It was subsequently shown that the ability of these drugs to provoke asthma in susceptible patients was related to their ability to inhibit cyclooxygenase and that the degree of cross-reactivity with aspirin was related to the degree to which these agents inhibited cyclooxygenase in vitro.Subsequently the discovery of isoforms of cyclooxygenase have revealed that the dominant form that is inhibited by low doses of aspirin, and capable of eliciting airways responses in AIA, is cyclooxygenase-1 (COX-1). Drugs that are less potent inhibitors of COX-1 but are structurally related to aspirin (e.g., sodium salicylate) at clinical doses do not provoke AIA. The association of AIA with the COX-1 isoform of the enzyme has been buttressed by studies performed with recently available specific inhibitors of COX-2, which, in clinical doses, nearly completely spare inhibition of COX-1. In two separate studies it has been shown convincingly that selective inhibitors of COX-2 (celecoxib and rofecoxib) do not provoke airway changes typical of AIA in patients known to have the disorder, or in those challenged in the laboratory de novo in the process of diagnosing the disease. Szczeklik et al challenged 12 known AIA patients with 12.5 and 25 mg of rofecoxib (typical doses given daily for arthritis) who failed to manifest a response physiologically and did not exhibit the increase in urinary leukotriene E4 (LTE4 ) levels expected after aspirin challenge. Stevenson and Simon performed a larger study, which involved 60 patients with documented AERD who received 12.5 and 25 mg of rofecoxib; none reacted. A follow-up study, using highest single doses of rofecoxib reserved for acute pain of limited duration, found that none reacted. Similar data is available for celecoxib at the highest clinical doses. Dahlen et al challenged 27 patients with AERD with doses up to 200 mg of celecoxib without reaction. Even higher doses (400 mg) used by Gyllfors et al were also tolerated by patients with AIA without airway changes (Fig. 47-2) or increases in urinary LTE4 levels. A list of NSAIDs reported to provoke AIA, and those not associated with AIA, is given in Table 47-1. A number of other analgesics have long been thought to be well tolerated in patients with AIA. They are also listed in Table 47-1. However, some analgesics formerly considered to be safe for use by patients with AIA were subsequently shown to be capable of provoking bronchospasm if given in large doses. For example, acetaminophen, in doses generally greater than 1000 mg and salicylate, in doses of 2000 mg or more, can provoke significant decreases in forced expiratory volume in 1 second (FEV1) in some aspirin-sensitive asthmatics. Reactions to high doses of these drugs, when they occur, tend to be milder than the reactions seen with aspirin.

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Table 47-1

Placebo Celcoxib

NSAIDs in Aspirin-Induced Asthma (AIA)

FEV1, L.

8 10 mg Suspension

30 mg Suspension

100 mg Suspension

NSAIDs that Can Provoke Airway Narrowing in AIA Carboxylic acids Salicylates Acetylsalicylic acid (aspirin, Easpirin, Zorpin) Acetic acids Indomethacin (Indocin) Sulindac (Clinoril) Tolmetin (Tolectin) Diclofenac (Voltaren) Ketorolac (Toradol) Zomepirac (Zomax) Propionic acids Ibuprofen (Motrin, Advil, Nuprin) Naproxen (Naprosyn) Fenamates Meclofenamate (Meclomen) Mefenamic acid (Ponstel) Enolic acids Piroxicam (Feldene)

0 −1

hours 10

FEV1, L.

8 200 mg Suspension

200 mg Capsule

0 −1

hours

Figure 47-2 Lack of airway bronchoconstriction to increasing doses of a COX-2 inhibitor in aspirin-sensitive asthmatics. FEV1 measured before and after oral challenge. Panel A: Double-blind crossover challenge. Panel B: Open label challenge. (From Gyllfors P, et al: Biochemical and clinical evidence that aspirin-intolerant asthmatic subjects tolerate the cyclo-oxygenase 2-selective drug celecoxib. J Allergy Clin Immunol 111:1116–1121, 2003.)

A similar phenomenon has been observed with meloxicam and nimesulide, drugs that inhibit COX-2 somewhat more than COX-1. At typical low clinical doses, they appear to be well tolerated in patients with AIA, however at high doses, cross-reactions may occur. It is important to note that reactions to NSAIDs (including aspirin, as well as COX-2 selective inhibitors) may be the result of prior sensitization to these drugs and the formation of NSAID-specific IgE antibodies. After a period of sensitization, patients may experience anaphylactic reactions to the specific NSAID; the reactions may manifest as wheezing, urticaria, angioedema, and in some instances, severe, life-threatening hypotension. Although this condition is much less common than non-IgE–mediated reactions to NSAIDs and aspirin which tend to occur after first exposure, it should be considered in the differential diagnosis in an appropriate clinical situation. Avoidance of the causative NSAID prevents relapses.

NSAIDs and Analgesics that Appear to Be Well Tolerated in AIA Sodium salicylate Choline salicylate Salicylamide Dextropropoxyphene Acetaminophen in low doses Selective COX-2 inhibitors

Although it was initially believed that tartrazine dyes were capable of provoking asthma exacerbations in patients with AIA, this has not been confirmed by further study. Tartrazine doses of 25 to 50 mg, used in a double-blind challenge of patients with proven AIA, did not provoke detectable changes in lung function. This observation supports the view that tartrazine intolerance is extremely rare and that true cross-reactivity with aspirin probably does not exist. Similar conclusions can be drawn regarding the cross-reactivity of other FD&C dyes, sodium benzoate, other benzoic acid derivatives, monosodium glutamate, and sodium and potassium sulfites. None of these agents has been associated with inhibition of COX-1, suggesting that their previous association with the syndrome may have been purely the result of serendipity. An interesting association has been made of AIA with sensitivity to hydrocortisone. Several case reports were followed by two larger studies demonstrating that a small percentage of patients with AIA may experience acute bronchospasm (15 to 30 min) after the intravenous or intramuscular injection of hydrocortisone. The vehicles and diluents used in the hydrocortisone preparations could not

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Membrane phospholipids PLA2 Arachidonic acid 5-LO

COX-1 COX-2

Cysteiny leukotrienes

PGG2 PGH1

-Inflammation -Broncho -Edema Prostacyclin ASTHMA RHINOSINUSITIS URTICARIA ANGIOEDEMA

Endothelium Kidney Platelets

TXA1

PGD1

PGE1

Most cells Platelets Vascular SM Brain Airways cells Macrophages Kidney

Brain Kidney Vascular SM cells Platelets

PGF1 Uterus Airways Vascular SM cells Eye

-Inflammation -Gastric protection COX-1 inhibitors GASTRIC ULCER BLEEDING

be linked to the reactivity. One of these studies showed no bronchoconstrictor response to methylprednisolone, dexamethasone, or betamethasone when given intravenously, demonstrating that these potent anti-inflammatory steroid preparations, related to hydrocortisone but with different chemical structure of their side chains, could be used safely. The mechanism of this reaction is not known, though corticosteroids can reduce phospholipase A2 (PLA2 ) activity (generally decreasing eicosanoid production) and broadly inhibit isoforms of cyclooxygenase, especially COX-2.

Pathogenesis Although understanding of the genetic predisposition to AIA and identification of provoking agents has increased over the last 5 years, the pathophysiological basis of AIA continues to be a subject of considerable study and is not yet solved, so that initiating and propagating stimuli of this condition are still not known. The dominant theory points to an alteration in the balance between leukotrienes and prostaglandins generated by the lipoxygenase– and cyclooxygenase–dependent pathways of arachidonic acid metabolism. Other attempts to explain the spectrum of symptoms are based on the release of other mediators, most likely from mast cells, basophils, or platelets. These theories include up-regulation of releasability of mast cell-basophil mediators by unknown substances that

Figure 47-3 Enzymatic pathways of arachidonic acid metabolism. (From Sanchez-Borges M, et al: Cutaneous reactions to aspirin and nonsteroidal anti-inflammatory drugs. Clin Rev Allergy Immunol 24:125–135, 2003.)

affect mast cell membranes, greater production than normal of histamine by basophils of patients with AIA, decreased production of prostaglandin E2 (PGE2 ) and enhanced production of leukotriene B4 (LTB4 ) by AIA basophils, and enhanced aspirin-induced release of serotonin and other mediators by AIA platelets. It has been proposed that complement activation may play an important role in these processes. However, the role of complement activation in AIA has been questioned by data that show no significant changes in CH50 and C4 levels in patients who experience an exacerbation of asthma after acute oral aspirin challenge. Alterations in arachidonic acid metabolism appear to play a central role in AIA. The major pathways of cyclooxygenase and lipoxygenase metabolism of arachidonic acid are illustrated in Fig. 47-3. Arachidonic acid is derived from membrane phospholipid by PLA2 . It is then metabolized via the cyclooxygenase pathway to prostaglandins (COX-2 more than COX-1) and thromboxanes (COX-1 more than COX-2) or via the lipoxygenase pathway to sulfidopeptide (cysteinyl) leukotrienes. The leukotrienes have a variety of effects, including the induction of contraction of bronchial smooth muscle. In contrast, the prostaglandins, in particular PGE2 , act as bronchodilators and may inhibit T- cell–mediated inflammatory responses in the lung. Aspirin and the other NSAIDs that cause AIA inhibit COX-1 activity. A shift occurs after the administration of aspirin or appropriate doses of the other

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agents, shunting approximately 90 percent of the arachidonic acid metabolism to the 5-lipoxygenase pathway, decreasing prostaglandin and thromboxane production, and increasing leukotriene generation. In comparison to normal individuals, patients with AIA generate leukotrienes in inordinate quantities after aspirin challenge. Discovery that patients with AIA produce less of the anti-inflammatory mediators lipoxin and 15-epimer lipoxin might enhance effects of this shift. Patients with AIA may also be more sensitive than normal subjects to the bronchoconstrictor properties of leukotrienes (particularly LTE4 ) and more susceptible to the loss of the bronchodilating, and potentially anti-inflammatory, effects of PGE2 . The data supporting these conclusions are briefly summarized below. Several groups have analyzed the nasal lavage fluid from aspirin-sensitive and control patients and found inducible levels of cysteinyl leukotrienes and plasma proteins when patients with AIA were challenged with oral or nasal aspirin. One study found that LTC4 and LTD4 levels were not significantly increased in normal subjects, but could be induced to some degree in patients with allergic rhinitis and in those with isolated nasal polyps (increasing by 93 and 69 percent, respectively, above baseline levels). Similarly, although histamine levels increased significantly in the AIA group (greater than threefold increase in total protein) the levels did not increase significantly in the control groups. Analysis of the nasal lavage fluids showed impressive increases in lactoferrin and lysozyme, suggesting that submucosal glands are stimulated by the challenges. In a follow-up study, the cellular source of these nasal abnormalities was investigated by analysis of nasal lavage fluids induced by aspirin challenge for the presence of mast cell tryptase and eosinophil cationic protein (ECP). Significant increases in nasal tryptase, histamine, and cysteinyl leukotrienes were observed after AIA was provoked in these patients. ECP levels at baseline were variable and did not increase significantly after challenge. These results support the idea that after aspirin challenge, the leukotrienes in the nasal secretions of patients with AIA are probably of mast cell origin. They also suggest that eosinophils are not as important as mast cells in the pathogenesis of the nasal manifestations of AIA. These findings are consistent with earlier work that showed similar increases in blood tryptase (4 h) and urinary LTE4 levels (6 h) and decreases in blood eosinophil counts ( p <0.01) (6 h) after aspirin challenge. The metabolism of arachidonic acid in the lung has not been studied as extensively. The available data show both similarities and differences with findings in the nose and circulation. For example, bronchoalveolar lavage fluid (BALF) obtained 30 min after inhalation of threshold doses of lysine-aspirin contained depressed levels of cyclooxygenasedependent mediators (PGE2 , PGD2 , thromboxane B2 (TXB2 ), and PGF2ﾎｱ). However, only small increases occurred in LTE4 and 5-hydroxyeicosatetraenoic acid (HETE) levels. Lysineaspirin inhalation also did not elicit a significant increase in tryptase levels in the BALF and led to a significant fall in ECP

levels even though baseline eosinophil and ECP levels were higher in the AIA group than in the placebo-treated nonasthmatics. The authors postulated that the altered pulmonary eicosanoid production might be related to the eosinophilic inflammation in the airways of patients with AIA. In order to dissect further the mechanism of bronchospasm in AIA, a number of investigators used inhibitors of leukotriene effector function. The first administered a specific sulfidopeptide leukotriene receptor antagonist via inhalation and noted that it attenuated AIA in five of six subjects by 43 to 74 percent. This was followed by a double-blind, placebo-controlled, crossover study that showed that a specific leukotriene receptor antagonist, given in a single oral dose 1 h before provocative challenge with perithreshold lysine-aspirin inhalant, could almost completely block the development of aspirininduced bronchospasm. This was achieved without evidence of any direct bronchodilatory effect of the drug before lysineaspirin challenge, confirming that leukotriene receptor antagonist was effective in preventing analgesic-induced (dipyrone) bronchospasm. Leukotriene effects in the lung can also be modulated by blocking 5-lipoxygenase activity. The efficacy of this approach was demonstrated in a randomized, double-blind, crossover study in which the 5-lypoxygenase inhibitor zileuton (600 mg orally, 4 times a day, for 6 to 8 days before aspirin challenge) led to a greater than 70 percent reduction in the baseline excretion of urinary LTE4 , a greater than 60 percent reduction in mean maximal urinary concentration of LTE4 after aspirin challenge, and almost complete suppression of subthreshold and threshold oral aspirin-induced bronchospasm. In addition, naso-ocular, gastrointestinal, and dermal symptoms were reduced to the levels of symptoms produced by placebo challenge. Similar data have been generated with the cysteinyl leukotriene receptor antagonists montelukast and zafirlukast. In summary, although the mechanism of AIA remains incompletely understood, there appears to be a clear role for lipoxygenase products in the pathogenesis of the disorder. The available data also suggest that mast cells, stimulated by aspirin directly or indirectly, discharge their leukotriene mediators in large amounts into nasal secretions but may not play the same role in the lung. The presence of increased numbers of eosinophils and altered eosinophil phenotype may be more relevant to the pathophysiology in the lung, linked to the airway inflammation that characterizes this disorder. The increased number of these cells probably reflects their recruitment secondary to the release of mast cell窶電erived mediators, including leukotrienes and cytokines.

Diagnosis Although some promise exists for the development of in vitro tests to identify patients with AIA based on differential in vitro and platelet responses to aspirin and NSAIDs, these methods have not yet been validated for routine use. AIA is still diagnosed by in vivo testing using placebo-controlled

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Table 47-2 Diagnosis of Aspirin-Induced Asthma: Aspirin (ASA) Challenge Protocols Single-Blind Oral 3-Day Aspirin Challenge Test days Time 1 2 0 Placebo ASA 30 mg 3h Placebo ASA 45–60 mg 6h Placebo ASA 60–100 mg

3 ASA 100–150 mg ASA 150–325 mg ASA 325–650 mg

Double-Blind Oral Aspirin Challenge Both tester and patient are blinded to eliminate potential bias. Bronchial Challenge with Lysine-Aspirin Time Challenge (Min) (Lysine-aspirin in mg/ml) 0 Placebo 45 Placebo 90 11.25 135 22.5 180 45 225 90 270 180 315 360 350 360 (10 breaths) Patients receive four breaths of all doses of lysine-aspirin unless otherwise indicated. Source: Data from DD Stevenson: Aspirin and NSAID sensitivity. Immunol Allergy Clin N Am 24:491–505, 2004; Stevenson DD, Simon RA: Sensitivity to aspirin and nonsteroidal antiinflammatory drugs, in Middleton E Jr, Reed CE, Ellis EF (eds), Allergy: Principles and Practice. St. Louis, CV Mosby, 1993; Phillips GD, Foord R, Holgate ST: Inhaled lysine-apirin as a bronchoprovocation procedure in aspirin-sensitive asthma: Its repeatibility, absence of a late-phase reaction, and the role of histamine. J Allergy Clin Immunol 84:232–241, 1989.

oral challenges of persons suspected of having this disorder (Table 47-2). This testing can be performed according to published protocols using single-blind or double-blind approaches. These protocols generally begin with a 3-mg dose of aspirin, although higher initial doses (30 mg) have been recently advocated since, if reactions occur at this dose, they are easily treated. The dosage is then increased to a maximum of 650 mg over a 3-day period. Spirometric pulmonary function is monitored serially during the challenge to assess the degree of bronchial constriction. Airway reactivity to methacholine is not a viable surrogate for spirometry, since aspirin does not consistently alter methacholine sensitivity. Aspirin challenge should probably be reserved for use in research centers experienced with its application and adverse effects. An alternative to oral challenge, used in some centers in Europe for the diagnosis of AIA, and increasingly elsewhere, is the inhalation of stabilized lysine-aspirin, followed by serial lung function measurements, or nasal provocation with aspirin or lysine-aspirin followed by serial rhinomanometry or acoustic rhinometry. Currently, lysine-aspirin is not yet available for clinical use in the United States.

Treatment Optimal treatment of patients with AIA requires knowledge of the proper approaches to treat acute aspirin-induced bronchial symptoms and associated nasal and sinus pathology. No specific therapy has emerged that can be recommended for the routine treatment of acute bronchospasm provoked by NSAIDs. It has been stated that corticosteroids are not effective after acute aspirin ingestion, and that theophylline and cromolyn sodium play no definite role. Treatment of symptoms after acute ingestion therefore relies mainly on β-adrenergic agonists to reverse bronchospasm, and topical vasoconstrictors for both nasal congestion and eye symptoms. Frequent applications of these agents usually are necessary to maintain nasal and airway potency over the 2- to 6-h duration of the reaction. On a chronic basis, the treatment of AIA depends on the correct diagnosis and avoidance of aspirin and other cyclooxygenase inhibitors that could cross-react to induce acute bronchospasm. Patients should be instructed that many over-the-counter medications contain aspirin or other

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Figure 47-4 Airway desensitization to aspirin challenge in AIA. Timeline of respiratory function and overall symptoms after serial aspirin dosing. The reappearance of respiratory compromise and symptoms after 4 days without aspirin shows the need for continuous aspirin administration to maintain desensitized state. (Based on data of Pleskow WW, et al: Aspirin desensitization in aspirin-sensitive asthmatic patients: Clinical manifestations and characterization of the refractory period. J Allergy Clin Immunol 69:11–19, 1982.)

NSAIDs, and they should carefully read package inserts before using any medication. Drug treatment of AIA should focus on treating the underlying asthma and the strict avoidance of aspirin and cross-reacting NSAIDs. Currently there also appears to be no role for systemic corticosteroids or theophylline in the prevention of AIA. Some investigators have found that antihistamines, such as clemastine and mast cell stabilizers such as ketotifen, cromolyn and nedocromil, can be effective prophylactically. However, not all subjects who are taking these drugs are protected against bronchoconstriction after aspirin challenge. The 5-lipoxygenase inhibitor zileuton was not found to be effective in preventing FEV1 decline or naso-ocular reactions to direct aspirin challenge, although it had been shown in a previous study to improve chronic asthma symptoms when added to conventional therapy. In contrast, experience with the cysteinyl leukotriene receptor antagonists has been variable, but mostly positive and may be more effective in those who carry the variant C allele of LTC4S than in noncarriers. Pretreatment with inhaled or systemic steroids or long-acting β-agonist (salmeterol) was shown to at least partially attenuate decrements in aspirin-induced respiratory lung function. The failure of tacrolimus (0.1 mg/kg) (a drug that could potentially affect both T-cell–generated cytokine responses and prevent release of mast cell histamine and leukotrienes) to prevent aspirin-induced respiratory reactions in patients with AERD on aspirin challenge suggests that this agent cannot be relied upon to prevent reactions

to aspirin-intolerant asthmatics and cannot be used to facilitate “silent” aspirin desensitization in the patient with AERD. In individuals in whom aspirin (or cross-reacting NSAIDs) cannot be avoided (i.e., in the setting of cardiovascular prophylaxis) or the efficacy of prophylactic measures cannot be assured, aspirin “desensitization” can be considered. Protocols are available for selected patients (Fig. 47-4). These methods can effectively protect many from experiencing symptoms on exposure to aspirin or NSAIDs and will maintain this level of desensitization as long as aspirin, in doses of 325 to 650 mg a day, is continued. In a study of 25 aspirin-sensitive asthmatics, such therapy decreased nasal symptoms by 67 percent and the severity of asthma by 48 percent. In the largest study of its kind, 172 patients with AERD were desensitized to aspirin from 1995 to 2000; they were subsequently treated then with 1300 mg of aspirin each day and followed for 1 to 5 years. Clinical improvements occurred during the first 6 months: measures of improvement included clinical course, reduction in dose of systemic corticosteroid, and improvement in global assessments; these effects were maintained, but not further enhanced, during the remainder of the study. Approximately 67 percent (115 of 172) improved, 16 failed to improve, 24 discontinued aspirin because of aspirin-related side effects, while another 17 dropped out for other reasons. It is interesting to note that although there are some reports of the development of increased methacholine reactivity

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in patients soon after aspirin challenge, baseline methacholine responsiveness does not seem to be successfully downregulated by aspirin desensitization. Also, there is no firm evidence that aspirin desensitization leads to abatement in skin disease in those with aspirin-urticaria syndrome. Inhaled PGE2 was shown to prevent bronchoconstriction in a high proportion of patients challenged with inhaled l-lysine aspirin in two small studies. In two studies using misoprostol, a stable analog of PGE1 , prior to challenge with l-lysine aspirin (400 µg 1 h before) or a predetermined threshold dose of aspirin (400 µg before, followed by 200 µg with the provocative dose of aspirin), evidence was provided of some protection in 7 of 11 patients ( p = 0.024) and in 6 of 7 patients (statistically only significant at time points 3 h after challenge), respectively. To test whether asthma symptoms might improve on treatment with misoprostol, another group performed a double blind crossover study that showed that misoprostol, given for a period of 6 weeks (at dose of 800 to 1600 µg/d) led to only a small improvement in nasal symptomatology without any effect on asthma control in 17 patients with proven AIA. Thus, evidence for a specific method to control AIA, other than the desensitization methods described above, has not proven to be reliable. Fortunately, for those who require aspirin to prevent disease, such as those on low-dose aspirin, given for cardiovascular prophylaxis, the threshold needed to provoke airway and skin reactions is above that of the dose required for cardiovascular prophylaxis. The potential contribution of chronic sinusitis to exacerbations of asthma is well established. Aspirin sensitivity, chronic sinusitis, and nasal polyposis are well documented to coexist in AIA. Thus, the presence of these upper-airway disorders must be considered in patients with AIA and effective treatment instituted if they are identified. High-dose topical intranasal corticosteroids can shrink polyp tissue and prevent obstruction of nasal passageways. In the setting of chronic sinusitis, standard approaches—including topical vasoconstrictors, antihistamines, and antibiotics—should also be used. Surgery to drain sinuses and remove polyps has been shown to be effective in the short term; however, polyps can regrow and the sinusitis often recurs. In selected patients in whom aspirin provokes nasal symptoms predominantly, administration of intranasal lysine-aspirin at increasing weekly doses has been used successfully to desensitize such patients and prevent regrowth of polyps in one study. A more recent and larger randomized clinical trial, although underpowered due to dropouts, used a crossover design after withdrawal of intranasal steroids. Lower doses of lysine-aspirin were administered more frequently (16 mg intranasally every 48 h). Results showed encouraging immunohistochemical changes in nasal submucosal inflammatory cells from turbinate tissue, characterized by decreased expression of CysLT1 but no clinical improvement (diary scores of nasal and chest symptoms) or improvement on rhinometry. Despite aspirin desensitization and careful treatment of the often-associated sinusitis, an appreciable proportion of patients with AIA do not achieve complete control of asthma or nasal symptoms. It is postulated that this failure may reflect

Aspirin- and Exercise-Induced Asthma

permanently remodeled airways or residual allergic triggers that require specific measures for allergy control and antiinflammatory therapy. Evaluation of the effect of strict avoidance of allergens, specific allergen immunotherapy, more intensive local management of the inflamed nasal mucosa and anti-IgE treatment may help to clarify the role of atopy in the persistence of symptoms after aspirin desensitization.

EXERCISE AND ASTHMA The first report of exercise-induced asthma (EIA) is attributed to John Floyer in 1698. Nearly 300 years later, interest in this subject grew when it was recognized that exercise or hyperventilation could provoke asthma attacks. EIA can be defined as a condition in which vigorous physical activity triggers acute airway narrowing in persons with heightened airway reactivity. It appears that EIA is always associated with the asthmatic diathesis, although EIA can be seen before other characteristic features of asthma emerge. Various reports indicate that EIA is common, affecting between 50 and 90 percent of all asthmatics and 40 percent of patients with allergic rhinitis without known asthma. Some have suggested that all asthmatics can be shown to manifest airway narrowing in response to thermal provocations of sufficient intensity, whether induced by exercise or hyperventilation. Other individuals susceptible to exercise-induced asthma are firstdegree relatives of asthmatics, atopic “nonasthmatics,” and patients with cystic fibrosis. Approximately 10 percent of pediatric patients have been found to have EIA, a prevalence higher than that of clinical asthma. Recent evidence suggests that elite athletes may be predisposed to develop EIA. Surveys conducted of athletes at the Atlanta (summer) and Nagano (winter) Olympic Games showed a prevalence of 16 to 17 percent. The prevalence may actually be higher in those who are regularly exposed to high minute ventilation of the cold, dry air which is typical of winter sports. The prevalence of EIA in figure skating (35 percent) and ice hockey (35 percent) may be responsible for increasing the overall frequency of EIA in winter sports; this high incidence has been documented by Wilber (referenced in Storms, 2005) to be as high as 23 percent.

Clinical Presentation Patients with EIA generally manifest a series of fairly predictable symptoms and alterations in pulmonary function (Fig. 47-5). Normal individuals and asthmatics generally respond at first to exercise by bronchodilation, probably mediated by the release of catecholamines. This response is shortlived, peaking at midexercise, and is followed by return of normal baseline airway tone at the end of exercise. In patients with EIA, the transient bronchodilation and reversal are followed by bronchoconstriction coincident with symptoms of cough, wheezing, dyspnea, and chest tightness typical of asthmatic attacks. Typically, when provoked by a brief, intense

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exercise if rechallenged with the same stimulus within 60 min, and thus appear to establish a refractory state. Neither baseline airway obstruction nor the degree of obstruction provoked by exercise can be used to determine who will be refractory to repeated exercise challenges. After 3 h, even patients who are refractory to repeated challenge will again respond to exercise with bronchoconstriction.

Pathophysiology

Figure 47-5 Typical pulmonary function changes induced by exercise in EIA. Transient bronchodilation during exercise and bronchospasm after exercise are noted. (Based on data of Anderson SD: Is there a unifying hypothesis for exercise-induced asthma? J Allergy Clin Immunol 73:660–665, 1984.)

exercise period in the laboratory, maximal bronchoconstriction occurs 5 to 10 min after the cessation of exercise and lasts for 30 to 60 min (Fig. 47-5). Rarely, although it can limit the performance of trained athletes, does this form of bronchoconstriction result in ventilatory failure. In addition to asthma after exercise, many athletes describe dyspnea during exercise. If these athletes are able to continue to exercise despite the initial airway constriction, especially if they can increase their level of activity, relief of bronchoconstriction often occurs. This relief is associated with symptomatic improvement with time that is described as “running through the attack.” The development of dyspnea during exercise is related to the development of bronchoconstriction at lower work intensities (simulating a postexercise state), which is avoided by interval training at higher intensities (simulating an exercise state). This has been taken as evidence that airway function during exercise reflects a balance between bronchoconstrictor and protective bronchodilator influences, and that this balance can be influenced by rapid changes in exercise intensity. The reproducibility of EIA is highly dependent on the specific characteristics of the stimulus and patient-related factors. The net influence of exercise intensity, the temperature and humidity of the inspired air, and the patient’s baseline airway reactivity are fundamental in determining whether exercise will lead to bronchoconstriction. The better the asthma is controlled at baseline, EIA may be more difficult to provoke. If climatic conditions vary, even though asthma is not well controlled, EIA may fail to develop. Classic work has shown that for a fixed minute ventilation, cold, dry air inspired during exercise is more likely to provoke EIA than warm, humid air. Thus, EIA is more likely to occur while jogging during the winter than while swimming indoors. It is interesting that about 50 percent of patients with EIA will not manifest a bronchoconstrictor response after

The mechanisms associated with exercise-induced bronchoconstriction have been studied intensively for more than two decades. Despite this intense scrutiny, and recent application of genetic and molecular techniques, the pathophysiology of this response is still a subject of debate. The theories now appear to have coalesced to two pathogenic schemas that may, or may not, be mutually exclusive. The two theories of pathogenesis focus on the roles of heat exchange, water loss and subsequent airway rewarming, and airway inflammation. The role of inflammation as a reaction to these stimuli or as an enhancer of the effects of these two principles’ pathophysiological pathways is probably tied to leukotrienes and related lipoxygenase products. Heat Exchange and Water Loss During tidal breathing, heat (via conduction and evaporation) and water (via evaporation) are transferred from the mucosa of the upper airways to the entering air. Since exercise requires marked increases in minute ventilation, exceeding the volume of air that can be inspired through nasal structures, air enters directly through the mouth, bypassing the normal warming and conditioning function of the nose. The lower respiratory mucosa attempts to compensate for the function of the bypassed nose. Heat and water fluxes occur first. The lower airways are cooled and dried and then subject to rewarming by warm blood carried by the bronchial circulation. In the late 1970s, a number of investigators postulated that EIA was the result of increased heat loss in the airway. This was based on the observation that cold, dry air caused a greater fall in FEV1 than did hot, dry air and on correlations between heat exchange and the degree of bronchoconstriction. Others, however, showed that the temperature of the inspired air was not crucial for inducing bronchoconstriction and that temperatures of dry inspired air varying as much as 60◦ could still provoke airway narrowing. This suggested that airway evaporative water loss might be more important than airway cooling. The water loss was predicted to change the osmolarity of the cellular and extracellular components of the airway wall, stimulating increased bronchial blood flow in order to increase the delivery of water. In addition, it was hypothesized that bronchial wall hyperosmolarity increased the release of proinflammatory mediators from resident airway inflammatory cells such as mast cells. This concept was supported by work that demonstrated that changes in the humidity of inspired air, and not temperature, determine the magnitude of EIA. Further support for this construct came

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from studies using cold gas mixtures with different watercarrying capacities, which showed a significant correlation between the airway response and the evaporative heat loss, but not the total heat loss or temperature gradient. In apparent contrast to these data is the considerable body of work that does not support the concept that osmolar changes precipitate EIA. The most important of these showed that increasing minute ventilation at constant humidity increases the severity of EIA. Airway Rewarming An important theory that also remains to be proven was offered by McFadden, who proposed that the process of airway rewarming is involved in the pathogenesis of the airway narrowing that occurs in EIA. This theory postulates that loss of heat during exercise leads transiently to a decrease in bronchial blood flow. At the end of exercise, the bronchi undergo reactive hyperemia characterized by vascular engorgement, which leads to compromise of airway caliber and edema of the walls of the airway. The strongest support for this theory is provided by studies that show that the severity of EIA can be controlled by regulation of the thermal gradient during exercise and the rate of rewarming after exercise. In summary, there is evidence that associates exerciseinduced bronchoconstriction with a sequence of events that includes heat loss, water loss, and airway rewarming. However, the degree to which these alterations in temperature and water exchange contribute to the pathogenesis of EIA is still a topic of debate and investigation. Inflammation and EIA Theories that postulate a role for inflammatory mediators in the pathogenesis of EIA have recently received new support and are being harmonized with the already considerable evidence that supports a role for inflammation in the pathogenesis of other forms of asthma. New information about exercise suggests that individuals predisposed to EIA, specifically elite athletes, may manifest a degree of airway inflammation that had not been previously recognized. Instead of demonstrating a lower rate of EIA, which would potentially enable a higher level of exercise performance, and which might be expected in those best equipped to excel in sports, elite athletes appear to exhibit a paradoxically higher incidence of EIA and a higher degree of airway inflammation without necessarily manifesting a higher prevalence of underlying clinical asthma. Older data on the role of inflammation in EIA did not necessarily support this link. One study analyzing the characteristics of BALF from patients with EIA 12 min after exercise failed to find evidence for mast cell mediator release since levels of BAL histamine, tryptase, LTC4 , and PGD2 were not altered. Similarly, studies performed 1 h and 25 h after exercise did not reveal significant differences in the cellularity of BAL or in the levels of histamine or tryptase. In contrast, one group studying elite cross-country skiers, found elevated airway T lymphocytes and eosinophils compared to controls. Several others have demonstrated

Aspirin- and Exercise-Induced Asthma

changes in exhaled nitric oxide, which generally decreased with exercise, suggesting a high basal level and ventilatory clearance of this gas associated with airway inflammation. A second group found increases in plasma adenosine after exercise. A third group documented the presence of a late phase airway response after exercise that was demonstrable in 50 percent of competitive athletes studied. Most importantly, the new concept that these changes might be provoked by exercise, rather than be a reflection of underlying inflammation in those who manifest EIA, is supported by studies of Helenius et al, who showed that athletes who stopped high-level training and modulated the amount of exercise they subsequently pursued, experienced reduced asthma symptoms and diminished bronchial responsiveness to histamine. Leukotrienes in EIA

To determine whether leukotrienes play a role in the pathogenesis of EIA, LTD4 receptor antagonists and 5-lipoxygenase inhibitors have been used. Studies using an intravenous LTD4 receptor antagonist administered 20 min before exercise demonstrated significant attenuation of the maximal provoked bronchoconstriction and a decrease in the mean time to recover from bronchoconstriction (8 min for the treatment group versus 33 min for placebo). Similar results were noted by others using oral or inhaled leukotriene antagonists. In general, although the protection was relatively small, it was significant and equivalent in potency to inhaled cromolyn. The results obtained with peptido-leukotriene antagonists are consistent with those obtained with the effects of a 5-lipoxygenase inhibitor on bronchoconstriction induced by cold, dry air. In the most important study of this kind, a 5-lipoxygenase antagonist was as effective as cromolyn or terbutaline in augmenting respiratory heat exchange. Thus, leukotrienes may mediate the airway inflammation and contribute to the pathogenesis of EIA.

Genetics Little information is available on the potential genetic underpinnings of EIA. However, this topic has recently received some attention. Using microarray analysis, one group demonstrated enhanced transcription of 5-lipoxygenase (ALOX5) and 5-lipoxygenase activating protein (ALOX5AP) genes. More recently, in studies conducted in a large cohort of Korean children with asthma, others have provided evidence of LTC4 synthase (A-444C) promoter polymorphisms in association with greater severity of EIA. These observations suggest the potential existence of disease-modifying genes in exerciseinduced bronchospasm.

Differential Diagnosis The diagnosis of EIA is most accurately established by employing validated exercise protocols coupled with pulmonary function testing. However, patients are commonly given a presumptive diagnosis based on their history and physical examination. Important points in the clinical history include the

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Table 47-3

there are patients who have exercise-induced cough without bronchospasm, and thus do not have EIA.

Differential Diagnosis of Exercise-Induced Asthma

Physiological Documentation

Cardiac Disease Coronary ischemia Mitral valve prolapse Atrial myxoma Cardiomyopathy Arrythmias

Functional abnormalities Vocal cord dysfunction Panic disorders General Deconditioning Anemia

Lung disease Fixed airway obstruction Interstitial lung disease Exercise-induced cough

level and type of exercise that provokes asthma, the timing of symptom onset, the situation that modifies the onset of symptoms, and the precise symptoms experienced. Many of the symptoms of EIA can mimic other conditions that would require an entirely different therapeutic approach (Table 47-3). For example, chest tightness with exercise should be unequivocally distinguished from coronary ischemia. Other cardiac disorders that can mimic EIA are arrhythmias, cardiomyopathies, atrial myxoma, and mitral valve prolapse, all of which can manifest with dyspnea and wheezing. The presence of a murmur, click, or other findings on physical examination should help to identify patients with these conditions. Exercise-induced anaphylaxis can also mimic EIA but will generally exhibit skin manifestations (urticaria), and respiratory symptoms will be less prominent. Two other conditions that have been reported to mimic EIA are fixed glottal and tracheal obstruction, which become noticeable during the increased ventilation of exercise and exercise-induced vocal cord/arytenoids dysfunction but are not present at rest. Some observers have also suggested that panic disorders and the excessive tachypnea associated with deconditioning can be confused with EIA. Symptoms due to these other conditions generally are greatest during exercise provocation rather than afterward, when airflow limitation due to EIA usually reaches its peak. Exercise-induced cough is another phenomenon that can mimic EIA. Both may be induced by changes in the osmolarity of the airways reflecting water loss from the respiratory tract during exercise. The inhalation of humid air also prevents both phenomena. However, EIA and exerciseinduced cough respond differently to Î˛-adrenergic agonists, suggesting that they are mediated by different underlying mechanisms. It is postulated that exercise-induced cough is the direct result of changes in osmolarity provoked by airway drying, whereas EIA is due to the release of mediators that results from the process of airway drying. Therefore, although nearly all patients with EIA cough when provoked by exercise,

Because a simple history of cough or wheezing may not reliably predict EIA, especially in those in whom a trial of preventive measures has not been successful, formal exercise testing may be required. The clinician needs to document airflow obstruction that reaches a peak during the recovery period, immediately after provocation. Two basic methods of provocation have been used, exercise and the inhalation of dry air (isocapnic hyperventilation, ISH). The latter is an acceptable surrogate for exercise, since the bronchoconstriction it induces is similar to that induced by exercise in terms of magnitude, time course, and refractory period. However, significant differences exist between the two provocation techniques. Exercise provocation, whether performed on an ergometer or a treadmill, leads to significantly greater increases in heart rate, metabolic rate, and oxygen consumption. Exercise, but not ISH, is accompanied by increased numbers of circulating basophils and increased circulating catecholamines and cyclic adenosine monophosphate. The differences in the last two parameters probably explain why the bronchodilatory response that characterizes exercise is not provoked by ISH. ISH does, however, have a number of advantages over exercise. The first relates to the ease with which the ISH protocol can be standardized; the other relates to the finding that oxygen consumption and heart rate are not increased with ISH. As a result, ISH is useful in differentiating EIA from occult cardiac disease and is especially valuable when elderly or cardiac patients are being evaluated. The most commonly used protocol for the diagnosis of EIA in the United States is that published by Oâ&#x20AC;&#x2122;Byrne et al and modified by Phillips et al (Fig. 47-6). This protocol registers changes in pulmonary function in response to varying rates of ventilation using dry air which contains a fixed CO2 content of 4.9 percent to maintain isocapnia. Each ventilatory challenge is performed for 3 min; spirometry is performed at intervals thereafter (usually 2, 5, and 10 min after the end of hyperventilation). Serial increase in hyperventilation is continued until maximal voluntary ventilation is reached. If the FEV1 falls 10 to 20 percent after provocation, the test is considered positive, confirming the diagnosis of EIA. Although some have pointed out that it is not necessary to condition air to subfreezing temperatures in order to perform the test, Scandinavian investigators have shown that assessing bronchoconstrictor responses to whole-body exposure to very cold air resulted in a significant increase in the number of asthmatic patients who experienced bronchoconstriction. Others have pointed out the need to assess athletes in the sport in which they compete, since they may not realize that a significant drop in FEV1 has occurred due to their conditioning; manifestations of disease during challenge may be needed to document the decrease in lung function. In order to optimize the validity, repeatability, and practicality of exercise testing for the diagnosis of EIA, a variety of

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Figure 47-6 Apparatus for isocapnic hyperventilation challenge to diagnose EIA. (Based on data of Phillips YY, et al: Eucapnic voluntary hyperventilation of compressed gas mixture: A simple method for bronchial challenge by respiratory heat loss. Am Rev Respir Dis 131:31–35, 1985.)

testing protocols have been used. Unfortunately, at times the criteria used to define a positive test in these different studies have been arbitrary. Although the optimal diagnostic algorithm for the assessment of EIA is still lacking, recent data reported on athletes from the 2002 Olympic Winter Games, compared eucapnic voluntary hyperventilation (EVH) with exercise testing outdoors in the cold (2◦ C and 45 percent humidity). The EVH test for 6 min with cold, dry air proved to be best in assessing the presence of EIA. In addition to the difficulties inherent in the standardization of the challenge protocol, the clinician must be aware of situations that can lead to false-negative evaluations. Specifically, it is important that all drugs that can attenuate bronchoconstrictor responses—such as calcium channel blockers, methylxanthines, cromolyn, and β-adrenergic agonists—be discontinued for a sufficient period before the evaluation.

Treatment The treatment of EIA depends, in part, on the treatment of the underlying asthma since in general, patients with more severe baseline asthma are most inconvenienced by EIA (Table 47-4). It has been shown that inhaled steroids attenuate the development of EIA during provocation in the laboratory and increase the clinical threshold for developing EIA. Prophylactic measures to prevent EIA include avoiding exercises that expose the patient to cold, dry air and favoring those that expose the patient to humid air during exercise. Patients can reduce the severity of their EIA by breathing through the nose rather than through the mouth during exercise. Face masks (e.g., 3M Cold Weather Mask) can be used by the many people who find it impossible to breathe through the nose during intense exercise. It is still unclear whether physical training

and improvement in work capacity can relieve symptoms of EIA. These methods should be useful, at least in theory, since a better-trained athlete may require a lower mandatory minute volume—which may lead to less water loss from the airways and less severe EIA. Two studies—one in Los Angeles and the other in Toronto—showed that exposure of patients with EIA to air high in ozone did not minimize EIA. This suggests that choosing a day to exercise on the basis of ozone will not help prevent EIA. A series of repeated short sprints has been shown to be effective in inducing the refractory state, which might then allow the athlete to exercise maximally without developing EIA. A warm-up period to induce the refractory period has been advocated to improve performance in the competitive athlete. However, this effect may not last for longer than 40 min. Several classes of drugs have been shown to prevent EIA if administered just before (10 to 15 min) exercise. The

Table 47-4 Treatment of Exercise-Induced Asthma (EIA) Treatment Immediately Before Exercise (10–20 min before) β-adrenergic agonists Cromolyn sodium Nedocromil ? Anticholinergics ? Inhaled furosemide ? Leukotriene receptor antagonists

Treatment of Underlying Disease (days before) Goal: Improved asthma control Inhaled corticosteroids Systemic corticosteroids ? Theophylline

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list includes β-adrenergic agonists, cromolyn sodium, anticholinergics, and possibly rapid-release theophylline (see Table 47-4). The β-adrenergic agonists are the most effective drugs for use against EIA. They are 90 percent effective in preventing EIA when used just before exercise. They are especially useful if the patient has some reversible airway obstruction, since they also improve lung function before exercise. Longer-acting β-adrenergic agonists, have also been found to be effective in preventing EIA. The duration of protection they confer may approach 10 h or more. This may be important in preventing EIA in patients who do not have immediate access to an inhaler and anticipate the need for prophylaxis due to exercise scheduled for later in the day (i.e., students). It is interesting that the cough so often associated with EIA, appears to occur independently of the bronchospasm provoked by exercise. Although exercise-induced airway narrowing is prevented by the inhalation of β-adrenergic agonists before exercise, the cough is not. Cromolyn sodium also has been shown to attenuate bronchoconstriction in most patients with EIA. Since it is not a direct bronchodilator, this medication will not be effective in those who seek reversal of pre-exercise bronchoconstriction. Cromolyn does, however, have two advantages over other agents. First, it does not contribute to tachycardia and is therefore useful in elderly patients or patients with cardiac problems. In addition, cromolyn has been shown to prevent the late bronchoconstrictor response to exercise. Related drugs (including nedocromil, minocromil, and oxatomide, but not ketotifen) have similarly been shown to be effective against EIA. Anticholinergics, such as ipratropium bromide, prevent airway narrowing after exercise in a high percentage of patients with EIA. They are especially useful in those who experience a rapid bronchodilating response to the drug. However, for most patients, the slow onset of action limits the effectiveness of these agents after bronchodilation has occurred. Theophylline with its weak bronchodilatory effects, high side-effect profile, and slow onset of action, is not recommended for routine use as pretreatment for EIA. However, it has been shown to confer protection against EIA if 100 to 200 mg is taken 2 h before exercise. Other orally administered drugs that are not commonly used, but have the potential to be helpful in preventing EIA, are terbutaline, albuterol (2 h before exercise), some α-adrenergic agonists, verapamil, and sublingual nifedipine (the last two if taken 30 min before exercise), as well as the inhaled antihistamine clemastine. In addition, terfenadine was shown by one group to prevent EIA. For the elite athlete, only a few of the above drugs are approved for use in competition by the International Olympic Committee. They include inhaled albuterol, terbutaline, cromolyn, and nedocromil and oral theophylline. Long-acting β-agonists and all oral sympathomimetics are not approved. Other directions in drug therapy for EIA hold promise for the future. Diuretics are known to be of some use in the prevention of EIA in adults. The most recent use of these agents indicates that inhaled furosemide (20 to 30 mg by

inhalation 20 min before exercise) also attenuates EIA in children and can be combined with nedocromil to increase the protective effects of the drug. Leukotriene antagonists have been advocated by some, if protection of short-acting β-agonists alone is insufficient. Because of their low sideeffect profile, leukotriene antagonists would appear to be well suited as single agents for use against EIA. However, additional head-to-head studies showing efficacy during exercise would be required before these agents can be favored over inhaled β-adrenergic agonists in routine prophylaxis against EIA. Increasingly, the use of performance-enhancing drugs has made it mandatory that competitive athletes with EIA specifically consult such organizations as the World AntiDoping Agency (WADA; www.wada-ama.org), the U.S. AntiDoping Agency (www.usantidoping.org), and other agencies such as the National Collegiate Athletic Association to assure that the treatments being used for the prevention of EIA are not prohibited for use in competition.

SUGGESTED READING Akahoshi M, Ohara K, Hirota T, et al: Functional promoter polymorphism in the TXB21 gene associated with aspirininduced asthma. Hum Genet 117:16–26, 2005. Ameisen JC, Capron A, Joseph M, et al: Aspirin-sensitive asthma: Abnormal platelet response to drugs inducing asthma attacks: Diagnostic and pathophysiological implications. Int Arch Allergy Appl Immunol 78:438–448, 1985. Anderson SD, Schoffel RE, Black JI, et al: Airway cooling as a stimulus to exercise-induced asthma: A re-evaluation. Eur J Respir Dis 67:20–30, 1985. Asano K, Shiomu T, Hasegawa N, et al: Leukotriene C4 synthase gene A(-444) C polymorphisms and clinical response to cys-LT (1) antagonist, pranlukast, in Japanese patients with moderate asthma. Pharmacogenetics 12:565– 570, 2002. Berges-Gimeno MP, Simon RA, Stevenson DD: Long term treatment with aspirin desensitization in asthmatic patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 111:180–186, 2003. Casadevall J, Ventura PJ, Mullol J, et al: Intranasal challenge with aspirin in the diagnosis of aspirin-intolerant asthma: Evaluation of nasal response by acoustic rhinometry. Thorax 55:921–924, 2000. Corrigan C, Mallet K, Ying S, et al: Expression of the cysteinyl leukotriene receptors cysLT(1) and cysLT(2) in aspirinsensitive and aspirin-tolerant chronic rhinosinusitis. J Allergy Clin Immunol 115:316–322, 2005. Cycar D, Lemanske RF Jr: Asthma and exercise. Clin Chest Med 15:351–368, 1994. Dahlen B, Malmstrom K, Nizankowska E, et al: Improvement in aspirin-intolerant asthma by montelukast, a leukotriene antagonist: A randomized, double blind, placebo-controlled trial. Am J Resp Crit Care Med 165:9– 14, 2002.

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Dahlen B, Szczeklik A, Murray JJ: Celecoxib in patients with asthma and aspirin intolerance. N Engl J Med 344:142, 2001. Dajani BM, Sliman NA, Shubair KS, et al: Bronchospasm induced by intravenous hydrocortisone sodium succinate (Solu-Cortef) in aspirin-sensitive asthmatics. J Allergy Clin Immunol 68:201–206, 1981. Deal EC Jr, McFadden ER Jr, Ingram RH Jr, et al: Role of respiratory heat exchange in production of exercise-induced asthma, J Appl Physiol 46:467–475, 1979. Fischer AR, Rosenberg MA, Lilly CM, et al: Direct evidence for a role of the mast cell in the nasal response to aspirin in aspirin-sensitive asthma. J Allergy Clin Immunol 94:1046– 1056, 1994. Floyer JA: Treatise of Asthma. London, R. Wilkens and W. Innis, 1698. Gyllfors P, Bochenek G, Overholt J, et al: Biochemical and clinical evidence that aspirin-intolerant asthmatics subjects tolerate the cyclo-oxygenase 2-selective drug celecoxib. J Allergy Clin Immunol 111:1116–1121, 2003. Hahn A, Anderson SD, Morton AR, et al: A reinterpretation of the effect of temperature and water content of the inspired air in exercise-induced asthma. Am Rev Respir Dis 130:575– 579, 1984. Helenius I, Rytila P, Srana S, et al: Effect of continuing of finishing high-level sports on airway inflammation, bronchial hyperresponsiveness, and asthma. A 5-year prospective follow-up study of 42 highly trained swimmers. J Allergy Clin Immunol 109:962–968, 2002. Ingenito E, Solway J, Lafleur J, et al: Dissociation of temperature gradient and evaporative heat loss during cold gas hyperventilation in cold-induced asthma. Am Rev Respir Dis 138:540–546, 1988. Israel E, Fischer AR, Rosenberg MA, et al: The pivotal role of 5lipoxygenase products in the reaction of aspirin-sensitive asthmatics to aspirin. Am Rev Respir Dis 148:1447–1451, 1993. Karjalainen EM, Laitinen A, Sue-Chu M, et al: Evidence of airway inflammation and remodeling in ski athletes with and without bronchial hyperresponsiveness to methacholine. Am J Respir Crit Care Med 161:2089–2091, 2000. Kim HB, Lee SY, Shim JY, et al: The leukotriene C4 synthase (A-444C) promoter polymorphism is associated with severity of asthma in Korean children. J Allergy Clin Immunol 117:1191–1192, 2006. Kim SH, Choi JH, Lee KW, et al: The human leukocyte antigen DRB1∗ 1302-DQB1∗ 0609-DPB1∗ 0201 haplotype may be a strong genetic marker for aspirin-induced urticaria. Clin Exp Allergy 35:339–344, 2005. Kowalski ML, Sliwinska-Kowalska M, Igarishi Y, et al: Nasal secretions in response to acetylsalicylic acid. J Allergy Clin Immunol 91:580–598, 1993. Manning PJ, Watson RM, Margolskee DJ, et al: Inhibition of exercise-induced bronchoconstriction by MK-571, a potent leukotriene D4-receptor antagonist. N Engl J Med 323:1736–1739, 1990.

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McFadden ER Jr: Exercise-induced airway obstruction. Clin Chest Med 16:671–682, 1995. O’Byrne PM, Ramsdale EH, Hargreave FE: Isocapnic hyperventilation for measuring airway hyperresponsiveness in asthma and chronic obstructive pulmonary disease. Am Rev Respir Dis 143:1444–1445, 1991. Parikh AA, Scadding GK: Intranasal lysine-aspirin in aspirinsensitive nasal polyposis: A controlled trial. Laryngoscope 115:1385–1390, 2005. Patriarca G, Berlioni P, Nucera, et al: Intranasal treatment with lysine acetyl salicylate in patient with nasal polyposis. Ann Allergy 67:588–592, 1991. Pauls JD, Simon RA, Daffern PJ, et al: Lack of effect of the 5-lipoxygenase inhibitor zileuton in blocking oral aspirin challenges in aspirin-sensitive asthmatics. Ann Allergy Asthma Immunol 85:40–45, 2000. Phillips YY, Jaeger JJ, Laube BL, et al: Eucapnic voluntary hyperventilation of compressed gas mixture: A simple method for bronchial challenge by respiratory heat loss. Am Rev Respir Dis 131:31–35, 1985. Ruddell KW, Anderson SD, Speiring BA, et al: Field versus laboratory eucapnic voluntary hyperventilation to identify airway hyperresponsiveness in elite cold weather athletes. Chest 125:909–915, 2004. Samter M, Beer RF: Intolerance to aspirin: Clinical studies and consideration of its pathogenesis. Ann Intern Med 68:975– 983, 1968. Sanak M, Levy BD, Clish CB, et al: Aspirin-tolerant asthmatics generate more lipoxins than aspirin-intolerant asthmatics. Eur Resp J 16:44–49, 2000. Sanak M, Pierzchalaka M, Bazan-Socha A, et al: Enhanced expression of the leukotriene C4 synthase due to overactive transcription of an allelic variant associated with aspirintolerant asthma. Am J Resp Cell Mol Biol 23:290–296, 2000. Sladek K, Dworski R, Soja J, et al: Eicosanoids in bronchoalveolar lavage fluid of aspirin-intolerant patients with asthma after aspirin challenge. Am J Respir Crit Care Med 149:940– 946, 1994. Stevenson DD, Mehra PK, White AA, et al: Failure of tacrolimus to prevent aspirin-induced respiratory reactions in patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 116:755–760, 2005. Stevenson DD, Simon RA: Lack of cross reactivity between rofecoxib and aspirin in aspirin-sensitive patients with asthma. J Allergy Clin Immunol 108:47–51, 2001. Stevenson DD, Simon RA, Mathison DA, et al: Montelukast is only partially effective in inhibiting aspirin responses in aspirin-sensitive asthmatics. Ann Allergy Asthma Immunol 85(6 pt 1):477–482, 2000. Stevenson DD, Zuraw BL: The pathogenesis of aspirinexacerbated respiratory disease. Clin Rev Allergy Immunol 24:169–188, 2003. Storms WW: Asthma associated with exercise. Immunol Allergy Clin North Am 25:31–43, 2005.

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Szczeklik A, Gryglewski RJ, Czerniawska-Mysik G: Relationship of inhibition of prostaglandin biosynthesis by analgesic to asthma attacks in aspirin-sensitive patients. Br Med J 1:67–69, 1975. Szczeklik A, Nizankowska E, Bochenek G, et al: Safety of a specific Cox-2 inhibitor in aspirin-induced asthma. Clin Exp Allergy 31:179–181, 2001. Szczeklik A, Stevenson DD: Aspirin-induced asthma: Advances in pathogenesis, diagnosis and management. J Allergy Clin Immunol 111:913–921, 2003. Szczeklik W, Sanak M, Szczeklik A, et al: Functional effects and gender association of Cox-2 gene polymorphism G-765-C

in bronchial asthma. J Allergy Clin Immunol 114:248–253, 2004. Vanselow NA, Smith Jr: Bronchial asthma induced by indomethacin. Ann Intern Med 66:568–572, 1967. Vizi E, Huzszar E, Csoma Z, et al: Plasma adenosine concentration increases during exercise: A possible contributing factor in exercise-induced bronchoconstriction in asthma. J Allergy Clin Immunol 109:446–448, 2002. Wasiak W, Szmidt M: A six-week double-blind, placebocontrolled, cross-over study of the effect of misoprostol in the treatment of aspirin-sensitive asthma. Thorax 54:900– 904, 1999.

48 Asthma: Clinical Presentation and Management Rodolfo M. Pascual JeRay J. Johnson

Stephen P. Peters

I. CLINICAL PRESENTATION AND DIAGNOSIS History Physical Examination Laboratory Studies

Asthma can be defined as an inflammatory disorder characterized by variable airflow obstruction; airway hyperresponsiveness to specific and nonspecific stimuli; and symptoms of wheezing, chest tightness, cough, and, occasionally, dyspnea. Heightened airway responsiveness is a pathognomic feature of asthma. Clinically, increased airway responsiveness manifests as intolerance to air pollution, smoke, strong odors or fumes, and particulate matter such as dust. Exposure to these agents typically results in transient symptoms of cough and chest tightness. Emotional factors such as laughing or crying may exacerbate symptoms in a large number of patients. Although asthma is frequently referred to as a disease, as if it were a single nosologic entity with a unique pathogenesis, experienced clinicians recognize that this is not the case. Asthma is more likely a syndrome, one that comprises multiple disorders manifesting common symptoms but having distinct and probably different pathogenetic and etiologic mechanisms. Phenotypic heterogeneity is evident not only in terms of the etiologic factors involved but also in terms of the severity and natural history of the disorder among different patients. Asthma has been classified as extrinsic or intrinsic, depending on the suspected role of allergens as etiologic factors. Atopic subjects are considered to have extrinsic asthma, while nonatopic subjects have intrinsic asthma. However, this nomenclature has been used with diminishing frequency, because it does not aid in establishing an etiologic diagnosis nor does it help in defining treatment strategies. The presence of atopy, often defined by the presence of skin test sensitivity

II. MANAGEMENT OF ASTHMA Chronic Stable Asthma Managing Asthma Exacerbations

to aeroallergens, does not, by itself, indicate that allergens are important triggers of asthma, since a large percentage of skin-sensitive persons report no allergic symptoms. Moreover, exercise and viral respiratory infections may play a more prominent role than allergens as triggers of symptoms in some atopic subjects. Classifying patients as having intrinsic asthma is problematic also, since it implies that all possible allergens in the environment have been excluded as etiologic factorsâ&#x20AC;&#x201D;a task that is nearly impossible to achieve. Although allergens are often triggers of acute asthma, there is a growing appreciation of their role as inducers of subclinical inflammation that may lead to enhanced airway responsiveness and greater susceptibility to the provocative effects of exercise and viral infections. In this regard, it is important to understand the distinction between triggers and etiologic factors. Whereas triggers may lead to symptoms, they do so only in susceptible persons who already possess the underlying asthmatic diathesis. In cases of occupational asthma, the disease can often be classified according to its etiology. In these circumstances, not only is the specific agent that triggers symptoms known, but the same agent is usually the underlying cause of asthma. Another category of asthma is that which is exercise induced. The term exercise-induced asthma is somewhat misleading, suggesting that exercise is the cause of the asthma. In fact, exercise is not a cause of asthma. Rather, it is one of many nonimmunologic triggers that produce symptoms in patients who already have the disease. Perhaps the most useful classification of asthma is that based on levels of severity. This approach has facilitated the

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development of rational treatment guidelines that have been endorsed by expert physicians throughout the world. This classification, as well as management strategies based on it, is discussed later in this chapter. However, patients move among different severity classes so these schemes have limited usefulness. Future guidelines should place increased emphasis on the burden that asthma places on patients as well as the risks that it poses for them.

CLINICAL PRESENTATION AND DIAGNOSIS The diagnosis of asthma is made clinically, usually on the basis of a history of typical symptoms and confirmatory, objective evidence of variable airflow obstruction. The diagnosis of asthma is usually made accurately, although the degree of diagnostic accuracy is probably patient-age dependent. For example, asthma diagnosis in young adults is usually not difficult, since there are few other conditions that mimic asthma or confound its clinical presentation. With increasing age, cardiovascular disease and other forms of chronic lung disease are more common, and the differential diagnosis of episodic chest symptoms is more extensive. Finding an irreversible component of airway obstruction in asthmatics adds to the challenge of distinguishing between asthma and tobacco-related chronic obstructive pulmonary disease (COPD), in current and exsmokers. Because the predictive value of clinical and laboratory findings in establishing the diagnosis of asthma appears to decline with advancing age, the probability of misdiagnosis is highest in the elderly, who have the same high asthma prevalence (4 to 7 percent) as younger adults. The following clinical and laboratory manifestations are important in consideration of the diagnosis of asthma.

History The history of symptoms, their pattern of occurrence, precipitating or aggravating factors, and the profile of a typical exacerbation are important elements of the clinical evaluation. During an acute episode, usual complaints include wheeze and a sensation of chest tightness. Breathlessness may also occur, although this symptom is often interpreted as a sensation of having difficulty inspiring, or â&#x20AC;&#x153;getting air in.â&#x20AC;? This sensation is probably due to dynamic lung hyperinflation that accompanies acute asthma episodes. When there is hyperinflation, further inspiratory efforts are made against a higher respiratory system recoil pressure. Cough may also be present; on occasion, it may be the sole presenting manifestation of an episode of asthma. Symptoms may occur abruptly or evolve slowly over days or weeks. The frequency and severity with which symptoms occur vary considerably within the asthmatic population. Although no single symptom is specific for asthma, wheezing is a useful sign, since most asthmatics complain of more than just rare episodes of wheezing, and nonasthmatics rarely report frequent wheezing. Especially in

younger patients, the symptom of chest tightness is also helpful, since it occurs more often in association with asthma than with other pulmonary or cardiac disorders. Chest symptoms that vary by season and are accompanied by symptoms of irritation of other mucous membranes, such as conjunctivitis and rhinitis, are typical of allergic asthma. Whereas pollens and some mold spores are likely to provoke seasonal symptoms, indoor allergens, such as house dust mites, cockroaches, and animal dander proteins are more apt to result in perennial symptoms. Early-morning symptoms or nocturnal episodes are very common in adult asthmatics. It is important to distinguish whether nocturnal symptoms are due to asthma, gastroesophageal reflux, or angina. Typically, nocturnal asthma symptoms occur between 4:00 and 6:00 a.m.; usually they are relieved with administration of inhaled bronchodilators. This contrasts with gastroesophageal reflux, which causes similar symptoms soon after the patient reclines at night, or cardiovascular symptoms, which can occur at any time. Viral respiratory infections are a common cause of exacerbations of asthma in adults. The viruses most commonly implicated are rhinovirus, respiratory syncytial virus, influenza virus, and parainfluenza virus. Mycoplasma and Chlamydia are also associated with exacerbations of asthma; other bacterial infections are not. It should be noted that viral respiratory infections can evoke an increase in airway responsiveness in otherwise healthy persons, causing self-limited episodes of chest tightness, cough, and wheezing that may last for as long as 8 to 12 weeks. Although these episodes are frequently diagnosed as asthma, the disappearance of symptoms after 8 to 12 weeks suggests that the illness was due to a temporary, postviral increase in airway responsiveness. Exercise-induced Asthma A history of symptoms after heavy exertion, especially in cold air, is highly suggestive of exercise-induced asthma. Typically, the patient experiences symptoms at the end of exercise, rather than during its performance. Excessive coughing after exercise, sometimes in the absence of wheezing, may also be a sign of asthma. Patients with COPD or heart failure may experience exertional dyspnea, but, as a rule, these patients do not develop symptoms of chest tightness, cough, and wheeze. Asthma and Aspirin Sensitivity The association of asthma and sensitivity to aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is well established. Of particular note is the triad of asthma, nasal polyps, and aspirin intolerance. This condition is thought to affect 2 to 3 percent of all asthmatic patients and up to 20 percent of patients with severe asthma. In this syndrome, the first symptom is usually rhinitis. This is followed several years later by the development of aspirin intolerance and asthma symptoms and finally, usually much later, nasal polyps. Nasal polyps are usually bilateral and originate from the turbinates, as well as the paranasal sinuses. Aspirin-induced asthma has been associated with enhanced leukotriene production and

817 Chapter 48

mast cell activation, but mechanisms responsible for these events remain unclear. Although aspirin-induced asthmatic episodes often resemble allergic reactions, there is no evidence that IgE-related immunologic mechanisms are at work. As a rule, aspirin intolerance is associated with severe asthma that is often resistant to therapy, including glucocorticoid therapy. The diagnosis of aspirin intolerance and asthma is made on the basis of the history and clinical findings of sinusitis and nasal polyps; it can be confirmed by aspirin challenge procedures. Î˛-Adrenergic receptorâ&#x20AC;&#x201C;blocking drugs, including those contained in topical ophthalmic preparations, can also precipitate severe, acute, and sometimes fatal asthmatic episodes. Accordingly, beta blockers are contraindicated during acute asthma exacerbations and the risk-benefit ratio should be considered before they are used in stable outpatients with asthma. Occupational Asthma Asthma related to occupational exposure can often be identified on the basis of a typical history of symptoms during the work week and improvement over the weekend. Symptoms may occur during exposure to the etiologic substance, or they may be delayed until the evening or night after the work day. It is important to distinguish between occupational asthma that is triggered by nonspecific irritants in patients with preexisting or concurrent asthma and asthma that arises de novo as a consequence of exposure to a specific etiologic agent. A number of natural and synthetic chemicals are known to cause asthma by IgE-mediated mechanisms, as well as by nonallergic mechanisms of unknown origin. The diagnosis of occupational asthma is based on a history of typical symptoms, the presence of variable airflow obstruction, and a demonstrable link between asthma and workplace exposure.

Physical Examination Wheezing, the most characteristic physical finding in asthma, is caused by turbulent airflow through narrowed airways. In asthma, wheezing is usually present during expiration, although it may be present during inspiration as well. The quality of wheezing should not be considered predictive of the degree of obstruction in an individual patient. Patients who are asymptomatic, or who complain only of cough, may demonstrate end-expiratory wheezing, although this is a nonspecific and insensitive sign of asthma. It is important to note that wheezing of any character is not specific for asthma; notably, in cases of very mild or very severe airway obstruction, wheezing may be absent. Clinical signs of rhinitis, sinusitis, and nasal polyps are seen more commonly in patients with asthma than in those with other chronic lower respiratory tract disorders or congestive heart failure. Chronic sinus disease may be difficult to diagnose on clinical grounds; imaging studies may be required. Marked weight loss or severe wasting is not seen in asthma but is commonly seen in severe emphysema. Signs of hyperinflation and diminished breath and heart sounds are usually observed during an acute exacerbation. Use of

Asthma: Clinical Presentation and Management

accessory muscles of respiration and the presence of pulsus paradoxus are signs of severe airway obstruction and are usually observed during acute episodes. Because ventilatory effort can be diminished with respiratory muscle fatigue, the absence of pulsus paradoxus does not preclude severe airway obstruction. Stridor, a high-pitched inspiratory sound, heard best with auscultation over the upper airways, should prompt a further search for causes of upper-airway obstruction, including vocal cord dysfunction, tracheal or bronchial stenosis, vocal cord paralysis, upper-airway tumors, and airway narrowing due to thyroid enlargement.

Laboratory Studies The use of laboratory studies in the diagnosis of asthma is largely restricted to spirometry. Skin testing and serologic studies may also be useful in defining allergic triggers of asthma in some patients, although the clinical history often provides more clinically relevant information regarding the relation between symptoms and exposure. Radiographic studies, blood tests, and more extensive lung function studies are used to exclude other conditions that may mimic asthma or complicate its clinical presentation. Pulmonary Function Tests Pulmonary function tests are important for confirming the diagnosis of asthma, establishing the severity of the disease, and monitoring the response to therapy. The diagnosis of asthma is usually confirmed by objective demonstration of airflow obstruction by spirometry. In addition, there should be evidence of significant improvement in the 1-s forced expired volume (FEV1 ) acutely after bronchodilator administration, or with repeated measurement over time. Unfortunately, there are no standard criteria for judging the degree of reversibility after bronchodilator administration for diagnostic purposes. Although a postbronchodilator increase in FEV1 of greater than 12 percent is often considered evidence of reversible airway obstruction, this level is arbitrary and lacks sensitivity or specificity for detecting asthma. Clinical experience has shown that there is substantial overlap in the degree of bronchodilator reversibility when one compares patients with asthma to those with COPD. Thus, while a marked spirometric response to inhaled bronchodilator confirms reversibility of airway obstruction and is strongly indicative of asthma, this finding does not rule out COPD, nor does the lack of an acute bronchodilator response rule out asthma. Since office spirometry is inexpensive and easy to perform, there seems to be little justification for sacrificing diagnostic sensitivity and specificity by using peak expiratory flow (PEF) measurements made in the office for the initial diagnosis of asthma. However, home monitoring of variability in PEF may be of diagnostic use, especially in patients with mild, intermittent symptoms who often demonstrate normal spirometry during physician visits. Measurement of lung volumes is useful for excluding restrictive lung disease. In asthma, an increase in residual volume is typically seen, reflecting airway closure at a lung

818 Part IV

Obstructive Lung Diseases

volume that is higher than normal. During acute asthmatic episodes, functional residual capacity and total lung capacity may also be increased. Measurement of diffusing capacity of the lung (DlCO ) deserves mention because of its value in differentiating patients with emphysema from those with asthma. Emphysema, characterized by alveolar septal destruction and loss of pulmonary capillary volume, is associated with a reduced DlCO ; by contrast, the DlCO is usually normal or supranormal in asthma.

siveness in former asthmatics predisposes to relapse later in life. Likewise, it is not known whether abnormal airway responsiveness predisposes to the subsequent development of asthma or COPD. Physical measures to assess airway responsiveness include exercise and isocapnic hyperventilation. Both stimuli induce airway obstruction as a consequence of cooling or drying of the airway mucosa. The requirement for strenuous physical work limits the use of such challenges to persons who are physically capable of performing them.

Bronchial Challenge Testing Abnormal airway responsiveness, a sine qua non for asthma, is detected in the laboratory by an exaggerated response to inhaled pharmacologic agents, such as histamine, adenosine, or methacholine; or physical stimuli, such as exercise and hyperventilation. The correlation between different airway challenge tests is remarkably good, especially between histamine and methacholine and, to a lesser extent, among other pharmacologic agents, and the physical measures exercise and cold air hyperventilation. The largest experience with pharmacologic challenge testing is with intermittent and continuous aerosol generation techniques using methacholine or histamine. The two techniques give remarkably similar results when airway responsiveness is expressed as the concentration of drug causing a 20 percent fall in FEV1 (PC20 ), as determined from doseresponse curves. Some studies have shown that 100 percent of patients with current asthma symptoms demonstrate a PC20 at histamine concentrations less than or equal to 8 mg/ml, while others, using methacholine, have reported a sensitivity of approximately 85 percent at the same PC20 threshold. False-negative results can be obtained in patients who experience only intermittent symptoms and are tested when they are asymptomatic. Indeed, atopic patients with seasonal asthma symptoms may demonstrate PC20 greater than 8 mg/ml when tested “out of season.” False-negative challenge responses may also occur in patients with occupational asthma if tests are performed remote in time from exposure to the etiologic agent. Whereas diagnostic tests are more likely to be performed in patients who have had recent symptoms, pharmacologic challenges are generally conceded to have a low falsenegative rate. Thus, when a diagnostic threshold PC20 of less than or equal to 8 mg/ml is used, pharmacologic challenges are sensitive tests with a high negative predictive value (i.e., a PC20 greater than 8 mg/ml excludes a diagnosis of asthma with a high degree of accuracy). Most surveys indicate that the specificity of pharmacologic challenge testing is approximately 90 percent when a PC20 of less than or equal to 8 mg/ml is used as the diagnostic threshold. The prevalence of abnormal responsiveness in nonatopic, nonasthmatic subjects who have no history of prior respiratory problems ranges from 5 to 10 percent; in such patients, the term “false-positive” should be used with caution. The significance of abnormal responsiveness in this population is uncertain. For example, it is not known whether the retention of abnormal respon-

Clinical Application of Bronchial Challenge Tests The specificity of bronchial challenge tests in the diagnosis of asthma is compromised further by the finding that abnormal airway responsiveness is associated with a number of other disorders, including cystic fibrosis, COPD, and heart failure. Moreover, conditions associated with airway injury or inflammation—such as viral respiratory infections, exposure to pollutants, and exposure to aeroallergens—can induce a temporary state of abnormal responsiveness. Accordingly, pharmacologic challenges are not useful for discriminating between asthma and COPD in patients with abnormal spirometry. Hence, airway challenge testing is used, perhaps most usefully, in evaluating patients who have unexplained chest symptoms and normal spirometry results. Since the clinical history, by itself, has little value in establishing a diagnosis of asthma in patients with atypical symptoms, bronchial provocation testing may be especially useful for excluding a diagnosis of asthma because of the low false-negative rate and high negative predictive value. Conversely, the finding of abnormal responsiveness in such patients may not be diagnostic of asthma because of the test’s poor positive predictive value and the possibility that hyperresponsiveness may also reflect self-limited pathology that occurs with transient airway inflammation secondary to viral infections. In any event, the demonstration of abnormal airway responsiveness may be taken as presumptive evidence of an association between symptoms and abnormal responsiveness, thus providing an objective basis for asthma therapy. Blood Tests Arterial blood gases are typically normal in patients with chronic, stable asthma. During an acute, severe episode, hypoxia is often present. Arterial PCO2 is typically reduced owing to hyperventilation. With severe obstruction, arterial PCO2 may rise because of respiratory muscle fatigue and an inability to maintain the required alveolar ventilation. Peripheral blood eosinophilia (greater than 4 percent or 300 to 400 per mm3 ) may be seen in both allergic and nonallergic asthmatics. When present, eosinophilia may be used to support a diagnosis of asthma; however, its absence is of no value in excluding asthma. Unusually high eosinophil counts (greater than 800 per mm3 ) suggest the presence of other disorders, such as allergic bronchopulmonary aspergillosis, Churg-Strauss syndrome, tropical eosinophilia, and Loeffler’s

819 Chapter 48

syndrome. It should be noted that eosinophilia may not be present if the patient is taking corticosteroids. Epidemiologic studies have demonstrated an association between asthma and total serum immunoglobulin E (IgE) levels, standardized for age and sex. Whether this association signifies that aeroallergens are prominent etiologic factors, or that immunologic processes in the pathogenesis of asthma are capable of stimulating IgE production as an unrelated phenomenon needs further definition. Studies have also shown a relationship between total serum IgE and asthma in patients with negative skin tests. In addition, other studies have reported that elevations in total IgE are strongly associated with asthma, whereas skin test reactivity is more closely related to allergic rhinitis. Importantly, IgE levels are used to calculate the dose of the anti-IgE antibody omalizumab, when it is used for asthma treatment as discussed below. Other blood tests may be useful for ruling out vasculitis or allergic bronchopulmonary fungal disease. However, these tests should be employed only when clinical suspicion warrants pursuit of uncommon causes of asthma symptoms. Sputum Examination In research studies sputum eosinophil counts have been shown to predict clinical outcomes, particularly exacerbations when corticosteroids are withdrawn, but more research needs to be done before sputum examination can be used as a clinical tool. Allergy Tests Tests to determine whether the patient is allergic and to investigate the role of specific allergens as a cause of asthma are of value in some patients, particularly when the clinical history suggests that specific aeroallergens are important triggers in a particular patient, and when asthma symptoms are accompanied by other symptoms typical of allergic disease, such as rhinitis and conjunctivitis. In selected populations, evaluations for perennial or indoor allergens, such as dust mite, cockroach, or animal dander have become increasingly important. The components of an allergic evaluation include a detailed history of the patientâ&#x20AC;&#x2122;s environment and possible triggers, followed by tests of allergic sensitivity. Sensitivity to a particular allergen (or the presence of specific IgE antibody) can be verified by skin tests or in vitro serum antibody studies. Allergy evaluation is useful for developing avoidance treatment strategies or, in selected cases, for developing immunotherapy regimens. Radiography Because the chest radiograph is generally unremarkable in patients with uncomplicated asthma, it is used primarily to exclude other causes of respiratory symptoms. Nonspecific radiographic findings, such as overinflation, prominent hilar vessels, and bronchial wall thickening may be seen. Computed tomography may demonstrate atelectasis, bronchial wall thickening, or mucus impaction.

Asthma: Clinical Presentation and Management

Exhaled Nitric Oxide In research studies low eNO values have demonstrated reasonable sensitivity and specificity in discriminating between subjects with asthma and normal subjects, but more research needs to be done before eNO can be used as a diagnostic tool.

Differential Diagnosis There are a number of conditions to consider in the differential diagnosis of asthma and these are listed in Table 48-1.

Table 48-1 The Differential Diagnosis of Asthma Condition Other airway diseases COPD

Comment

Significant smoking history Airflow obstruction less reversible Reduced DlCO

Bronchiectasis

Maybe secondary to numerous disorders Patients usually produce purulent sputum Computed tomography usually diagnostic

Reactive airways viral syndrome

Transient, usually resolves after several weeks

Rhinosinusitis

Usually report nasal congestion and post nasal drip Common co-morbid illness accompanying asthma

Gastroesophageal reflux disease

Usually have other complaints but may be silent Common co-morbid illness accompanying asthma

Congestive heart failure

Usually have exertional dyspnea but not at rest Echocardiography helpful

Laryngeal dysfunction

Stridor Diagnosis challenging, laryngoscopy helpful May co-exist with asthma

Upper airway obstruction

May or may not exhibit stridor Flow-volume loop may be helpful Endoscopy diagnostic

820 Part IV

Obstructive Lung Diseases

MANAGEMENT OF ASTHMA Successful management of the asthmatic patient requires an appreciation of two basic principles. First, asthma exhibits considerable heterogeneity with respect to etiology, clinical presentation, severity, natural history, and response to therapy. Because of this heterogeneity, it is unlikely that a single management approach will work for all patients. Thus, therapy must be tailored to the individual patient. The second principle recognizes that in each patient, symptom severity may vary considerably over time. For example, some patients may experience a remission of symptoms during adolescence, only to have them recur with even greater severity later in life. Even when the disease remains relatively stable over long intervals, intercurrent flares that arise as a result of seasonal allergies or infection are the rule in asthma. Thus, the patient should be monitored regularly, and treatment should be modified on an ongoing basis to meet the patient’s current needs.

Chronic Stable Asthma A number of comprehensive treatment guidelines drafted by multidisciplinary expert committees have been published. In the following discussion, no attempt is made to recapitulate published guidelines; rather, there is an effort to summarize the recommended general approaches, point out gaps in information, and highlight areas where controversy exists. The management of persistent asthma in adults is highlighted in Table 48-2. Nonpharmacologic Therapy Recent studies suggest that patient education and environmental control programs are effective in reducing asthma morbidity, although additional research is needed to better determine which methods are the most effective and which patients benefit the most.

agement of physical activity. However, the provision of written materials alone may be sufficient to decrease hospital and emergency room use. Personal contact with a knowledgeable professional is considered superior to provision of either audiovisual or written materials. Like drug therapy, the educational program, as well as the method and frequency of reinforcement, should be tailored to the individual. The educational program should impart to the patient an understanding of the disease, including the knowledge that symptoms are a product of airflow obstruction and therapy is designed to both prevent and relieve the obstruction. The patient should understand that asthma is a chronic disorder, unlikely ever to go into complete remission, and appreciate that symptoms will fluctuate and occasional exacerbations are to be expected. In addition, reassurance should be provided that, with proper treatment, these events can be minimized; in most cases, a normal lifestyle and life expectancy can be anticipated. Since educational programs that include self-management strategies are superior, they should also encompass a discussion of the patient’s individual treatment plan, including the purpose of different drugs, as well as their side effects. Distinguishing between drugs that control or prevent symptoms and those that relieve symptoms is necessary to reinforcing the importance of “controller” medications that offer no immediate relief of symptoms. Instruction in the proper use of inhaled medications is of obvious importance; so, too, is a description of likely triggers of episodes of asthma and ways to avoid such triggers. Finally, teaching the patient to recognize and intervene in exacerbations during their earliest stages can be helpful in avoiding more serious morbidity and, in some cases, mortality. Educating the patient in self-administration of oral glucocorticoids and providing a telephone number where professional assistance is available around the clock are, in our experience, crucial elements of a management program designed to reduce morbidity and hospitalizations.

Education

Environmental Control

The goal of asthma education is to improve patient understanding of the disease and its management and, consequently, to improve adherence to treatment recommendations. Another aim is to engage the patient in selfmanagement practices, especially in terms of identifying and avoiding asthma triggers and recognizing and treating exacerbations of asthma in their earliest stages. Controlled trials evaluating structured education and self-management programs for adult asthmatics generally show that such programs result in better asthma control and decreased emergency room visits and hospitalizations. The success of patient education programs is, to a large extent, dependent on their format. For example, individual one-onone educational sessions and sessions with small groups of patients have been shown to be of comparable efficacy; both are more effective than provision of written materials alone in terms of symptom control, use of proper inhaler technique, application of environmental control practices, and encour-

An important, often overlooked part of the management plan for all asthmatics, especially those with severe asthma who remain symptomatic despite intensive drug therapy, consists of measures to control environmental triggers. Avoidance of aeroallergens, viral respiratory pathogens, air pollution, and certain drugs can prevent exacerbations, reduce the need for drug treatment, and decrease utilization of emergency facilities. Of perhaps greater importance is avoidance of factors that may contribute to longer-term, airway inflammation responsible for abnormal airway responsiveness. Allergens from house dust mites, cockroaches, molds, and pets, particularly cats and dogs, have been associated with asthma. While the house dust mite is recognized as a significant cause of asthma throughout the developed world, the relative importance of different indoor allergens may vary among populations. For example, cockroach allergen may play a more prominent role in asthma in inner-city populations. Complete removal from exposure to house dust mites has been shown to reduce

821 Chapter 48

Asthma: Clinical Presentation and Management

Table 48-2 Management of Persistent Asthma in Adults Asthma Severity∗

Mild∗

Daytime symptoms

2–6 days/week Daily Usually no reduction in activity Exacerbations reduce activity

Continual Significant reduction in activity

Nocturnal awakenings

More than two monthly

More than once weekly

Most nights

Relief medication use

Less than daily

Daily

Several times daily

Lung function FEV1

>80% Predicted

60–80% Predicted

<60% Predicted

PEE variability

<30%

>30%

Controller medications

Low-dose ICS (highly preferred) OR Leukotriene receptor antagonist OR Theophylline SR

Low–moderate dose ICS + long acting β-agonist OR Low–moderate dose ICS + Leukotriene receptor antagonist OR Low–moderate dose ICS + theophylline SR

Moderate–high dose ICS + long acting β-agonist AND Oral steroids Anti-IgE therapy

Relief medications

Short-acting MDI

Short acting MDI Consider HFN

Manage environment

Treat rhinosinusitis

Treat rhinosinusitis Assess for GERD with esophageal pH study

Written action plans

Consider

Recommended, base on PEF/FEV1

Immunotherapy

Consider

Contraindicated

Monitoring

Annual spirometry

Annual office spirometry Monitor PEF Consider home spirometry

Office visits

Annual

2–3/year

At least every 3 months

Diagnose and treat other Manage environment conditions

Moderate∗

Severe∗

ICS = inhaled corticosteroid; PEF = peak expiratory flow; FEV1 = one second forced expiratory volume; SR = sustained release. Usual or initial outpatient status.

asthma severity and airway hyperresponsiveness. However, incomplete or partial reductions of dust mite counts are of questionable benefit in improving asthma control. Occupational asthma due to low-molecular-weight chemicals is also more likely to abate if patients are completely removed from exposure to the offending agent early in the course of their disease. Most patients with chronic asthma have numerous triggers. Therefore, the impact of avoidance of any

single trigger is likely to vary considerably from patient to patient. Vaccination

Inactivated influenza vaccine may be safely administered to patients with asthma. It seems likely that influenza vaccination would decrease the incidence of exacerbations of asthma; however, this has not conclusively been shown. Patients with

822 Part IV

Obstructive Lung Diseases

asthma should receive inactivated influenza vaccine if there are no other contraindications and especially if they are elderly or have other co-morbid conditions that increase the risk of death from influenza infection. Immunotherapy

Allergen immunotherapy also appears to be of benefit in highly selected patients with defined allergic triggers. As a rule, patients who have many allergic triggers tend to benefit less from immunotherapy than those with a single trigger. Patients who have mild- or moderate- persistent asthma not adequately controlled with inhaled medications may be considered for immunotherapy, but those with concomitant nasal symptoms appear to benefit the most. Although serious complications from immunotherapy are rare, they occur more frequently in patients with asthma. Furthermore, because of a high incidence of adverse systemic reactions, persons whose FEV1 is less than 70 percent of predicted should be considered at high risk of complications from immunotherapy. Pharmacologic Management Current guidelines advocate classifying asthma according to clinical severity using symptoms, lung function, and drug use as variables. Disease stratification guides the rational use of controller agents, as discussed below. Drugs currently available to treat asthma (listed in Tables 48-3 and 48-4) are classified as long-term control medications or “controllers” and quick-relief medications or “relievers” on the basis of their principal pharmacodynamic and clinical effect. Thus, short-acting bronchodilators such as inhaled beta agonists or anticholinergics are considered quick-relief medications. Corticosteroids, long-acting beta agonists, leukotriene pathway inhibitors, cromolyn sodium, nedocromil sodium, sustained-release theophylline, and omalizumab are considered long-term control medications, since they are used to achieve and maintain control of symptoms and are usually used daily on a long-term basis. Former nomenclature that classified drugs according to whether or not they had bronchodilator or anti-inflammatory properties is discouraged, since some medications have anti-inflammatory as well as bronchodilator properties. β-Adrenergic Agonists Inhaled β2 -adrenergic agonists are the drugs of choice for relief of symptoms due to acute airway obstruction. Shortacting beta agonists have a rapid onset of action and 3- to 6-hour duration of activity. At recommended doses, inhaled beta agonists have few adverse effects. Since regular use of short-acting beta agonists has not been shown to be superior to as needed use of these agents, we recommend that these agents be used as needed. Long-acting inhaled beta agonists have at least 12 hours duration of action and are not generally recommended for the short-term relief of acute symptoms, although formoterol has an onset of action as rapid as albuterol and can be used as

a reliever. Importantly, whereas long-acting beta agonists are generally the preferred agents to be used with inhaled steroids in combination therapy, they should not be used as monotherapy for the control of asthma of any severity. The combination of formoterol and budesonide has been demonstrated to be effective when used as both a controller and relief agent and thus provides the advantage of a single device used for both purposes. Theophylline

Theophylline now is primarily used as an adjunctive therapy, and for its steroid sparing effects, due to its narrow therapeutic index and the availability of safer and more effective alternatives. The steroid sparing effects of theophylline seem to occur at levels below the traditional therapeutic range of 10 to 20 mg/L. Thus, we recommend that the drug be titrated to steady-state serum concentrations of 5 to 10 mg/L or peak concentrations of no higher than 15 mg/L. Anticholinergic Agents

These agents induce airway smooth-muscle relaxation by blocking muscarinic receptors on airway smooth muscle, inhibiting vagally mediated cholinergic tone. In general, the short-acting anticholinergic agent ipratropium is not as effective as beta agonists as bronchodilators in asthma. It remains to be seen whether the long-acting anticholinergic drug tiotropium will prove to be useful as an asthma treatment. Glucocorticoids

Glucocorticoid steroids are the most effective agents available for treating persistent asthma. Inhaled steroids improve lung function when compared with placebo and reduce exacerbation rates. Patients with persistent asthma stabilized on inhaled steroids experience increased exacerbations when the steroids are withdrawn. Importantly, retrospective data suggest that the consistent use of inhaled steroids reduces asthma mortality. Finally, although the efficacy of inhaled glucocorticoids is clear, they suffer from important limitations. For example, the dose-response curve of inhaled steroids is relatively flat, meaning that higher doses are only incrementally better than low to medium doses. When there are persistent symptoms, rather than increasing the inhaled steroid dose the addition of long-acting beta agonists, leukotriene receptor antagonists, or theophylline provide superior bronchodilation and improve other outcomes, so that combination therapy is preferred. Cromolyn Sodium and Nedocromil Sodium

Cromolyn sodium and nedocromil sodium are classified as controller agents, and because they are remarkably safe, these drugs are considered first-line agents in the treatment of children with asthma, although they are inferior to inhaled steroids with respect to most relevant outcomes. In adults, however, the drugs are most often prescribed for patients with mild disease, since responses are unpredictable.

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Asthma: Clinical Presentation and Management

Table 48-3 Asthma Medications Type

Class

Drugs

Indication/Comment

Quick-relief

Short-acting β-adrenergic agonists

Albuterol: PO, MDI, HFN Levalbuterol: HFN, MDI Pirbuterol: MDI Metaproterenol: PO, MDI, HFN Terbutaline: PO, MDI, SC Isoproterenol: MDI, HFN, IV, SL Bitolterol: MDI, HFN

First-line agents for fast relief of bronchospasm, used for all severity classes MDI β2 -selective adrenergic agonists are preferred

Adrenergic agonist

Epinephrine: MDI, SC

Anti-cholinergic

Ipratropium bromide: MDI, HFN

Also useful for patients intolerant of β-adrenergic agonists

Inhaled Corticosteroids

Beclamethasone dipropionate: MDI Budesonide: MDI, HFN Flunisolide: MDI Fluticasone: MDI Mometasone furoate Triamcinolone acetonide: MDI Ciclesonide∗

Persistent asthma of any severity, may be used in combination with systemic steroids

Systemic Corticosteroids

Methylprednisolone: IV, PO Prednisolone: PO Prednisone: PO

Severe persistent asthma not controlled with high dose inhaled steroids or for asthma exacerbations

Cromones

Cromolyn sodium: MDI, HFN Nedocromil: MDI

Mild persistent asthma

Long acting β-adrenergic agonists

Salmeterol: MDI Formoterol: MDI Sustained release albuterol: PO

Moderate–severe persistent asthma

Anticholinergic

Tiotropium

FDA approved for COPD only

Methylxanthines

Theophylline: PO

Alternate therapy for mild persistent asthma, add on to steroids for moderate–severe persistent asthma

Leukotriene pathway inhibitors

Montelukast: PO Zafirlukast: PO Zileuton: PO

Alternate therapy for mild persistent asthma, add on to steroids for moderate–severe persistent asthma

Combinations

Fluticasone/Salmeterol: MDI Budesonide/Formoterol: MDI∗

Moderate–severe persistent asthma

Monoclonal anti-IgE antibody

Omalizumab: SC

Moderate–servere allergic asthma, has steroid sparing properties

Long-term controllers

PO = oral; MDI = inhaler; HFN = liquid for high flow nebulizer; IV = parenteral; SC = subcutaneous; SL = sublingual. ∗ Not FDA approved.

Class

Symptom Short-acting reliever β2 -adrenergic agonist

Type

β-adrenergic agonist selective for type 2 beta receptor, increases cAMP, activates protein kinase A, and induces bronchodilation by multiple mechanisms

Mechanism(s)

Name/route(s)

Side Effects

Nebulized every 6 to 8 h

Inhaled: 1 to 2 puffs every 4 to 6 h Oral: 1 tab 3–4 times per day Inhaled: 2 puffs every 4 h inhaled Nebulized: every 4 to 6 h

Pirbuterol: Inhaled Metaproterenol: oral, inhaled, and nebulized

Fewer side effects than racemic albuterol

Tachycardia, Oral: 1 tab every palpitations, 3–4 h, slow nervousness, release form hypokalemia, available tremor Inhaled: 2 puffs every 4 h, or 30 min prior to exercise for prevention of bronchoconstriction Nebulized: every 3–4 h

Dose

Levalbuterol: Nebulized

First-line agents for Albuterol: oral, fast relief of inhaled, and bronchospasm nebulized

Indication

Rare adverse cardiac events have been reported. Not recommended as first-line drug.

Levo enantomer of albuterol, nebulized combination with ipratropium not studied for compatability. Not been shown to be significantly superior to albuterol.

First choice for bronchodilation. Inhaled route is preferred over oral route for faster onset of action and fewer side effects. Increased use or decreased effectiveness may be sign or worsened control. Not recommended for long-term treatment. Chlorofluorocarbon (CFC) propellent in MDI being phased out. HFA formulation has no CFCs. Nebulized solution may be mixed with ipratropium.

Comments

Part IV

Detailed Asthma Medications

Table 48-4

824 Obstructive Lung Diseases

Epinephrine: Inhaled, subcutaneous

Nonselective (β1 ,β2 ,α) adrenergic agonist

(Continued )

As for isoproterenol Not recommended as plus convulsions, first-line medication chills, fever, hallucinations

Chapter 48

Inhaled: 1–2 puffs every 3 h Subcutaneous: 0.2–0.5 mg every 2 h needed

Used for anesthesia-induced bronchospasm.

Tachycardia, Inhaled: 1–2 puffs palpitations, every 4 h nervousness, Nebulized: 5–15 hypokalemia, breaths every tremor, 5–10 min, max of headache, 5 times per day seizure, Sublingual: 10–20 paradoxical mg every 3–4 h, bronchospasm max 60 mg per day Intravenous: 2–10 µg per min.

Isoproterenol: inhaled, nebulized, sublingual, intravenous

Cannot be mixed with other medications in nebulized solution.

Inhaled: 2 puffs every 8 h Nebulized: every 6–8 h

Bitolterol: inhaled, nebulized

Nonselective beta (β1 ,β2 ,)adrenergic agonist

Not recommended as first-line drug as beta agonist side effects more commonly encountered. Intravenous solution available for tocolysis.

Terbutaline: oral, Oral: 1 tab every 6 h inhaled, (max 15 mg/d) subcutaneous Inhaled: 2 puffs every 4–6 h Subcutaneous: 0.25 mg, may repeat after 30 min, max 0.5 mg in 4 h

825

Asthma: Clinical Presentation and Management

Ipratropium bromide: inhaled, nebulized

Name/route(s)

Beclomethasone dipropionate Budesonide Flunisolide Fluticasone Mometasone furoate Triamcinolone acetonide

First line controller Fluticasone/ agents for salmeterol moderate–severe Budesonide/ persistent asthma formoterol

Inhaled Anti-inflammatory: Mild persistent–severe corticosteroids effects are broad, persistent asthma bind to glucocorticoid receptors and mediate transcriptional repression of a variety of inflammatory mediators, decreases infiltration of

Combine the antiinflammatory properties of glucocorticoids and the bronchodilation of long-acting beta-agonists

Muscarinic receptor Quick relief of antagonist, symptoms (subtypes M3 and M2 ), blocks action of acetylcholine on airway smooth muscle resulting in bronchodilation, reduction in mucus secretion

Anticholinergic

Indication

Mechanism(s)

Class

Long-term Combination controllers inhalers

Type

Side Effects

Same as for individual components

Skin thinning, easy 1–3 puffs twice bruising, adrenal daily suppression, One puff twice daily cataracts, 2–4 puffs per day osteoporosis, 1–3 puffs per day oral candidiasis, mild growth retardation in 2–3 puffs four times children, daily or 4–6 puffs hoarseness twice daily

Inhaled: 1 puff twice daily Not available in the U.S.

Inhaled: 2 puffs Dry mouth, bitter every 4–6 h taste, nasal Nebulized: every 6 h congestion

Dose

Mouth washing after use reduces risk of oral candidiasis.

Alternative for patients intolerant of beta agonists. May be mixed with albuterol in nebulized solution. Slower onset of action than beta agonists.

Comments

Part IV

(Continued )

Table 48-4

826 Obstructive Lung Diseases

Mild persistent asthma

Anti-inflammatory

β adrenergic agonist selective for type 2 beta receptor, increases cAMP, activates protein kinase A, and induces bronchodilation by multiple mechanisms

Cromones

Long-acting beta agonists

1 tab every 12 h

1 puff every 12 h

2 puffs 4 times per day

2–4 puffs 4 times per day

5–60 mg daily or every other day

60–500 mg daily in divided doses

Tachycardia, anxiety, headache, hypokalemia

Cough Cough, bitter taste

Skin thinning, easy bruising, adrenal suppression, cataracts, osteoporosis, oral candidiasis, psychosis, hyperglycemi a fluid retention

(Continued )

Inhaled form has fewer side effects than oral. Salmeterol has both CFC and dry powder forms. Long-acting beta agonists should not be used to treat acute attacks. LABAs should always be used in combination with anti-inflammatory medications for asthma.

Favorable safety profile, maximum benefit may take 4 to 6 wk.

Dose should be titrated to minimum required for desired asthma control

Chapter 48

Moderate–severe Salmeterol: persistent asthma inhaled Formoterol: inhaled Sustained release albuterol

Cromolyn sodium: inhaled, nebulized Nedocromil: inhaled

Methylprednisol Severe persistent one: asthma not intravenous controlled with Prednisolone: high-dose oral inhaled corticosteroids or Prednisone: oral used in taper dosing for asthma exacerbations

Systemic Anti-inflammatory corticosteroids

airways by several inflammatory cell types, reduces cytokine and chemokine secretion by several cell types

827

Asthma: Clinical Presentation and Management

Type

1 tab once daily

Montelukast: Alternate therapy Cysteinyloral for mild leukotriene persistent asthma Zafirlukast receptor type 1 antagonists, blocks action of leukotrienes LTC4 and LTD4 , reduces inflammation, and causes bronchodilation Add-on to steroids Zileuton 5-lipoxygenase for inhibitor, reduces moderate–severe production of asthma LTB4 , LTC4 , and LTD4 by a variety of cell types, reduces inflammation, and is a modest bronchodilator

Leukotriene pathway inhibitors

1 tab 4 times daily

1 tab twice daily

Variable dosing schedules

Alternate therapy Theophylline: for mild sustained persistent asthma release: oral Add-on to steroids for moderate– severe asthma

Dose

Phosphodiesterae inhibitor, increases cAMP, activates protein kinase A, and induces bronchodilation by multiple mechanisms

Name/route(s)

Methylxanthines

Indication

Mechanism(s)

Class

(Continued )

Absorption and dosing dependent on several factors including brand, comorbidities, and medication interactions. Monitoring of drug levels required.

Comments

Rare— Association with neurologic/hepatic Churg-Strauss syndrome complications initially reported but reported likely due to steroid withdraw and not leukotriene inhibitor.

Nause/vomiting. Toxic level—seizures, tachycardia, arrhythmia

Side Effects

Part IV

Table 48-4

828 Obstructive Lung Diseases

Binds IgE antibodies

Tiotropium

Add-on to steroids Omalizumab for moderateâ&#x20AC;&#x201C;severe persistent allergic asthma

Long-acting anti- Muscarinic receptor Not FDA approved cholinergic antagonist, M3 for asthma type selective Consider as add-on controller for severe persistent asthma

Anti-IgE monoclonal antibody

1 puff daily

150â&#x20AC;&#x201C;375 mg subcutaneously every 2 or 4 wks; dosage determined by IgE level before first treatment and body weight Not indicated if atopy not present as determined by RAST or skin testing

Dry mouth, urinary Should not be used with retention ipratropium because of excessive anticholinergic side effects

Injection site reaction, rash, headache, anaphylaxis

829

Chapter 48 Asthma: Clinical Presentation and Management

830 Part IV

Obstructive Lung Diseases

Lipoxygenase Inhibitors and Leukotriene Receptor Antagonists

Leukotriene pathway inhibitors are a group of compounds that alter the pathophysiologic effects of leukotrienes derived from the 5-lipoxygenation of arachidonic acid. Two classes of agents are available: inhibitors of the 5-lipoxygenase (5-LO) enzyme and cysteinyl-leukotriene receptor type 1 antagonists. Although inhaled corticosteroids are superior asthma controllers, leukotriene pathway inhibitors may be substituted for ICS in selected patients with mild disease and are especially useful when steroids are poorly tolerated, steroid use is not desired by the patient, or there is significant, concomitant rhinosinusitis. Furthermore, leukotriene pathway inhibitors are useful as add-on therapy to inhaled steroids in selected patients with moderate to severe asthma and have steroid sparing effects. Anti-IgE Monoclonal Antibodies

A monoclonal antibody to IgE (omalizumab) rapidly reduces serum IgE and is an adjunctive agent for atopic asthmatic patients dependent on corticosteroids. Several studies of its use in patients with moderate to severe corticosteroid dependent asthma have shown a significant steroid-sparing effect and a reduction in exacerbation frequency. We recommend that omalizumab be considered for moderate to severe atopic asthmatics, especially when high doses of inhaled steroids or oral steroids are required for disease control. It is most likely to be useful when patients require more than 800 Âľg of inhaled steroids, take daily oral steroids, have an FEV1 less than 65 percent predicted, or have required emergency room treatment within the prior year. Treatment Regimens Based on Severity Classification The classification of asthma as mild intermittent, mild persistent, moderate persistent, or severe persistent, as presented in published treatment guidelines, allows for a stepwise approach to controller drug therapy (Table 48-2). Current guidelines suffer from significant limitations because patients may frequently move amongst severity groups. Future guidelines will probably more precisely stratify patients based on estimates of asthma burden that account for usual disease severity and the risk posed by individual patientâ&#x20AC;&#x2122;s asthma. This approach recognizes that severity may vary with time and facilitates treatment as a dynamic process, with increments and decrements in drug dosages dictated by changes in severity of illness. Importantly, rigorous adherence to guideline-based therapy will lead to improved asthma control in the majority of patients no matter what the baseline disease severity; this has been demonstrated in a large multinational randomized controlled trial. Although errors in management are most often related to undertreatment with drugs, overtreatment can also be a problem, especially in patients with moderate to severe asthma. In such patients there is a tendency to maintain a static treatment regimen, even after symptoms are controlled and clinical stability is achieved. Treatment goals established in these guidelines include no limitations in activities or missed school or work, no chronic nighttime

or daytime symptoms, minimal to no exacerbations, nearnormal spirometry, minimal use of quick-relief medications, and minimal to no medication side effects. For all asthma patients, short-acting beta agonists used in recommended doses and delivered by metered dose inhaler are the preferred agents for the relief of acute symptoms though short acting anticholinergic agents are a reasonable alternative. Escalating need for relief medications is an important marker of poorly controlled disease or an exacerbation and should prompt consideration of a step-up in controller therapy or for more severe exacerbations, the initiation of a protocol for acute exacerbations as described later in the chapter. Mild Intermittent Asthma

Some asthmatic patients experience only mild, intermittent symptoms that are of brief duration. In fact, in a review of drug utilization records from a large health maintenance organization with a pharmacy benefit plan, it was found that approximately 70 percent of patients with asthma use fewer than four canisters of a short- or intermediate-acting beta agonist per year (Fish JE and Peters SP, unpublished observations). The use of inhaled beta agonists on an as-needed basis as sole therapy is usually recommended and is likely to provide satisfactory results with no major side effects for most of these asthmatics. Patients whose symptoms occur under predictable circumstances (e.g., with exercise or exposure to airborne allergens such as dander and occupational agents) benefit from preventive treatment with an inhaled beta agonist, leukotriene inhibitor, or cromolyn sodium. The treatment of choice is, of course, avoidance of the offending agent, although that is not always possible. Mild Persistent Asthma

Current treatment guidelines recommend the addition of a long-term control medication on a scheduled, daily basis when mild symptoms are no longer intermittent. Longterm control medications are those that are assumed to alleviate the underlying inflammatory basis of asthma. The low-dose inhaled glucocorticoids are the preferred medications in this group, although alternatives include leukotriene inhibitors, cromolyn, or nedocromil. Although as-needed inhaled steroids have been compared with scheduled inhaled steroids for mild persistent asthma in one randomized trial with promising results, insufficient evidence exists at this time to recommend this approach. Moderate Persistent Asthma

Current guidelines recommend low-dose inhaled steroids combined with a long acting beta agonist or medium-dose inhaled steroids as preferred therapy. Alternatively, lowerdose inhaled steroids may be combined with a leukotriene receptor antagonist or theophylline based on data from studies demonstrating the steroid-sparing properties of these agents. The anti-IgE antibody omalizumab may be useful, and immunotherapy may be considered in carefully selected

831 Chapter 48

patients. Allergen specific immunotherapy should be utilized only when strict environmental avoidance and medications, including inhaled steroids, have failed to control a patientâ&#x20AC;&#x2122;s asthma and only after careful consideration of the risks. Immunotherapy should only be administered by physicians expert in its use.

Severe Persistent Asthma

For purposes of discussion, severe asthma can be defined as asthma in which symptoms persist despite treatment with high-dose inhaled glucocorticoids and additional therapy in the form of long-acting beta agonists, leukotriene pathway inhibitors, or theophylline. Since severe asthma is frequently caused by poor adherence to drug regimens or exposure to environmental factors or drugs such as aspirin or beta blockers, a thorough investigation of these factors is indicated before the start of additional drug therapy. For the patient with severe asthma, chemotherapeutic options are quite limited. Although doses of inhaled glucocorticoids can be increased, dosages of theophylline and longacting beta agonists are limited because of the risk of toxicity. Options include increasing the dose of inhaled glucocorticoids, adding sustained-release theophylline or a leukotriene modifier in patients already taking inhaled glucocorticoids and long-acting beta agonists, and adding a long-acting beta agonist to the regimen for patients already taking inhaled glucocorticoids and theophylline or a leukotriene modifier. As for moderate persistent asthma, the addition of the monoclonal anti IgE antibody omalizumab has been shown to be useful in severe persistent disease. Multiple, well-designed studies have shown benefits in this population including a significant reduction in IgE levels, asthma exacerbations, beta agonist use, and glucocorticoids as well as incremental improvements in lung function. Leukotriene inhibitors have been studied in patients requiring moderate to high doses of inhaled corticosteroids to maintain control and have been found to have a steroidsparing effect. In one study, inhaled steroid doses were able to be reduced by nearly 50 percent in those patients taking montelukast. However, further studies are needed to determine the role of leukotriene inhibitors in patients with severe persistent asthma already taking maximal pharmacologic therapy, including high-dose inhaled corticosteroids and long-acting beta agonists. Allergen-specific immunotherapy may be considered in this group; however, the risk of severe events including death is highest in patients with severe asthma. Patients who fail to achieve symptom control, despite treatment with high-dose inhaled glucocorticoids and one or more long-acting bronchodilators are considered candidates for systemic glucocorticoid therapy. When chronic systemic steroids are needed, oral glucocorticoids are favored over parenteral formulations and, in principle, should be given in the lowest dose possible daily or every other day. For exacerbations or to achieve initial control, oral glucocorticoids may be given in moderate to high doses (0.25 to 1.0 mg/kg/d) for 8 to 21 days, followed by a tapering course to the lowest dose

Asthma: Clinical Presentation and Management

that maintains control. This approach is often sufficient to modify the underlying disease process and to permit better control at lower doses. Although a â&#x20AC;&#x153;threshold doseâ&#x20AC;? of glucocorticoids is required to maintain stability in some patients, this approach may achieve results that are good enough to permit complete discontinuation of oral glucocorticoids. Whereas potent and higher-dose formulations of inhaled glucocorticoids are now available, it is reasonable to ask whether the administration of increasing doses of inhaled glucocorticoids is more appropriate than prescribing oral steroids. For equivalent therapeutic effects, inhaled glucocorticoids have been shown to produce fewer steroid-related side effects than oral glucocorticoids. Moreover, comparisons of oral prednisolone (40 mg/d) with budesonide (3.2 mg/d) have demonstrated greater systemic toxicity with prednisolone, despite greater efficacy with budesonide. Patients who require high doses of oral glucocorticoids to maintain control of symptoms are referred to as steroid-dependent asthmatics. This is in contrast to steroid-resistant patients, who fail to demonstrate an improvement in lung function on reasonably high doses of systemic steroids, despite demonstrable improvement with inhaled beta agonists. Steroid resistance may be a primary defect due to an unknown intrinsic abnormality, or it may be a secondary defect related to increased steroid metabolism or the effects of drugs that alter steroid activity. Steroid dependence, on the other hand, is thought to be a reflection of severe disease with intense airway inflammation. In fact, these may simply be semantic differences, since intense airway inflammation itself may alter steroid responsiveness, and steroid dependence may be nothing more than an intermediate form of true resistance. Glucocorticoid resistance in asthma and its potential mechanisms have been reviewed. In patients with severe asthma manifesting steroid dependence or resistance, consideration should be given to the use of alternative anti-inflammatory agents.

Alternative Anti-inflammatory Therapies

Because of the complex array of inflammatory mechanisms putatively at work in asthma, there has been hope that agents such as macrolide antibiotics, gold salts, methotrexate, cyclosporine, colchicine, and others might prove effective in management. Studies of the steroid-sparing effects of macrolide antibiotics in asthma management have yielded discordant results. Macrolides may alter steroid metabolism, treat chronic, subclinical airway infection from mycoplasma and chlamydia bacteria, or have other anti-inflammatory effects. In one controlled study, the administration of clarithromycin to subjects with asthma resulted in improvements in lung function, but only in those with demonstrable evidence of mycoplasma or chlamydia infection. Because of the lack of long-term efficacy or safety data, the usefulness of gold salts in asthma should be considered unproved. Several controlled studies of the efficacy of methotrexate in the management of severe asthma have been carried out

832 Part IV

Obstructive Lung Diseases

with mixed results. In general, the discordant results obtained from these trials suggest that the benefits of methotrexate are not universal and are, perhaps, of questionable significance, particularly in light of the potential for significant adverse reactions to the drug. In the only controlled trial of cyclosporine (5 mg/kg/d) in steroid-dependent asthmatics, peak flow improved and fewer exacerbations occurred in the treated group during the 12-week trial. However, the treated group experienced frequent side effects, including headache, hypertension, hypertrichosis, paresthesias, and infections with herpes zoster while significant reduction in oral prednisone dose was achieved. More evidence is needed before the use of cyclosporine as a steroid-sparing agent can be recommended. Colchicine has been shown to relieve symptoms and reduce rescue bronchodilator usage in patients with allergic asthma. Colchicine was compared with placebo as an alternative agent to inhaled steroids in one large study of moderate asthmatics. The main study finding was that colchicine was not superior to placebo as an alternative agent to inhaled steroids. We therefore do not recommend that colchicine be used in lieu of inhaled steroids. Agents designed to inhibit the effects of cytokine products, such as IL-4 and IL-5, have been studied in clinical trials with disappointing results. Because of the specificity of newer agents, it is likely that some agents will prove more effective in certain patients than others, and the variability in response will reflect differences in the relative importance of different pathogenetic pathways. Treatment of Associated Conditions Successful management of asthma often requires treatment of conditions that are thought to aggravate asthmatic symptoms. Asthma may coexist with a number of disorders that affect lung function. Gastroesophageal reflux disease, obesity, and chronic sinusitis are the most common of these disorders associated with poorly controlled asthma. Gastroesophageal Reflux Disease

Respiratory symptoms including cough, breathlessness, and wheeze have been associated with gastroesophageal reflux disease for more than 40 years. The widely accepted notion that gastroesophageal reflux disease (GERD) can aggravate asthma is based, to a large extent, on empiric observations that antireflux therapy often improves asthma control. In general, most studies, whether they have examined the effect of medical or surgical therapy for GERD on asthma-related outcomes, have employed small numbers of subjects and have suffered from poor study design. A recent meta-analysis in which only data from controlled trials was included, failed to show a consistent effect of anti-reflux therapy on asthma outcomes, including asthma symptoms, medication use, lung function, or nocturnal asthma. In spite of the lack of data from rigorous clinical trials (or meta-analyses for that matter), many clinicians will assess the possibility that GERD may be aggravating asthma.

Ambulatory intraesophageal pH monitoring is a sensitive and specific diagnostic test to verify the diagnosis of GERD. While a negative study is valuable in excluding GERD as a cause of asthma symptoms, a positive study does not indicate that GERD is the cause of asthma symptoms. As a rule, an empiric course of antireflux therapy is necessary to establish a causal relationship. The diagnosis of GERD should be considered in patients with worsening asthma symptoms after meals or with reclining, patients with intractable nocturnal asthma, patients whose disease is poorly controlled on antiasthma medications, those who require either systemic or high-dose inhaled glucocorticoid therapy, and elderly patients with new-onset asthma. Because of the costs and potential side effects of longterm anti-reflux treatment and the growing appreciation that chronic GERD may have serious consequences, we recommend specialty consultation or ambulatory intraesophageal pH monitoring prior to the initiation of treatment. Empiric treatment should especially be avoided when patients do not have classic reflux complaints. Antireflux therapy should be offered to patients with confirmed GERD who complain of reflux symptoms (heartburn, water brash, regurgitation, dysphagia, hoarseness, and choking) in association with wheezing or other asthma symptoms. Medical management of GERD consists of weight loss when appropriate, elevation of the head of the bed, avoidance of large meals or recumbency after meals, and medications that raise gastric pH like histamine2 -receptor antagonists or proton-pump inhibitors. Usually high doses of medications are needed for adequate acid suppression. Alternatively, studies have demonstrated the efficacy of surgical approaches to GERD, although the effect of anti-reflux surgery on asthma outcomes is not clear. Chronic Rhinosinusitis

The relationship between asthma and chronic sinusitis is well established, although the underlying mechanisms are not clear. In general, the association between asthma and chronic sinusitis is limited to patients with extensive disease, as determined by patency of the nasal passages and ostiomeatal complex and thickening of the sinus mucosa. Although aggressive treatment of chronic sinusitis is generally believed to result in improved asthma control, there is little published supportive evidence. The treatment of choice for sinusitis includes antibiotics, decongestants, and intranasal topical glucocorticoids. Patients who fail to respond to medical therapy may benefit from endoscopic sphenoethmoidectomy. It should be noted, however, that the results of endoscopic sinus surgery are poorest in patients with asthma, especially those with aspirin sensitivity and polyposis. Specific allergen immunotherapy is particularly useful in asthmatics with concomitant allergic rhinosinusitis and considered after careful consideration of risks and benefits. Obesity

It has long been felt that obesity contributes to the morbidity of asthma. There is growing epidemiologic evidence that

833 Chapter 48

obesity is associated with asthma. Most prospective studies show an association between body mass index (BMI) and the subsequent development of asthma, however nearly all the studies relied on patient-reported asthma. Indeed in one important study (NHANES III) obese patients reported having more asthma, wheezing, and bronchodilator use but they were less likely to demonstrate airflow obstruction than non-obese patients. Thus, it appears that obese patients are more likely to be misdiagnosed with asthma and to be incorrectly treated. Importantly in one prospective study where the asthma was physician diagnosed, a BMI greater than or equal to 28 was associated with asthma, and this effect appeared to be driven by obese female subjects. The reasons for these associations are not known but are an area of active research. Finally, since intervention studies have shown that weight loss can favorably affect asthma outcomes, it seems prudent to aggressively treat obesity in the asthmatic patient. Patient Monitoring In an individual patient, asthma severity may fluctuate with time, owing to changes in environmental exposure or improved disease management, or because of the natural history of the disease. Ongoing treatment should remain consistent with the current disease severity. Hence, just as therapy is “stepped-up” to gain control in symptomatic patients, a gradual reduction in medications, starting with the medication with the greatest toxicity, should be attempted once stability is achieved and sustained for several months. Long-term monitoring of the asthmatic patient is essential for proper adjustment of the management plan. Published guidelines have emphasized the importance of objective measurements over symptoms because of poor patient perception of airway obstruction, especially in patients with long-standing asthma. On the other hand, for some patients, symptoms may be a more sensitive indicator of deterioration than are peak expiratory flow measurements. Clearly, the best strategy for monitoring asthma on a long-term basis is to use both objective and subjective measures. The amount of rescue beta agonist used on a daily basis is also a useful barometer of asthma control.

Asthma: Clinical Presentation and Management

have included an enthusiastic recommendation that patients use peak expiratory flow measurements not only to monitor their course but also to dictate self-administered treatment regimens. This recommendation is based on studies showing improvement in subjective, as well as objective, measures of asthma control when patients used peak flow measurements related to their personal best peak flow to adjust medication usage. Moreover, one retrospective study suggested that the usage of action plans was related to reduced mortality. The combination of home monitoring and a comprehensive education and self-management program has been shown to increase pulmonary function, reduce physician visits and emergency room admissions, and reduce use of inhaled beta agonists and prednisone when compared with a program of minimal education and no self-management. Given the variable nature of asthma and the people it afflicts, it seems unlikely that either peak flow- or symptomguided self-management would benefit all patients at all times. Clearly, no single treatment algorithm is apt to be the best therapeutic plan for all patients with the same change in peak flow. Likewise, not all patients are capable of executing, or even comprehending, complicated treatment plans. Future studies should focus on whether the benefits of peak flow– guided self-management, if any, outweigh the risks of over treatment that might result from its use. Severely asthmatic patients using home peak flow monitoring tend to use more oral glucocorticoids. Although this may be viewed as a potential benefit of peak flow monitoring, it is unclear whether the increased use is always appropriate or medically warranted. Although the correspondence between peak expiratory flow and its variability and symptoms or other measures of asthma severity is quite good, it is not absolute. It is the authors’ opinion that if used, action plans should be written using clear, simple language and should be individualized based on patients’ understanding of their asthma, its severity, and their demonstrated ability to comply with instructions. Adherence may be assessed during an initial 2-week assessment period in which patients chart their daily symptoms and lung function measurements. An example of a written action plan is provided in the online supplement.

Peak Expiratory Flow, Spirometry, and Action Plans

Markers of Airway Inflammation

Whereas spirometry is recommended to diagnose airway obstruction in the initial assessment of the asthmatic patient, we believe that spirometry and peak flow measurements provide comparable information for monitoring patients on a long-term basis. The historical advantage of peak flow measurements has been their relative ease of performance and lack of expense with self-monitoring on a daily basis. The recent development of hand-held, automated spirometers providing digital output of FEV1 and data storage capability offers an alternative for home monitoring. Studies have demonstrated that patients can perform home spirometry skillfully after adequate training; however, built-in software that assesses the quality of the forced vital capacity maneuver oftentimes does not perform well. Asthma treatment guidelines

The importance of using markers of airway inflammation to monitor disease activity is uncertain. While asthma symptoms, airway responsiveness, and numbers of airway inflammatory cells correlate, the correlations are primarily of statistical interest and are not predictive of one another in an individual patient. For example, there is considerable overlap in airway responsiveness between patients who require only occasional therapy and those who are steroid dependent. That asymptomatic asthmatics with normal lung function have evidence of ongoing airway inflammation is also well established. Defining the marker that best reflects the inflammatory diathesis of asthma is an important scientific challenge. As discussed above the measurement of bronchial hyperresponsiveness (BHR) is a sensitive tool used for the initial

834 Part IV

Obstructive Lung Diseases

diagnosis of asthma. Measuring BHR may also have additional utility in the subsequent management of asthma. For example, in one study it was shown that a treatment strategy aimed at specifically reducing BHR was superior to a strategy based on symptoms, medication usage, and PEF measurements (i.e., that suggested by most published guidelines) with regard to reducing exacerbations and improving lung function. Because of their poor sensitivity and specificity, blood eosinophil counts are not recommended in routine monitoring of asthma severity or as a barometer of airway inflammation. In contrast, sputum eosinophils counts have been shown to predict exacerbations when steroids are withdrawn; however, further study will be needed before measurement of sputum eosinophils can be widely used to monitor patients. Levels of nitric oxide (NO) in mixed expired gas have been found to be elevated in asthmatics as compared with normal subjects. The level may reflect the degree of underlying airway inflammation. Mixed expired concentrations of NO have been shown to fall during glucocorticoid therapy in patients with severe exacerbations of asthma, suggesting a possible role for NO as an index of disease severity or treatment efficacy. Exhaled NO measurements have been used successfully to titrate inhaled steroids without any loss of asthma control; thus, eNO may be used as a tool in conjunction with other clinical measures to optimize asthma management as recommended by guidelines (i.e., achieving disease control using the lowest doses of medications possible).

Managing Asthma Exacerbations Asthma especially in its severe forms is characterized by disease exacerbations, and such exacerbations result in substantial morbidity, occasional mortality, and considerable medical and economic costs. The majority of randomized controlled trials of asthma therapies and most studies performed in humans examining asthma pathogenesis have been done in patients with milder asthma. Clinical experience has shown that the majority of exacerbations occur in a minority of asthma patients. Exacerbation-prone patients seem to be at increased risk for attacks of near-fatal asthma. Importantly, when deaths from asthma have been analyzed, most decedents had experienced worsening symptoms of a period of several hours to several days—highlighting the importance of identifying and educating the at-risk patient. It must be recognized that lifethreatening episodes can develop in patients whose asthma appears to be mild at baseline. Patients who have baseline severe, poorly controlled disease, those who frequently access the ER, or are frequently hospitalized—essentially those with prior life-threatening episodes—seem to be at the highest risk. These patients should be identified and targeted for intensive disease management including patient education, pharmacologic therapy, and close disease monitoring. Nonpharmacologic Therapy Fortunately, the need for mechanical ventilation for acute, severe asthma is an uncommon event because barotrauma oc-

curs frequently in this group. These patients suffer from lung hyperinflation and are difficult to ventilate, but more recently the appreciation that avoidance of barotrauma reduces mortality in acute, severe asthma has resulted in the utilization of lung protective strategies. High transpulmonary pressures can be ameliorated by hypoventilation with resultant permissive hypercapnia, and the use of high inspiratory flow rates that increase expiratory flow time and facilitate lung emptying. Noninvasive positive pressure ventilation may be used safely in carefully selected patients; however, clinical trial data are lacking. Pharmacologic Management The cornerstone of therapy for an exacerbation of asthma involves the escalation of both glucocorticoids and quick-relief medications, usually inhaled β2 -adrenergic agonists, with frequent reassessment of the degree of airflow obstruction. Glucocorticoids

Surprising little is known with regards to the optimal dosing of systemic glucocorticoids in acute asthma, although it is generally felt, for reasons that are poorly understood, that inflammation in acute asthma is relatively resistant to glucocorticoids, hence systemic steroids are often used. For those exacerbations requiring hospitalization typically parenteral steroids in doses ranging from 1 to 10 mg/kg/d of prednisolone or the equivalent in divided doses are used and the steroids tapered at a rate determined by the patient’s response. Oftentimes a few days of therapy are required before a noticeable improvement in lung function occurs. Important side effects with parenteral steroids include delirium, hyperglycemia, and fluid retention. Steroids may be tapered once there is a response but it is the authors’ opinion that systemic steroids should be tapered over a 2-week period in cases of severe asthma exacerbation. In instances in which there is a prompt response to therapy in the emergency department and the patient is not admitted, lower doses of steroids may be used but systemic therapy is still advised for at least several days and tapering should be done with close outpatient follow-up. In instances in which outpatient oral glucocorticoids are used for less severe exacerbations, we recommend doses in the range of 0.25 to 1 mg/kg/d tapered over a 7- to 14-day period, the initial dose and tapering regimen determined by prior history (i.e., previously successful regimens), severity of the exacerbation, and response. Very mild or subacute exacerbations in asthmatics with mild persistent disease may be managed in some cases by escalating the dose of or initiating inhaled steroids in cases in which patients are taking low-dose steroids or no steroids, respectively. Bronchodilators

Exacerbations of asthma should never be treated by escalating bronchodilators alone. Fatalities from asthma usually result when patients fail to promptly seek medical attention and commonly patients who died from asthma had self-medicated with escalating doses of quick-relief

835 Chapter 48

medications or long-acting bronchodilators. Although systemic β2 -adrenergic agonists are available it is clear that inhaled β2 -adrenergic agonists are safer and equally efficacious. Inhaled β2 -adrenergic agonists may be used safely in quite high doses with close monitoring. For example, continuous administration of albuterol at doses of 10 mg per hour is a commonly used protocol for acute severe asthma in hospital emergency departments. Intravenous aminophylline, terbutaline, or epinephrine may be used, but the risks of toxicity are much greater than when inhaled β2 -adrenergic agonists are used. Inhaled ipratropium appears to provide further bronchodilation in acute severe asthma. Other Considerations

Antibiotics are not indicated for acute asthma exacerbations unless there is objective evidence of bacterial pneumonia or co-existing bacterial sinusitis. Oxygen therapy should be used to avoid hypoxia (i.e., oxygen saturation greater than or equal to 92 percent). Oxygen should be titrated to the lowest dose needed since the use of excessive oxygen concentrations can lead to CO2 retention and a respiratory acidosis in some patients. Prophylaxis for deep venous thrombosis is indicated for the hospitalized asthma patient. Stress ulcer prophylaxis is also indicated given the increased risks imparted by the use of systemic steroids, and this is especially true in the rare patient requiring mechanical ventilation. Patient Monitoring Most patients that present to the emergency department with acute severe asthma require intensive bronchodilator therapy and supplemental oxygen. Hypoxia is to be avoided at all costs, so continuous monitoring of oxygen saturation is needed until there is a meaningful response to treatment. High-dose bronchodilator therapy, while generally well tolerated, occasionally causes arrhythmia; therefore, continuous EKG monitoring is also required. Patients who continue to manifest severe airflow obstruction after initial intensive treatment should be admitted to an intensive care unit. When there is clinical improvement but significant obstruction remains, hospitalization is required. In less severe exacerbations patients who promptly respond to treatment in the emergency department may be discharged but close outpatient follow-up is essential.

SUGGESTED READING Bateman ED, Boushey HA, Bousquet J, et al: Can guidelinedefined asthma control be achieved? The Gaining Optimal Asthma Control study. Am J Respir Crit Care Med 170:836– 844, 2004. Boushey HA, Sorkness CA, King TS, et al: Daily versus asneeded corticosteroids for mild persistent asthma. N Engl J Med 352:1519–1528, 2005.

Asthma: Clinical Presentation and Management

Burrows B, Barbee RA, Cline MG, et al: Characteristics of asthma among elderly adults in a sample of the general population. Chest 100:935–942, 1991. Castro M, Dozor AJ, Fish JE, et al: The safety of inactivated influenza vaccine in adults and children with asthma. N Engl J Med 345:1529–1536, 2001. Childhood Asthma Management Program Research Group: Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med 343:1054–1063, 2000. Evans DJ, Taylor DA, Zetterstrom O, et al: A comparison of low-dose inhaled budesonide plus theophylline and highdose inhaled budesonide for moderate asthma. N Engl J Med 337:1412–1418, 1997. Fish JE, Peters SP, Chambers CV, et al: An evaluation of colchicine as an alternative to inhaled corticosteroids in moderate asthma. National Heart, Lung, and Blood Institute’s Asthma Clinical Research Network. Am J Respir Crit Care Med 156:1165–1171, 1997. Gibson PG, and Powell H. Written action plans for asthma: an evidence-based review of the key components. Thorax 59:94–99, 2004. Global Strategy for Asthma Management and Prevention. Bethesda, MD, NIH Publication No 02-3659, 2005. Greening AP, Ind PW, Northfield M, et al: Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Allen & Hanburys Limited UK Study Group. Lancet 344:219–224, 1994. Laviolette M, Malmstrom K, Lu S, et al: Montelukast added to inhaled beclomethasone in treatment of asthma. Montelukast/Beclomethasone Additivity Group. Am J Respir Crit Care Med 160:1862–1868, 1999. Lazarus SC, Boushey HA, Fahy JV, et al: Long-acting beta2agonist monotherapy vs continued therapy with inhaled corticosteroids in patients with persistent asthma: A randomized controlled trial. Jama 285:2583–2593, 2001. Lemanske RF, Jr., Sorkness CA, Mauger EA, et al: Inhaled corticosteroid reduction and elimination in patients with persistent asthma receiving salmeterol: A randomized controlled trial. Jama 285:2594—2603, 2001. Lofdahl CG, Reiss TF, Leff JA, et al: Randomised, placebo controlled trial of effect of a leukotriene receptor antagonist, montelukast, on tapering inhaled corticosteroids in asthmatic patients. Br Med J 319:87–90, 1999. Milgrom H, Fick RB, Su JQ, et al: Treatment of allergic asthma with monoclonal anti-IGE antibody. rhuMAb-E25 Study Group. N Engl J Med 341:1966–1973, 1999. National Asthma Education Program, Expert Panel: Guidelines for the Diagnosis and Management of Asthma. Bethesda, MD, NIH Publication no. 97-4051, 1997. National Asthma Education Program, Expert Panel: Guidelines for the Diagnosis and Management of Asthma, Update on Selected Topics 2002. Bethesda, MD, NIH Publication no. 02-5074, 2002.

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O’Byrne PM, Bisgaard H, Godard PP, et al: Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma. Am J Respir Crit Care Med 171:129–136, 2005. Pauwels RA, Lofdahl CG, Postma DS, et al: Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. N Engl J Med 337:1405–1411, 1997. Platts-Mills TA, Tovey ER, Mitchell EB, et al: Reduction of bronchial hyperreactivity during prolonged allergen avoidance. Lancet 2:675–678, 1982. Reid M.J, Lockey RF, Turkeltaub PC, et al: Survey of fatalities from skin testing and immunotherapy 1985–1989. J Allergy Clin Immunol 92:6–15, 1993.

Smith AD, Cowan JO, Brassett KP, et al:Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. N Engl J Med 352:2163–2173, 2005. Sont JK, Willems LN, Bel EH, et al: Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. The Ampul Study Group. Am J Respir Crit Care Med 159:1043–1051, 1999. Suissa S, Ernst P, Benayoun S, ET AL: Low-dose inhaled corticosteroids and the prevention of death from asthma. N Engl J Med 343:332–336, 2000. Woolcock A, Lundback B, Ringdal N, et al: Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. Am J Respir Crit Care Med 153:1481–1488, 1996.

49 Allergic Bronchopulmonary Aspergillosis (Mycosis) Geoffrey Chupp Carolyn L. Rochester

I. PATHOGENESIS

III. DIAGNOSTIC STUDIES

II. CLINICAL FEATURES Diagnostic Guidelines Clinical Staging of ABPA

IV. TREATMENT

Allergic bronchopulmonary aspergillosis (ABPA) is an idiopathic inflammatory lung disease characterized by an allergic inflammatory response to the colonization of Aspergillus or other fungi in the lung. It was first described in 1952 by Hinson and coworkers and then again in 1967, when Scadding recognized an association of this disease with proximal bronchiectasis in areas previously affected by infiltrates (predominantly in the upper lobes). The first adult case of ABPA in the United States was described in 1968. Although most cases entail hypersensitivity to Aspergillus spp. (especially A. fumigatus) the finding of a virtually identical clinical syndrome associated with immune sensitivity to Candida albicans, Helminthosporium spp., Curvularia lunata, Drechslera hawaiiensis, Stemphylium languinosum, Saccharomyces cerevisiae, and Pseudallescheria boydii has led to the term allergic bronchopulmonary mycosis to describe this syndrome. The precise prevalence of ABPA is unknown, owing in part to variability in diagnostic criteria used in various studies, the lack of distinction between ABPA and mold-sensitive asthma, and to delays in the diagnosis of patients with long-standing disease. Given this consideration it is estimated that ABPA complicates approximately 7 to 14 percent of cases of chronic steroid窶電ependent asthma and 7 to 15 percent of cases of cystic fibrosis. Most cases of ABPA are recognized in the third to fifth decade of life, but may also present during childhood. In some patients it is likely that ABPA started early in life and continued, unrecognized, until adulthood. Interestingly, familial cases have been reported. The spectrum of disease

V. PROGNOSIS

is broad and can be severe and debilitating, requiring lung transplantation; however, if recognized early and managed aggressively, ABPA is treatable, can remit indefinitely, and progressive lung damage can be avoided. For the purposes of this review, ABPA will be discussed; however, clinicians should be cognizant that diagnostic testing for other fungi needs to be pursued when organisms other than Aspergillus spp. are suspected culprits.

PATHOGENESIS Although the pathogenesis of ABPA is incompletely understood, it is believed to result from a complex immunological reaction to chronic airway colonization by Aspergillus (or other relevant fungal) species. Aspergillus spp. are ubiquitous, thermotolerant organisms that reside in decaying organic matter. Inhaled spores colonize the airway, proliferate, and result in chronic antigenic stimulation of the airway, tissue injury, and the clinical features of ABPA. While the pathogenesis of ABPA remains poorly understood, it does appear that susceptibility to ABPA, the presence and magnitude of tissue response to Aspergillus and the development of clinical disease depend on host factors such as genetic background and T-cell responsiveness to Aspergillus antigens. Investigations into the genetic links to ABPA have produced some interesting results. Best characterized is the

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possible link between gene mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) and the pathogenesis of ABPA. CFTR mutations are more common among patients with ABPA compared to the general population and asthmatics without sensitivity to Aspergillus fumigatus. Another genetic link to ABPA is that Th2-type T-cell reactivity to selected Aspergillus antigens is determined by the presence of MHC Class II DR2 or DR5 alleles, which may predispose patients to the disease, whereas the MHC DQ2 allele may be protective. At the microscopic level ABPA is characterized by an intense eosinophilic and mononuclear cell inflammatory response that leads to airway injury and bronchiectasis. A role for type I hypersensitivity reactions is strongly suggested by the elevated serum levels of total and Aspergillus-specific IgE. Type III hypersensitivity is suggested by the presence of Aspergillus precipitins and circulating immune complexes during disease exacerbations. A type IV cell-mediated immune reaction may also be at work, based on the finding of dual (immediate and delayed) cutaneous reactions and in vitro lymphocyte transformation to Aspergillus antigen stimulation in some patients. There has been a substantial amount of work done on the immune response in ABPA. A pathogenetic role for helper T lymphocytes is suggested by a number of findings, including: the presence of increased numbers of airway Th2 cells and levels of soluble interleukin 2 receptors (suggesting T-cell activation) in the circulation of persons with active ABPA; the derivation of Aspergillus-specific T-cell clones with T helperâ&#x20AC;&#x201C; 2 (Th2) patterns of cytokine production from the blood of patients with ABPA; the correlations between activated T-cell number, the levels of the T cellâ&#x20AC;&#x201C;derived cytokines IL-4 and IL-5, and the number of airway eosinophils in the disease; the critical role IL-5 plays in murine models of ABPA; and the increased reactivity of Th2 cells to Aspergillus antigens among patients with ABPA as compared with patients with asthma and skin reactivity to Aspergillus. In addition to lymphocytes, eosinophils and basophils may contribute to local airway injury and neutrophils likely play a role in airway inflammation and destruction in ABPA as evidenced by the fact that sputum IL-8 levels correlate with sputum neutrophilia, matrix metalloproteinase levels, and FEV1 among patients with ABPA. It is also clear that the fungus itself is of substantial pathogenetic importance. Aspergillus-derived proteases likely cause epithelial cell injury and protective barrier disruption, which triggers immune hypersensitivity by inducing inflammation or by allowing increased penetration of fungal antigens into the airway wall. Aspergillus-derived proteases may also stimulate proinflammatory cytokines such as IL-8, release of growth factors, and may cause tissue damage leading to bronchiectasis. In addition, a variety of other Aspergillusderived antigens (including cytotoxins and heat shock proteins) with demonstrated ability to bind IgE and IgG derived from the blood of patients with ABPA each initiate and drive both the IgE (hypersensitivity) and IgG immune response. Aspergillus-derived proteases with antibody-binding capac-

ity can also amplify the inflammatory response. Aspergillus antigens such as Aspf1 (a cytotoxic protein), Aspf2 (a fibrinogen binding protein), Aspf5 (a metalloprotease), Aspf6 (manganese superoxide dismutase), Aspf8 (a ribosomal protein), Aspf13 and Aspf18 (serine proteases), as well as Aspf3 and Aspf4 have all been implicated in these processes. Lastly, host response to Aspergillus fumigatus antigens includes surfactant proteins (SP) A and D that may play a protective role against ABPA by interfering with binding between Aspergillus fumigatus antigens and IgE, although SPD levels do not correlate with acute exacerbations of ABPA in humans.

CLINICAL FEATURES Although ABPA typically presents in patients with a history of difficult to control asthma, the spectrum of presentation is highly variable and needs to be considered in any patient with moderate to severe asthma and hypersensitivity to Aspergillus fumigatus. Typical presenting complaints are nonspecific and include dyspnea, wheezing, poor asthma control, cough (commonly productive of thick, brown mucus plugs), malaise, low-grade fever, and occasionally, hemoptysis. There may be an antecedent history of recurrent asthma exacerbations in conjunction with pneumonias without a cultureidentified bacterial source. In addition, a history of atopy with rhinitis, drug allergy, and/or allergic conjunctivitis are common. It is often not until a patient has been repeatedly ill over weeks to months and unresponsive to standard treatments that the diagnosis is considered.

Diagnostic Guidelines In general, the diagnosis of ABPA is based on appropriate clinical features in combination with supporting radiological and serological findings. While there are no absolutely specific diagnostic criteria (along with the lack of specific clinical findings on presentation and overlap with other common diseases such as asthma, allergy, and bronchiectasis) guidelines have been proposed to aid clinicians in the diagnosis of ABPA (Table 49-1). These guidelines have evolved over time and may be somewhat confusing; however, they can allow for the early detection of ABPA before lung damage occurs and take into account the effect corticosteroids can have on suppressing some clinical features of the disease. ABPA is generally considered to present in two different forms; ABPA-seropositive and ABPA-central bronchiectasis (CB). Patients with ABPAS may display the following diagnostic criteria proposed by Greenberger and Patterson: (1) history of asthma; (2) total IgE >1000 IU/ml; (3) elevated serum anti-AF IgE and IgG; (4) positive immediate hypersensitivity skin test to Aspergillus; and (5) serum precipitins to Aspergillus fumigatus or other relevant fungus. (This criterion is considered positive by the presence of an anti-Aspergillus fumigatus IgG titer.) These patients may have normal radiographic studies. Patients with ABPA-CB have all of the criteria of ABPA-S and also have

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Table 49-1 Criteria for the Diagnosis of ABPA Seropositive ABPA (ABPA-S) History of Asthma (often difficult to control) Elevated total serum IgE (usually >1000 IU/ml) Immediate skin test reactivity to Aspergillus fumigatus Elevated specific serum IgE to Aspergillus fumigatus Presence of serum precipitins or elevared specific serum IgG to Aspergillus fumigatus ABPA central bronchiectasis (ABPA-CB) Above criteria are positive Central bronchiectasis by high resolution CT scan Other supportive clinical findings Peripheral blood eosinophilia (often absent especially if patient is on oral corticosteroids) Patchy, fleeting infiltrates (often absent especially if patient is on oral corticosteroids) Expectoration of brown mucuc plugs Mucoid-impacted bronchi evident on radiographic studies Sputum culture positive for Aspergillus fumigatus

central bronchiectasis on high-resolution CT scan or chest x-ray. Patients with ABPA-S tend to have fewer symptoms, lower IgE levels, less severe airflow obstruction, and fewer exacerbations than persons with ABPA-CB. IgE levels fluctuate with disease activity, and a normal IgE level in a symptomatic untreated person virtually excludes the diagnosis. It remains unclear whether ABPA-S is a milder form of the disease (e.g., representing a different host response) or an earlier stage of illness. In addition, patients may have a history of current or previous pulmonary infiltrates, peripheral blood eosinophils (â&#x2C6;ź10,000 cells/m) or expectoration of brown mucus plugs. Identification of Aspergillus (or other relevant fungus) in the sputum and dual (immediate and delayed) cutaneous reactions to challenge with Aspergillus are also common clinical features of ABPA. Rare cases lacking a history of asthma but meeting the other major diagnostic criteria have been reported. The differential diagnosis of ABPA includes corticosteroid-dependent asthma without ABPA, tuberculosis, parasitic infections, hypersensitivity pneumonitis, Churg-Strauss syndrome, acute eosinophilic pneumonia (including drug-induced pneumonitis), chronic eosinophilic pneumonia, lymphoma, idiopathic hypereosinophilic syndrome, autoimmune disease, crack/cocaine use, CF, and other causes of bronchiectasis. In addition, the diagnosis of ABPA in patients with mold-sensitive asthma and CF poses particular diagnostic difficulty. This is especially true in asthmatics in the absence of bronchiectasis. Serum precipitins to Aspergillus spp. may be present in up to 10 percent and posi-

Allergic Bronchopulmonary Aspergillosis (Mycosis)

tive immediate skin tests to Aspergillus in up to 25 percent of asthmatics. Persons with mold-sensitive asthma or ABPA can have peripheral blood eosinophilia and/or elevated serum total IgE levels. However, most persons with ABPA have 2to 20-fold higher serum levels of Aspergillus-specific IgE and total IgE than do mold-sensitive asthmatics without ABPA. In addition, as mentioned, proximal bronchiectasis is not seen in mold-sensitive asthma but is common in ABPA. A more confusing diagnostic conundrum occurs when considering the diagnosis of ABPA in patients with CF, because patients with CF alone can manifest chronic airflow obstruction, recurrent exacerbations with infections and/or bronchoconstriction, underlying bronchiectasis, pulmonary infiltrates, chronic sputum production, Aspergillus colonization of the airways, and positive serum precipitins. Distinguishing ABPA in CF patients is critical because infectious CF exacerbations and the presence of ABPA require different treatments. The steroid treatment required for ABPA may be detrimental in the setting of infection, yet antibiotics alone given for infection may be inadequate to control the inflammation associated with ABPA. Among patients with CF factors associated with the risk of ABPA include: adolescent age, atopy, severe lung disease, and colonization with Pseudomonas aeruginosa. ABPA should be suspected in patients with CF who develop clinical deterioration, exhibit a greater than fourfold increase in total serum IgE (especially >1000 IU/ml), have immediate cutaneous reactivity to Aspergillus or increase in Aspergillus-specific IgE or IgG, and show change in baseline CXR. Annual screening of total serum IgE is recommendedâ&#x20AC;&#x201D;if the level rises >500 IU/ml, immediate cutaneous hypersensitivity testing for reactivity to Aspergillus fumigatus or testing for serum anti-Aspergillus fumigatus IgE is recommended. One study suggests that the presence of IgE reactive against the purified Aspergillus allergens Aspf3 and Aspf4 are useful to distinguish patients with ABPA and CF or Aspergillus-sensitive asthma from patients without ABPA.

Clinical Staging of ABPA Five clinical stages of ABPA have been recognized based on clinical, serological, and radiographic characteristics (Table 49-2). Stage I, the acute stage, is characterized by symptoms of moderate to severe asthma, elevated total IgE (typically >1000 IU/ml), an elevated anti-Aspergillus fumigatus IgE or hypersensitivity skin test to Aspergillus fumigatus, infiltrates on chest radiograph (with or without proximal bronchiectasis), peripheral blood eosinophilia (frequently >2000/mm3 ), and positive precipitating or anti-IgG antibodies to A. fumigatus (up to fivefold concentration of serum may be required for detection of the precipitating antibodies). Patients with stage II ABPA have disease that is in remission. This is characterized by the resolution of symptoms, radiographic clearing, and decreased stabilization of total IgE levels. Remissions are of varying length, can last several months to years or may be permanent, allowing corticosteroid treatment to be tapered or discontinued. Patients with stage III ABPA have recurrent

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Table 49-2 Client Stages of ABPA Stage I: Acute Acute asthma symptoms Elevated serum IgE (>1000 IU/ml) Peripheral blood eosinophilia (may be absent in patients treated with oral coricosteroids) Fleeting infiltrates on chest x-ray (may be absent in patients treated with oral coricosteroids) Positive specific IgE, IgG, skin test reactivity, and precipitins to A. fumigatus Responds to steroids/antifungal therapy Stage II: Remission Resolution of symptoms Resolution of pulmonary infiltrates Improvement in eosinophilia and A. fumigatus specific blood abnormalities Stage III: Exacerbation/recurrence Recurrence/worsenning of clinical symptoms Recurrent pulmonary infiltrates Rising IgE levels

Stage IV: Steroid-dependent-asthma Refractory steriod-dependent asthma Persistently elevated serum IgE levels Persistently elevated A. fumigatusâ&#x20AC;&#x201C;specific blood abnormalities Stage V: Fibrotic lung disease Refractory steriod-dependent asthma Fibrotic lung disease (irreversible obstructive and restrictive defects with impaired diffusing capacity) Chronic bronchiectasis symptoms (sputrum production, frequent infections)

disease or disease exacerbations (Fig. 49-1). Their disease is characterized by the development of new pulmonary infiltrates or by a >100 percent increase in total IgE. Elevation of IgE may precede clinical or radiological worsening during this stage, and an isolated increase in severity of bronchospasm does not constitute an exacerbation. Although a majority of disease exacerbations are associated with a concomitant increase in symptoms, exacerbations may occur in the absence of any increase in symptoms. Indeed, since up to one-third of patients with radiographic infiltrates may be asymptomatic, evolving progressive lung damage may remain unrecognized. Total serum IgE levels should be monitored every 1 to 2 months for at least a year after diagnosis, and chest radiographs should be performed intermittently. Aspergillus-specific IgA levels may also be elevated in the acute or exacerbation stages of disease. Exacerbations are more

Figure 49-1 A 27-year-old man with a history of moderate asthma, recurrent bronchitis, and mild hemoptysis. Serological studies were consistent with ABPA (IgE 9,490 IU/ml) and radiographic studies are consistent with bronchiectasis. A. PA chest x-ray shows hyperinflated lungs, bronchial dilatation, and right lower lobe opacity consistent with mucoid impaction. B . Highresolution CT scan image of impacted bronchus (arrow) and chronic inflammatory changes. C . Dilated central bronchus consistent with cylindrical/central bronchiectasis.

likely to occur during seasons or environments when mold counts are high. Stage IV ABPA is defined as steroid-dependent asthma. In stage IV disease, total IgE, Aspergillus precipitins, and Aspergillus-specific IgE and IgG typically remain elevated

841 Chapter 49

Allergic Bronchopulmonary Aspergillosis (Mycosis)

DIAGNOSTIC STUDIES

Figure 49-1 (Continued )

despite chronic steroid therapy. The frequency of exacerbations may increase. Stage V is defined as pulmonary fibrosis. Stage V patients have prominent symptoms of dyspnea; are often steroid dependent because of persistent bronchospasm; frequently have chronic sputum production, recurrent respiratory infections, and irreversible pulmonary function abnormalities (obstruction, restriction, and/or gas exchange abnormalities), and may have cyanosis or clubbing. The serological profile of patients with stage IV disease persists during stage V. Stage V disease is generally thought to be the consequence of longstanding, often unrecognized disease, but may occur occasionally among patients with little prior clinical evidence to suggest the diagnosis (Fig. 49-2).

Figure 49-2 Representative CT image of the lungs of a 41-yearold woman who presented with stage V ABPA (IgE 1500 IU/ml). Pulmonary function studies demonstrated severe combined obstructive and restrictive defects. CT shows bilateral upper lobe scarring and emphysematous changes.

In addition to the blood abnormalities described in the preceding, analysis of BAL fluid from patients with ABPA reveals a moderate eosinophilia and increased levels of Aspergillusspecific IgE and IgA but not IgG. On bronchoscopy mucoid impaction may be evident, and bronchial brushings may reveal mucus containing aggregates of eosinophils, fungal hyphae, and eosinophil-derived Charcot-Leyden crystals. Pulmonary function tests typically reveal an obstructive ventilatory defect (due to bronchospasm or mucus impaction of the bronchi) during stages I, III, IV, and often V and may not correlate with the duration of ABPA or asthma. Persons with stage V disease typically also have a restrictive ventilatory defect with a reduced DLCO (Fig. 49-2). The typical radiographic manifestations of ABPA include parenchymal infiltrates and bronchiectasis (Figs. 491 to 49-3). The infiltrates are often irregular and transient (1 to 6 weeks). They have a predilection for upper lobes, although all lobes may be affected. The bronchiectasis is classically cylindric and proximal (central), occurring within the proximal two-thirds of the lung (Fig. 49-1B). Mucoid impaction in dilated bronchi leads to a characteristic (but nonspecific) radiographic appearance of ABPA termed the “finger in glove” opacity. “Tramline shadows” (parallel linear shadows extending from the hilum in bronchial distribution and reflecting longitudinal views of inflamed, edematous bronchi), “toothpaste shadows” (representing mucoid impaction of the bronchi), “ring shadows” (dilated bronchi with inflamed bronchial walls seen on end), local consolidation, or lobar collapse are also common features. Involvement of the small airways may lead to centrilobular nodules and branching tree-in bud opacities (Fig. 49-1). Less common radiographic findings include bullous changes, pneumothorax, pleural effusion, cavitating nodular lesions, aspergilloma (Figs. 49-2 and 49-3) and migratory parenchymal opacities, some of which have a ground-glass appearance.

Figure 49-3 A 21-year-old woman with ABPA who responded to treatment with oral corticosteroids and chronic antifungal therapy developed an aspergilloma and hemoptysis (arrow). Amphotericin paste injection failed and the patient ultimately underwent a right upper lobe lobectomy.

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High-resolution CT scanning is the most reliable noninvasive means of detecting proximal bronchiectasis. Open lung biopsy is usually not required to establish the diagnosis of ABPA. Histopathological findings in this disease include intense bronchocentric inflammation with prominent eosinophilia as well as lymphocytes, plasma cells, and monocytes. Bronchi may be filled and/or impacted with copious mucus plugs containing fibrin, Charcot-Leyden crystals, Curschmann spirals, and fungal hyphae. Bronchiectasis of segmental and subsegmental bronchi may be evident. Regions of bronchocentric granulomatosis, eosinophilic pneumonia, eosinophilic microabscess, lymphocytic or desquamative interstitial pneumonitis, proliferative or obliterative bronchiolitis, lipoid pneumonia, or interstitial fibrosis may also be seen.

TREATMENT Goals in treating ABPA consist of controlling symptoms, preventing exacerbations, and preserving normal lung function. Systemic corticosteroids are the mainstay of therapy for ABPA. Since without treatment ABPA can cause marked chronic lung impairment due to bronchiectasis or pulmonary fibrosis, initiation of appropriate treatment early in the course of disease is essential. Although most data are derived from small uncontrolled trials and there is no definitive proof that corticosteroid therapy prevents the development of central bronchiectasis, retrospective studies have suggested that early therapeutic intervention with corticosteroids may prevent progression to lung fibrosis. Therapy for stage I or III disease should include prednisone, 0.5 to 1 mg/kg a day for 2 weeks, followed by 0.5 mg/kg every other day for 6 to 8 weeks. A subsequent taper (by 5 to 10 mg every 2 weeks) over the ensuing 3 months can then be tried. The duration of treatment must be guided by stage and severity of disease. A low maintenance dose (e.g., 7.5 mg/day) may be required long term to control the disease and prevent recurrence in some patients. Corticosteroid therapy leads to relief of symptoms and decreased airflow obstruction, decreased (>35 percent decrease) serum IgE, reduction in peripheral blood eosinophils, and resolution of pulmonary inflammation and infiltrates. IgE levels should be monitored within 1 to 2 months of an acute episode or exacerbation and should be followed every 2 months thereafter since levels may rise, reflecting disease activity prior to or in the absence of clinical symptoms. Escalation of steroid therapy should be considered if IgE levels rise more than 100 percent. CXR should be monitored every 3 months within the first year of an acute episode or exacerbation, and may be followed yearly thereafter if the disease is quiescent. Pulmonary function testing should be followed up yearly as well. Although treatment of acute exacerbations is believed to be helpful to prevent fibrotic lung disease, it is not clear that early detection and treatment of disease flares that are asymptomatic affect disease progression. Patients with CF and ABPA may derive some symptomatic or functional

improvement from steroid treatment. However, patients with CF who are on steroids should be followed closely for development of invasive aspergillosis. It is unclear whether the development of ABPA alters the course of CF disease progression. Although not advocated as primary treatment, inhaled corticosteroids are useful for control of bronchospasm and can help minimize the dose of systemic steroid necessary to control wheezing. They have been used occasionally as a steroid-sparing agent for the treatment of symptomatic exacerbations and pulmonary infiltrates, and may help maintain stability of lung function. In addition, adjuvant treatment with bronchodilators and antibiotics also helps control bronchospasm and secondary respiratory infection. In the last decade, the development of oral antifungal agents has brought new hope to patients with ABPA. Even though the current concept is that ABPA is not an â&#x20AC;&#x153;infection,â&#x20AC;? evidence is mounting to support the use of the antifungal agent itraconazole in patients with ABPA. In one randomized controlled study, itraconazole (200 mg bid for 16 weeks) led to significant reductions in corticosteroid dose, decreased IgE levels, greater resolution of pulmonary infiltrates, as well as gains in exercise tolerance or pulmonary function. Among several clinical studies, itraconazole treatment also reduces Aspergillus antibody titers, and reduces eosinophilia as compared with placebo. Itraconazole treatment (200 mg/day or every other day) is generally recommended for patients with ABPA who are steroid dependent, have frequent relapses, and in whom the cost and risks are not felt to outweigh the potential benefits. Itraconazole also has demonstrated utility in ABPA associated with CF. If itraconazole is used, steady-state levels should be checked after 1 to 2 weeks, 4 hours after the dose is given, to assess drug absorption, since itraconazole interferes with the hepatic metabolism of several medicines, including cyclosporine, oral hypoglycemics, tacrolimus, terfenadine, cisapride, and midazolam. Particular caution should be exercised in its use among patients taking any of these medications. In addition, physicians must be mindful of adrenal insufficiency associated with itraconazole treatment among patients with ABPA taking inhaled corticosteroids, as itraconazole may cause reduced steroid clearance and/or possible direct suppression of adrenal steroid production. Interval screening for adrenal insufficiency should be considered among such persons. In contrast, the efficacy of itraconazole in ABPA may be less among persons taking agents that raise gastric pH, as this can dramatically reduce drug absorption. Other antifungal agents, including nystatin, amphotericin B, miconazole, clotrimazole, and natamycin, are generally ineffective in controlling ABPA. Ketoconazole may be effective, but its utility is limited by hepatotoxicity. Efficacy of voriconazole has not yet been studied in ABPA, but anecdotal reports from our center and others suggest similar results to itraconazole. Last, the new biologically engineered antibody omalizumab, directed against IgE, is an intriguing consideration but has not been extensively studied. Given the pharmacokinetics of this agent

843 Chapter 49

omalizumab may be most useful in patients with relatively low IgE levels. In addition to medical therapy, patients with ABPA should avoid areas and environmental conditions associated with high mold count, such as decomposing organic materials and moldy indoor environments. One should consider the use of HEPA filter devices if such exposures are unavoidable.

PROGNOSIS With appropriate treatment long-term control of ABPA is feasible, and durable remissions are common. Treatment of stage I disease with corticosteroids typically results in decreased sputum production, improved control of bronchospasm, >35 percent reduction in total IgE within 8 weeks, clearing of precipitating antibodies, and resolution of radiographic infiltrates. IgE levels typically do not completely normalize but rather decrease by approximately one-half of peak levels seen in the acute stage. Progression of stage IV disease to pulmonary fibrosis can be prevented if patients are maintained on low-dose steroids, and most patients with stage V disease have a stable course over several years. Persons with an FEV1 persistently <0.8 L have a worse prognosis. In addition to severe airflow obstruction and pulmonary fibrosis, longterm complications of ABPA occasionally include the development of an aspergilloma (Fig. 49-3), chronic or recurrent lobar atelectasis, allergic Aspergillus sinusitis, or Aspergillus tissue invasion and semi-invasive Aspergillosis. Transplantation has been undertaken successfully among patients with ABPA, however, post-transplant recurrence of ABPA has been reported.

SUGGESTED READING Allen JN, Davis WB: Eosinophilic lung diseases. Am J Respir Crit Care Med 150:1423–1438, 1994. Allen JN, Davis WB, Pacht ER: Diagnostic significance of increased bronchoalveolar lavage fluid eosinophils. Am Rev Respir Dis 142:642–647, 1990. Allen JN, et al.: Acute eosinophilic pneumonia as a reversible cause of noninfectious respiratory failure. N Engl J Med 321:569–574, 1989. Banerjee B, et al.: C-terminal cysteine residues determine the IgE binding of Aspergillus fumigatus allergen Asp f 2. J Immunol 169:5137–5144, 2002. Bosken CH, et al.: Pathologic features of allergic bronchopulmonary aspergillosis. Am J Surg Pathol 12:216–222, 1988. Greenberger PA: Allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol 110:685–692, 2002. Greenberger PA, Patterson R: Diagnosis and management of allergic bronchopulmonary aspergillosis. Ann Allergy 56:444–448, 1986.

Allergic Bronchopulmonary Aspergillosis (Mycosis)

Greenberger PA, Patterson R: Allergic bronchopulmonary aspergillosis. Model of bronchopulmonary disease with defined serologic, radiologic, pathologic and clinical findings from asthma to fatal destructive lung disease. Chest 91:165S–171S, 1987. Knutsen AP, et al.: Serum anti-Aspergillus fumigatus antibodies by immunoblot and ELISA in cystic fibrosis with allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol 93:926–931, 1994. Kurup VP: Aspergillus antigens: Which are important? Med Mycol 43:S189–196, 2005. Lee TM, et al.: Stage V (fibrotic) allergic bronchopulmonary aspergillosis. A review of 17 cases followed from diagnosis. Arch Intern Med 147:319–323, 1987. Malde B, Greenberger PA: Allergic bronchopulmonary aspergillosis. Allergy Asthma Proc 25:S38–39, 2004. Marchand E, et al.: Frequency of cystic fibrosis transmembrane conductance regulator gene mutations and 5T allele in patients with allergic bronchopulmonary aspergillosis. Chest 119:762–767, 2001. Moss RB: Pathophysiology and immunology of allergic bronchopulmonary aspergillosis. Med Mycol 43:S203– 206, 2005. Neeld DA, et al.: Computerized tomography in the evaluation of allergic bronchopulmonary aspergillosis. Am Rev Respir Dis 142:1200–1205, 1990. Ogawa H, Fujimura M, Tofuku Y: Allergic bronchopulmonary fungal disease caused by Saccharomyces cerevisiae. J Asthma 41:223–228, 2004. Patterson R, et al.: Allergic bronchopulmonary aspergillosis: Staging as an aid to management. Ann Intern Med, 96:286– 291, 1982. Patterson R, et al.: Prolonged evaluation of patients with corticosteroid-dependent asthma stage of allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol 80:663–668, 1987. Richeson RB 3rd, Stander PE: Allergic bronchopulmonary aspergillosis. An increasingly common disorder among asthmatic patients. Postgrad Med 88:217–219, 222, 224, 1990. Ricketti AJ, Greenberger PA, Patterson R: Serum IgE as an important aid in management of allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol 74:68–71, 1984. Rosenberg M, et al.: Clinical and immunologic criteria for the diagnosis of allergic bronchopulmonary aspergillosis. Ann Intern Med 86:405–414, 1977. Safirstein BH, et al.: Five-year follow-up of allergic bronchopulmonary aspergillosis. Am Rev Respir Dis 108:450– 459, 1973. Skov M, et al.: [Adrenal cortex insufficiency after combination therapy with itraconazole and budesonide]. Ugeskr Laeger 165:2198–2201, 2003. Skov M, Hoiby N, Koch C: Itraconazole treatment of allergic bronchopulmonary aspergillosis in patients with cystic fibrosis. Allergy 57:723–728, 2002.

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Stevens DA, et al.: A randomized trial of itraconazole in allergic bronchopulmonary aspergillosis. N Engl J Med 342:756–762, 2000. Stevens DA, et al.: Allergic bronchopulmonary aspergillosis in cystic fibrosis: State of the art. Cystic Fibrosis Foundation Consensus Conference. Clin Infect Dis 37:S225–264, 2003. Vlahakis NE, Aksamit TR: Diagnosis and treatment of allergic bronchopulmonary aspergillosis. Mayo Clin Proc 76:930– 938, 2001. Wark PA, et al.: Anti-inflammatory effect of itraconazole in stable allergic bronchopulmonary aspergillosis: A ran-

domized controlled trial. J Allergy Clin Immunol 111:952– 957, 2003. Weller PF: The immunobiology of eosinophils. N Engl J Med 324:1110–1118, 1991. Williams J, et al.: Diagnosis of pulmonary strongyloidiasis by bronchoalveolar lavage. Chest 94:643–644, 1988. Winn RE, Kollef MH, Meyer JI: Pulmonary involvement in the hypereosinophilic syndrome. Chest 105:656–660, 1994. Zielinski RM, Lawrence WD: Interferon-alpha for the hypereosinophilic syndrome. Ann Intern Med 113:716–718, 1990.

SECTION TEN

Other Obstructive Disorders

50 CHAPTER

Upper Airway Obstruction in Adults Sidney S. Braman

Muhanned A. Abu-Hijleh

I. HISTORICAL PERSPECTIVE II. CLINICAL FEATURES Upper and Lower Airway Obstruction Symptoms and Signs of Upper Airway Obstruction Physiological Assessment Radiographic Assessment III. CAUSES OF UPPER AIRWAY OBSTRUCTION Infection Upper Airway Malignancy Laryngeal and Tracheal Stenosis Tracheomalacia Extrinsic Compression of the Central Airway

The upper airway is the segment of the conducting airways that extends between the nose (during nasopharyngeal breathing) or the mouth (during oropharyngeal breathing) and the main carina, located at the distal end of the trachea. Air passes through five conducting compartments on its way to the lung: oral cavity, nose, pharynx, larynx, and trachea. Physiological points of narrowing are the nostrils, the velopharyngeal valve (at the passage between the nasopharynx and oropharynx), and the glottis. Clinically significant obstruction in adults may occur within any compartment (see Chapter 2 for detailed anatomic description). The incidence and prevalence of upper airway obstruction in adults is not known. Malignant etiologies and benign strictures related

Foreign Body Aspiration Trauma Neuromuscular Disorders Vocal Cord Dysfunction Angioedema Miscellaneous Etiologies IV. MANAGEMENT OF UPPER AIRWAY OBSTRUCTION General Management Securing the Airway Cricothyroidotomy Tracheostomy Bronch oscopy and Interventional Pulmonology Airway Stents

to airway interventions are becoming more prevalent. Other common etiologies of upper airway obstruction in adults include infection, inflammatory disorders, trauma, and extrinsic compression related to pathology of adjacent structures. Initial management focuses on securing the airway and stabilizing the patient. Some conditions require bypassing the obstruction using translaryngeal intubation or tracheostomy. Definitive management depends on the underlying etiology and may include both medical and surgical interventions. The field of interventional pulmonology offers various new management modalities. This chapter provides a brief overview of upper airway obstruction in adults and focuses on clinical features, assessment, etiology, and management.

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HISTORICAL PERSPECTIVE Obstruction of the upper airway and its management concerned physicians for centuries. In the first century b.c., Asclepiades described tracheostomy to improve upper airway obstruction. In the mid-sixteenth century, the first successful tracheostomy was performed to relieve upper airway obstruction caused by a pharyngeal abscess. In the early nineteenth century, the procedure was used to treat croup, and, subsequently, diphtheria. Reports from the same period indicated that 25 percent of children in Paris who were dying from diphtheria were saved by the procedure. By the turn of the twentieth century, rigid bronchoscopy was used to remove a foreign body from the trachea. Finally, Ikeda introduced the flexible bronchoscope in 1967. New causes of upper airway obstruction, radiologic techniques to detect upper airway obstruction, and treatment strategies have evolved in recent decades. Malignancy and related obstruction of the upper airway have become more prevalent with increasing tobacco use and exposure to modern environmental toxins. Complications of endotracheal intubation and tracheostomy have become well recognized causes of benign upper airway stenosis. Improvement in pharmacologic agents to treat infectious, inflammatory, and malignant etiologies, as well as developments in radiation oncology, have had significant effects on management of upper airway obstruction. More recently, advances involving anesthetic agents and anesthesia techniques, along with development of sophisticated surgical procedures for reconstruction of the larynx, trachea, and bronchi, have had a considerable impact on the management of this condition. Development of new endoscopic and imaging techniques and introduction of interventional pulmonology also have proved useful in the management of upper airway obstruction.

CLINICAL FEATURES Upper and Lower Airway Obstruction The causes of upper airway obstruction are considerably less common than diseases of the lower airways, such as chronic obstructive pulmonary disease (COPD) and asthma. However, symptoms (e.g., dyspnea, noisy breathing,) and clinical signs (e.g., wheezing, diminished breath sounds) may be identical, leading to diagnostic confusion. Since COPD and asthma are much more common, they are often assumed to be the cause of the patientâ&#x20AC;&#x2122;s symptoms. Significant upper airway obstruction may be obscured for a considerable period of time, resulting in delayed diagnosis and possible catastrophic outcome. When the obstruction develops acutely, asphyxia and death may result within minutes to hours. Therapy for acute asthma or an exacerbation of COPD is ineffective in this setting. When upper airway obstruction develops slowly, a delay in diagnosis may predispose patients to unnecessary complications, including bleeding or respiratory failure, and, in the case of an upper airway malignancy, to advanced and incurable disease.

Symptoms and Signs of Upper Airway Obstruction The main symptoms of upper airway obstruction are dyspnea and noisy breathing. These symptoms are especially prominent during exercise and also may be aggravated by a change in body position. The patient may complain that breathing is labored in the recumbent position and may have a severely disrupted sleep pattern. Upper airway obstruction in such patients causes sleep apnea syndrome (see Chapter 97), which may resolve completely when the obstruction is relieved. Therefore, daytime somnolence may be a prominent feature of upper airway obstruction. In severely affected patients, cor pulmonale may occur as a result of chronic hypoxemia and hypercarbia. Typically, significant anatomic obstruction precedes overt symptoms. For example, by the time exertional dyspnea occurs, the airway diameter is likely to be reduced to about 8 mm. Dyspnea at rest develops when the airway diameter reaches 5 mm, coinciding with the onset of stridor. Stridor is a loud, musical sound of constant pitch that usually connotes obstruction of the larynx or upper trachea. Although it should be easy to distinguish stridor from wheezing, which emanates from lower airways, sound recordings from the neck and chest have shown that the sound signals from the asthmatic wheeze and stridor are of similar frequency. This explains why errors in diagnosis can be made and an upper airway obstruction due to a tumor or foreign body may be mistakenly treated as asthma. Unlike wheezing, which is characteristic of diffuse lower airway narrowing and occurs predominantly during expiration, the musical sounds of stridor usually occur during inspiration and are heard loudest in the neck. Maneuvers that increase air flow, such as voluntary hyperventilation, accentuate stridor. Neck flexion may change the intensity of stridor, suggesting a thoracic outlet obstruction. When the obstructing lesion is below the thoracic inlet, both inspiratory and expiratory stridor may be heard. At times, the character of a patientâ&#x20AC;&#x2122;s voice may be a clue to an upper airway obstruction. Hoarseness may be a sign of a laryngeal abnormality. Muffling of the voice without hoarseness may represent a supraglottic process.

Physiological Assessment Just as upper airway obstruction must be quite advanced before development of symptoms, physiological abnormalities do not become apparent on lung function testing until severe obstruction occurs. Studies of subjects breathing through tubes of varying diameters suggest that upper airway obstruction must narrow the airway lumen to less than 8 mm in diameter in order to produce abnormalities on a flow-volume loop (see below). This corresponds to an obstruction of more than 80 percent of the tracheal lumen. The forced expiratory volume in 1 s (FEV1 ) remains above 90 percent of control until a 6-mm orifice is created. Therefore, spirometry, which is often the first screening test for pulmonary symptoms, may not be an effective way to detect upper airway abnormalities. The peak expiratory flow rate (PEFR) and maximal voluntary

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Figure 50-1 Normal flow-volume loop following maximal expiratory (above) and inspiratory (below) effort. Small vertical lines denote seconds.

ventilation (MVV) are more sensitive than the FEV1 in detecting upper airway obstruction. The flow-volume loop, which is a recording of maximal inspiratory and expiratory flow at various lung volumes, is an important tool for the diagnosis of upper airway obstruction. The configuration of the normal flow-volume loop is shown in Fig. 50-1. During a forced expiratory maneuver from total lung capacity (TLC), the maximal flow achieved during the first 25 percent of the forced vital capacity is dependent on effort, i.e., an increase in driving pressure (effort) may result in increased flow. During the remaining 75 percent of the forced vital capacity maneuver, flow is determined by the mechanical properties of the lungs and is not effort dependent. During this portion of forced exhalation, a linear deceleration of flow is caused by dynamic compression of the intrathoracic airways (Fig. 50-2 A). An increase in effort and therefore pleural pressure causes further compression of the intrathoracic airways and a further limitation of airflow. At higher lung volumes, flow may be limited by an upper airway obstruction. At low lung volumes, flow may not be affected by an upper airway obstruction, since measurement of flow in this effort-independent portion of the curve represents the function of the peripheral airways. Since the FEV1 reflects a large portion of flow at these lower lung volumes, it is not a sensitive test for upper airway obstruction.

Figure 50-2 Forces acting on intra- and extrathoracic airway walls during inspiration and expiration. 0 = atmospheric pressure; + = positive pressure; â&#x2C6;&#x2019; = negative pressure. A. During inspiration, extrathoracic tracheal pressure (PTR) falls below atmospheric pressure (PATM), favoring narrowing of the lumen (arrows). Intrapleural pressure (PPL) becomes negative, favoring airway enlargement (arrows). B . During expiration, the extrathoracic tracheal pressure (PTR) becomes positive and, therefore, greater than PATM, favoring enlargement of the lumen (arrows). Intrapleural pressure (PPL) is positive, causing dynamic compression of the intrathoracic trachea (arrows).

Because the PEFR reflects flow at higher lung volumes, it may be abnormal when the FEV1 is not. In generating the flow-volume loop, forced inspiratory flow is limited by effort during the entire inspiratory maneuver. Flow increases from residual volume to near the

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Flow (L/s)

Volume (L) A

Figure 50-3 A, B . Flow-volume loop in fixed upper-airway obstruction due to laryngeal abscess in a 56-year-old man who developed persistent wheezing, hoarseness of voice, and intermittent stridor for 3 months after a brief intubation for asthma exacerbation. Computed tomography scan of the neck shows a laryngeal abscess with significant impingement on the laryngeal inlet. The flow-volume loop demonstrates a plateau of flow during inspiration and expiration; the FEF50% /FIF50% ratio is near 1.

midportion of the curve, where it becomes maximal at the peak inspiratory flow rate. Flow then declines until TLC is reached. The pressure surrounding the extrathoracic portion of the upper airway is atmospheric. The turbulent nonlaminar airflow, which occurs during forced inspiration and causes airway pressure to fall in this portion of the airway, favors slight narrowing of the extrathoracic airway (Fig. 50-2B). Peak inspiratory flow, therefore, is less than peak expiratory flow in normal subjects. Because of the dynamic compression of the intrathoracic airways that occurs during exhalation, flow during the middle of inspiration, i.e., the forced inspiratory flow at 50 percent of the forced vital capacity (FIF50% ), is usually greater than flow during the middle of forced expiration, i.e., the forced expiratory flow at 50 percent of the forced vital capacity (FEF50% ). Typical patterns of the flow-volume loop may be seen, depending on whether the obstruction to flow is “fixed” or “variable,” and whether the site of the obstruction is above or below the thoracic outlet or suprasternal notch. Fixed obstructions of the upper airway are those whose cross-sectional area does not change in response to transmural pressure differences during inspiration or expiration. A fixed obstruction may occur in either the intrathoracic or extrathoracic airways. Irrespective of the site of the obstruction, a fixed lesion results in the flattening of the flow-volume loop. A variable obstruction is one that responds to transmural pressure changes, eliciting varying degrees of obstruction during the respiratory cycle. Since the stresses on the intrathoracic and extrathoracic airways are different, changes seen in the flow-volume loop vary according to the site of the obstruction. A number of conditions have been associated with nondistensible narrowing of the upper airway and fixed airway obstruction. Benign strictures and malignancy are

common examples. Maximal inspiratory and expiratory flow-volume loops with fixed obstruction show constant flow, represented by a plateau during both inspiration and expiration (Fig. 50-3 A, B). On the expiratory curve, the plateau effect is seen in the effort-dependent portion of the curve near TLC; very little change is noted in the effort-dependent portion near residual volume. Since the inspiratory curve is similar in appearance, the ratio of FEF50% to FIF50% is normal (close to 1). The forced inspiratory volume in 1 s (FIV1 ) and FEV1 are nearly the same in fixed upper airway obstruction. Vocal cord paralysis is a common cause of variable extrathoracic obstruction. A variable extrathoracic airway obstruction increases the turbulence of inspiratory flow, and intraluminal pressure falls markedly below atmospheric pressure. This leads to partial collapse of an already narrowed airway and a plateau in the inspiratory flow loop (Fig. 504A, B). Expiratory flow is not significantly affected, since the markedly positive pressure in the airway tends to decrease the obstruction. The ratio of FEF50% to FIF50% is high (usually greater than 2). Similarly, the FEV1 is greater than the FIV1 . A variable obstruction in the intrathoracic airways reverses the situation. A predominant reduction in maximal expiratory flow is associated with a relative preservation of maximal inspiratory flow. This association occurs because intrapleural pressure becomes markedly positive during forced expiration and causes dynamic compression of the intrathoracic airways. The obstruction caused by an intrathoracic lesion is accentuated and a plateau in expiratory flow occurs on the flow-volume loop (Fig. 50-5 A, B). A plateau of flow suggests that the lesion has caused the airway lumen to reach its minimal size. A flow peak may precede the plateau, suggesting that the obstruction may not affect flow until a certain lung volume is reached. During inspiration, intrapleural

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Figure 50-4 Variable extrathoracic obstruction due to thyroid cyst in a 32-year-old woman with dyspnea on exertion. A. Computed tomography of the neck shows a 10- × 4-cm cystic mass (large arrow) in the thyroid gland compressing the trachea (small arrow). B . Flow-volume loop shows inspiratory obstruction. FEF50% /FIF50% is very high, and the inspiratory curve is flattened.

pressure is markedly negative; therefore, the obstruction is decreased. The ratio of FEF50% to FIF50% is very low and may approach 0.3. Similarly, the FEV1 is considerably lower than the FIV1 . Although the flow ratios are similar to those seen in patients with COPD and chronic asthma, these disorders often can be distinguished by the appearance of the flow-volume loop. Thus, the expiratory curve in patients with COPD and asthma is primarily altered in the effort-independent portion of the curve, leading to a characteristic shape unlike the plateau configuration of an upper airway obstruction (Fig. 50-6). When a hospital laboratory or physician’s office is not equipped to perform flow-volume loops, results of other tests,

Figure 50-5 Variable intrathoracic obstruction due to squamous cell carcinoma of the trachea. A. Computed tomography of the chest shows a tracheal lesion (arrow), which was not readily apparent on plain chest radiograph. B . Superimposed flowvolume loops show a plateau of expiratory flow preceded by a peak of flow at higher lung volumes. The forced inspiratory flow is preserved in comparison to expiratory flow, but it is also reduced. FEF50% /FIF50% is 0.4.

such as routine spirometry, may be helpful. If the forced spirogram shows that the PEFR is reduced disproportionately to the reduction in FEV1 , an upper airway obstruction should be suspected. Other findings that suggest the diagnosis include a ratio of less than 1.0 for the inspiratory flow between 25 percent and 75 percent of the inspired vital capacity (FIF25–75% ) and a value of less than 1.0 for the expiratory flow between 25 percent and 75 percent of the expired vital capacity (FEF25–75% ). Another indication is an FEV1 that is decreased to the same degree as the FEF25–75% . The MVV may also be a useful test, since it measures both inspiratory and expiratory flows. A ratio of MVV to FEV1 of less than 25 percent is often found with upper airway obstruction. Whenever the MVV is reduced in association with a normal FEV1 , a diagnosis of upper airway obstruction should be considered.

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Figure 50-6 Flow-volume loop typical of chronic obstructive lung disease. Very low FEF50% /FIF50% and typical curvilinear shape are noted.

In contrast to the situation in patients with diffuse obstructive disease of the lower airways (e.g., COPD, asthma), the distribution of ventilation in the lungs is normal, and ventilation-perfusion mismatch does not occur. Hypercarbia is not seen unless the degree of obstruction is very severe, although nocturnal hypercarbia may occur while daytime levels of Pco2 are normal. Hypoxemia is also not present except during exercise and with severe airflow limitation, when it may accompany increases in the level of PCO2 . In contrast to asthma and many instances of COPD, the airflow obstruction caused by an upper airway lesion does not resolve following the inhalation of a bronchodilator.

Radiographic Assessment When acute airflow obstruction occurs as a result of an abnormality of the extrathoracic airway, roentgenographic studies of the soft tissues of the neck in the emergency setting may be helpful (Fig. 50-7). However, computed tomography (CT) has afforded the most important approach to imaging of the extrathoracic airways (Fig. 50-8). The standard chest roentgenogram is often not helpful in detecting the presence, or the cause, of upper airway obstruction. Occasionally, in patients with chronic airway obstruction, generalized hyperinflation of the lungs may occur; in the absence of asthma or COPD this finding may raise suspicion of occult disease in the central airways. The trachea is usually well visual-

Figure 50-7 Acute epiglottitis. Lateral soft-tissue radiograph of the neck of a patient with stridor shows swelling of the epiglottis (large arrow) and loss of normal convexity of the edematous aryepiglottic folds (small arrow).

ized on the posteroanterior (PA) and lateral views in chest roentgenograms of good quality. It is located in the midline and is moderately deviated at the level of the aortic arch. However, many standard roentgenograms are underpenetrated so that the trachea may become a â&#x20AC;&#x153;blind spot.â&#x20AC;? In one study, only 13 of 53 tracheal tumors were evident to the radiologist on the standard PA roentgenogram. The use of digital imaging techniques may avoid such pitfalls. However, thoracic CT studies have become the procedure of choice for imaging the upper airway. The sensitivity of CT scanning for detecting upper airway disease surpasses that of the routine chest roentgenogram (97 percent versus 66 percent, respectively). Helical CT scanning (HCT) minimizes artifacts due to respiratory motion and provides imaging of the whole thoracic volume during a single breath hold. The technique represents an improvement over conventional CT scanning in that it allows detection of intraluminal, submucosal, and extraluminal lesions (Fig. 509A, B) and (Fig. 50-10). Since the early 1990s, HCT has become the preferred noninvasive modality for evaluation of the central airways. The use of HCT using multidetector technology and thin collimation provides high-resolution images of

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Figure 50-8 Computed tomography scan of the neck demonstrating a large laryngocele compressing the lateral wall of the larynx (arrow) causing positional air flow obstruction. B

the entire thorax, improved special resolution, greater speed of image acquisition, and excellent contrast enhancement. HCT techniques using multiplanar and three-dimensional reconstruction can provide virtual images of the thorax that enhance the perception of local and diffuse anatomic lesions of the upper airways (Fig. 50-11). The images may demonstrate the degree of tracheal widening or narrowing, show the location and longitudinal extent of abnormalities, assess tracheal wall thickness, and demonstrate associated extratracheal diseases. The use of paired inspiratory-dynamic and expiratory multislice HCT has proved helpful for the diagnosis of tracheomalacia. Because the maximal degree of collapse in tracheomalacia usually occurs during exhalation rather than at end-expiration, dynamic expiratory imaging is preferable to end-expiratory imaging. If complete collapse is not demonstrated during expiration, then one should confirm the diagnosis by quantitatively measuring the degree of airway luminal narrowing during expiration. Tracheomalacia is generally defined as a reduction in cross-sectional area of greater than 50 percent on expiratory images. The degree of dynamic airway collapse correlates well with findings on bronchoscopy. Another novel CT-based imaging technique is virtual bronchoscopy. The use of volumetric imaging allows for an intraluminal three-dimensional reconstruction of the airways and surrounding tissues. The technique has been used with a high degree of accuracy in assessing the width, length, and contour of fixed airway lesions, but it has not been effective in defining dynamic airway lesions, such as laryngotracheomalacia.

Figure 50-9 A. Computed tomography scan of the chest demonstrating marked narrowing of the trachea with intraluminal calcified nodular projections in a patient with tracheopathia osteoplastica. B . Computed tomography scan of the chest demonstrating multiplanner reformation of the trachea in the sagittal plane of the same patient.

Magnetic resonance imaging (MRI) is another modality that may be used to assess the central airways and surrounding mediastinal structures. MRI provides a multiplane image of the chest without the need for contrast material.

Figure 50-10 Computed tomography scan of the chest demonstrating marked extraluminal compression of the trachea caused by intrathoracic goiter.

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Figure 50-11 Helical computed tomography scan of the chest with three-dimensional reconstruction of the upper airway showing focal tracheal compression (A, B ).

However, the technique is best used to investigate vascular structures surrounding central airways, such as vascular rings or aneurysms that may compress the trachea, rather than the airways themselves, which are better visualized using CT scanning.

CAUSES OF UPPER AIRWAY OBSTRUCTION Infection Deep Cervical Space Infections Deep cervical space infections occur in potential spaces bounded by the deep cervical fascia. The cervical fascia is divided into a superficial and, a more complex, deep layer. This configuration and complexity divides the neck into functional units. Infection can spread along the planes formed by the cervical fascia. Infections affecting the deep neck tissues may result in life-threatening upper airway obstruction. Patients with deep cervical space infections may present with sore throat, odynophagia, neck swelling, pain, fever, and dyspnea. Stridor and profound respiratory difficulty are signs of significant upper airway obstruction. Parapharyngeal, peritonsillar, submandibular, and retropharyngeal ab-

scesses appear to be common locations in adults. The bacteriology and initiating event of deep cervical infections appear to have changed over time. Mixed infections caused by aerobic and anaerobic infections are common and have been reported in up to two-thirds of cases. Streptococcus viridans and Klebsiella pneumonia are common pathogens. Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Escherichia coli, and Haemophilus influenzae are other agents that are commonly reported. Alpha and beta hemolytic streptococci appear to have significantly declined in frequency. Overall, an odontogenic origin is probably most common, with upper respiratory tract infections as an important etiology in children. Intravenous drug abuse, mandibular fractures, iatrogenic and non-iatrogenic traumatic injury to the upper airway, underlying malignancy, and poor underlying immune status are associated conditions. Ludwig’s angina—an infection of the submandibular space and the floor of the mouth—is potentially lethal and is commonly associated with significant upper airway obstruction. This entity is usually a cellulitic process and can affect the submandibular spaces bilaterally. In one report, 75 percent of the cases with true Ludwig’s angina required tracheostomy.

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Treatment of deep cervical infections involves maintenance of oxygenation and ventilation by securing an adequate airway, administration of appropriate antibiotics, and when indicated, use of surgical drainage. Complications of deep cervical infections include upper airway obstruction, Lemierreâ&#x20AC;&#x2122;s syndrome (see below), distant infection, septic embolization, carotid artery rupture, pulmonary embolism, direct extension of infection resulting in mediastinitis and empyema, and rupture of the abscess during intubation or other interventions. One particularly virulent cervical infection, known as Lemierreâ&#x20AC;&#x2122;s syndrome, arises from a nasopharyngitis or peritonsillar abscess. This lateral pharyngeal space infection results in suppurative thrombophlebitis of the internal jugular vein, septicemia, and metastatic abscess formation, particularly in the lungs and joints. Fusobacterium necrophorum is usually the causative agent and has been cultured from blood in over 80 percent of cases. Symptoms begin with a sore throat, fever and painful swelling in the neck, followed by tender lymphadenopathy and tenderness along the sternocleidomastoid muscle (representing thrombophlebitis of the internal jugular vein). Dysphagia, trismus, and upper airway obstruction may occur as a result of swelling of the lateral pharyngeal space. Contrast-enhanced CT scan of the neck is most useful in establishing the diagnosis of thrombosis of the internal jugular vein and may demonstrate soft-tissue abscesses, fasciitis, and myositis, which may require extensive surgical debridement. Without the use of early and appropriate antibiotics, such as high-dose penicillin with metronidazole, or monotherapy with clindamycin, the mortality rate approaches 100 percent. Epiglottitis Epiglottitis is an infectious process that causes variable degrees of inflammation and edema of the epiglottis and supraglottic structures. Supraglottitis may be more appropriate term in adults, since the supraglottic structures usually are involved with variable involvement of the epiglottis. This condition can be life threatening. Its prevalence is 0.18 to 9.7 cases per million adults; the mortality rate may be as high as 7.1 percent. Clinical presentation includes odynophagia, with inability to swallow secretions, sore throat, dyspnea, hoarseness, fever, tachycardia, and stridor. In one review, 44 percent of the patients had a normal routine oropharyngeal examination. Fiberoptic laryngoscopy is necessary to make the diagnosis. The procedure is safe in adults with suspected epiglottitis and should be done without delay. Radiographic studies can be helpful in ruling out other etiologies with similar presentations and in evaluating potential complications. However, the airway must be secured, and radiographic studies should not delay diagnosis or management. Supraglottitis may involve the base of the tongue, uvula, pharynx, and false vocal cords. The disease may be increasing in prevalence among adults and declining in children, perhaps, reflecting introduction of haemophilus-b conjugate vaccines. Young adult males are commonly affected. The disorder appears to be more prevalent in colder, winter months and

Upper Airway Obstruction in Adults

in smokers. Blood cultures are positive in less than one-third of cases. Although Haemophilus influenzae is the most common organism isolated in children, adult supraglottitis may be caused by a variety of organisms, including Haemophilus influenzae, pneumococci, group A streptococci, Staphylococcus aureus, Streptococcus viridans, a variety of anaerobic organisms, mycobacteria, fungi, and viruses. Throat cultures can be helpful in diagnosis and management; however, treatment should not be delayed while awaiting culture results. Illicit drug use may be associated with epiglottitis, with inhalation of heated objects (e.g., metal pieces from a crack cocaine pipe or the tip of a marijuana cigarette) causing thermal injury to supraglottic structures. Signs, symptoms, and roentgenographic and laryngoscopic findings are similar to infectious epiglottitis. Initial antibiotic therapy using a third-generation cephalosporin or extended-spectrum penicillin is reasonable. The prevalence of resistant organisms should be taken into account when choosing empiric antibiotic coverage. Corticosteroids often are used in management of acute epiglottitis despite lack of evidence to support their use. Based on anecdotal case reports, epinephrine is also used. Patients should be observed closely and experienced staff should be available immediately to secure the airway by intubation or surgical approach, if needed. Securing the airway is extremely important in patients who develop stridor and other signs of significant airway obstruction. Mortality in this group has been reported to be as high as 17.6 percent. Laryngotracheobronchitis and Bacterial Tracheitis Laryngotracheobronchitis (croup), an acute viral respiratory illness commonly seen in children, is characterized by narrowing of the subglottic area, causing symptoms of stridor, barking cough, and hoarseness. Adult croup is a rare condition. Rare instances of diphtheric croup have been described in adults; noninfectious membranous tracheitis related to trauma also has been reported. Acute bacterial tracheitis refers to involvement of the subglottic trachea by bacterial infection and usually follows an episode of viral laryngotracheobronchitis. Thick, purulent exudates and mucosal edema may cause symptoms of upper airway obstruction. Staphylococcus aureus appears to be the predominant organism. Prompt antibiotic therapy, close observation with attention to airway compromise, and frequent suctioning are important. Data to suggest effectiveness of steroids or epinephrine in adults are lacking. Rhinoscleroma is a chronic, progressive granulomatous infection of the upper airway that may cause airflow obstruction. This disorder affects primarily the nose and paranasal sinuses, but also may involve the nasopharynx, larynx, trachea, and bronchi. The causative organism is Klebsiella rhinoscleromatis. Rhinoscleroma is endemic in Africa, Asia, and South America and is rare in North America. About 5 percent of patients have diffuse narrowing of the trachea. Prolonged antibiotic therapy with trimethoprim-sulfamethoxazole is effective.

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Tuberculosis The incidence of laryngeal tuberculosis may be on the rise due to the epidemic caused by the human immune deficiency virus. This form of the infection is relatively uncommon, accounting for less than 1 percent of tuberculosis cases. Laryngeal tuberculosis may present as progressive hoarseness and ulceration or a laryngeal mass. In the appropriate clinical context, a positive purified protein derivative (PPD) skin test and acid-fast bacilli in sputum may suggest the diagnosis. However, a biopsy from the laryngeal abnormality usually is required. Biopsy features include granulomatous inflammation, caseating granulomas, and acid-fast bacilli. The true vocal cords and epiglottis are the areas most likely affected. Treatment with antituberculous medications is usually adequate and should be instituted promptly, since the disease is highly contagious. Surgical interventions, including tracheostomy, are reserved for airway obstruction and long-term complications and, in one report, were required in 12 percent of the cases. Endobronchial tuberculosis may result in significant airflow limitation that is related to the initial lesion or subsequent stricture formation. A barking cough and sputum production are common findings. The diagnosis of tuberculosis can be delayed while the diagnosis of malignancy is being entertained. Early diagnosis and treatment with antituberculous medications should decrease the development of fibrostenosis and resultant airflow limitation. The role of steroids in reducing the incidence of fibrostenotic complications remains unclear and controversial. Management may require endoscopic or surgical approaches.

Upper Airway Malignancy Head and Neck Cancer Head and neck cancers, which represent the fifth most common cancer worldwide, develop in the upper aerodigestive tract, including the oral cavity, pharynx, larynx, and related structures. The great majority are squamous cell carcinomas. These cancers share common risk factors, prognosis, treatment, and epidemiology. A 23 percent decline in head and neck cancers has been observed in the United States over the last two decades. The reported annual incidence was 11.2 cases per 100,000 per year from 1992 to 1999, as compared with 14.6 cases per 100,000 per year from 1976 to 1983. The clinical presentation of head and neck cancer depends on the location and stage. Symptoms include hoarseness, hemoptysis, sore throat, and otalgia; life-threatening upper airway obstruction may be seen. Five percent of newly undiagnosed laryngeal cancers (a subcategory of head and neck cancers) present with severe dyspnea or stridor and may require emergency laryngectomy or tracheostomy. Tracheal Malignancy Tumors of the trachea and carina may produce a gradual decrease in airway diameter. Primary malignancies of the trachea are rare in comparison with other upper airway and

bronchogenic tumors. In one study, lung cancer was 140 times more common than primary tracheal cancer. Adenoid cystic carcinoma and squamous cell carcinoma comprise the majority of primary malignant tracheal tumors. Adenoid cystic carcinoma appears to be slightly more common. Dyspnea, cough, hemoptysis, wheeze, and stridor are frequent presenting symptoms. Surgery remains the most effective management. Emergency treatment with procedures to recanalize the airway, including airway stenting, may be necessary pending definitive surgery. Postoperative radiation therapy appears useful for primary tracheal malignancies, particularly when surgical margins are positive. Palliative radiation is used for local control when surgery is contraindicated. Five-year survivals for adenoid cystic and squamous cell carcinomas are reported at 52 percent and 39 percent, respectively. Favorable prognostic factors include negative airway margins at the time of resection and adenoid cystic histology. Tumor metastases to the tracheal mucosa or direct tracheal extension of lung cancer from parenchymal lesions or lymph nodes are manifestations of locally advanced or metastatic disease, perhaps the most common cause of malignant tracheal obstruction. Metastases to central airways from nonpulmonary malignancy also may occur. Endobronchial metastases from breast, colorectal, renal, ovarian, thyroid, uterine, testicular, nasopharyngeal, and adrenal carcinomas, as well as sarcomas, melanomas, and plasmacytomas, have been described. In an autopsy series of over 1300 patients with solid tumors, metastatic disease to central airways occurred in 2 percent; other series report a higher incidence.

Laryngeal and Tracheal Stenosis Postintubation and Post-tracheotomy Concentric scar formation in the larynx or trachea may lead to narrowing and obstruction to airflow. Significant stenosis, defined as obstruction exceeding 50 percent of the lumen, can lead to serious symptoms and functional limitations. Endotracheal intubation, tracheostomy, and prior laryngotracheal instrumentation account for most cases of laryngotracheal stenosis. The reported frequencies of tracheal stenosis following tracheostomy or laryngotracheal intubation vary widely (0.6 percent to 65 percent). Although injury to the laryngotracheal airway is common following intubation or tracheostomy, the incidence of symptomatic stenosis, demonstrated by radiographs or bronchoscopy, appears to be much lower (less than 2 percent). Tracheal stenosis in the region of the tube cuff is related to pressure-induced ischemic injury of the mucosa and cartilage and its risk can be minimized by use of large-volume, low-pressure cuffs. The duration of translaryngeal intubation also affects the frequency and severity of laryngotracheal stenosis. Stenosis following tracheostomy may be above the stoma, at the level of the stoma, at the cuff site, or at the tip of the cannula. Damage to the cartilage above the stoma is a common cause of tracheal stenosis after tracheostomy.

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In addition to ischemic mucosal injury and ischemic chondritis, anterior and lateral tracheal wall damage, with “buckling in” fractures of the cartilage, is an important factor. The fractures can be minimized by avoiding excessive pressure on the cartilage during the procedure, selecting the appropriate size and length of the tracheostomy tube, avoiding infection, and using the lowest possible cuff pressure. Percutaneous tracheostomy is growing in popularity as an alternative to the standard procedure. The ideal anatomic site for percutaneous tracheostomy is between the second and third, or first and second, tracheal rings (not the subglottic space). The incidence of symptomatic tracheal stenosis following percutaneous tracheostomy is comparable to the incidence that occurs after open techniques. When symptomatic tracheal stenosis and tracheomalacia are included as longterm complications, the incidence has been reported to be less than 2.5 percent. Other Causes of Tracheal Stenosis Other causes of laryngeal and tracheal stenosis are uncommon. They include airway trauma, including external injury; inhalational burns, irradiation; tracheal infections, including bacterial tracheitis, tuberculosis, and diphtheria; Wegener’s granulomatosis; sarcoidosis; amyloidosis; collagen vascular diseases, including relapsing polychondritis, polyarteritis; inflammatory bowel disease; and congenital disorders. Wegener’s granulomatosis may present with significant subglottic stenosis, a complication reported in 16 to 23 percent of patients. Subglottic stenosis may be the only manifestation of Wegener’s granulomatosis and have a clinical course distinct from other manifestations of the disease. Endoscopic biopsy of suspected sites of involvement is positive in only 5 percent to 15 percent of cases. Sarcoidosis may be associated with granulomatous infiltration and obstruction of the upper airways. Laryngeal involvement is more common, but tracheostenosis has been described. Radiographs may show diffuse tracheostenosis, which progresses despite corticosteroid therapy. Bronchoscopy may reveal extensive tracheal narrowing. Pulmonary amyloidosis includes tracheobronchial manifestations. The chest roentgenogram may show diffuse narrowing and wall thickening involving a long tracheal segment. Involvement is diffuse and circumferential, often with ossification of the amyloid deposits. Bronchoscopy demonstrates multiple plaques on tracheal walls or localized tumorlike masses. Relapsing polychondritis is a rare systemic disease characterized by recurrent episodes of inflammation of cartilaginous structures. Respiratory manifestations are often severe and may be life threatening. Inflammation occurs in all cartilage types, including the elastic cartilage of the ears and nose, hyaline cartilage of all peripheral joints, and axial fibrocartilage. The most common presenting symptom is pain in the external ear due to auricular chondritis. Respiratory tract involvement may develop years after the first occurrence of auricular chondritis. Symptoms include hoarseness, apho-

Upper Airway Obstruction in Adults

nia, and choking. Tenderness over the thyroid and laryngeal cartilages may be present. When the trachea is involved, endoscopic examination shows inflammation and stenosis. CT demonstrates major airway collapse caused by destruction of cartilaginous rings or airway narrowing due to inflammatory edema and fibrosis. CT findings also include diffuse, smooth thickening of the trachea and proximal bronchi; thickened, densely calcified cartilaginous rings; tracheal wall nodularity; and diffuse narrowing of the tracheobronchial lumen. The posterior tracheal membrane is spared. Tracheopathia osteoplastica is a rare, benign disease of the trachea and major bronchi in which cartilaginous or osseous nodules project into the airway lumen, often causing considerable airway deformity. The posterior membranous portion of the tracheal wall is spared. The disorder may begin just below the larynx, but most often it affects the lower twothirds of the trachea. Extension into the proximal portions of the major bronchi may be noted. The condition usually occurs over the age of 50 years and may cause severe airflow obstruction. Its etiology is unknown. On rare occasion, inflammatory bowel disease produces tracheobronchial stenosis and severe airflow obstruction. The associated airway mucosal inflammation may be steroid responsive early in the course of illness. If fibrosis ensues, medical management has limited success. Laryngopharyngeal reflux may contribute to subglottic stenosis and, when documented, merits treatment. Idiopathic progressive subglottic stenosis may be diagnosed in the absence of a clear, underlying etiology. Since most affected patients are female, a hormonal etiology has been proposed. However, estrogen receptors have not been demonstrated in specimens studied. In addition to medical management, repeated rigid and flexible bronchoscopy-based interventions aimed at reestablishing airway patency may be necessary, particularly in those who are not considered to be surgical candidates or in whom the area of stenosis is complex or extensive. Some experts propose laser-based bronchoscopy as initial management in patients with benign laryngotracheal stenosis, reserving surgery for bronchoscopic failures (see Chapter 36). Others advocate primary surgical intervention, when possible. A multidisciplinary approach incorporating medical and surgical specialists is utilized in many centers.

Tracheomalacia Tracheomalacia refers to loss of tracheal rigidity and resulting susceptibility to collapse. Tracheomalacia may be diffuse or localized to a tracheal segment. The affected portion may be intrathoracic, in which airway obstruction is accentuated during expiration. Less common is extrathoracic obstruction, in which airway obstruction is most marked during inspiration. Tracheobronchomalacia is the term used to describe the condition when the mainstem bronchi are involved. Tracheomalacia in adults may be classified as congenital or acquired. The congenital form, described more extensively in children, is related to a variety of congenital

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disorders and associated syndromes. The disorder may persist into adult life and is referred to as “idiopathic giant trachea,” “tracheomegaly,” or the “Mounier-Kuhn syndrome.” Bronchiectasis and recurrent respiratory infections are common. Tracheal diverticuli have been reported in more advanced disease. Although atrophy of the longitudinal elastic fibers and muscularis layer has been described, the etiology of these changes is unclear. The diagnosis is made when the diameters of the trachea or right or left mainstem bronchi exceed the upper limits of normal by 3 or more standard deviations. Acquired or secondary tracheomalacia in adults may be related to a variety of conditions. Tracheostomy and endotracheal intubation are probably the most common etiologies. Usually, limited, focal weakness of the trachea and dynamic airway obstruction are present. Tracheomalacia may be caused by conditions that are associated with chronic pressure on the tracheal wall, inflammation of the cartilaginous support or mucosa, interference with tracheal blood flow, or chronic infection. Traumatic injury to the central airways or surgical interventions also may lead to tracheomalacia. Symptoms of tracheomalacia include dyspnea, cough, sputum production, and hemoptysis. Wheezing and stridor may be present in patients with significant airway obstruction. Tracheomalacia is diagnosed by using direct bronchoscopic visualization to confirm significant narrowing of the tracheal lumen during regular, forced expiration. Assessment of the central airways using end-expiratory, dynamic, threedimensional CT images is useful. Application of continuous positive airway pressure (CPAP) has been reported as beneficial. Surgical intervention may be useful in selected patients. Optimal medical management includes treatment of associated infections.

Extrinsic Compression of the Central Airway The upper airway is subject to extrinsic compression by a variety abnormalities that involve adjacent structures. The compression may affect the intrathoracic trachea or extrathoracic trachea and upper airway. Mediastinal Masses and Lymphadenopathy Rarely, mediastinal masses present with serious limitation to airflow that develop either acutely or indolently. Common symptoms include chest pain, fever, dyspnea, and cough. Based on one large series, approximately 40 percent of mediastinal masses are malignant; 25 percent are cystic. The anterosuperior compartment is the most common site of mediastinal malignancies. Thymic neoplasms and lymphoma are the most common malignancies, followed by neurogenic tumors and teratomas. Both Hodgkin’s and non-Hodgkin’s lymphomas may be manifested by severe respiratory compromise due to airway compression. A similar syndrome may be due to a metastatic tumor to the mediastinal lymph nodes arising from bronchogenic or other carcinomas. Patients with large mediastinal masses present a challenge during the perioperative period because of the po-

tential for development of acute upper airway obstruction and other respiratory complications. In adults, complete airway obstruction during induction of anesthesia is rare. Serious pulmonary complications develop intra- and postoperatively in about 4 and 7 percent of patients, respectively. Complications may occur while the patient is placed in the supine position, during induction, or following extubation. Patients with severe symptoms, including stridor, and those with greater than 50 percent airway obstruction appear at high risk for respiratory complications; asymptomatic patients are at significantly less risk. Patients with reduced peak expiratory flow and mixed obstructive-restrictive patterns on pulmonary function testing also appear to be at increased risk for postoperative complications. Middle mediastinal masses include benign cysts that are bronchogenic, enterogenous (duplication), pericardial, pleural, and thymic in origin. Most bronchogenic cysts are asymptomatic. However, some evoke cough, chest pain, and dyspnea. Severe respiratory distress and compressive symptoms can occur. Usually, cyst contents appear to have the density of water on CT or MRI. However, mucoid contents may give the impression of solid appearance on CT. Surgical resection and transthoracic or transbronchial drainage are options for management. Surgical intervention appears to be the preferred treatment in patients who are symptomatic. The role of interventions, including surgery, in asymptomatic patients is controversial. Enterogenous cysts are usually removed surgically. Enlarged mediastinal lymph nodes which compress the airway may arise from infectious and noninfectious benign etiologies. One notable example is fibrosing mediastinitis, defined as the presence of excessive mediastinal fibrous tissue that tends to invade and destroy normal structures. The entity is thought to represent a reaction to an infectious granulomatous disease, especially histoplasmosis. The incidence in populations exposed to histoplasmosis remains low. Constriction of the central airways and vessels and the resulting cardiopulmonary limitations may develop several years after the initial infection. Hemoptysis is common, as are cough, dyspnea, and chest pain. CT imaging shows mediastinal fibrosis, calcification, and compression of mediastinal structures. Bronchoscopic findings include concentric airway narrowing and mucosal edema with hyperemia. Unfortunately, hemoptysis tends to be recurrent, and the disease does not respond to corticosteroids or antifungal agents. Surgical intervention is generally ineffective and may be hazardous. Neck and Thyroid Causes Retrosternal extension of a diffuse goiter may cause extrathoracic or intrathoracic airway obstruction. Up to 90 percent of patients with substernal goiter report respiratory symptoms. A choking sensation occurs in about one-third of patients with diffuse thyroid enlargement and 14 percent in patients with solitary thyroid nodules. Orthopnea is prevalent when the goiter is intrathoracic and may be enhanced by obesity. Flow-volume loops show evidence of upper airway

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obstruction in one-third of patients. Lack of correlation has been reported between symptomatic obstruction and CT findings. Laryngoceles and saccular cysts, which are abnormal dilatations of the laryngeal saccule (ventricle), are rare. Saccular cysts usually are filled with mucous. Laryngoceles communicate with the laryngeal lumen, resulting in air-filled structures noted on radiographic studies. Laryngoceles may be internal (i.e., confined to the larynx), external (i.e., extending into the thyrohyoid membrane superiorly), or combined. Most are asymptomatic. Hoarseness, dysphagia, pain, or signs of airway obstruction or infection may occur. A neck mass during the Valsalva maneuver may be detectable. Pyocele formation (i.e., infection in the laryngocele) may result in airway obstruction, aspiration pneumonia, or infection of the lateral pharyngeal space. The incidence of laryngeal carcinoma in association with laryngoceles makes close evaluation necessary. Endoscopic and surgical approaches may be employed in management. Parathyroid cysts may be located in the neck or mediastinum. Fifty percent are accompanied by clinical hyperparathyroidism. Paroxysmal symptoms of airway obstruction can develop. Surgical excision is the treatment of choice; results are generally good. Cervical osteophytes, common in the elderly, related to either degenerative spinal arthritis or more generalized idiopathic skeletal hyperostosis; the osteophytes may be associated with dysphagia. In addition, airway narrowing and ulcerations due to osteophytes have been reported. The airway compression may make even elective endotracheal intubation difficult, despite adequate preoperative evaluation. Finally, significant upper airway compression may arise from cervical lymph node involvement with infectious or malignant disorders, hematomas or pseudoaneurysms (related to trauma, surgical interventions, central line placement, or coagulation abnormalities), abscess formation, or other expanding lesions in the soft tissue of the neck. Esophagus Involvement of the trachea, glottis, or vocal cords by advanced esophageal cancer is common and associated with a poor prognosis; estimated 1-year survival is less than 10 percent. Airway obstruction requiring stent placement is associated a median survival of 1 to 4 months after the placement. Tracheal obstruction may develop if an esophageal stent is placed in the setting of significant tracheal compromise. Development of tracheoesophageal fistula represents a devastating complication. Placement of stents simultaneously in the trachea and esophagus is effective palliation for a tracheoesophageal fistula. If such double stenting is anticipated for a fistula or for simultaneous esophageal and tracheal obstructions, the tracheal stent is placed first to ensure patency of the airway, followed by the esophageal stent. Palliative external or local radiation therapy, chemotherapy, or other treatment modalities (e.g., photodynamic therapy) may be effective with or without

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accompanying airway interventions. The risk of esophageal disruption and rupture should be considered if stenting is performed after these local measures are employed. Achalasia may cause a variety of pulmonary complications, including cough, aspiration with pneumonia or abscess formation, and rarely upper airway obstruction. Tracheal compression by a dilated megaesophagus is the usual etiology. Ensuring patency of the airway and decompressing the esophagus are necessary in urgent management. Vascular Causes Vascular rings, defined as anomalies of the aortic arch or its branches that compress the trachea or esophagus, are rare in adults (incidence less than 0.2 percent). Respiratory symptoms are common. Right-sided aortic arch occurs in less than 0.1 percent in adults and may be associated with complete vascular rings, while double aortic arch and right-sided aortic arch with aberrant left subclavian artery appear to be the most common etiologies of vascular rings in adults. The right-sided aortic arch usually crosses over the right mainstem bronchus and descends on either the right or the left side. The vascular ring usually is completed by the ligamentum arteriosum arising from the descending aorta, an aberrant left subclavian artery, or an aortic diverticulum. With a double aortic arch, the left arch crosses over the left mainstem bronchus and joins the descending aorta to complete the ring; the ligamentum arteriosum does not contribute to the vascular ring. Symptoms, resulting from malacia of the compressed airway and resultant dynamic airway obstruction, may be misdiagnosed as exercise-induced asthma. An increase in aortic diameter due to rising blood pressure during exercise, intravenous fluid administration, or anatomic changes with aging may contribute to symptoms. Surgical intervention is indicated in symptomatic patients. Pulmonary artery sling with anomalous origin of the left pulmonary artery from the right pulmonary artery is very rare in adults. In neonates, the condition is symptomatic and can be fatal without surgical intervention. However, in adults the condition is usually diagnosed incidentally on imaging a patient who has no significant symptoms. This disorder may be associated with a complete tracheal ring, forming the â&#x20AC;&#x153;sling-ringâ&#x20AC;? complex. This condition may present with a right paratracheal mass noted on the chest radiograph. Compression of the trachea by large aortic or innominate artery aneurysms or pseudoaneurysms may occur and complicate management in the perioperative period. Surgical repair is indicated to relieve symptoms.

Foreign Body Aspiration Foreign body aspiration, more common in children than adults (in whom the peak incidence is in the sixth decade), is usually recognized from the patientâ&#x20AC;&#x2122;s history. Foreign bodies commonly lodge in the bronchi after migrating through the trachea. In adults, food products are the most commonly aspirated material. The penetration syndrome, defined as the

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sudden onset of choking and intractable cough after aspirating a foreign body, with or without vomiting, is often followed by persistent cough, fever, chest pain, dyspnea, and wheezing. Impairment of the normal protective airway mechanisms is common; among the frequent associations are neurologic disorders, trauma with loss of consciousness, sedative or alcohol use, poor dentition, and advanced age. Emergency measures, entailing a food extractor or the Heimlich maneuver, can be life saving. Flexible bronchoscopy is usually successful in removing foreign bodies, although back-up rigid bronchoscopy should be available and is preferred as the primary procedure at some centers. A complicating chemical bronchitis from aspiration of vegetables or nuts may affect visualization and management of the foreign body.

involving the face indicate a high likelihood of inhalation injury. Early fiberoptic bronchoscopy remains important in evaluation and management of patients with inhalation injuries, enabling the assessment of the extent and severity of the injury, procurement of samples for bacteriologic studies, and fiberoptic intubation, as necessary. Translaryngeal intubation is the standard method of securing the airway in inhalation injury; early tracheostomy is used in some centers. A role for prophylactic corticosteroids or antibiotics is currently not supported by published reports. Significant tracheal stenosis may develop in patients who survive the initial insult, especially when translaryngeal intubation or tracheostomy is necessary.

Trauma

Endotracheal Tube−Related Trauma Postextubation stridor, due to glottic edema, laryngospasm, or laryngotracheal stenosis is a serious event. Reintubation rates for upper airway obstruction due to endotracheal tube– related trauma in critically ill patients have been reported to range from 4 percent to 33 percent. An “acceptable” rate is considered to be 5 percent to 15 percent. The cuff leak test does not accurately predict success or failure of extubation. Although the efficacy of corticosteroids or racemic epinephrine in the management of postextubation stridor is not substantiated, both are used extensively in clinical practice. Translaryngeal intubation may also produce vocal cord paralysis, accounting for 10 to 15 percent of all cases. Paralysis may be unilateral or bilateral. Affected patients present with hoarseness or airway obstruction. Findings may occur immediately after extubation or be delayed. Prolonged intubation, use of a large endotracheal tube (number 8 or larger), placement of the tube cuff close to the vocal cords, or use of excessive cuff pressure are risk factors. The condition usually resolves spontaneously within 10 weeks. Vocal cord (contact) granuloma may develop 4 to 6 weeks after intubation. Symptoms include prolonged hoarseness, exertional dyspnea, and stridor. Management, using antireflux medications, inhaled and systemic corticosteroids, antibiotics, botulinum toxin injection, speech therapy, smoking cessation, and rest of the voice are usually successful. Surgical intervention is reserved for cases that fail conservative management. On occasion, dislocation of the arytenoid cartilages occurs during intubation. Rheumatoid arthritis that affects the cricoarytenoid cartilage is a risk factor for this condition. Rigid bronchoscopy or surgical interventions may be needed to reduce the dislocation. Other disorders that may cause complications during intubation include hyperostosis of the cervical spine due to ankylosing spondylitis and cricoarytenoid joint disease due to systemic lupus erythematosus.

Facial Trauma Emergency access to the airway is necessary in up to 6 percent of cases of facial trauma complicating motor vehicle accidents and other causes of crush injuries. If intubation is difficult or impossible due to the injury or related airway obstruction, emergency cricothyroidotomy or tracheostomy must be considered. Laryngotracheal Injuries Blunt and penetrating injuries to the laryngotracheal airway are rare. Without a high index of suspicion, clinicians may miss the diagnosis. The incidence of penetrating injuries appears to be increasing. Stridor, wheezing, dysphonia, hemoptysis, and general neurological deficits are common. Cervical crepitus and subcutaneous emphysema also may be present. Cervical ecchymoses and hematomas, pneumomediastinum, and pneumothorax should prompt consideration of a laryngotracheal injury. Management includes prompt securing of the airway, but blind endotracheal intubation should be avoided, since it carries the risk of complete airway obstruction. Some experts recommend tracheostomy as the primary airway management strategy. Awake fiberoptic intubation can be useful. Flexible fiberoptic laryngoscopy, rigid or flexible bronchoscopy, and CT imaging may be helpful in assessing the degree of injury. Unfortunately, the mortality of laryngotracheal injuries remains high (20 to 40 percent). Thoracic injuries and closed head injuries are commonly associated pathologies that can influence management and prognosis. Inhalation Injuries Thermal and chemical injuries to the upper respiratory tract may lead to serious consequences, including airway obstruction. Unfortunately, the mortality rate increases significantly when burns are accompanied by inhalational injury. Symptoms can be delayed in becoming manifest, making early recognition and intervention vital in the management of patients with inhalational injuries. The presence of cough, dyspnea, hoarseness, or loss of consciousness; or the findings of singed nasal hairs, carbonaceous sputum, or burns

Neuromuscular Disorders Neuromuscular disorders may affect the bulbar muscles, many of which surround the upper airway. When this occurs, resistance to airflow is increased, and the flow-volume loop

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often shows an inspiratory flow plateau typical of variable extrathoracic upper airway obstruction. In addition, a pattern of flow oscillations during inspiration (“sawtooth pattern”) may be seen. The abnormal flow pattern, first noted in patients with sleep apnea, is commonly seen in extrapyramidal disorders, myasthenia gravis, and motoneuron disease; it may also be seen in patients who have functional stridor and wheezing (see below). In extrapyramidal disorders, the flow oscillations correspond to vocal cord tremor. In motoneuron diseases, muscle denervation causes irregular muscle fasciculations, resulting in tremor of upper airway muscles. Upper airway symptoms may be seen in Shy-Drager syndrome with extrapyramidal involvement and in Parkinson’s disease. Patients may present with symptoms of chronic dyspnea or with stridor and respiratory failure relieved by endotracheal intubation. Bilateral vocal cord paralysis also results in abnormalities of inspiratory flow and a distinctive flow-volume loop. Bilateral vocal cord paralysis may be a cause of nocturnal stridor, oxygen desaturation, and sleep disruption or, in extreme cases, acute respiratory failure. In adults, causes include familial bulbar spinal muscle atrophy, postpoliomyelitis syndrome, Parkinson’s disease, multiple sclerosis, acute poliomyelitis, amyotrophic lateral sclerosis, Guillain-Barr´e syndrome, brain stem stroke, and large cerebral hemisphere stroke. Non-neurologic causes include laryngeal nerve injury following neck surgery, endotracheal intubation injury, laryngeal trauma, infection, trauma, and thoracic aortic aneurysm. Dystonic extrapyramidal reactions due to neuroleptic medications (e.g., haloperidol) may cause significant upper airway obstruction. The usual reactions to these medications are akathisia, dyskinesia, dysarthria, and dystonic reactions, such as torticollis. Laryngeal-pharyngeal dystonia may cause severe upper airway dysfunction. If not reversed, symptoms can last for days or lead to respiratory arrest.

Vocal Cord Dysfunction The glottis plays an active role in adjusting airflow, both voluntarily and through reflex control from laryngeal and pulmonary receptors. Normally, the glottic opening widens dur-

Upper Airway Obstruction in Adults

ing inspiration and narrows during expiration. Occasionally, the glottis can become dysfunctional in the absence of organic disease. The disorder, called vocal cord dysfunction, laryngeal wheezing, or laryngeal asthma is characterized by paradoxical closure of the vocal cords intermittently during inspiration. The mechanism is unknown, but psychogenic factors appear to be more likely than a disordered processing of neural input to the larynx. Signs and symptoms of vocal cord dysfunction resemble those of laryngeal edema, laryngospasm, vocal cord paralysis, or asthma. Wheezing or stridor and shortness of breath are typical and are often so dramatic that they suggest acute asphyxia and respiratory failure. Intubation and other emergency measures are used frequently. Slightly more than half of patients also have asthma. Patients without asthma are predominantly women who have been misdiagnosed as having asthma for an average of 5 years previously. Typically, patients have been treated with large doses of oral corticosteroids; frequent emergency room visits, hospitalizations, and endotracheal intubations characterize the clinical course of many patients. Psychiatric disorders are common in these patients. Major psychiatric disorders, personality disorders, and sexual and physical abuse are commonly uncovered. Whereas many patients are unaware of their self-induced wheeze or stridor, others appear to derive secondary gain from their symptoms and manifest factitious illness. A high index of suspicion is warranted when the adventitious sounds are loudest over the neck in a patient who presents with wheezing, stridor, or both. Despite their respiratory distress, patients often have little difficulty completing full sentences and can hold their breath; the laryngeal-induced sounds disappear during a panting maneuver. On pulmonary function testing, patients with vocal cord dysfunction demonstrate a pattern of variable extrathoracic airway obstruction, resulting in an increase in the ratio of FEF50% to FIF50% . Some patients show a pattern of “sawtoothing,” or fluttering of the inspiratory limb of the flow-volume loop, representing fluctuations in the abnormal cord motion (Fig. 50-12). Often, attempts to perform the flow-volume loop maneuver generate variable results from

Figure 50-12 Variable extrathoracic obstruction due to vocal cord dysfunction. Two consecutive flow-volume loops from a young woman with inspiratory stridor. Variable effort accounts for the differences in configuration. FEF50% /FIF50% in each is very high. The inspiratory loop is flat and demonstrates a sawtooth pattern. This pattern has also been associated with sleep apnea syndrome and various neuromuscular disorders.

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test to test. A normal alveolar-arterial oxygen gradient and absence of bronchial hyperresponsiveness are other clues to the diagnosis. The diagnosis of vocal cord dysfunction is made during direct visualization of the vocal cords during an attack. Inspiratory, anterior vocal cord closure with a posterior glottic chink is seen. Treatment includes discussion of the diagnosis with the patient, discontinuation of unnecessary medications, and referral to a speech therapist or psychotherapist. The response to bronchodilator therapy is usually poor. Administration of an inhaled helium-oxygen mixture may alleviate symptoms during an acute attack.

Angioedema Angioedema is characterized by well-demarcated swelling of the face, lips, tongue, and mucous membranes of the nose, mouth, and throat. When the larynx is involved, upper airway obstruction may occur and is fatal in as many as 25 percent of patients. In most instances, the cause of angioedema is unclear; prior exposure to common allergens, such as drugs, chemical additives, and insect bites should be suspected. Contrary to what might be thought, the most common causes of angioedema are not IgE initiated. They include reactions to histamine-releasing drugs, such as narcotics and radiocontrast materials, to aspirin and other nonsteroidal antiinflammatory drugs, and to angiotensin-converting enzyme inhibitors. Hereditary angioedema, a rare cause of upper airway obstruction, is an autosomal-dominant trait that occurs in all races. The underlying mechanism is a deficiency in production or function of C1 esterase inhibitor, a serum protease inhibitor that regulates the complement, fibrinolytic, and kinin pathways. Hereditary angioedema is characterized by painless nonpitting edema of the face and upper airway. The disorder usually begins in childhood and becomes more prominent in adolescence. Swelling progresses over many hours and then resolves spontaneously over 1 to 3 days. Despite the slow progression, death may occur from laryngeal obstruction. Physical stimuli (cold, heat, stress) and circulating immune complex diseases (e.g., due to serum sickness or systemic lupus erythematosus) are also known to cause angioedema. Emergency management includes securing the airway, administration of corticosteroids, and use of antihistamines and epinephrine.

Miscellaneous Etiologies A variety of uncommon etiologies also may produce upper airway obstruction. Postpneumonectomy syndrome refers to compression of the left main bronchus between the aortic arch and left pulmonary artery following a right pneumonectomy. The syndrome also may be seen following a left pneumonectomy, sometimes in the setting of a right-sided aortic arch. Medi-

astinal repositioning prostheses, with or without additional fixation methods, may be useful in selected patients. Mucus ball formation related to transtracheal oxygen catheters has been well described. Although transtracheal oxygen delivery decreases supplemental oxygen flow requirements by approximately 50 percent during rest and 30 percent during activity, development of symptomatic mucus balls (occurring in up to one-third of patients) remains a major disadvantage of the technique. Death and life-threatening events secondary to airway obstruction have been reported. Recurrent respiratory papillomatosis in adults, caused by human papilloma virus types 6 or 11 (or, much less commonly, types 16 or 18) may result in upper airway obstruction and death. Although the larynx is most commonly affected, the tracheobronchial tree may be involved, with a predilection toward areas with prior mucosal injury, including tracheostomy sites and tracheal injuries. Lesions tend to progress down through the tracheobronchial tree. Pulmonary parenchymal involvement is rare, but it may be severe, and bronchiectasis, pulmonary nodules, and abscess formation may occur. Malignant transformation is also possible. The course of the disease is difficult to predict. Recurrent endoscopic interventions (debulking), with attendant risk of airway stenosis, are usually required. No controlled trials on the role of antiviral therapy have been conducted. Available data suggest beneficial effects of intralesional cidofovir. Favorable effects also have been reported with the use of interferon-a. Chemotherapy, radiation therapy, and targeted surgical resection are utilized for confirmed malignant transformation.

MANAGEMENT OF UPPER AIRWAY OBSTRUCTION General Management The primary goals in management of any patient with upper airway obstruction are assurance of adequate oxygenation and ventilation and management of the underlying condition. If airway obstruction is partial, and the patientâ&#x20AC;&#x2122;s condition is stable, close monitoring and diagnostic studies are appropriate. Depending upon the underlying etiology, temporary measures may include close observation in an intensive care unit, elevation of the head of bed, administration of humidified oxygen, use of a helium-oxygen inhalation mixture (see below), systemic corticosteroids, and inhaled racemic epinephrine, pending definitive medical or surgical management. A heliumâ&#x20AC;&#x201C;oxygen gas mixture (Heliox) may be useful in management of upper airway obstruction when the obstruction is temporary and reversible. The physiologic rationale for Heliox is based upon a reduction in work of breathing achieved through administration of a low-density gas. In particular, Heliox has a lower density than does oxygen, room air, or a mixture of the two, resulting in conversion of the predominantly turbulent flow at the site of obstruction to a more laminar pattern. Furthermore, since laminar flow requires a

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smaller pressure gradient than turbulent flow to achieve the same flow rate, the accompanying work of breathing is less (see Chapter 9). The major limitation of the modality is an inability to deliver gas with an FIO2 of more than 40 percent. Despite physiological evidence and clinical reports of efficacy, prospective, randomized studies demonstrating improved outcome in patients receiving Heliox are lacking, as are data supporting use of corticosteroids or inhaled epinephrine in airway obstruction from a variety of causes.

Securing the Airway Although under controlled circumstances, a significant portion of so-called difficult airways and intubations may be identified in the course of a thorough preoperative assessment, the patient with impending airway obstruction presents a challenge. Under such circumstances, a critical first concern is deciding whether an artificial airway is needed emergently. Regardless of the airway utilized, emphasis is placed on ensuring adequate oxygenation and ventilation. Airways judged unsafe for routine management may be addressed according to the “difficult airway algorithm” recommended by the American Society of Anesthesiologists (see also Chapter 163). A difficult airway is defined as a clinical circumstance in which a conventionally trained anesthesiologist experiences difficulty using face mask ventilation, endotracheal intubation, or both. Airway access in emergency situations may be challenging because the patient frequently is critically ill and can deteriorate quickly. The likelihood of a difficult intubation can be estimated by using the Mallampati score or a modification of the score to assess potential laryngeal exposure and prospects for adequate airway visualization. A number of parameters, such as mouth opening distance, jaw size, thyromental distance, and cervical range of motion, have been incorporated into airway assessment scoring systems; each parameter has limited sensitivity and specificity. Combining scoring systems provides better accuracy of prediction. The “rule of threes,” which is a useful, simple bedside tool, predicts successful direct laryngoscopy if the examiner can place three finger breadths (approximately 6 to 7 cm) between the upper and lower teeth, the mandible and hyoid bone, and the thyroid cartilage and sternal notch. In the emergency setting of upper airway obstruction, the most experienced physician available should secure the airway. Appropriate equipment and monitoring, along with back-up resources for alternative and invasive airway management, should be available. A variety of invasive and noninvasive techniques are available as alternatives to standard, laryngoscopy-guided orotracheal intubation. Invasive methods include surgical and percutaneous tracheostomy, surgical and percutaneous transtracheal (needle) cricothyrotomy, translaryngeal guided or “retrograde” intubation, fiberoptic endotracheal intubation, and use of a rigid ventilating bronchoscope. Noninvasive techniques include use of specialized laryngoscope blades, guiding and lighted stylets, directional tip control

Upper Airway Obstruction in Adults

tubes, and esophageal-tracheal (Combitube) or laryngeal mask airways. In selected circumstances, tactile intubation, nasotracheal intubation, or blind orotracheal intubation may be employed.

Cricothyroidotomy Cricothyroidotomy (either surgical or based on Seldinger technique) has a long history of use in emergency access to the airway when more conservative approaches fail or are contraindicated. Currently, surgical cricothyroidotomy is performed by surgeons, anesthesiologists, and intensive care specialists. In early reports, a high incidence of laryngeal stenosis during intermediate and long-term follow-up was noted, perhaps related to the presence of infectious laryngeal disease or the use of large-bore tubes. In addition, the risk of subglottic stenosis also appears high in patients with prolonged prior intubation. Hence, although the procedure is useful for short-term airway control, tracheostomy should be considered if prolonged airway access is required.

Tracheostomy Most tracheostomies are performed on intubated patients in the intensive care unit. Percutaneous tracheostomy is rapidly becoming the method of choice in the intensive care unit and is associated with acceptable intraoperative and postoperative complication rates. Advantages of the technique over the traditional procedure include low cost, short procedure time, low complication rate, and elimination of the need to transport critically ill patients to the operating room. Adaptation of percutaneous techniques for emergency situations also has been described. In a review of over 1100 patients who underwent tracheostomy, 76 percent were performed in patients who required prolonged ventilation, 6 percent for upper airway obstruction, 7 percent for extensive maxillofacial trauma, and 11 percent as an adjunct for head and neck or chest surgeries; only 0.26 percent were performed as emergency procedures. Overall mortality was 0.7 percent.

Bronchoscopy and Interventional Pulmonology Bronchoscopy, including interventional bronchoscopic techniques, is discussed in Chapter 36. Use of these techniques for managing upper airway obstruction is well established and is briefly summarized below. Rigid bronchoscopy allows oxygenation, ventilation, and application of various therapeutic interventions, including “coring out” of obstructing lesions, control of bleeding, and removal of foreign bodies. Complications include airway rupture, bleeding, and granulation tissue formation related to mucosal injury. Electrocautery can be applied through rigid or flexible bronchoscopy. Side effects include bleeding, perforation, and airway fire. Laser therapy, including use of Nd:YAG, argon, and CO2 lasers, may be useful as well.

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Photodynamic therapy, based on creation of a phototoxic cell reaction achieved after activating a drug trapped in target cells by nonthermal laser light, has been employed in treatment of upper airway obstruction. Disadvantages include delay in effect compared with laser therapy and electrocautery and need for follow-up debridement. Bleeding and obstruction from necrotic tumor and edema are potential complications. Cryotherapy, based on repeated freeze-thaw cycles to achieve cell necrosis and tissue damage is used in benign and malignant disorders of the upper airway. Cryotherapy has excellent hemostatic effects; the incidence of perforation or bleeding is low. Due to the delayed beneficial effect, cryotherapy is not usually used under emergent conditions. Finally, external beam radiation and brachytherapy are useful modalities for palliative management of airway obstruction and hemoptysis. For external beam radiation, unwanted exposure of adjacent structures is a limiting factor, while hemorrhage, radiation bronchitis, and fistulae with surrounding structures are complications of brachytherapy.

Airway Stents Airway stents are used in the palliative management of both benign and malignant airway obstruction. Available tracheal stents include expandable metal and silicone prostheses. Major complications include stent migration, granulation tissue formation, and stent interference with mucociliary clearance. In a series of over 1500 patients who had stents placed for upper airway obstruction due to benign or malignant disorders, stent migration was reported in 9.5 percent, granulation tissue formation in 7.9 percent, and obstruction in 3.6 percent.

SUGGESTED READING Ames WA, Ward VM, Tranter RM, et al: Adult epiglottitis: An under-recognized, life-threatening condition. Br J Anaesthesiol 85:795–797, 2000. Ashiku SK, Kuzucu A, Grillo HC, et al: Idiopathic laryngotracheal stenosis: Effective definitive treatment with laryngotracheal resection. J Thorac Cardiovasc Surg 127:99–107, 2004. Ayers ML, Beamis JF Jr: Rigid bronchoscopy in the twentyfirst century. Clin Chest Med 22:355–364, 2001. Boiselle PM, Feller-Kopman D, Ashiku S, et al: Tracheobronchomalacia: Evolving role of dynamic multislice helical CT. Radiol Clin North Am 41:627–636, 2003. Carden KA, Boiselle PM, Waltz DA, et al: Tracheomalacia and tracheobronchomalacia in children and adults: An in-depth review. Chest 127:984–1005, 2005. Chan KP, Eng P, Hsu AA, et al: Rigid bronchoscopy and stenting for esophageal cancer causing airway obstruction. Chest 122:1069–1072, 2002.

Ernst A, Feller-Kopman D, Becker HD, et al: Central airway obstruction. Am J Respir Crit Care Med 169:1278–1297, 2004. Freitag L, Tekolf E, Steveling H, et al: Management of malignant esophagotracheal fistulas with airway stenting and double stenting. Chest 110:1155–1160, 1996. Gaissert HA, Grillo HC, Shadmehr MB, et al: Long-term survival after resection of primary adenoid cystic and squamous cell carcinoma of the trachea and carina. Ann Thorac Surg 78:1889–1896; discussion 1896–1887, 2004. Goldenberg D, Ari EG, Golz A, et al: Tracheotomy complications: A retrospective study of 1130 cases. Otolaryngol Head Neck Surg 123:495–500, 2000. Grillo HC: Development of tracheal surgery: A historical review. Part 1: Techniques of tracheal surgery. Ann Thorac Surg 75:610–619, 2003. Grillo HC: Development of tracheal surgery: A historical review. Part 2: Treatment of tracheal diseases. Ann Thorac Surg 75:1039–1047, 2003. Kost KM: Endoscopic percutaneous dilatational tracheotomy: A prospective evaluation of 500 consecutive cases. Laryngoscope 115:1–30, 2005. Lorenz RR: Adult laryngotracheal stenosis: Etiology and surgical management. Curr Opin Otolaryngol Head Neck Surg 11:467–472, 2003. Mayo-Smith MF, Spinale JW, Donskey CJ, et al: Acute epiglottitis. An 18-year experience in Rhode Island. Chest 108:1640–1647, 1995. Owens GR, Murphy DM: Spirometric diagnosis of upper airway obstruction. Arch Intern Med 143:1331–1334, 1983. Practice guidelines for management of the difficult airway: an updated report by the American Society of Anesthesiologists Task Force on Management of the Difficult Airway. Anesthesiology 98:1269–1277, 2003. Riordan T, Wilson M: Lemierre’s syndrome: More than a historical curiosity. Postgrad Med J 80:328–334, 2004. Sikora AG, Toniolo P, DeLacure MD: The changing demographics of head and neck squamous cell carcinoma in the United States. Laryngoscope 114:1915–1923, 2004. Sue RD, Susanto I: Long-term complications of artificial airways. Clin Chest Med 24:457–471, 2003. Swanson KL, Edell ES: Tracheobronchial foreign bodies. Chest Surg Clin North Am 11:861–872, 2001. Torchio R, Gulotta C, Perboni A, et al: Orthopnea and tidal expiratory flow limitation in patients with euthyroid goiter. Chest 124:133–140, 2003. Wang LF, Kuo WR, Tsai SM, et al: Characterizations of lifethreatening deep cervical space infections: A review of one hundred ninety-six cases. Am J Otolaryngol 24:111–117, 2003. Wick F, Ballmer PE, Haller A: Acute epiglottis in adults. Swiss Med Wkly 132:541–547, 2002. Yencha MW, Linfesty R, Blackmon A: Laryngeal tuberculosis. Am J Otolaryngol 21:122–126, 2000.

51 Cystic Fibrosis Judith Voynow Thomas F. Scanlin

I. GENETICS II. PATHOGENESIS III. PATHOPHYSIOLOGY Respiratory Tract Gastrointestinal Tract Reproductive Organs Sweat Glands IV. DIAGNOSIS V. CLINICAL EVALUATION Chest Radiography Pulmonary Performance Sputum Culture Pancreatic Function Liver Function Semen Analysis Mutation Analysis VI. ATYPICAL CLINICAL PRESENTATIONS

VIII. NATURAL HISTORY AND PROGNOSIS IX. COMPLICATIONS Hypoelectrolytemia and Metabolic Alkalosis Intestinal Obstruction Liver Disease Atelectasis Pneumothorax Hemoptysis Infection with Unusual Organisms Respiratory Failure Complications Related to Lung Transplantation X. PSYCHOSOCIAL ISSUES General Special Considerations in Adult Patients XI. REPRODUCTIVE ISSUES XII. FUTURE DIRECTIONS Pharmacologic Approaches Gene Therapy

VII. TREATMENT Management of the Pulmonary Disease Nutritional Support

Cystic fibrosis (CF) is a common inherited disease that has a high frequency in Caucasians. The disorder affects all exocrine glands, with symptoms involving the lungs and pancreas usually dominating the clinical picture. Two aspects of the disease make CF particularly difficult to both diagnose and manage: tremendous variability in the degree and pattern of involvement of organs in different persons and lack of information about the precise details of the molecular and cellular pathogenesis of the disease, even though the gene responsible for CF and its gene product, an integral membrane glycoprotein, have been identified. This chapter focuses on the pathophysiology and management of CF. Our current understanding of the genetics and underlying molecular biology are highlighted. Complications of the disorder are addressed,

and a brief discussion of relevant psychosocial and reproductive issues is provided. Finally, potential future directions in treatment are described, including gene therapy.

GENETICS CF demonstrates an autosomal-recessive pattern of inheritance. In the United States, the incidence of the disease is approximately 1 in 3000 in Caucasians, 1 in 6000 in Hispanics, and 1 in 10,000 in African Americans. The frequency of unaffected heterozygote carriers of a CF mutation is estimated to be 1 in 26 in persons of Northern European ancestry.

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CF is caused by mutations in a single gene named the cystic fibrosis transmembrane conductance regulator (CFTR). This gene was identified with an approach known as positional cloning, which permitted mapping of the gene without prior knowledge of the biochemical defect through use of polymorphic DNA markers. The first genetic marker that was found to be linked to CF was paraoxonase. In 1985, the demonstration of the linkage of CF to two DNA markers, D7S15 and D7S8, and to the met oncogene established the localization of the CF gene to the long arm of chromosome 7. Following a series of molecular cloning experiments, which included “chromosome walking” and “jumping,” a candidate gene was identified. This was proved to be the CF gene in 1989, largely through the discovery of a frequent mutation. Formal proof that this was the CF gene came in 1990 with correction of the chloride secretory defect in CF cells in vitro following transfection of the CFTR gene. The CF gene spans approximately 230 kb of DNA and contains 27 exons. The mRNA is 6.5 kb and is detected in a variety of tissues, including lungs, pancreas, and sweat glands, which are predominantly affected in pathogenesis of the disease. The deduced polypeptide was predicted to be an integral membrane glycoprotein containing 1480 amino acids (Fig. 51-1; see “Pathogenesis”). Several major and minor splicing variants in the transcripts have been described in individuals with and without CF. In most cases, however, the significance of the alternative splicings is not clear. The most common CF mutation, and the first to be described, is a three-base deletion in exon 10 that causes

Figure 51-1 Domain model of the cystic fibrosis transmembrane conductance regulator (CFTR). Based on hydrophobicity plots, CFTR has twelve transmembrane spanning domains, two nucleotide (N) binding domains (NBD 1 and NBD 2), and a regulatory (R) domain. The twelve transmembrane domains form the ion channel ‘‘pore.” In the closed state, the ‘‘R” domain is believed to obstruct the channel. Channel opening requires binding of two adenosine triphosphates (ATPs) to the nucleotide binding domains. This model is similar to other ATP-binding cassette transporter proteins that bind ATP and transport ions or micronutrients. (Modified from Riordan J, Rommens JM, Kerem B, et al: Identification of the cystic fibrosis gene: Cloning and characterization of complementary DNA. Science 245:1066–1073; erratum 1437, 1989.)

a deletion of phenylalanine from position 508 ($F508) of the CFTR glycoprotein. This mutation accounts for 66 percent of CF mutations. However, more than 1000 CF mutations have now been reported, and the list continues to grow. In addition, a number of benign sequence variations have been described. A listing of the most common mutations and their relative frequency is included in Table 51-1. The large

Table 51-1 Most Common CFTR Mutations in the United States Name of Mutation $F508 G542X G551D 3120+1G→A W1282X N1303K R553X 621+1G→T 1717–1G→A 3849+10kbC→T R117H 1898+1G→T $I507 2789+5G→A G85E R347P R334W R1162X R560T 3659delC A455E 2184delA S549N 711+1G→T R75X 406–1G→A I148T 2307insA A559T $F311 G480C 405+3A→C S1255X

Frequency (%) 66 2.4 2.1 1.5 1.4 1.3 0.9 0.9 0.7 0.7 0.7 0.4 0.3 0.3 0.3 0.2 0.2 0.2 0.2 0.2 0.2 0.1 0.1 0.1 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2

Population with High Prevalence

Spanish English African American, Arabian Jewish-Ashkenazi Italian Hispanic Multi-ethnic Italian Hispanic East Asian Hispanic

Multi-ethnic Multi-ethnic

Multi-ethnic Hispanica Hispanica Hispanic/Frencha African Americanb African Americanb African Americanb African Americanb African Americanb African Americanb

Data based on the most frequent mutations found overall in the United States. Mutations that are expressed at higher frequency in Hispanic (a) or African American (b) populations are indicated. source: Bobadilla JL, Macek M Jr., Fine JP, et al: Cystic fibrosis: A worldwide analysis of CFTR mutations-correlation with incidence data and application to screening. Hum Mutat 19:575–606, 2002.

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number of mutations makes accurate detection of a satisfactory percentage of carriers extremely difficult, and carrier screening for the general population has not been recommended or implemented. Testing for 32 of the most common mutations is widely available; such testing will detect approximately 90 percent of the carriers in Caucasians of Northern European descent. In families with an affected individual and known mutations, prenatal diagnosis and carrier testing using direct detection of mutations is accurate and available. In families with a member diagnosed as having CF, but with undetected mutations, sequencing of the complete CFTR coding region and critical intronic regions is now also available to detect rare mutations.

PATHOGENESIS Discovery of the gene responsible for CF and description of its product, CFTR, have provided the necessary foundation for understanding the pathogenesis of the disorder at the molecular and cellular levels. CFTR is an integral membrane glycoprotein of approximately 170 kD that is expressed in epithelial cells of affected organs. CFTR contains 1480 amino acids, which are arranged in twelve transmembrane domains, two nucleotide binding domains, and a putative regulatory domain (Fig. 51-1). The most common mutation, $F508, is a three-base deletion that causes deletion of phenylalanine from position 508, located in the proposed first nucleotide-binding domain. The original structural model, which was based on hydrophobicity plots, has proved to be essentially correct in its main features. CFTR shares many structural features with the â&#x20AC;&#x153;adenosine triphosphate (ATP)-binding cassetteâ&#x20AC;? transporter family, which includes P glycoproteins, as well as a number of bacterial transporters. CFTR has been clearly shown to function as an apical chloride channel in airway epithelial cells. The localization of CFTR to the apical aspect of airway epithelial cells, to the ciliated duct of submucosal gland cells, and to submucosal serous cells, and the role of CFTR as an apical chloride channel fits nicely with the simplest hypothesis to account for the pathogenesis of pulmonary disease in CF: Decreased secretion of chloride and water by airway epithelial cells results in dehydrated mucus (Fig. 51-2). However, CFTR may have other functions, such as regulation of other ion channels, including the epithelial sodium channel. Loss of CFTR causes increased reabsorption of sodium; increased epithelium sodium channel activity alone alters regulation of ions and water, resulting in mucus obstruction of airways. CFTR transports bicarbonate; loss of CFTR function may result in acidification of the small intestinal lumen and, possibly, the airway lining fluid. Alternatively, CFTR may also function in intracellular membranes (e.g., endoplasmic reticulum, endosomes, and clathrin-coated vesicles). A consequence of the altered function of CFTR in intracellular membranes may be the mislocalization of glycosyltransferases. Together, these observations may explain abnormalities of

Cystic Fibrosis

Figure 51-2 Simplified model of ion transport in airway epithelium. A. Normal airway cell with multiple apical ion channels. At the top, two different chloride channels are represented, the outwardly rectifying chloride channel (ORCC) and the Ca++ -gated chloride channel. In the center, cyclic adenosine monophosphate (cAMP)-gated cystic fibrosis transmembrane conductance regulator (CFTR) is shown. The apical sodium channel is depicted at the bottom. Experimental data suggest that CFTR interacts with the other channels, although the type of interaction is not clear (solid arcs). B . CF cell with nonfunctioning cAMP-gated apical chloride transport. The function of the other channels is affected in an unknown manner (dashed arcs). The net result of ion channel activity on the pericellular fluid composition (hatched area) is under investigation. Many questions remain concerning the function of CFTR and ion transport in the airway.

CF glycoproteins: increased sulfation of respiratory mucins, with decreased sialylation and increased fucosylation of both secreted and membrane glycoproteins. Altered glycosylation of airway glycoproteins may significantly impact bacterialepithelial interactions and innate immune functions in the lung. In addition to the effect of CFTR on epithelial ion channels and glycoprotein processing, loss of CFTR function negatively impacts innate immunity and accentuates inflammation. Absence of CFTR function is associated with impaired bacterial killing in vitro and defective function of antimicrobials including human beta-defensin 1 and lysozyme. Absence of CFTR is also associated with increased interleukin-8 (IL8) production and decreased IL-10 in vitro. Furthermore, the presence of excessive, unopposed neutrophil elastase in the airway cleaves complement and immunoglobulins, potentially interfering with bacterial opsonization. CF airways have increased oxidant stress due to neutrophilic inflammation and reduced antioxidants such as glutathione. Finally, tissues in CF have an increased ratio of arachidonic acid metabolites to docosahexaenoic acid metabolites when compared to healthy controls, reflecting an increase in inflammatory lipids in affected tissues, and decreased levels of lipoxin, an anti-inflammatory lipid mediator in airway surface fluid. Together, these factors synergistically increase the inflammatory milieu in the airways in CF. CFTR mutations have been grouped into four or five classes, depending on the effect of the mutation on the expression, processing, and function of the protein (Fig. 51-3). The most common mutation, $F508, is a processing mutation in which very little of the mutant protein reaches the apical

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Figure 51-3 Classification of cystic fibrosis transmembrane conductance regulator (CFTR) mutations by molecular and biochemical abnormalities. This schematic depicts the effect of different classes of CFTR mutations on expression and function in the cell. Class I mutations block mRNA transcription. Class II mutations prevent normal CFTR protein processing and localization. Class III mutations permit CFTR localization at the apical membrane but inhibit chloride channel conductance. Class IV mutations result in partial chloride channel conductance. Class V mutations affect transcription, translation, or protein processing resulting in reduced CFTR expression at the apical membrane. Examples of mutations in each class are depicted below the cell models. Epithelial cell models with fingerlike projections depict cilia at the apical surface. Fully processed CFTR protein is depicted by the gray circles embedded among the cilia at the apical surface of the cells. (From Welsh MJ and Smith AE: Molecular Mechanisms of CFTR Chloride Channel Dysfunction in Cystic Fibrosis. Cell 73:1251–1254, 1993, with permission.)

surface. If the mutant protein escapes normal intracellular processing, however, $F508 protein functions normally in the apical membrane. Furthermore, only 25 percent of normal CFTR transcripts are properly processed and transported to the cell surface. The remaining 75 percent are degraded before being processed. These data suggest that one therapeutic strategy to overcome the defect in CF is to disrupt normal intracellular processing mechanisms.

PATHOPHYSIOLOGY In CF, all exocrine glands appear to be affected primarily, albeit to varying degrees. Because exocrine glands perform highly specialized functions in a variety of organs—e.g., in the skin, respiratory tract, gastrointestinal tract, and reproductive system—the number of possible symptoms and complications in CF is large. Table 51-2 highlights the complications and symptoms of CF according to the age groups in which they most often occur. Obstruction of exocrine ducts by viscous secretions appears to play a cardinal role in the pathogenesis of almost all manifestations of the disease. In 10 to 20 percent of patients, the initial manifestation is often meconium ileus—i.e., obstruction of the intestine by thick, viscous meconium stool. Chronic pulmonary disease, pancreatic insufficiency, and focal biliary cirrhosis progress gradually throughout the course of the disease, albeit at different rates in different patients. Progressive obstruction of exocrine ducts is a regular feature of the disease except in sweat

glands, where obstruction of ducts has not been implicated in pathogenesis.

Respiratory Tract In the lungs, hypersecretion of viscid mucus and chronic bacterial infection combine to produce a progressive and distinctive type of chronic obstructive airway disease that eventually leads to diffuse, severe bronchiectasis. The earliest pathological lesions are found in the distal bronchioles. Whether the viscid secretions are primary or are secondary to chronic bacterial infections remains unsettled. In favor of a primary disturbance is the demonstration of mucus obstructing submucosal gland ducts in the airways of neonates with CF, who have not yet developed any evidence of bacterial infection or chronic colonization of the airways. With the use of sophisticated culture methods, bacterial pathogens can almost invariably be isolated from the respiratory tract of patients with CF. The most common pathogens isolated from sputum cultures are Staphylococcus aureus and Pseudomonas aeruginosa. Less commonly found are Escherichia coli, Klebsiella, and Haemophilus influenzae. In later stages of the disease, Pseudomonas usually predominates. By adulthood, more than 80 percent of patients are colonized with P. aeruginosa. Neutrophil-dominated lower-airway inflammation also plays a primary role in the pathogenesis of the characteristic central bronchiectasis of CF. Bronchoalveolar lavage fluid (BALF) demonstrates increased neutrophils and various cytokines, especially IL-8, even in infants whose BALF is sterile.

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Table 51-2 Complications and Presenting Symptoms of Cystic Fibrosis by Age Group Infancy

Childhood

Adolescence/Adulthood

Meconium ileus

Pulmonary infections with Staphylococcus and Pseudomonas

Chronic bronchitis

Obstructive jaundice

Malnutrition with steatorrhea and pancreatic insufficiency

Pansinusitis

Edema with hypoproteinemia, anemia, and hypoprothrombinemia

Heat prostration with hypoelectrolytemia and metabolic alkalosis

Hemoptysis

Failure to thrive

“Atypical asthma” with clubbing and/or bronchiectasis

Chronic abdominal pain

Intussusception

Esophageal varices

Delayed sexual development

Volvulus

Hypersplenism

Obstructive aspermia

Rectal prolapse

Nasal polyps

Recurrent pneumonia/bronchiolitis

Typically, respiratory secretions increase when a patient with CF, already chronically colonized with Pseudomonas, develops a viral respiratory tract infection. In turn, the increase in secretions leads to a gradual increase in cough and sputum production and then to an exacerbation of the pulmonary disease, usually manifested by increase in respiratory rate; retraction of the chest during inspiration; and diffuse, coarse inspiratory crackles. Fever and leukocytosis are common. The chest radiograph demonstrates worsening hyperinflation. Both peribronchial thickening and nodular or cystic densities are more marked than usual. Pulmonary function tests show a worsening over baseline. Usually, residual volume (RV) increases; forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1 ) decrease; the forced expiratory flow between 25 and 75 percent of the exhaled vital capacity (FEF25–75% ) also decreases. Treatment using antibiotics and chest physiotherapy generally succeeds in restoring most indices of pulmonary function to, or almost to, baseline. However, Pseudomonas and Staphylococcus persist in sputum cultures. The most attractive hypothesis to account for the pattern of response to treatment is that therapy reduces the number and, probably, virulence of organisms. Despite the virtual return to baseline after an exacerbation, however, the cumulative effect of repeated episodes is progressive bronchiectasis or atelectasis, or a combination of the two, accompanied by a gradual and irreversible decrease in pulmonary function. The striking degree of airway destruction and relative sparing of the pulmonary parenchyma at autopsy are shown in Fig. 51-4. A simplified

scheme illustrating the evolution of the process is shown in Fig. 51-5.

Gastrointestinal Tract Although pancreatic function may be either normal or abnormal at birth, it gradually becomes increasingly abnormal in most patients with CF as the pancreatic ducts become progressively obstructed by thick, viscous secretions from the exocrine portion of the organ; pancreatic enzymes that are trapped within the ducts lead to autodestruction of the pancreas. A cycle of destruction and obliteration of the ducts is set into motion, leading to cystic dilatation of ducts proximal to sites of obstruction and fibrosis of the body of the pancreas. In advanced stages of the disease, pancreatic fibrosis sometimes causes obliteration of the islets of Langerhans and, consequently, diabetes mellitus. The liver and biliary tract are also affected in CF. Here too, the primary mechanism appears to be obstruction of ducts by abnormally viscid secretions. The earliest pathological change is focal biliary cirrhosis that may be present in early infancy. In some patients, focal cirrhosis progresses to diffuse cirrhosis and portal hypertension. Some newborn infants with CF develop the inspissated bile syndrome, characterized by prolonged obstructive jaundice starting at 2 to 8 weeks of age. The jaundice often clears without therapy. In approximately 20 to 30 percent of patients, the gallbladder is small, presumably because of underdevelopment due to obstruction by viscid secretions. Compared with age-matched controls, the risk of cholelithiasis and cholecystitis is increased in adults with CF.

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Figure 51-5 Simplified scheme for pathogenesis and progression of pulmonary disease in CF.

changes occur in the female reproductive tract in patients with CF. In the male reproductive tract, however, the vas deferens is either atretic or absent at birth. Although the pathogenesis of this lesion is not certain, viscous secretions may contribute to obstruction in utero, followed by failure of development of the vas deferens. Spermatogenesis and testicular development are otherwise normal. Because of either partial or complete obstruction of the vas deferens, approximately 98 percent of males with CF are aspermic. Figure 51-4 Section of lung from autopsy of a patient with CF, demonstrating remarkable dilation of large airways and preservation of intervening pulmonary parenchyma. (Courtesy of Dr. S. Moolten.)

The most striking pathological change in the intestines is hyperplasia of the mucous glands and goblet cells. Biochemical abnormalities in intestinal mucins may contribute to malabsorption of specific nutrients and bile acids. Much of the malabsorption in CF can be corrected by administration of pancreatic enzymes. However, the abnormal mucins may lead to slowing of intestinal transit time; the slowing, combined with maldigestion of food substances, sometimes causes fecal impaction in the terminal ileum and ileocecal area, a condition referred to as meconium ileus equivalent or distal intestinal obstruction syndrome. The fecal impaction, in turn, occasionally causes volvulus or intussusception of the bowel (Fig. 51-6).

Reproductive Organs Except for an increase in viscosity and an abnormal midcycle ferning pattern in cervical mucus, no consistent pathological

Sweat Glands The sweat glands of patients with CF manifest no distinctive histological changes. Nonetheless, their function is abnormal. Micropuncture experiments have shown that the precursor solution secreted by the sweat glands is isotonic to plasma, both in CF patients and in normal subjects. In normal persons, as the sweat flows along the duct of the gland, sodium and chloride are reabsorbed, so that by the time that the opening at the skin surface is reached, sweat is hypotonic to plasma with respect to both sodium and chloride concentrations. In CF, the relative impermeability to chloride ions is thought to be responsible for the elevated chloride and sodium concentrations which are the basis for the diagnostic test, the quantitative pilocarpine iontophoresis sweat test, and are also responsible for the characteristic increase in potential differences across isolated, perfused sweat glands from CF patients.

DIAGNOSIS The diagnosis of CF requires the demonstration of abnormally high concentrations of sodium and chloride in the sweat

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Figure 51-6 Distal intestinal obstruction syndrome (DIOS). A. Presenting Gastrografin enema of a child who had crampy abdominal pain and a right lower-quadrant mass. Fecal impaction with intussception is demonstrated. B . Partial resolution of the obstruction following Gastrografin administration. C . Complete resolution of the intussception and fecal impaction.

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of a person who has the characteristic history and symptoms of CF. The most prominent clinical features are chronic pulmonary disease and pancreatic insufficiency. The most compelling family history for the diagnosis is CF in a sibling. If the clinical picture and/or the family history support the diagnosis, and if two sweat tests using the quantitative pilocarpine iontophoresis method are clearly positive, the diagnosis of CF can be made with assurance. Identification of two pathological mutations, in addition to the characteristic clinical picture, is accepted as a criterion for the diagnosis. However, CF is a complex syndrome (Table 51-2) whose clinical manifestations are sometimes subtle. In addition, the family history is not always straightforward. Therefore, a high index of suspicion, coupled with a battery of clinical tests, is sometimes required to establish the diagnosis, especially in adolescents or young adults. Since CF occurs with a high frequency in the general population, the diagnosis should be considered routinely in a broad array of differential diagnoses. Although Table 51-2 categorizes symptoms according to the age at which they most often occur, symptoms at any age should prompt consideration of the diagnosis of CF. The most consistent feature of CF is an abnormally high concentration of sodium and chloride in sweat. Measurement of the chloride concentration is recommended for clinical testing. The only reliable sweat test is based on iontophoresis of pilocarpine, followed by quantitative determination of the concentration of chloride in an adequate, measured volume of sweat. Seventy-five milligrams of sweat is the minimum acceptable amount. When a preweighed, measured pad is used, this amount ensures that an adequate sweat flow rate (1 g/m2 per min) has been achieved and that the sample is large enough for the determination of chloride by titration. In children, concentrations of chloride of less than 40 mEq/L are usually regarded as normal. However, the average of values for sodium and chloride concentrations are about 20 mEq/L for normal subjects and 95 mEq/L for those with CF. In children, values between 40 and 60 mEq/L are borderline elevated; such values call for further evaluation. As a result of recent experience with CF newborn screening, it has been suggested that sweat chloride values above 40 mEq/L may be diagnostic in the first few months of life. The concentration of sodium and chloride in sweat increases gradually with age. An age-corrected scale of normal, abnormal, and borderline values of sodium concentration in sweat is available (Fig. 51-7). Conditions other than CF in which the concentrations of sodium and chloride in sweat are abnormally high include malnutrition, adrenal insufficiency, hereditary nephrogenic diabetes insipidus, ectodermal dysplasia, and fucosidosis. Except in some instances of malnutrition, these conditions are readily distinguished from CF. The finding of abnormal concentrations of sodium and chloride in sweat should automatically prompt evaluation of the patient to determine if, and to what extent, other organs are affected. Genetic analysis can be used to confirm the diagnosis of CF. In patients with minimal symptoms, the diagnosis of

Figure 51-7 Graph of sweat test results vs. age: normal, elevated, and borderline (stippled).

CF can be made with certainty if two CF-associated alleles are present. As mentioned previously, screening for 32 of the most common alleles yields an overall sensitivity of 90 percent due to undetected alleles. Therefore, a negative mutation analysis does not rule out a diagnosis of CF, and atypical patients should be followed carefully. Prenatal screening is standard practice for 11 states. The initial stage of screening uses the neonatal blood spot to determine the concentration of immunoreactive trypsinogen. If this is elevated, secondary screens vary from repeat immunotrypsinogen determination to $F508 or 25-32 mutation screen. The screening programs have a sensitivity ranging from 87 to 99 percent. Risks vs. benefits and the relative costs of the screening programs are being evaluated to determine the best approach.

CLINICAL EVALUATION The evaluation of patients with CF includes chest radiography, tests of pulmonary performance, sputum culture, and assessment of pancreatic, hepatic, and reproductive functions. Each is described below.

Chest Radiography Rarely is the chest radiograph completely normal in CF. In the person with minor pulmonary symptoms, the manifestations may be questionable (e.g., mild hyperinflation and minimal peribronchial thickening). However, the radiographic findings become more distinctly abnormal as the disease increases in severity. Peribronchial thickening, which is often most prominent in the upper lobes of the lungs early in the course of the disease, usually progresses to affect all lobes. In the advanced stage of pulmonary involvement, ring shadows, cystic lesions, and nodular densities are increasingly apparent, as are areas of bronchiectasis and atelectasis. The central pulmonary artery often enlarges in the middle stages of the disease, but the cardiac silhouette remains within normal

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limits until the disease is far advanced. The variability in the chest radiograph is illustrated in Fig. 51-8 for three siblings with CF when each was 17 years old. High-resolution computed tomography (HRCT) scans are more sensitive than plain radiographs. The most common abnormalities described are “ground glass opacities.” Early bronchiectasis is easily detected on the CT scan, even when routine chest radiographs are normal, as seen in Fig. 51-9.

Pulmonary Performance The lungs of patients with CF are usually morphologically and functionally normal at birth. Over time, accumula-

Figure 51-8 Chest radiographs of three siblings with CF taken when the patients were 17 years of age. A. Mild hyperinflation; otherwise normal. Patient is now 32 years old and has been hospitalized once for treatment of electrolyte depletion. B . Diffuse peribronchial thickening, mild hyperinflation, and cystic changes in both upper lobes. The patient was hospitalized seven times for pulmonary exacerbations, once for diabetes, and once for hemoptysis. She died at age 34 following complications from lung transplantation. C . Severe hyperinflation, diffuse peribronchial thickening, multiple infiltrates, and increased pulmonary vascular markings and heart size. The patient died 1 month later from respiratory failure complicated by congestive heart failure.

tion of tracheobronchial secretions and recurrent infections progressively impair pulmonary function in almost all patients. In the fully developed clinical syndrome, all the pulmonary function abnormalities seen in chronic bronchitis, emphysema, and asthma may occur. However, one complicating regular feature of CF—bronchiectasis—modifies pulmonary performance. Chronic, local infection and airway damage increase the compliance of bronchiectatic airways, resulting in airway collapse during rapid expirations or cough. The usefulness of pulmonary function testing in CF is twofold: tracing the natural history of the disease and assessing the value of therapeutic interventions.

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asthma. Indeed, exaggerated bronchomotor responses in CF raise the possibility of superimposed asthma. In distinguishing between contributions to airway obstruction by intrinsic airway disease caused by CF and asthma, maximal expiratory flow-volume curves are sometimes helpful. Because of the bronchiolar locus of the early lesions in CF, abnormalities in breathing frequency–dependent tests (e.g., dynamic lung compliance), in volume-dependent tests (e.g., closing volume), and in maximal expiratory flow (VEmax ) at low lung volumes are demonstrable, even though results of tests of large-airway function (e.g., FEV1 and airway resistance) are still normal.

Figure 51-9 High-resolution chest computed tomography scan from a patient with CF. Marked bronchiectasis with peribronchial thickening is shown in the upper lobes.

The earliest stages of the pulmonary disorder are the most difficult to quantify. In infants, tests are limited almost entirely to those that do not depend on the patient’s understanding and cooperation. A variety of methods to measure infant pulmonary function have been devised; one method, the raised volume rapid thoracoabdominal compression technique, requires sedation of infants but provides values most similar to standard spirometric values, and has detected reduced pulmonary function in infants with CF. After age 6 years, pulmonary function tests originally designed for adults may be performed quite readily on children. Changes in pulmonary performance throughout the natural history of CF can be described with confidence. Obstruction in Small Airways The small airways—i.e., the bronchioles—are vulnerable to obstruction early in the course of CF. At this stage, as in cigarette smokers, results of tests for small-airway disease are apt to be abnormal, while those of tests for obstruction of large airways are still normal. Three factors interact in causing the obstruction: (1) intrinsic disease of the smaller airways, often in association with bronchiectasis in the proximal, larger airways; (2) viscid secretions, impaired ciliary action, and impaired cough; and (3) progressive decrease in lung elastic recoil. The progressive reduction in lung elastic recoil in CF is predominantly a function of overinflation due to intrinsic airway disease, rather than loss of pulmonary parenchyma. This mechanism differs from that in chronic bronchitis and emphysema, in which the combined effects of parenchymal destruction and overinflation are responsible for the decrease in elastic recoil. Emphysema is not a regular feature of CF. In some patients, emphysema occurs only late in the course of the disease (Fig. 51-4). Airway smooth-muscle tone increases only slightly in CF. Exercise elicits bronchodilation, followed shortly thereafter by bronchoconstriction. Both the bronchodilation and bronchoconstriction are far less impressive in CF than in

Change in Lung Volumes As with chronic bronchitis, emphysema, and asthma, RV in CF increases. Thereafter, an increase in functional residual capacity and, sometimes, in total lung capacity is seen. Later during the course of the disease, air-trapping occurs, manifest as an elevated ratio of RV to total lung capacity. This change decreases the compliance of the lung and increases the work of breathing. Abnormalities in Gas Exchange Early in the evolution of the pulmonary abnormalities in CF—i.e., when tests of small-airway function alone are abnormal—ventilation-perfusion abnormalities usually result in widening of the alveolar-arterial oxygen gradient and an increase in the ratio of dead space to tidal volume (VD /VT ). These abnormalities portend increasing inhomogeneities in alveolar ventilation and blood flow as the affected child grows to adulthood. The diffusing capacity for carbon monoxide (DlCO ) is low at rest and does not increase normally during exercise. This observation is difficult to reconcile with the preservation of the gas-exchanging surface of the lungs (in the absence of emphysema) until late in the course of the disease (Fig. 51-4). As obstructive disease of the airways progresses and exaggerates the imbalances between alveolar ventilation and blood flow, arterial hypoxemia develops; pulmonary hypertension, cor pulmonale, and right ventricular failure follow, in turn. Late in the course of the disease, hypercapnia and respiratory acidosis contribute to the final picture of respiratory failure. At this juncture, the ventilatory response to inhaled CO2 is depressed. Bouts of infection punctuate the course of the illness; during each episode, pulmonary function deteriorates, but it usually returns toward baseline, except in the preterminal stages of the disorder.

Sputum Culture The unique respiratory flora isolated from sputum cultures from patients with CF are helpful in establishing the diagnosis and in guiding the antimicrobial therapy for acute exacerbations. In many patients with CF, P. aeruginosa and S. aureus are found alone, or in combination with other organisms, in the sputum. Once present, the organisms, especially Pseudomonas, are rarely eradicated, despite use of intermittent or

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continuous antibiotics administered intravenously, orally, or by nebulization. Although these organisms are sometimes found in sputum cultures from patients with pulmonary diseases other than CF, their association with the disorder is so consistent that a dedicated attempt to obtain a sputum culture is an integral part of the evaluation of all patients, including infants and young children, suspected of having CF. Conversely, isolation of S. aureus or P. aeruginosa in sputum in a child or young adult should raise the suspicion of CF.

Pancreatic Function The evaluation of pancreatic function is an important part of establishing the diagnosis of CF, since almost 90 percent of patients have pancreatic insufficiency. In infants with pancreatic insufficiency due to CF, the most striking feature of the history and physical examination is often failure to thrive; the record of bowel movements may disclose only loose or frequent stools. In the older child, whose diet includes more fat and protein, a history of bulky, foul, malodorous stools is often easier to elicit. Documentation of malabsorption is best accomplished by collection of stools for 72 h while the patient is ingesting a known quantity of fat (approximately 100 g per day) and measurement of the stool fat content. A malabsorption coefficient of greater than 7 percent is usually considered abnormal; in patients with CF, the malabsorption coefficient often is around 20 to 30 percent. In infants and young children, the determination of trypsin or chymotrypsin activity in a properly collected stool specimen is an accurate way to determine the content of pancreatic enzymes. In older patients, however, trypsin or chymotrypsin activity in a stool sample may be artificially low because of a delayed transit time that causes partial inactivation of the enzyme. In some instances, a secretin stimulation test may be helpful in demonstrating pancreatic insufficiency. For this purpose, a triple-lumen tube is introduced into the duodenum. The response to secretin is usually abnormal: the volume of secretion is small, the fluid is viscid, and the bicarbonate ion concentration is low. This test is not often used in children because it is cumbersome to perform. More recently, determination of fecal elastase-1 in a stool sample has been described as an accurate, easily obtained screening test to classify patients with CF as pancreatic insufficient or pancreatic sufficient. For infants, the serum immunoreactive assay for trypsin is used in some centers as a screening test for pancreatic insufficiency. As a rule, serum levels of trypsin are abnormally high in CF, usually reflecting ongoing destruction of the pancreas. However, the assay does not provide an accurate measure of pancreatic function. Endocrine function of the pancreas is usually preserved in children, but approximately 50 percent of all adult patients are overtly diabetic by age 30 years.

Liver Function Evaluation of liver function is an important part of the evaluation of CF. In infants and children, the concentrations of

Cystic Fibrosis

bilirubin and transaminases in serum sometimes increase transiently. However, concentrations of these substances are usually normal, even in patients with mild or moderate focal biliary cirrhosis. The prothrombin time is sometimes prolonged, owing to a combination of malabsorption and decreased synthesis of clotting factors by the liver. Occasionally, patients present with bleeding esophageal varices from advanced cirrhosis; endoscopy and upper gastrointestinal contrast studies are often helpful in demonstrating the varices.

Semen Analysis Occasionally, a man who is found to have aspermia during the course of an evaluation for infertility is found to have CF. In men with CF, a complete semen analysis is part of the evaluation. Azoospermia is found in more than 98 percent of men with the disorder.

Mutation Analysis Numerous attempts have been made, with limited success, to characterize phenotype on the basis of genotype. In general, homozygotes for $F508 have pancreatic insufficiency; patients with CF who have pancreatic insufficiency tend to have a worse prognosis. Several mutations, including R117H, are associated with pancreatic sufficiency and a mild phenotype. However, a direct association of a particular genotype with progression of the pulmonary disease has not been found. An interesting genotype-phenotype correlation is the increased frequency of genotype R117H in males with congenital bilateral absence of the vas deferens (CBAVD). Males affected with this recessive disorder lack a vas deferens, but they are otherwise completely healthy and have normal sweat test results. Approximately 35 percent of chromosomes of patients with CBAVD carry a CF-associated mutation. To complicate this phenotype-genotype correlation further, 8 percent of patients with CBAVD without clinical CF have two CF-associated mutations. Genetic testing is not required to establish or confirm the diagnosis of CF when a compatible history and physical examination and abnormal sweat test results are found. Genetic testing is useful in identifying patients who have a compatible history and physical examination but whose sweat test results are negative. Certain alleles associated with CF (e.g., 3849 + 10kbC → T) are associated with nasal polyposis and bronchiectasis but normal sweat test results. The diagnosis of CF can be made with confidence in these patients. More problematic are persons with atypical presentations, normal sweat test results, and at least one CFassociated mutation. For example, mutations in at least one CFTR allele are associated with idiopathic chronic pancreatitis. More extensive genotyping should be attempted for all patients with a high clinical suspicion for CF (see “Genetics”) because mutation analyses may become clinically relevant if specific therapies depend on the types of mutations present (see “Genetics” and “Future Directions”). Patients with the same genotype may have dramatically different phenotypes, raising the possibility that modifier

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genes play an important role in determining the CF phenotype. Several potential candidate modifier genes are being evaluated for their impact on lung disease severity, including α1 -antitrypsin, HLA antigens, nitric oxide synthase, mannose-binding lectin, transforming growth factor β (TGFβ), tumor necrosis factor α (TNFα), and β2 -adrenergic receptor. Polymorphisms of TGFβ, have been associated with severe lung disease in a large, well-characterized cohort. Modifier genes may also affect function of other organs in CF; a modifier locus on chromosome 19 is associated with meconium ileus.

Median survival age

Part IV

30 20 10 0 1930 1940 1950 1960 1970 1980 1990 2000 2010

Calendar year

ATYPICAL CLINICAL PRESENTATIONS Atypical clinical presentations confound the diagnosis of CF in adults; a high index of suspicion is required to establish the diagnosis. Approximately 6 percent of all CF is diagnosed after age 18 years. Late presentations of CF tend to occur in persons with pancreatic sufficiency; indeed, overweight or well-nourished persons may have CF. Recovery of unusual gram-negative organisms, mucoid Pseudomonas species, or S. aureus from sputum of asthmatics with persistent sputum production, chest radiographic abnormalities, or clubbing should prompt referral for sweat testing. Recurrent sinusitis and nasal polyposis may be the only manifestations of CF in a mildly affected person. Isolation of P. aeruginosa from deep nasal cultures should raise the suspicion of CF. Frequently, the sinus findings on CT mimic fungal sinusitis, demonstrating concentric, inhomogeneous material. Occasionally, persistent inflammation produces bony destruction that is mistaken for previous surgical intervention. Sweat testing and referral to a CF center should be considered for men with azoospermia or CBAVD.

TREATMENT Intensive, comprehensive CF treatment programs designed to deal with particular symptoms, correct deficiencies, and prevent progression and complications of the disease have led to a dramatic increase in the median age of survival (Fig. 51-10). Although the value of comprehensive treatment is beyond question, far less certain are the utility of each component of the treatment plan and the level of each component necessary in a given patient. At present, the best approach still appears to be determination of the type and degree of abnormality in individual patients and design of a treatment program that will improve or maintain function of the organ systems affected. To ensure that the treatment regimen meets the needs of the individual patient, that necessary treatment is not omitted, or that side effects of prescribed treatments do not go unnoticed, it is often desirable to hospitalize the patient for diagnosis and evaluation. Hospitalization also provides an excellent opportunity for counseling the patient, parents, and

Figure 51-10 Median survival in patients with CF at various times since the first description of CF. Data before 1970 are gleaned from then-current literature. Data since 1985 are from CF Foundation Data Registry and represent projections of median survival age for a child born in that year with CF. (From Davis PB: Cystic fibrosis since 1938. Am J Respir Crit Care Med 173:474–482, 2006, with permission.)

family about the diverse aspects of the diagnosis, treatment, prognosis, and inheritance pattern of CF. Hospitalization provides the opportunity to monitor the response of individual patients to each component of the therapeutic program. An important aspect of the care of patients with CF is the network of more than 100 CF centers that exist throughout the United States and the larger network throughout the world. Most larger centers use a team approach to the care of patients. A CF care team usually includes physicians, nurses, respiratory therapists, physical therapists, nutritionists, social workers, and genetic counselors.

Management of the Pulmonary Disease More than 90 percent of the patients with CF die from respiratory failure or pulmonary complications. The goals of treating the pulmonary disorder in CF are to prevent and treat the complications of airway obstruction and infection. Although management of the pulmonary disorder consists of many components applied in combination, the individual components of therapy are discussed separately below. Chest Physiotherapy Almost all treatment programs for CF include a strategy intended to clear pulmonary secretions in order to prevent complications arising from airway plugging by viscous secretions. Chest physiotherapy—i.e., “percussion and postural drainage”—performed regularly, is the most widely prescribed method. In infants and young children, chest physiotherapy is generally performed routinely, twice daily. In addition to manual chest percussion and postural drainage, there are several other effective modalities for chest physiotherapy. These alternative measures include the high-frequency chestwall oscillatory vest; the flutter device, a small pipelike device that produces an oscillating resistance during a forced expiratory maneuver; the acapella device that produces both positive expiratory pressure and an oscillating resistance

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during forced expiratory maneuver; positive expiratory pressure mask; intrapulmonary percussive ventilation; autogenic drainage and active cycle of breathing; and exercise. Some form of physiotherapy that is effective in mucus clearance is required daily because without chest physiotherapy, pulmonary function deteriorates. At present, most CF centers recommend that all patients with CF attempt to maintain clearance of pulmonary secretions with a method that is applied regularly (e.g., twice daily). An additional recommendation is that chest physiotherapy be applied more often during an exacerbation of the chronic pulmonary infection. Unfortunately, the recommendation of chest physiotherapy on a regular basis—a time-consuming and often arduous form of treatment—is difficult to implement without considerable support and encouragement from family and health professionals. Antibiotics During the past few decades of treatment of CF, antibiotics have proved to be the key element responsible for increased survival. A reasonable approach balances the dangers of overzealous administration of antibiotics against progressive airway damage and bronchiectasis resulting from untreated infection. The approach is based on sputum culture at the time of diagnosis and at regular intervals thereafter. When signs and symptoms herald an exacerbation of pulmonary infection (i.e., increased cough or sputum production, dyspnea, decreased exercise tolerance, decreased appetite) or new abnormalities on the physical examination (i.e., increased respiratory rate, use of accessory muscles, changes on auscultation of the chest including decreased breath sounds, new crackles or wheezes, weight loss), new abnormalities on the chest radiograph, or a decline in pulmonary function tests, chest physiotherapy is increased and appropriate antibiotics are given orally, or for severe exacerbations, intravenously. Currently useful agents for treating staphylococcal infections include dicloxacillin, cephalexin, the newer cephalosporins, clavulanic acid combinations, and macrolides. Early in the course of the pulmonary disease, a small fraction of Pseudomonas strains may be sensitive to tetracycline, trimethoprim-sulfamethoxazole, or chloramphenicol. Occasionally, even Pseudomonas strains considered resistant according to laboratory sensitivity tests apparently respond to these antibiotics. A mechanism that has been proposed to account for this phenomenon is that even though the antibiotic is not bactericidal, it may inhibit either growth of the organism or its production of exotoxin and proteases. Ciprofloxacin, a quinolone derivative that can be given orally, is initially effective against many strains of Pseudomonas and has gained widespread use in the outpatient management of CF. A major disadvantage in its use is that resistance often develops after a few courses of treatment. For treatment of a severe pulmonary exacerbation of CF caused by methicillin-resistant Staphylococcus, vancomycin or linezolid are indicated. For Pseudomonas, a combination of an aminoglycoside given intravenously and a semisynthetic penicillin is generally used. This combination is presumed to

Cystic Fibrosis

act synergistically on Pseudomonas, and the Pseudomonas is less likely to become resistant to either antibiotic. The most popular antibiotic combination currently in use is tobramycin and ceftazidime. In order to achieve high levels of antibiotics in the airways and in secretions, the aminoglycoside is generally administered in higher doses. For example, tobramycin, 10 mg/kg per day in three divided doses, is given instead of 7.5 mg/kg per day in three divided doses. The resulting concentrations in serum are monitored. Instead of the usual therapeutic serum levels for tobramycin of 4 to 8 µg/ml, the goal in treating patients with CF is a serum level of 8 to 10 µg/ml; some centers advocate even higher levels. Serum antibiotic concentrations, renal function, and hearing acuity are monitored to avoid toxic reactions. The higher serum levels of 8 to 10 µg/ml do not seem to elicit greater toxicity than the usual levels. No advantage has been demonstrated for further increments in dosage. Some of the newer antibiotics—e.g., piperacillin, meropenem, and ceftazidime—are also quite effective against Pseudomonas. Although they may be effective at first when given alone, resistance often develops quickly. Usually, these agents are used in combination with an aminoglycoside. Because the sensitivity and resistance patterns of the Pseudomonas often change, various combinations are tried at different times, with clinicians relying on sensitivities from recent isolates to determine which is most effective for the particular strain of Pseudomonas. For other resistant gram-negative organisms, such as Burkholderia cepacia, Stenotrophomonas maltophilia, and Achromobacter xylosoxidans, other antibiotic combinations are indicated, including ceftazidime, meropenem, ciprofloxacin, minocycline, aztreonam, chloramphenicol, or trimethoprim/sulfamethoxazole Staphylococcus, Pseudomonas, and other gram-negative organisms, such as B. cepacia, A. xylosoxidans, and S. maltophilia, once found in the sputum, are rarely eradicated. However, most other manifestations of an exacerbation of pulmonary disease abate during a 2-week course of antibiotics administered intravenously; for example, the densities seen on the chest radiograph decrease, the white blood cell count decreases, fever and respiratory rate decrease, and pulmonary function test results, which often deteriorate at the start of an exacerbation, return to their previous baseline. Although many patients begin to show improvement after 5 to 7 days, most CF centers continue antibiotics intravenously for at least 2 weeks in order to decrease the relapse rate and to avoid a decrease in the interval between exacerbations. Indeed, some centers routinely recommend a 3- to 4-week course of intravenous antibiotics to treat an exacerbation of a pulmonary infection. In the occasional hospitalized patient who experiences a relapse or manifests an increase in symptoms shortly after administration of intravenous antibiotics is stopped, long-term intravenous administration of an aminoglycoside can be continued with use of a heparin lock. This technique may be helpful in allowing the patient to return home while still receiving effective doses of aminoglycosides. Another approach that has been advocated is administration of antibiotics by inhalation—the rationale of which

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is to increase antibiotic concentrations in airways infected by Pseudomonas. Although it has been argued that inhalation will not deliver effective concentrations to diseased portions of the lungs because of interference with ventilation by local airway obstruction, inhaled antibiotics appear to be helpful in some instances. Inhaled, preservative-free tobramycin, 300 mg twice daily for 28 days on and 28 days off (cycling therapy), improved pulmonary function (FEV1 increased by 10 percent) at the end of the third treatment cycle (20 weeks) compared to placebo. One concern about inhaled tobramycin as a chronic therapy is the risk of bacterial resistance. In addition, questions regarding selection of patients and timing and duration of treatment remain unanswered. Another antibiotic which has been studied as a chronic therapy in CF is azithromycin. Azithromycin, 250 mg or 500 mg thrice weekly, was evaluated in CF patients colonized with P. aeruginosa. After 6 months of therapy, patients on azithromycin had a modest improvement in FEV1 (6.2 percent), increased weight gain, and decreased rates of pulmonary exacerbations. However, the same issues are raised for chronic azithromycin therapy as were raised for chronic inhaled tobramycin: the long-term issues of benefit, risk of antibiotic resistance, and cost. Mist and Mucolytics Mist therapy, delivered by having the patient sleep in a mist tent or through intermittent inhalation of an aerosol, was a common form of treatment of CF several decades ago. The goal was to â&#x20AC;&#x153;liquefyâ&#x20AC;? respiratory secretions. However, the treatment could not be demonstrated to be helpful, and the use of mist tents has been discontinued. Intermittent aerosols are still used to deliver bronchodilators and mucolytics. A number of mucolytic agents have been tried over the years. One that has endured is N-acetylcysteine. In the test tube, this agent is quite effective in dissolving mucin components and in decreasing the viscosity of sputum from patients with CF. Although some centers have found this agent to be a useful adjunct to therapy in CF, others have encountered an inordinate frequency of complicating bronchospasm or tracheitis. Some difficulties noted in the past can now be attributed to the use of a 20 percent (undiluted) solution of N-acetylcysteine, which can be irritating because of its extremely high osmolarity. The incidence of side effects may be decreased greatly by use of a 5 percent solution; during an exacerbation, when cough and sputum production increase, the 5 percent solution is inhaled two or three times per day, before chest physiotherapy. Should the patient develop bronchospasm, demonstrated by physical examination or by pulmonary function testing, a bronchodilator is used. If successful, the bronchodilator and the N-acetylcysteine are administered jointly by inhalation. However, should the bronchospasm persist despite use of the bronchodilator, N-acetylcysteine is not administered. In 1994, Pulmozyme, a DNA-cleaving enzyme, was approved for use in patients with CF following a large phase III multicenter trial. More than 900 patients were enrolled for

a 6-month period. Three dosing regimens were employed: placebo, 2.5 mg inhaled once daily, and 2.5 mg inhaled twice daily. The treatment groups showed a 5 percent improvement in FEV1 over placebo, as well as a slightly lower relative risk of exacerbation of lower respiratory tract infection after 6 months. There was no difference between the onceand twice-daily treatment groups. A second study revealed that Pulmozyme, inhaled once daily over 96 weeks, maintained pulmonary function and decreased the relative risk of respiratory tract exacerbations in young CF patients with normal FEV1 (â&#x2030;Ľ85 percent). Currently, this drug is in fairly widespread use for CF. However, questions regarding patient selection and timing and duration of use of this expensive drug remain unanswered. Inhaled therapy with hypertonic saline was recently evaluated in CF. Patients inhaled 7 percent hypertonic saline twice daily following a bronchodilator for 48 weeks; results revealed only a modest improvement in FEV1 , but a significant reduction in the number of pulmonary exacerbations and days lost from school or work. It remains to be established how this therapy will fit into the maintenance therapy program for CF patients. Bronchodilators and Anti-Inflammatory Agents Bronchodilators are often used in treating the pulmonary manifestations of CF. Their use should be individualized. For example, in many patients, bronchospasm that is reversible with bronchodilators at one point in the course of the illness may prove refractory a short time later. Some patients undergo deterioration in pulmonary function following use of bronchodilators. In infants who are audibly wheezing, a bronchodilator can be tried. In older patients, pulmonary function testing provides a more objective and quantitative measure of bronchodilator effectiveness. Corticosteroids have been used with good results in infants with severe obstructive airway disease that does not respond to antibiotics and bronchodilators and in patients with CF in whom the pulmonary disease is complicated by severe asthma or allergic bronchopulmonary aspergillosis. Preliminary observations initially suggested that patients with CF would benefit from long-term administration of alternateday corticosteroids, based on the presumption that corticosteroids would decrease the airway inflammatory response. However, in a large, placebo-controlled, multicenter trial of alternate-day corticosteroids administered in two dosage regimens (1 mg/kg and 2 mg/kg), the development of many side effects precluded a general recommendation for long-term corticosteroid treatment in CF. Subgroup analysis led to the suggestion that patients with moderately severe obstructive airway disease and those with chronic Pseudomonas infection might benefit from treatment for periods of less than 1 year. Beneficial effects were sufficient to prompt further studies of anti-inflammatory agents in CF. A controlled 4-year trial of high doses of ibuprofen in 40 patients with CF showed improvement in the rate of decline of pulmonary function in children. Questions remain whether side effects that might

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accrue with continued therapy will justify the gains. In concert, these two studies suggest that future development of a lung-specific anti-inflammatory agent with fewer systemic side effects may offer a promising approach.

Nutritional Support Patients with CF require careful evaluation to determine if partial or complete pancreatic insufficiency is present and to design a nutritional program to correct any deficiencies. The mainstay in managing the pancreatic insufficiency of CF is use of pancreatic enzyme preparations currently available in the form of enteric-coated capsules containing coated microspheres. These pancreatic enzymes are ingested along with any food that contains protein, fat, or complex carbohydrates. The dosage is adjusted to ensure a relatively normal pattern of bowel movements, adequate weight gain or maintenance of ideal weight for height, and a decrease in bowel symptoms, such as cramping and flatulence. The development of colonic strictures was first noted following the introduction of pancreatic enzymes with lipase contents of 25,000 units per capsule. Capsules with more than 20,000 units are no longer available. Subsequent recommendations urge caution in prescribing high total doses of lipase with any preparation; recommendations are to limit use to less than 2500 units/kg per meal. Since strictures have apparently developed in several patients using doses as low as 6000 units/kg per meal, it has been recommended that for patients who require higher doses to maintain nutritional status or to control bowel symptoms, the enzyme requirement be documented by measuring the coefficient of fat absorption and other causes pursued to account for symptoms. As a rule, patients with CF are advised to consume a double dose of a multivitamin preparation and a vitamin E supplement each day. Infants, those in whom the prothrombin time is prolonged, and those who take antibiotics uninterruptedly require supplemental vitamin K. Vitamin A supplementation is required in children with significant fat malabsorption and failure to thrive; however, care must be taken to avoid hypervitaminosis A. Supplemental salt is needed by patients in order to prevent electrolyte depletion, metabolic alkalosis, and heat prostration. For infants, 1 to 2 g of salt per day is added to the feeding formula; children and adults are encouraged to salt their foods liberally and to take salt-containing liquids and snacks during hot weather. Although it is true that pulmonary function is the predominant factor in determining morbidity and mortality in CF, it is becoming increasingly clear that overall patient status is closely tied to nutritional status. Importantly, achieving and maintaining normal weight for age and height for age are closely associated with maintenance of lung function in young children and adults. Data from the national 2004 CF Registry indicate that 15.7 percent of CF patients are below the fifth percentile of weight for age and that mortality is increased in this group. Despite use of pancreatic enzyme replacement, the correction of pancreatic insufficiency is incomplete; accordingly,

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patients require more than 100 percent of recommended caloric intake. In some, an even greater caloric intake is necessary because of increased energy expenditure due to increased work of breathing secondary to chronic pulmonary infection. Aggressive nutritional supplementation, using either oral supplements or nocturnal nasogastric feeding of hydrolyzed formulas, has been helpful in the short term in promoting weight gain at this stage of disease. Hyperalimentation is occasionally required in infants with meconium ileus and in other special circumstances.

NATURAL HISTORY AND PROGNOSIS A comprehensive treatment program for CF has unequivocally improved overall survival of patients. Thirty years ago, the median survival was only a few years of age; currently, it is about 35 years (Fig. 51-10). However, because CF is a complex disorder that affects different organs to different degrees, it is difficult to describe a â&#x20AC;&#x153;typical courseâ&#x20AC;? for a patient with CF. Some patients die in childhood or adolescence, while others survive beyond age 40 years. An important determinant of the natural history of CF is the severity of the pulmonary disease and the rate at which it progresses. Although most patientsâ&#x20AC;&#x2122; condition improves in response to therapy, skillful management does less to influence the course of the severely affected than that of the mildly affected patient. A variety of scoring systems have been devised for CF. The clinical scoring system devised by Shwachman and Kulczycki and the chest radiograph scoring system devised by Brasfield and associates are widely used. However, although these and more elaborate scoring systems are useful in categorizing patients according to the severity of illness, none has proved useful in prognosticating the course of an individual patient. Because CF is a genetic disease, the question of a familial pattern of severity is often raised. Figure 51-8 shows chest radiographs of three siblings with CF; the radiographs demonstrate mild, moderate, and severe disease in individuals in the same family. The capsule histories, which are included in the figure legend, also illustrate the variability in courses experienced. Patients with CF can be categorized not only with respect to severity of illness, but also with regard to survival. For example, more than half of patients with CF who underwent surgery for meconium ileus before 1965 died in the first 2 months of life. Although this situation had improved markedly by 1976, the survival rate for patients with meconium ileus was still not as good as for all other patients with CF. In addition, the survival rate was much lower for females than for males, especially in adolescents. In recent years, differences between the patients in these groups have declined or disappeared. Because of improvements in the collection of mortality statistics, comparison of current data with those from previous years may be somewhat misleading, but

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Table 51-3 Hypoelectrolytemia and Metabolic Alkalosis in Two Cystic Fibrosis Patients

molar enema, surgery is required. Careful pre- and postoperative management is essential to avoid the deterioration in pulmonary function that may follow the use of anesthesia.

Liver Disease

Hypoelectrolytemia and metabolic alkalosis are serious complications that are especially apt to occur during periods of hot weather, when losses of sodium and chloride increase. Electrolyte depletion may be life-threatening, especially in infants and young children (Table 51-3). Prompt fluid replacement with isotonic saline is critical.

Cholestasis is often asymptomatic and detected by elevated serum alkaline phosphatase and transaminases on routine yearly studies. To prevent the progression to fibrosis and cirrhosis, treatment with the hydrophilic bile acid, ursodeoxycholic acid, should be initiated. Persistent hepatomegaly or splenomegaly, persistently elevated transaminases, or complications of portal hypertension establish significant liver involvement. Although cirrhosis occurs in fewer than 5 percent of people with CF, esophageal varices and portal hypertension may cause upper gastrointestinal bleeding in these patients. Once bleeding has been identified as due to varices and hemoptysis has been excluded, therapeutic endoscopy with a sclerosing agent or band ligation is undertaken. For patients with severe involvement, transjugular intrahepatic portosystemic shunting or surgical portosystemic shunts can effectively decompress esophageal varices by decreasing portal pressure. Liver transplantation is another option for many patients with CF who have end-stage liver disease. Bleeding esophageal varices or vitamin Kâ&#x20AC;&#x201C;resistant prolongation of the prothrombin time should prompt evaluation for liver transplantation. Criteria for priority transplantation include bleeding varices not responsive to sclerosis, severe ascites, and encephalopathy. Ideal candidates are those with an FEV1 of at least 50 percent of predicted. Colonization with a multidrugresistant or panresistant strain of Pseudomonas is a relative contraindication to transplantation. In patients in whom poor pulmonary function or drug-resistant pulmonary infection is an issue, double organ (liver and lung) transplantation may be considered. However, this surgery has been successfully accomplished only several times to date. Despite concerns about worsening airway infection during transplantassociated immunosuppression, liver transplantation in patients with CF does not worsen their pulmonary status.

Intestinal Obstruction

Atelectasis

Acute or chronic crampy abdominal pain attributable to some degree of intestinal obstruction is common in patients with CF. If the obstruction is incomplete and manifested solely by a tender right lower-quadrant mass, medical therapy using oral N-acetylcysteine and mineral oil, GoLytely, or MiraLax is recommended. If these measures are unsuccessful, hyperosmolar enemas using an agent such as methylglucamine diatrizoate (Gastrografin) may dislodge the fecal mass. Patients with a history of crampy abdominal pain are occasionally noted to have radiographic evidence of intestinal obstruction, manifested by dilated bowel loops and air-fluid levels. After the neonatal period, intestinal obstruction is referred to as meconium ileus equivalent. An impacted fecal mass may serve as the leading edge for a volvulus or intussusception (Fig. 51-6). If either of these is present and not resolved with hyperos-

Atelectasis of a lung segment or lobe sometimes occurs in CF. Acute atelectasis is generally associated with few symptoms (Fig. 51-11A). If it is untreated, however, the end result of atelectasis is a severely bronchiectatic segment or lobe (Fig. 51-11B). Vigorous chest physiotherapy, in conjunction with antibiotics, is often successful in reexpanding the affected lung region. Bronchoscopy is occasionally helpful. As a rule, however, bronchoscopy is no more effective than chest physiotherapy and pulmonary pharmacotherapy. Resection of a persistently atelectatic or bronchiectatic lobe is undertaken only when the remaining areas of the lung are in relatively good condition, overall pulmonary function is good, and the evidence convincing that the affected segment is responsible for intolerable symptoms (fever, cough, or sputum production).

Serum Electrolytes, mEq/L Patient

CO2

Serum pH

No. 1 No. 2

123 125

2.2 2.4

49 55

48 41

7.60 7.63

source: Modified from Scanlin TF: Cystic fibrosis, in Fleisher G, Ludwig S (eds), Textbook of Emergency Pediatrics. Baltimore, Williams & Wilkins, 1983, pp 532â&#x20AC;&#x201C;556, with permission.

50 percent-survival age has not been increasing as rapidly in recent years as in the 1970s and 1980s (Fig. 51-10). Furthermore, there is a difference in outcomes among individual CF centers.

COMPLICATIONS The course of CF is often characterized by a gradual decrease in pulmonary function, punctuated by further abrupt declines during exacerbations. Malnutrition, when present despite therapy, usually correlates best with the severity of the pulmonary disease. However, the course of CF may be suddenly altered by certain complications of the disease.

Hypoelectrolytemia and Metabolic Alkalosis

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Cystic Fibrosis

Figure 51-11 Chest radiographs of patients with pulmonary complications of CF. A. Atelectasis of the right upper lobe in a 4-month-old boy. The atelectasis resolved with antibiotics and chest physiotherapy. B . The same patient at 9 years of age with mild hyperinflation, central bronchiectasis, resolving right upper lobe infiltrate. The diagnosis of allergic bronchopulmonary aspergillosis was made, and the patient improved after treatment with prednisone. C . Pneumothorax of the right lung (arrows) in a 13-year-old boy. The pneumothorax resolved after tube thoracostomy and tetracycline sclerosis. The patient died 3 years later from respiratory failure with congestive heart failure. There were no recurrences of the pneumothorax. D and E . A 43-year-old man showing hyperinflation and diffuse peribronchial thickening. The radiograph was taken during an episode of significant hemoptysis, and no acute changes were seen on the radiograph. He works full-time and has not had another episode of hemoptysis in the last 12 years.

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Pneumothorax Recurrent pneumothorax is common in CF, particularly in older patients (Fig. 51-11C ). Tension pneumothorax occurs in up to 30 percent of patients with CF who develop pneumothorax. Tube thoracostomy is indicated when the pneumothorax occupies more than 10 percent of the area of the hemithorax seen on the posteroanterior chest radiograph. Because the frequency of recurrence of pneumothorax is high, attempts are often made at the time of the initial event to achieve chemical or surgical pleurodesis. Surgical pleurodesis is more effective at preventing recurrence of a pneumothorax and is no longer considered a contraindication to lung transplantation.

Hemoptysis Expectoration of a small amount of blood-streaked sputum is a fairly common occurrence in CF and is generally managed by intensifying home therapy for pulmonary infection. In contrast, hemoptysis (the expectoration of at least 30 to 60 ml of fresh blood) requires hospitalization, even with a chest radiograph that is virtually unchanged (Fig. 51-11D). The probable mechanism underlying most instances of hemoptysis in CF is the erosion of an area of localized infection into a bronchial vessel. Massive hemoptysis (blood loss of 300 to 2500 ml) is uncommon in CF. However, it represents a potentially life-threatening situation. Bronchoscopy, and sometimes thoracic surgery, may be required to control the hemorrhage. Bronchial artery embolization has been used successfully in patients with CF and is now the treatment of choice when a physician experienced in the procedure is available.

Infection with Unusual Organisms CF produces central bronchiectasis, even though the disease initially is in the small bronchioles. Bronchiectatic airways are frequently colonized with unusual organisms, including Aspergillus and atypical mycobacteria. As is the case with pathogenic bacteria, eradication of these organisms from the airways is virtually impossible. The focus of therapy is directed toward verifying that the organisms are resulting in worsening of the disease and controlling the infection, rather than effecting a microbiologic cure. Mycobacteria The prevalence of infection with mycobacteria in CF is approximately 12 to 15 percent. Frequently, the sputum culture is overgrown with pathogenic bacteria; accordingly, the culture should be handled specially to enhance isolation. Patients with CF should be screened for Mycobacterium tuberculosis infection with yearly PPD skin tests. Prophylaxis and treatment of M. tuberculosis in CF are the same as for patients without CF. A decision about therapy for isolation of atypical mycobacteria is based on the likelihood that the organism is contributing to airway infection and a decline in pulmonary function. Isolation of the same organism on several occa-

sions, positive smears, presence of progressive chest radiographic changes, further decline in pulmonary status despite vigorous antipseudomonal (or antistaphylococcal) therapy, persistent night sweats, and fever are clinical clues that the atypical mycobacteria are contributing to disease. Demonstration of tissue infection with transbronchial lung biopsy is rarely recommended. A clinical database has been established by the CF Foundation to track results of treatment for atypical mycobacterial infections in patients with CF. Aspergillus In an analogous fashion, molds, especially Aspergillus, are occasionally isolated from patients with CF. Approximately 5 to 15 percent of patients have allergic bronchopulmonary aspergillosis (ABPA). The diagnosis of ABPA in CF is difficult because of overlapping symptoms between the two disorders. Diagnostic criteria for ABPA are (1) reversible airway obstruction, (2) proximal bronchiectasis, (3) history of pulmonary infiltrates, (4) skin test positivity to aspergillus antigens, (5) precipitating serum antibodies to A. fumigatus, (6) elevated total serum immunoglobulin E (IgE), (7) elevated specific serum IgE and serum immunoglobin G (IgG) to Aspergillus, and (8) peripheral eosinophilia. A negative skin test for Aspergillus effectively rules out the diagnosis of ABPA. During the active phase of ABPA, elevations in total IgE and eosinophil count are seen. Rises in Aspergillus-specific titers (IgE and IgG) are more specific for ABPA than are serum precipitins. ABPA in patients with CF is treated with corticosteroids and itraconazole. Gram-Negative Bacteria In the late 1970s and early 1980s, the importance of Burkholderia cepacia (formerly Pseudomonas cepacia) was recognized. B. cepacia is a gram-negative, oxidase-positive rod that is uniformly resistant to polymyxin and, frequently, panresistant. Isolation of B. cepacia requires plating on special OFPBL (oxidative fermentive polymyxin B bacitracin lactose) or PC (P. cepacia) agar plates to retard growth of other gramnegative rods and enhance growth of B. cepacia. The plates must be maintained for a minimum of 4 days. B. cepacia colonization has been associated with septicemia, which is very rarely seen with P. aeruginosa. The clinical course after acquisition of B. cepacia may be fulminant, with death occurring in a matter of months. However, most patientsâ&#x20AC;&#x2122; disease follows a more benign course. Carefully controlled epidemiologic studies are needed to better define risk factors and to establish the true virulence of B. cepacia. Experimental evidence exists that at least one strain of B. cepacia may be transmitted in an epidemic fashion. The combination of a poor clinical course after acquisition of B. cepacia and the evidence supporting epidemic transmission has led to cohorting or isolation of patients with CF infected with B. cepacia, as recommended by the CF Foundation and the Centers for Disease Control (CDC). In addition to being colonized with Pseudomonas and Burkholderia species, patients with CF may be colonized with

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other gram-negative, oxidase-positive organisms, such as S. maltophilia, Pseudomonas oryzihabitans, and A. xylosoxidans. These are pathogenic organisms, similar in importance to P. aeruginosa. Antibiotic therapy should be directed toward these bacteria when they are isolated from the patient with CF who is experiencing an acute exacerbation. The prolonged, prophylactic, aggressive use of antibiotics in CF has led to emergence of resistant organisms. A multiply resistant Pseudomonas is an organism that is resistant to all agents in at least two different classes of antibiotics. Resistance to oral fluoroquinolones occurs after about 3 weeks of therapy; if the agent is withheld, the organism occasionally becomes sensitive again.

Respiratory Failure As the pulmonary disease of CF progresses and the degree of hypoxia increases, patients are at risk to develop pulmonary hypertension and cor pulmonale. An increase in hypoxia often occurs during exacerbations of the pulmonary disease. During the acute episode, antibiotic treatment for the underlying pulmonary disorder is intensified and supplemental oxygen is added. Expectant monitoring and aggressive treatment of nocturnal hypoxemia (maintaining SaO2 â&#x2030;Ľ 95 percent) prevent the onset of cor pulmonale. When respiratory failure develops in CFâ&#x20AC;&#x201D;i.e., hypercarbia (PaCO2 at least 55 mmHg) in addition to hypoxemiaâ&#x20AC;&#x201D;management becomes extremely difficult. Noninvasive mechanical ventilation using bilevel positive airway pressure has been used successfully in patients with end-stage CF awaiting lung transplant; it improved oxygenation, reduced respiratory rate, and was successfully transitioned to home nocturnal use. Mechanical ventilation is generally instituted when an acute episode, such as viral pneumonia or status asthmaticus, thrusts the patient into acute respiratory failure. This approach is particularly indicated in the patient who has had good pulmonary function before the acute episode. Mechanical ventilation is less apt to be successful if the patient has previously experienced a bout of respiratory failure. When respiratory failure marks the end of a chronic course of progressive pulmonary insufficiency despite adequate medical therapy, mechanical ventilation is usually unhelpful. None of the indications or contraindications for mechanical ventilation are absolute, however, and the clinical outcome depends, to a large extent, on the availability of a dedicated and skilled intensive care team experienced in caring for patients with CF.

Complications Related to Lung Transplantation Lung transplantation has emerged as an option for patients with end-stage CF. Despite initial concerns about immunosuppression in patients with suppurative lung disease, the outcome for those with CF who undergo lung transplantation is among the best reported for this procedure. Two major problems prevent lung transplantation from becoming widely recommended for CF. One is the lack of suitable organs for

Cystic Fibrosis

transplantation. Forty percent of patients with CF who are awaiting transplantation die before an organ is made available. The attrition is due, in part, to the allocation of lungs on the basis of wait-list time alone, rather than on the basis of severity of disease; this practice has changed to permit the most severely ill patients access to transplant. The median waiting time is currently more than 12 months, but wide variability exists. The organ shortage, especially from pediatric donors, has driven the development of living related-donor transplants. The second major problem with lung transplantation for CF is the occurrence of obliterative bronchiolitis following transplantation. Obliterative bronchiolitis is a progressive occlusion of the bronchiolar lumina by inflammatory cells and submucosal fibrosis. The cause is probably chronic allograft rejection; transient improvement in airflow is seen following augmentation of immunosuppression. About 50 percent of transplant patients develop obliterative bronchiolitis after the second year following the procedure. The disease pursues a relentless downhill course, with a median survival of about 2 years following the initial diagnosis. The poor prognosis associated with obliterative bronchiolitis has several important implications for patient selection and timing of referral for transplantation. First, the main reason for seeking lung transplant is to improve the quality of life, rather than to improve survival. Second, the timing of referral for lung transplantation necessitates weighing the risks of dying while on the waiting list against the possibility of developing obliterative bronchiolitis. Appropriately timed referral for transplantation includes consideration of (1) the average length of waiting time, (2) the natural history of the disease, (3) the natural history of lung transplantation, and (4) the requirement that the patient be fully ambulatory. Therefore, ideal candidates for lung transplantation are those who have less than 2 years to live and have significant functional impairment but are capable of participating in a pulmonary rehabilitation program. Results from clinical studies may aid with proper timing of referral for lung transplantation in CF. A study of 673 patients with CF revealed that patients with an FEV1 less than 30 percent of predicted have a 50 percent 2-year mortality. Other important clinical parameters useful in determining the timing of transplantation are the presence of hypoxemia (Pao2 under 55) and hypercarbia (PaCO2 above 50). Of interest, in both single and multivariate analyses, female gender is associated with an increased relative risk, suggesting that for female patients, referral for lung transplantation should be considered at an even earlier stage. Because CF is a multisystem disorder, both management and proper selection of patients are more complicated than for other diseases managed with lung transplantation. Among the most difficult challenges presented by patients with CF before transplantation is the microbiology of their lower airways. As discussed previously, colonization with multidrug-resistant B. cepacia, specifically the genotype, genomovar III, has been associated with a poor clinical outcome. For poorly understood reasons, patients with CF

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100

Survival (%)

75 50 25 0 0

Years

Figure 51-12 Kaplan-Meier survival for CF adult lung transplantation recipients (n = 1934) performed between January 1994 and June 2003. The CF lung transplant recipients had better survival outcomes than patients transplanted for idiopathic pulmonary fibrosis or primary pulmonary hypertension. (From Trulock EP, Edwards LB, Taylor DO, et al: Scientific registry of the International Society for Heart and Lung transplantation: Twenty-second official adult lung and heart-lung transplant report 2005. J Heart Lung Transplant 24:956â&#x20AC;&#x201C;967, 2005.)

metabolize drugs differently from those without CF, complicating the dosing of medications, including cyclosporine. The difficulties in achieving an optimal drug dose may be related to malabsorption or enhanced excretion of the drug. Nutritional issues also complicate the posttransplantation management of patients with CF. About 50 percent of all patients with CF over 30 years of age are overtly diabetic, and administration of corticosteroids induces diabetes in another 10 percent. Maintenance of proper nutrition is important in CF, especially for rapid postoperative recovery. Finally, gastroesophageal reflux may negatively impact pulmonary outcomes following transplantation. Despite all the special challenges to successful lung transplantation posed by patients with CF, their actuarial survival is quite good (Fig. 51-12). The 5-year survival is about 59 percent, reinforcing the tenet that lung transplantation is done principally to improve quality of life.

PSYCHOSOCIAL ISSUES A number of psychosocial issues are important in the management of patients with CF. Special circumstances should be recognized for adults with the disorder.

General Careful attention to the emotional, social, and financial wellbeing of the patient with CF and his or her family has considerable value in favorably influencing the course of the disease. At the time of diagnosis, it is important to strike an optimistic note while educating the patient about the illness and its management. As part of the early encounter with the patient, the importance of identifying and reinforcing the emotional and financial strengths of the family, as well as weaknesses that

will need buttressing, should be recognized. Medical care for CF patients is costly, especially if hospital admissions are required. Many states have programs for children with disabilities that provide support for patients and families. Several states have also established special programs for adults with CF. As the disease runs its course, counseling and feedback about disease progression are essential. As the patient and family go about setting educational, career, and family goals, they need guidance in realistic planning. It is vital that the physician develop and maintain a positive attitude. The patient who gives up hope is liable to undergo rapid deterioration. Conversely, even patients with severe pulmonary disease can continue to function well and be productive. At the stage when medical therapy is of no further avail, however, the patient and family require considerable emotional support to accept the inevitable. In recent years, many CF centers have allowed patients to die at home, rather than in the hospital. The family requires specific instructions about how to provide physical and emotional comfort for the patient in the home. Usually, home visits by some members of the CF team are required. Not all families have the strength or resources to care for the patient dying at home.

Special Considerations in Adult Patients In 2004, the median life expectancy for patients with CF was about 35 years. Managing a chronic illness becomes more complicated when patients must also begin to manage their independence and make life decisions regarding education, marriage, children, careers, insurance, and self-care. Intense support for both patients and their families is required. Patients with a relatively mild clinical course of disease form healthy and satisfying relationships in a manner similar to that of their healthy, age-matched peers. With advanced disease, patients with CF have more difficulty in forming intimate relationships. Disturbances in body image, decreased mobility, and lack of opportunity to meet suitable partners are cited as reasons for the decreased ability to form intimate relationships in the severely affected young adult with CF. The adult patient with CF faces unique problems with self-care. Families of patients with CF provide a tremendous amount of care that is expensive and time-consuming to replace for the independently living adult. When the disease flares, patients must â&#x20AC;&#x153;step upâ&#x20AC;? their level of care at precisely the time when they are least able to do so. Judicious use of hospitalization and home care must be provided if the patient is to recover. The trend toward home management of a pulmonary exacerbation using intravenous antibiotics alone ignores the obvious contributions of nutrition, airway clearance, and rest toward resolution of the problem.

REPRODUCTIVE ISSUES More than 98 percent of male patients with CF are sterile, secondary to bilateral absence of the vas deferens. Microsurgical

883 Chapter 51

epididymal sperm aspiration (MESA), coupled with in vitro fertilization, has been successful in producing pregnancies in a few carefully selected patients. Not all males with CF are sterile, however. In addition to counseling, these men should be offered semen analysis. Pregnancy for women with CF is increasingly common, and several important issues remain unsolved. In 2004, 191 women with CF were pregnant. This stands in marked contrast to the total of 13 pregnancies in 10 patients recorded from 1960 to 1966 (data from the 1994 CF Foundation Data Registry). Maternal clinical status before pregnancy is the most important prognostic factor of maternal outcome. In a study of 25 women with 38 pregnancies, no significant difference was seen between pre- and postgravid gas exchange or nutritional status. A small but statistically significant decline in spirometry was noted. However, the decline was not outside the range of expected decline for the natural progression of the disease. More severely affected women suffer an irreversible decline in clinical status during pregnancy. Without an appropriately matched control group of nongravid women with CF, it is impossible to determine whether pregnancy per se is responsible for the decline or whether the decline is a reflection of the natural history of the disease. Recommendations about pregnancy for women who are either mildly affected or severely affected is straightforward. For the woman with moderately compromised pulmonary status (i.e., FVC under 50 to 60 percent of predicted), an overall assessment of the clinical situation is recommended, although no firm guidelines can be given. Increased incidence of fetal prematurity is noted in women with a pregravid FVC below 50 percent of predicted, lending additional weight against recommending pregnancy to women with moderate to severe airflow obstruction. In any woman with CF who is contemplating pregnancy, thorough evaluation and treatment of nutritional deficiencies and pulmonary exacerbations are required. Frequent use of antibiotics is unavoidable, and the teratogenic risk of many antibiotics is unknown. Despite this theoretical risk, good maternal and fetal health depend on aggressive management of pulmonary exacerbations, including use of antibiotics. Management of the gravid patient with CF is best accomplished in a CF center that has a program in high-risk obstetrics. For men with CF who opt for MESA and for women with CF who are contemplating pregnancy, all offspring are obligate heterozygotes for CF. These offspring need to be counseled that their risk of having a child with CF is about 1 in 50 if the genotype of the spouse is not known. Although genetic testing of children from affected parents is not recommended, they should receive genetic counseling on reaching adolescence. Parents with CF also need to consider the ethical issues of a premature parental death and its effect on the family. Discovery of the CF gene in 1989 led to the hope that prenatal diagnosis would eventually decrease the incidence of the disease. However, affected families either are choosing not to test at-risk pregnancies or, if tested and found to be

Cystic Fibrosis

affected, are choosing to continue the pregnancy. Similarly, there has not been a large increase in the number of therapeutic abortions of fetuses with CF among women with the disorder who have a good clinical status. Obviously, the expected survival and quality of life for the child with CF must be sufficiently promising to explain these parentsâ&#x20AC;&#x2122; decisions.

FUTURE DIRECTIONS Concern exists that the marked improvement in survival of patients with CF noted over the past two decades is approaching a plateau. To further enhance survival in CF, physicians must look to insights gained from basic research. Although much work needs to be done, much has already been accomplished, warranting a realistic expectation that major breakthroughs will soon occur in the treatment of the disorder. Important areas for future development include new pharmacologic approaches and gene therapy.

Pharmacologic Approaches Infection with Pseudomonas organisms is a critical aspect of CF that has attracted a great deal of attention. To date, Pseudomonas species have demonstrated a remarkable capacity to change expression of phenotype and to develop resistance to new antibiotics. One management strategy that is being employed more frequently is performance of synergy testing on isolates of Pseudomonas that are resistant to multiple antibiotics. Frequently, such testing directs the use of nontraditional combinations and doses of antibiotics with good therapeutic results. However, this strategy may be successful for only a limited period before panresistance develops. Pharmacologic approaches to the basic defect in CF may offer treatment alternatives or additional benefit to the anticipated use of directed gene therapy (see below). As described earlier, many of the mutations in CF have been classified into five categories, depending on the functional consequences of the mutation on the gene product, which is an integral membrane glycoprotein. A CFTR mutation in the first category with a premature stop codon, G542X, can be activated by treating patients with intravenous gentamicin; this approach produced changes in nasal potential difference consistent with some improvement in chloride efflux. The most common mutation, $F508, is a class II or processing mutation in which most of the gene product remains in the endoplasmic reticulum, with only a very small amount localized to the surface membrane prior to degradation. Since CFTR has been shown to interact with several chaperones during processing, these molecules provide an attractive theoretical target for pharmacologic intervention, although, to date, there has been no functional correction with this approach. However, two agents, 4-phenylbutyric acid and glycerol, have been shown to increase cell surface localization of CFTR in vitro by an unknown mechanism. Since analogs

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of 4-phenylbutyric acid have been employed clinically in treatment of sickle cell disease, a phase II clinical trial was performed. Other agents which have the property of “correcting” CFTR processing and localization to the apical membrane are being sought by the technique of high-throughput screening. Other classes of compounds shown to “potentiate” or increase the chloride conductance of cells with the $F508 mutation are also being sought. Since infection and inflammation play a critical role in the pathophysiology of the lung disease of CF, efforts have been directed at decreasing airway inflammation. The approaches are both pharmacologic (e.g., use of ibuprofen and prednisone) and physiological (e.g., prevention of Pseudomonas binding to airway cells and immunization against Pseudomonas). The insufficient antioxidant capacity in CF airways is also being addressed by studies to evaluate antioxidant augmentation with nacystelyn and glutathione.

Gene Therapy Improvements in gene transfer technology represent an important future direction in CF. Because the disease is inherited as an autosomal-recessive trait, only one normal copy of the gene needs to be provided to cells. Vectors proposed thus far for carrying the normal CFTR gene include adenovirus, adeno-associated virus, cationic liposomes, and DNA-protein complexes. Several human clinical trials of gene therapy in CF have been initiated, based on use of adenoviral vectors, adeno-associated viral vectors, and nonviral vectors. Results have been remarkably similar among the trials. In a few patients, patchy expression of the transgene has been demonstrated in both the nose and lung using immunohistochemistry or in situ hybridization; overall efficacy has been poor. Dose-dependent inflammation has been encountered; in one study, a patient became acutely ill for several days following instillation in the lung of a high titer of replication-deficient adenovirus. Physiological correction of cyclic adenosine monophosphate (cAMP)-mediated chloride secretion in the nose has not been convincingly demonstrated after gene transfer, although a trend toward correction of the basal potential difference has been observed. Finally, because the immune response to viral vectors constitutes a significant impediment to successful gene transfer, several approaches are currently being developed. These include production of less immunogenic viral vectors, immune suppression, development of nonimmunogenic, nonviral vectors, and using smaller molecules for gene repair inhibition of gene expression. Progress toward cure of CF will require a multidisciplinary approach. Management of the lung disease in CF will probably be based on combined methods. However, the momentum gained from recent improvements in our understanding of basic pathogenetic mechanisms provides a basis for realistic optimism that specific therapy will result in better outcomes for patients with CF.

SUGGESTED READING Bobadilla JL, Macek M Jr, Fine JP, et al: Cystic fibrosis: A worldwide analysis of CFTR mutations-correlation with incidence data and application to screening. Hum Mutat 19:575–606, 2002. Borowitz D, Baker S, Duffy L, et al: Use of fecal elastase-1 to classify pancreatic status in patients with cystic fibrosis. J Pediatr 145:322–326, 2004. Bronsveld I, Mekus F, Bijman J, et al: Chloride conductance and genetic background modulate the cystic fibrosis phenotype of $F508 homozygous twins and siblings. J Clin Invest 108:1705–1715, 2001. Clancy JP, Bebok Z, Ruiz F, et al: Evidence that systemic gentamicin suppresses premature stop mutations in patients with cystic fibrosis. Am J Respir Crit Care Med 163(7):1683–1692, 2001. Cuthbert AW: Disease genes: Flattery and deception. Trends in Pharmacol Sci 23:504–509, 2002. Davis PB: Cystic fibrosis since 1938. Am J Respir Crit Care Med 173:474–482, 2006. de Almeida MB, Bussamra MH, Rodrigues JC: Allergic bronchopulmonary aspergillosis in paediatric cystic fibrosis patients. Paediatr Respir Rev 7:67–72, 2006. Drumm ML, Konstan MW, Schluchter MD, et al, for the Gene Modifier Study Group: Genetic modifiers of lung disease in cystic fibrosis. N Engl J Med 353:1442–1453, 2005. Ebert DL, Olivier KN: Nontuberculous mycobacteria in the setting of cystic fibrosis. Clin Chest Med 23(3):655–663, 2002. Elkins MR, Robinson M, Rose BR, et al: A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. N Engl J Med 354:229–240, 2006. Freedman SD, Blanco PPG, Zaman MM et al: Association of cystic fibrosis with abnormalities in fatty acid metabolism. N Engl J Med 350:560–569, 2004. Gawande A. The bell curve. The New Yorker Dec 6:82–91, 2004. Gibson RL, Burns JL, Ramsey BW: Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med 168:918–951, 2003. Karp CL, Flick LM, Park KW, et al: Defective lipoxin-mediated anti-inflammatory activity in the cystic fibrosis airway. Nat Immunol 5:388–392, 2004. Konstan MW, Butler SM, Wohl ME, et al, Investigators and Coordinators of the Epidemiologic Study of Cystic Fibrosis: Growth and nutritional indexes in early life predict pulmonary function in cystic fibrosis. J Pediatr 142:624– 630, 2003. Kreda SM, Mall M, Mengos A, et al: Characterization of wild-type and deltaF508 cystic fibrosis transmembrane regulator in human respiratory epithelia. Molec Biol Cell 16:2154–2167, 2005. LiPuma JJ: Update on the Burkholderia cepacia complex. Curr Opin Pulm Med 11:528–533, 2005.

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Riordan J, Rommens JM, Kerem B, et al: Identification of the cystic fibrosis gene: Cloning and characterization of complementary DNA. Science 245:1066–1073; erratum 1437, 1989. Scanlin TF: Cystic fibrosis, in Fleisher GR, Ludwig S (eds): Textbook of Pediatric Emergency Medicine, 4th ed. Philadelphia, Williams & Wilkins, 2000, pp 1087– 1092. Scanlin TF, Glick MC: Terminal glycosylation in cystic fibrosis, in Schachter H (ed): Molecular Basis of Disease. Biochim Biophys Acta 1455:241–253, 1999. Sokol RJ, Durie PR: Recommendations for management of liver and biliary tract disease in cystic fibrosis. Cystic Fibrosis Foundation Hepatobiliary Disease Consensus

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Group. J Pediatr Gastroenterol Nutr 28(Suppl 1):S1–13, 1999. Trulock EP, Edwards LB, Taylor DO, et al: Scientific registry of the International Society for Heart and Lung Transplantation: Twenty-second official adult lung and heart-lung transplant report—2005. J Heart Lung Transplant 24:956– 967, 2005. Welsh MJ, Ramsey BW, Accurso F, et al: Cystic fibrosis, in Scriver CR, Beaudet AL, Sly WS, et al (eds): The Metabolic and Molecular Basis of Inherited Diseases, 8th ed. New York, McGraw-Hill, 2001, pp. 5121–5188. Wilfond BS, Gollust SE: Policy issues for expanding newborn screening programs: The cystic fibrosis newborn screening experience in the United States. J Pediatr 146:668–674, 2005.

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52 Bronchiolitis Talmadge E. King, Jr.

Brent W. Kinder

I. DEFINITION AND CLASSIFICATION Clinical Classification Radiologic Classification Histopath ological Classification Path ogenesis II. INHALATIONAL LUNG INJURY CAUSING BRONCHIOLITIS Toxic Gases Other Irritant Gases Mineral Dusts Organic Dusts Volatile Flavoring Agents III. INFECTIOUS CAUSES OF BRONCHIOLITIS Infectious Bronchiolitis in Children Infectious Bronchiolitis in Adults IV. IDIOPATHIC FORMS OF BRONCHIOLITIS Cryptogenic ‘‘Adult’’ Bronchiolitis Respiratory Bronchiolitis-Associated Interstitial Lung Disease Cryptogenic-Organizing Pneumonia Localized Bronchiolitis Obliterans-Organizing Pneumonia

Bronchiolitis is a fibrotic lung disease that primarily affects the small conducting airways, often sparing a considerable portion of the interstitium. Commonly occurring diseases with prominent involvement of the small airways (asthma, bronchitis, bronchiectasis) are described elsewhere in this book. However, several additional, uncommon small-airway diseases are important to recognize and treat. These “bronchiolar syndromes” frequently accompany infections, drug reactions, connective-tissue diseases, toxic gas or fume exposure, and organ transplantation. Bronchiolitis is an intellectual challenge to clinicians and pathologists. The “gold standard” approach is a multidisciplinary one, including clinical, radiological, and histopathological expertise, to establish the final

V. CONNECTIVE-TISSUE DISEASES Rheumatoid Arthritis and Constrictive Bronchiolitis Rheumatoid Arthritis and Bronchiolitis ObliteransOrganizing Pneumonia Rheumatoid Arthritis and Follicular Bronchiolitis Sj¨ogren’s Syndrome Systemic Lupus Erythematosus Progressive Systemic Sclerosis Polymyositis and Dermatomyositis VI. DRUG-INDUCED CAUSES OF BRONCHIOLITIS Bronchiolitis Associated with Gold Compounds Amiodarone-Induced Bronchiolitis Sauropus Androgynus-Induced Bronchiolitis VII. ORGAN TRANSPLANTATION Bone Marrow Transplantation Heart-Lung Transplantation Lung Transplantation VIII. DIFFUSE PANBRONCHIOLIS IX. PRIMARY DIFFUSE HYPERPLASIA OF PULMONARY NEUROENDOCRINE CELLS

diagnosis. This chapter reviews the clinical, radiographic, and histopathological findings of the bronchiolar syndromes.

DEFINITION AND CLASSIFICATION Although bronchiolitis has been recognized since the 1800s, it was not until 1901 that the first detailed description of the clinicopathological syndrome appeared and the phrase bronchiolitis obliterans was applied. Bronchiolitis is an inflammatory reaction that follows damage to the bronchiolar epithelium of the small conducting airways. Subsequent

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healing leads to excessive proliferation of granulation tissue within the airway walls, lumen, or both. Depending on disease stage, the repair process may cause narrowing and distortion of the small airways (constrictive bronchiolitis) or complete obliteration (bronchiolitis obliterans). Alveoli adjacent to the injured small airways are almost always affected, but a considerable portion of the pulmonary interstitium is often spared. Repair occurs in numerous clinical settings, with a variable clinical course and histological appearance. Consequently, a clear understanding of pathogenesis is lacking. The nomenclature applied to the bronchiolar syndromes has been confusing. The following terms have been used: bronchiolitis obliterans, bronchiolitis fibrosa obliterans, bronchiolitis obliterans and interstitial pneumonia, bronchiolitis obliterans-organizing pneumonia (BOOP), cryptogenic-organizing pneumonia, and follicular bronchiolitis. Unfortunately, the terms are often used interchangeably to describe what are now believed to be separate and distinct clinical entities. Before the description of BOOP in 1985, most cases described as idiopathic bronchiolitis obliterans were actually cases of BOOP. Since some degree of inflammation, narrowing, and obliteration of the small airways is present in most patients, we have chosen the term bronchiolitis to refer to the broad spectrum of histopathological processes. Bronchiolitis obliterans refers to a histological lesion characterized by polypoid obliteration of the lumen of bronchioles, without involvement of the distal lung parenchyma by inflammation or organizing pneumonia—i.e., constrictive bronchiolitis. BOOP refers to disorders characterized histologically by intraluminal polyps in the respiratory bronchioles, alveolar ducts, and alveolar spaces, accompanied by organizing pneumonia in the more distal parenchyma. Bronchiolitis obliterans syndrome (BOS) is a clinical term that refers to the progressive airflow limitation secondary to small-airway obstruction which commonly complicates lung transplantation that is defined not by histology, but by lung function changes. In BOOP, the alveolar walls show a mild to moderate chronic inflammatory infiltrate, type II cell hyperplasia, and foamy macrophages in the alveolar spaces; a “proliferative” bronchiolitis is present. Since only a minority of cases showing the “BOOP pattern” represent the idiopathic syndrome described in 1985, and since patients with idiopathic BOOP manifest a distinctive clinical syndrome, this group is referred to as “cryptogenic-organizing pneumonia,” in order to distinguish the syndrome from other causes of the BOOP pattern. Three classification schemes appear useful in defining cases of bronchiolitis: (1) a clinical classification based on the etiology; (2) a histopathological classification that includes two major morphologic types: proliferative bronchiolitis and constrictive bronchiolitis; and (3) a radiologic classification based on the findings of thinsection, high-resolution computed tomography (HRCT). The histopathological-radiologic classification appears most useful, since histopathological-radiologic changes correlate best with clinical manifestations.

Clinical Classification The clinical classification of bronchiolitis is based on etiology (Table 52-1): inhalation injury, infections, drug reactions, and idiopathic causes. The first three categories are frequently recognized from their association with an acute illness or known exposure before the onset of disease. Idiopathic cases often have a more insidious onset, characterized by cough or dyspnea; initially, they may be confused with more common problems, such as chronic obstructive pulmonary disease or interstitial lung disease, depending on the predominant histopathological pattern.

Radiologic Classification HRCT is an excellent way to examine the morphology of small-airway diseases. Consequently, it has become the method of choice for assessing these airways, often replacing the need for surgical lung biopsy. Several studies have examined the patterns found on computed tomography (CT) scans and correlated the patterns with histopathological findings. Based on radiologic features, investigators have classified bronchiolar diseases into three predominant CT patterns: (1) nodules and branching lines; (2) ground glass opacification (hazy increased attenuation, i.e., increased density of the lung with preservation of bronchial and vascular margins) and consolidation (hazy increased parenchymal attenuation in which the bronchial and vascular margins are obscured); and (3) low attenuation (i.e., decreased density of lung or “black lung”) and mosaic perfusion (a patchwork of regions of varied attenuation, interpreted as secondary to regional differences in perfusion). The mosaic perfusion pattern appears to be most helpful in suggesting the presence of bronchiolitis obliterans.

Histopathological Classification The histopathological classification (Table 52-2) of bronchiolitis includes proliferative and constrictive varieties. Each type, including the presumed pathogenesis, is described below. Proliferative Bronchiolitis Proliferative bronchiolitis—the “BOOP pattern”—is characterized by an organizing intraluminal exudate and is found, to some degree, in a variety of pulmonary disorders. It is particularly extensive and prominent in cryptogenic-organizing pneumonia (also called idiopathic BOOP). The intraluminal fibrotic buds (Masson bodies) are seen in respiratory bronchioles, alveolar ducts, and alveoli (Fig. 52-1). Proliferative bronchiolitis most frequently is associated with diffuse infiltrates on chest radiograph and a restrictive defect on pulmonary function testing, especially when cryptogenic organizing pneumonia is present. Constrictive Bronchiolitis Constrictive bronchiolitis is characterized by alterations in the walls of membranous and respiratory bronchioles which

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Table 52-1 Clinical Syndromes Associated with Bronchiolitis Inhalational injury Toxic gases (e.g., oxides of nitrogen) Grain dusts Irritant gases (e.g., chlorine) Mineral dusts Organic dusts (hypersensitivity pneumonitis) Cigarette smoke Free-base cocaine Fire smoke Flock worker’s lung (fine nylon fiber) Volatile flavoring agents Postinfectious (mostly in children) Acute bronchiolitis Common Respiratory syncytial virus Parainfluenza (types 1, 2, and 3) Adenovirus (types 1, 2, 3, 5, 6, 7, and 21) Mycoplasma pneumoniae Uncommon Coronavirus Rubeola Drug-induced reactions Penicillamine Hexamethonium l-Tryptophan Busulfan Gold Cephalosporin Sulfasalazine Amiodarone Acebutolol Sulindac Paraquat poisoning

cause concentric narrowing or complete obliteration of the airway lumen (Fig. 52-2). Often these lesions occur without extensive changes in alveolar ducts or alveolar walls. The changes of constrictive bronchiolitis may be extremely subtle, and frequently they are identified only after step-sectioning and special staining (e.g., use of stains to identify remnants of airway walls) of the lung biopsy. The range of histopathological changes includes: (1) subtle cellular infiltrates around the small airways; (2) extensive cellular infiltrates and smoothmuscle hyperplasia; (3) bronchiolectasia with mucus stasis, distortion, and fibrosis; and (4) total obliterative bronchiolar scarring. These lesions are seen most often in patients with progressive obstructive lung disease. A normal chest radiograph may be present. Cases of constrictive bronchiolitis are very rare.

Idiopathic No associated disease Cryptogenic constrictive bronchiolitis Respiratory bronchiolitis-associated interstitial lung disease Cryptogenic-organizing pneumonia (also called idiopathic bronchiolitis obliterans-organizing pneumonia, BOOP) Diffuse panbronchiolitis Primary diffuse hyperplasia of pulmonary neuroendocrine cells Associated with other disease Associated with organ transplantation Bone marrow Heart-lung Lung Associated with connective-tissue diseases Rheumatoid arthritis Sj¨ogren’s syndrome Systemic lupus erythematosus Polymyositis dermatomyositis Distal to bronchial obstruction (“obstructive pneumonitis”) Ulcerative colitis Chronic eosinophilic pneumonia Other rare associations Radiation pneumonitis Aspiration pneumonitis Idiopathic pulmonary fibrosis Malignant histiocytosis Acute respiratory distress syndrome Vasculitis, especially Wegener’s granulomatosis Chronic thyroiditis

Pathogenesis A similar sequence of events may lead to both histopathological patterns of bronchiolitis. However, differences appear to relate to the type of insult, extent and severity of the initial insult, and predominant site of the injury (bronchioles, alveolar ducts, or both). In some diseases associated with bronchiolitis, varying degrees of both proliferative and constrictive bronchiolitis can be found on histological examination. The initial lesion in constrictive bronchiolitis usually involves airway epithelial injury and destruction (Fig. 52-3). An inflammatory response follows, with accumulation of neutrophils at the site of injury. Neutrophils cause further injury to the airway epithelium and matrix by release of inflammatory mediators. Persistence of the injury

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Table 52-2 Comparison of Key Pathological, Radiologic, and Physiological Features in Proliferative and Constrictive Bronchiolitis Feature

Proliferative Bronchiolitis

Constrictive Bronchiolitis

Histopathological manifestations

Common finding Nonspecific reparative reaction to bronchiolar injury Organizing intraluminal exudate Most prominent in alveolar ducts Inflammatory changes in surrounding alveolar walls Foamy macrophages in alveoli

Very uncommon finding Obliterans not a constant feature Variety of histological changes: bronchiolar inflammation to progressive concentric fibrosis; smooth-muscle hyperplasia, bronchioloectasia with mucous stasis; distortion and fibrosis of small-airway walls with bronchial metaplasia extending onto peribronchiolar alveolar septa Follicular bronchitis (lymphoid hyperplasia) Cellular bronchiolitis Diffuse panbronchiolitis

Radiographic abnormalities

Bilateral patchy airspace opacities Interstitial opacities Small rounded opacities Opacities may be recurrent and migratory

May be normal Progressive increase in lung volume on serial radiographs HRCT scan may show marked heterogeneity of lung density

Pulmonary function

Restrictive defect (a mixed pattern may be seen)

Obstructive defect with hyperinflation

Clinical syndromes

Cryptogenic-organizing pneumonia (idiopathic BOOP) Collagen vascular disease (e.g., rheumatoid arthritis, dermatomyositis, SLE) Organizing acute infection (especially influenza or Nocardia asteroides, Mycoplasma, Pneumocystis carinii, Legionella pneumophila, cytomegalovirus, or HIV infection) Chronic eosinophilic pneumonia Hypersensitivity pneumonitis Organizing diffuse alveolar damage/(ARDS) Vasculitides, especially Wegener’s granulomatosis Organ transplantation (rare) Drug-induced reactions (hexamethonium, l-tryptophan, busulfan, free-base cocaine, gold, cephalosporin, sulfasalazine, amiodarone, acebutolol, sulindac) Other uncommon associations: chronic thyroiditis, ulcerative colitis, irradiation pneumonitis, aspiration pneumonitis, distal to bronchial obstruction, “obstructive pneumonitis,” chronic heart or renal failure, common variable immunodeficiency syndrome

Allograft recipients (bone marrow, heart-lung, lung) Collagen vascular disease (especially rheumatoid arthritis) Postinfectious (especially respiratory syncytial virus, adenovirus, influenza, parainfluenza, Mycoplasma) Inhaled toxins (e.g., nitrogen dioxide, sulfur dioxide, ammonia, chlorine, phosgene) Drugs (e.g., penicillamine, lomustine) Cigarette smoke Mineral dust airway disease (asbestosis, silica, iron oxide, aluminum oxide, talc, mica, and coal) Idiopathic Hypersensitivity reactions

(Continued)

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Table 52-2 (Continued) Feature

Proliferative Bronchiolitis

Constrictive Bronchiolitis

Natural history

Corticosteroid responsive and usually reversible

Relatively corticosteroid unresponsive and usually progressive with the development of irreversible airflow obstruction and air trapping. May respond to macrolide antibiotics.

HRCT, high-resolution computed tomography; BOOP, bronchiolitis oblitevans-organizing p¨neumonia; SLE, Systemic lupus erythematosus; HIV, human immunodeficieny virus; ARDS, acute respiratory distress syndrome.

may determine whether there is resolution and recovery or progression to a less reversible state, manifested by intramural and intraluminal fibrosis. The repair process results in the characteristic obliterative bronchiolar lesions. In general, “proliferative” bronchiolitis appears to be a common “early” lesion that may resolve completely or partly. Intermediary steps in the development of intraluminal, extracellular matrix synthesis have been clarified. First, a florid alveolitis with edema occurs as a result of damage to the alveolar lining. The degree of alveolar lining destruction and disruption of the basal lamina, with resulting gaps on the basement membrane, appears to determine the extent of intraalveolar fibrosis. Although the alveolar basement membrane is most frequently damaged, minor changes are also noted in the endothelial basement membrane. The alveolitis coincides with the presence of inflammatory proteins in the airspace, in-

cluding immunoglobulins (IgG, IgA, and IgM), fibronectin, and procoagulant factors (fibrinogen and factors VII and X). The cellular response includes neutrophils, eosinophils, macrophages, and lymphocytes. Many mast cells are also present in the septal and intra-alveolar compartments. After development of the alveolitis, fibroblasts migrate into the lesion, proliferate, and secrete matrix proteins. This results in the formation of Masson bodies, polypoid buds of fibroblasts, and extracellular matrix projecting into the lumina of respiratory bronchioles, alveolar ducts, and alveoli. The matrix of the Masson bodies stain positive for type III collagen and fibronectin (cell and plasma in origin). The fibroblasts in the Masson bodies also stain strongly for procollagen type I. Delicate fibrils within the matrix of some Masson bodies contain type IV collagen. Inflammatory changes in surrounding alveolar walls, including prominent foamy

Figure 52-1 Bronchiolitis obliterans-organizing pneumonia (BOOP). Photomicrograph of open lung biopsy from a patient with cryptogenic-organizing pneumonia (COP). Polypoid masses of granulation tissue fill the lumens of a respiratory bronchiole and alveolar ducts. Adjacent alveolar interstices are broadened by a lymphoplasmacytic inflammatory infiltrate. (Pentachrome stain, ×156.)

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Figure 52-2 Constrictive bronchiolitis. Photomicrograph of open lung biopsy from a patient with constrictive bronchiolitis following toxic gas exposure. A. Slightly dilated but otherwise normal bronchiole with normal intervening lung. (Pentachrome stain, ×156.) B . Step-section of specimen. Marked concentric narrowing of the bronchiolar lumen due to fibrosis is apparent. (Pentachrome stain, ×156.)

macrophages in alveoli spaces (i.e., organizing pneumonia) are commonly present.

INHALATIONAL LUNG INJURY CAUSING BRONCHIOLITIS The inhalation of fumes, gases, mists, mineral dusts, or organic material constitutes a significant industrial and environmental hazard in many settings (Table 52-3). Exposure can result in subtle or severe clinical illness, usually associated with immediate development of pulmonary edema and late development of constrictive bronchiolitis with airflow limitation.

Toxic Gases The inhalation of gases or fumes (i.e., fine particulates) is a rare cause of bronchiolitis, with or without obliterans. Oxides of nitrogen are the most common and best-described agents leading to acute and chronic lung injury. Silo filler’s disease is a well-studied example (Fig. 52-4). The estimated annual incidence of silo filler’s disease is 5 cases per 100,000 siloassociated farm workers per year. Most cases occur during the harvest period (September and October). Mechanism of Injury The distribution and extent of the lung injury are determined by the concentration of the agent, duration of exposure, route

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Table 52-3 Toxic Exposures Associated with Bronchiolitis, with or without Obliterans

Figure 52-3 Proposed pathogenetic mechanism for airway injury in constrictive bronchiolitis. (See text for details.)

and pattern of breathing, solubility and biologic reactivity of the agent, and biologic susceptibility of the individual. Nitrogen dioxide (NO2 ) and nitrogen tetroxide are responsible for the injury. NO2 is relatively insoluble. After inhalation, the gas reaches the periphery of the lung, where it combines with water to form nitric and nitrous acids and nitric oxide, which are powerful oxidants capable of causing severe tissue injury. Unlike highly water-soluble gases, such as chlorine, ammonia, and sulfur dioxide, NO2 is less irritating to the mucous membranes of the nasal and upper airways. The gas produces a yellow to brown haze and an acrid, ammonia-like odor that is irritating. Clinical Findings Clinical manifestations of exposure to NO2 depend on the concentration of the inhaled gas and the duration of exposure. Three clinical patterns or phases may follow exposure. All phases may not appear in an individual patient. Progression to death may be an outcome at any stage. Acute Phase

Acutely, during milder exposures, people may develop upperairway and visual disturbances, cough, dyspnea, fatigue, cyanosis, vomiting, hemoptysis, hypoxemia, vertigo, somnolence, headache, emotional difficulties, and loss of consciousness. These findings usually resolve within hours, but they may persist for several weeks; complete recovery without obvious sequelae is usually observed. At higher concentrations of exposure, pulmonary edema (so-called, “chemical pneumonitis”) is a frequent

Nitrogen dioxide (“nitrous fume”)∗ Spillage of nitric acid (component of jet and missile fuels) Metal pickling Silo gas Chemical manufacturing (explosives, dyes, lacquers, celluloid) Detonation of explosives Electric arc or acetylene gas welding Contamination of anesthetic gases (nitrous oxide gas cylinder) Nitrocellulose combustion Tobacco smoke Fire smoke (firemen, astronauts, others exposed to burning materials)∗,† Sulfur dioxide† Burning of sulfur-containing fossil fuels Bleaching of wool, straw, wood pulp Sugar refining, fruit preserving Fungicides Refrigerants Ore smelting Acid production Ammonia† Fertilizer and explosives, production, refrigeration Chlorine‡ Bleaching, disinfectant and plastic making Phosgene∗ Chemical industry, dye and insecticide manufacturing Chloropicrin Trichlorethylene Ozone Arc welding and air, sewage, and water treatment Cadmium oxide Ore smelting, alloying, and welding Methyl sulfate Hydrogen sulfide Natural gas retrieval, paper pulp, sewage treatment, tannery work Hydrogen fluoride Etching, petroleum industry, silk working Talcum powder (hydrous magnesium silicate) Stearate of zinc powder Oxygen toxicity Asbestos (chrysotile and amphibole) Iron oxide§ Aluminum oxide§ Silica§ Sheet silicates (talc, mica, etc.)§ (Continued )

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Table 52-3 Toxic Exposures Associated with Bronchiolitis, with or without Obliterans Coal§ Activated charcoal Talc Free-base cocaine∗ Chemical weapons (mustard gas and the nerve gases, sarin, VX, and tabun)† ∗ These

agents have been associated with development of bronchiolitis obliterans (intraluminal polyps). † These agents have been associated with development of constrictive bronchiolitis. ‡ These agents have been associated with development of histological focal bronchiolitis without significant clinical disease. § These agents have been associated with development of respiratory bronchiolitis.

complication in the early stages. Patients may be asymptomatic at the time of exposure, only to later develop (in 3 to 30 h) the clinical picture of severe acute respiratory distress syndrome. During this acute phase, patients who develop pulmonary edema and acute respiratory distress syndrome have significant pulmonary dysfunction. Hypoxemia is secondary to ventilation-perfusion mismatching as a result of altered airway dynamics and interstitial and alveolar edema, impaired diffusing capacity, and methemoglobinemia that occurs when nitrate ions react with hemoglobin. Severe metabolic acidosis occurs because of the dissolution of NO2 in body fluids, resulting in formation of nitrous and nitric acid, as well as the lactic acidosis resulting from tissue hypoxia. Systemic hypertension may be present. Recovery without long-term sequelae is usual, but death may occur at this stage. The radiographic manifestations during this stage include pulmonary edema (i.e., alveolar filling). In survivors, these changes clear rapidly. Physiological studies reveal the simultaneous occurrence of restrictive and obstructive ventilatory defects; the former is manifest as a shift in the static pressure-volume curve downward and to the right. These abnormalities gradually resolve in survivors. Histopathological findings, as determined from autopsy studies, include marked intra-alveolar edema and exudation, as well as thickening of the alveolar walls with lymphocytic cellular infiltrates. Subacute Phase

In patients who progress to the second phase, physiological disturbances include hypoxemia at rest or with exercise and associated restrictive or obstructive pulmonary function abnormalities. The radiographic pattern in this late stage may be variable. A normal chest film may be seen; however, a miliary, or discretely nodular, pattern is thought to be characteristic of bronchiolitis obliterans. Occasionally, only pulmonary hyperinflation is seen, usually accompanied by a progressive and irreversible obstructive ventilatory defect noted on lung function testing.

Chronic Phase

After recovery from the acute illness, or in patients with no symptoms following exposure, recurrence or new onset of clinical illness may be seen 2 to 6 weeks later. This phase is characterized by the progressive onset of cough and dyspnea. These patients may be identified in an early, asymptomatic stage from the appearance of mild hypoxemia. Tachypnea is present, and crackles are usually heard. Widespread proliferative bronchiolitis with marked intraluminal fibrous tissue proliferation arising in the bronchiolar wall (without organizing pneumonia) is found, especially in those with preceding pulmonary edema; however, these findings may occur as the initial manifestation of previous exposure. Management The treatment of patients exposed to NO2 or other toxic gases or fumes should include observation in the hospital for 48 h, followed by weekly or biweekly evaluations for 6 to 8 weeks. When dysfunction occurs, treatment with corticosteroids should be started immediately. Corticosteroid therapy has been demonstrated to be useful in the management of both the acute phase (pulmonary edema) and the late phase (bronchiolitis obliterans). Corticosteroids should be continued for a minimum of 8 weeks, since relapses have been reported with the earlier cessation of therapy. Bronchodilators are occasionally helpful, but antibiotics should be used only when clinically indicated; they should be directed at a specific pathogen. If methemoglobinemia is present, methylene blue should be administered at a dose of 2 mg/kg intravenously, followed by doses titrated according to the concentration of methemoglobin in the blood. For patients in whom this diagnosis is suspected, and for whom open lung biopsy or general anesthesia is planned, some have suggested that nitrous oxide not be used as an anesthetic because of concern that it might lead to disease progression. Prognosis In general, the prognosis for survivors of toxic gas or fume inhalation (fewer than one-third die acutely) is good. Some authors have suggested that lasting pulmonary disability is uncommon in silo filler’s disease; others have identified a wide variety of functional derangements. What functional abnormalities result from chronic, low-level exposure to NO2 are not clear. Education is key in preventing this disease, since simple measures to reduce the NO2 levels and use of approved respiratory protection equipment will eliminate the risk of injury.

Other Irritant Gases A number of irritant gases have occasionally been associated with bronchiolitis, with or without obliterans (Table 52-3). Since lung biopsies have not been performed in all cases, it is not always clear that the pulmonary injury associated with these inhalation exposures is only bronchiolitis obliterans. However, sulfur dioxide, chlorine gas, “smoke inhalation” or inhalation burns, hydrogen chloride, ammonia, phosgene,

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Figure 52-4 Exposure to nitrogen oxides and silo fillerâ&#x20AC;&#x2122;s disease. The upright concrete stave silo is the most common type of silo. Chopped silage is blown through the filling pipe (on right of silo) to the top of the silo and dispersed evenly. A. Exposure usually occurs 1 to 4 days after silo filling, when the farmer enters to level the silage, to prepare for unloading, or to spread a plastic sheet over the top. B . Silo gas is heavier than air and accumulates in low places within the silo. Descent into these areas may be fatal. C . Opening a door just above the silage may result in concentrated exposure, causing rapid loss of consciousness and a fall down the silo chute. D .Entry immediately after completion of silo filling may not be safe, since gas from 1- to 2-day-old silage may leak out through the silo doors and be drawn into the working spaces by a chimney-like updraft. (Based on data from Douglas WW, Colby TV: Fume-related bronchiolitis obliterans, in Epler GR (ed), Diseases of the Bronchioles. New York: Raven Press, 1994, pp 187â&#x20AC;&#x201C;213, with permission.)

and chloropicrin produce a disease with clinical, physiological, and radiographic manifestations similar to those described for NO2 exposure. Respiratory bronchiolitis after exposure to photochemical air pollutants, ozone, and NO2 , has been reviewed.

Mineral Dusts Pathological changes in the small airways (respiratory bronchiolitis) may be found secondary to exposure to inorganic mineral dusts, including asbestos, silica, iron oxide, aluminum oxide, several different sheet silicates, and coal.

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Clinical relevance of the changes remains to be better defined. Nonetheless, development of an obstructive, rather than restrictive, pattern is increasingly recognized in subjects with inorganic mineral dust exposure. Pathologically, these lesions are characterized by marked abnormalities in the small airways, particularly in the membranous and respiratory bronchioles. The principal finding is fibrosis in small-airway walls and, occasionally, in alveolar ducts. The lesions appear to extend down into the airway and often are accompanied by pigment deposition. Abnormalities are seen in nonsmokers, but occur most commonly in heavily exposed workers who are cigarette smokers. The pathogenesis is unclear, but a synergistic role for cigarette smoking appears likely. The injury appears to result from the inflammatory response that follows deposition of mineral particles or fibers in the walls of the small airways.

Organic Dusts Numerous agents are associated with the development of hypersensitivity pneumonitis, a topic discussed elsewhere (see Chapter 69). Interstitial pneumonitis is seen in virtually 100 percent, and granulomas in approximately 70 percent, of patients with hypersensitivity pneumonitis; unappreciated is that bronchiolar lesions are also seen in essentially all cases. The bronchioles contain granulomas within the walls or luminaâ&#x20AC;&#x201D;or show tufts of granulation tissue, as seen in bronchiolitis obliterans. A reversible restrictive process is the most common physiological abnormality in hypersensitivity pneumonitis. However, small-airway dysfunction may be present in patients with early hypersensitivity pneumonitis. As the disease progresses, either obstructive or restrictive physiology may arise, depending on the predominant histopathological process present.

Volatile Flavoring Agents A recent report described development of severe, fixed obstructive lung disease in nine former employees of a microwave popcorn factory. Four of the patients were on lung transplant lists. All had a respiratory illness resembling bronchiolitis obliterans, with symptoms of cough and dyspnea on exertion. Their median duration of employment was 2 years (range, 1 to 17 years). Each of the workers first became symptomatic between 1993 and 2000, while employed by the factory, after a median of 1.5 years of employment (range, 5 months to 9 years). Cough, shortness of breath, and wheezing were the presenting symptoms. Most patients identified had normal results on pre-placement spirometry. These values subsequently fell precipitously, with development of moderate to severe, nonreversible airway obstruction. HRCT scans showed evidence of air trapping. The presumed inciting exposure was to a mixture of soybean oil, salt, flavorings, and coloring agents that was mixed in a large heated tank. This process produced visible dust, aerosols, and vapors with a strong buttery odor. More than 100 volatile organic compounds were identified in the

air samples from the mixing room area of the plant. Diacetyl (2, 3)-butanedione, a ketone with butter-flavor characteristics, was the predominant compound isolated. The highest incidence of illness occurred in workers who worked nearest the mixing tank and who were more likely to have inhaled mixing tank substances. Preliminary animal studies at the Division of Respiratory Disease Studies, National Institute for Occupational Safety and Health (NIOSH), suggested severe damage to airway epithelium after inhalation exposure to high air concentrations of butter-flavoring vapors (diacetyl) used at one of the worksites. After removal from exposure, patients did not recover, but they did appear to have no further loss of lung function. However, NIOSH has been investigating whether similar cases have occurred in workers at other microwave popcorn factories or who work with food-flavoring agents that might be heated and aerosolized. The general population using microwave popcorn products does not appear to be at any risk.

INFECTIOUS CAUSES OF BRONCHIOLITIS Infection is the most common cause of acute bronchiolitis, although infectious causes are more frequent in children than adults. The usual agents include viruses and Mycoplasma pneumoniaeâ&#x20AC;&#x201D;organisms that have a propensity to infect and injure epithelial cells of the respiratory tract. Constrictive bronchiolitis is the most common histopathological pattern observed after bronchiolar infection.

Infectious Bronchiolitis in Children Acute bronchiolitis is a common illness in infants and young children, occurring primarily as a result of a viral infection. Pathogens include respiratory syncytial virus (approximately 34 percent of cases), parainfluenza virus types 1, 2, and 3 (approximately 30 percent of cases), adenoviruses (approximately 7 percent of cases), influenza A and B, and Mycoplasma pneumoniae (approximately 11 percent of cases) (Table 52-1). Males are more commonly affected with respiratory syncytial virus than are females (1.5 to 1.8:1 male-to-female ratio). Reviews of bronchiolitis in children have been published previously. Infectious bronchiolitis obliterans is rarely seen in persons older than 2 years. Adenovirus types 3, 7, and 21 are the most common etiological agents. Other causes are measles, whooping cough due to Bordetella pertussis, M. pneumoniae, and influenza A. Severe infectious bronchiolitis obliterans leading to hospitalization and death is rare. Clinical Findings The usual presentation is an acute viral-like illness with mild coryza and sneezing occurring during the winter months. Several days later, cough, dyspnea, tachypnea, tachycardia, fever, chest wall retractions, sibilant and sonorous crackles,

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expiratory wheezing, and, in severe cases, cyanosis, develop. Prostration and respiratory failure are unusual. Radiographic Findings The radiographic pattern of childhood bronchiolitis is variable. The chest radiograph may be normal or show hyperinflation with increased bronchial markings. Subsegmental consolidation and collapse may be seen. A pattern similar to that of diffuse interstitial pneumonia, often in association with hyperinflation, is seen. Some patients demonstrate a diffuse nodular or reticulonodular pattern, whereas others may show patchy alveolar or ground glass opacities. Those with a nodular pattern frequently have “pure” bronchiolitis obliterans on lung biopsy; those with a reticulonodular pattern are likely to have more interstitial inflammation and scarring. The role of HRCT has not been adequately defined, but it is thought to be important in ruling out other diagnoses, especially bronchiectasis. Ventilation-perfusion lung scans may be very helpful, since a markedly abnormal pattern of patchy, matched ventilation and perfusion defects is often seen, even when the plain chest film is unremarkable. Bronchography may reveal saccular bronchiectasis and ballooning of the airways at the blind end when the airways are distended by positive pressure; passage of contrast medium into the alveoli does not occur. Bronchography has largely been abandoned with the advent of HRCT. Physiological Findings Tests of lung function may be normal. However, obstructive changes with air trapping can often be documented. Pulmonary function testing has not been well studied in infants with this disease. Resting hypoxemia is frequently present. Histopathological Findings In this setting, open lung biopsy is the gold standard for the diagnosis of bronchiolitis obliterans. The earliest change is necrosis of the respiratory epithelium, followed by epithelial proliferation. Dense plugs of alveolar debris and strands of fibrin are seen within small bronchi and bronchioles, causing partial or complete obstruction. These findings may develop as soon as 8 days after the onset of the illness. A lymphocytic infiltrate, including collections with germinal centers, may be seen in the airway wall. Severe and widespread destruction of the respiratory epithelium may cause denudation and a pronounced inflammatory response that involves the adjacent peribronchial space and alveolar walls. Depending on the stage at which the biopsy is obtained, findings consistent with proliferative bronchiolitis (“early”), constrictive bronchiolitis (“late”), or both may be seen. The pathogenetic mechanisms in development of obliterative bronchiolitis secondary to infections and the reason for the predilection in infants are unknown. Treatment Treatment is symptomatic, including administration of supplemental oxygen and adequate hydration. Bronchodilators,

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antibiotics, antiviral agents, and corticosteroids are frequently used in management, but few controlled clinical trials on their efficacy have been performed. Mechanical ventilation is rarely required; it may be necessary if progressive respiratory failure ensues. Lung transplantation has been performed in severe cases. Prognosis Recovery is usual and occurs in days or weeks. Whether or not bronchiolitis in infancy predisposes to asthma or chronic obstructive pulmonary disease (COPD) in later life remains unproved. Swyer-James (MacLeod) syndrome—unilateral hyperlucent lung—is a long-term complication of bronchiolitis in children, especially after adenoviral infection occurring in infancy. The affected child may be asymptomatic, but more often he or she has recurrent pulmonary infections and eventually develops bronchiectasis. Dyspnea on exertion, hemoptysis, and chronic productive cough are seen. Patients may have localized, unilateral, or bilateral involvement. The chest radiograph demonstrates lobar or unilateral hyperlucent lung; normal or reduced volume of the affected lung is noted on full inspiration. Severe airway obstruction occurs during expiration. The affected lung has a diminished pulmonary vascular bed, decreased pulmonary blood flow, and reduced peripheral vascular markings. Bronchography demonstrates diffuse bronchiectasis with absence of filling of the terminal bronchioles (“pruned tree” appearance). HRCT is the procedure of choice for identifying the characteristic changes in SwyerJames syndrome. The final size of the affected lung in Swyer-James syndrome relates to the age of the patient at the time bronchiolitis occurs. If it occurs early in life, the lung fails to grow normally and appears smaller than the opposite lung. If the bronchiolitis occurs later in childhood, the lung may be of normal size. Pulmonary function tests reveal airflow obstruction and a reduced total lung capacity in cases where concomitant pulmonary fibrosis exists. The syndrome has been reported with a number of etiological agents and must be distinguished from congenital absence of the pulmonary artery, pulmonary artery occlusion, partial obstruction of a lobar or main bronchus, and congenital lobar emphysema. CT and pulmonary angiography are helpful in distinguishing among these conditions.

Infectious Bronchiolitis in Adults Acute bronchiolitis in older children and young adults has been associated primarily with M. pneumoniae ; however, a number of other viruses (e.g., respiratory syncytial virus, especially in the elderly) and bacterial agents have been identified (Table 52-1). Only sporadic cases of bronchiolitis obliterans secondary to infections have been reported in adults (Fig. 52-5). The clinical presentation of infectious bronchiolitis in adults is ill defined; no systematic study has been reported. Most patients have a history of an upper respiratory tract

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Figure 52-5 Acute infectious bronchiolitis. Photomicrograph showing acute bronchiolitis in a patient with adenovirus infection. An intraluminal infiltrate associated with epithelial necrosis (lower left) is present. In addition, a peribronchiolar infiltrate of acute and chronic inflammatory cells is demonstrated. (H&E stain, ×156.)

illness that precedes the onset of dyspnea with exertion, cough, tachypnea, fever, and wheezing. Measles, varicellazoster, and pertussis have been reported to cause bronchiolitis obliterans in adults. A number of adults have developed an acute or subacute diffuse ventilatory obstruction that has occasionally been fatal.

IDIOPATHIC FORMS OF BRONCHIOLITIS Several clinicopathological syndromes associated with prominent bronchiolar impairment have been reported recently. Although no specific origins have been identified, the constellation of findings in reported cases suggests that these syndromes are unique and must be distinguished from more common problems, including COPD, pneumonia, and pulmonary fibrosis. In the discussion below, three syndromes are highlighted: cryptogenic adult bronchiolitis, respiratory bronchiolitis-associated interstitial lung disease (RB-ILD), and cryptogenic-organizing pneumonia (COP) or idiopathic BOOP.

Cryptogenic ‘‘Adult’’ Bronchiolitis Cryptogenic adult bronchiolitis is a rare clinicopathological syndrome that must be distinguished from asthma, chronic bronchitis, emphysema, cystic fibrosis, bronchiectasis, and α1 -antitrypsin deficiency. Few cases have been reported, and it is not entirely clear that all of those reported are the same entity. For example, many patients have had a significant cigarette smoking history and may have smoker’s bronchiolitis. Despite these concerns, the constellation of findings in reported cases is unique and suggests that adult bronchiolitis represents a distinct, definable clinicopathological entity that is a diagnostic challenge to clinicians and pathologists.

The pathogenesis of cryptogenic adult bronchiolitis is unknown. The true incidence of the disease is also unknown, but has been estimated to be approximately 4 percent of all causes of obstructive lung diseases. The disorder is diagnosed largely by exclusion and requires a high index of suspicion, along with an awareness of its unique clinical features. Clinical Findings Most patients are middle-aged women who have a nonproductive cough, shortness of breath, or other nonspecific chest complaints, usually of relatively short duration (6 to 24 months). Most are identified because of an accelerated, severe obstructive respiratory disorder that is clinically distinct from the more commonly encountered obstructive disorders. A history of cigarette smoking, chronic sputum production, frequent chest infections, wheezing, known connectivetissue disorder, and immunoglobulin deficiency are absent. No association with inhalation injury or viral infection has been identified. Physical findings are unremarkable, although wheezing or crackles may be heard. Diagnostic Studies The chest radiographic findings are normal or nonspecific. Increased bronchial wall thickening may be seen. Hyperinflation (without marked flattening or hyperlucent areas) may be the only abnormality noted. HRCT scanning is normal or shows airway dilatation. Pulmonary function testing yields a variety of results. Most patients have increased lung volumes and airflow limitation. A few patients who have had pressure-volume curves performed show an upward shift and a normal slope, consistent with airflow limitation. The diffusing capacity is reduced, and resting hypoxemia may be present. Exercise testing shows gas exchange abnormalities associated with an abnormal [dead space/tidal volume ratio (VD /VT )].

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Bronchoalveolar lavage (BAL) studies demonstrate marked neutrophilia associated with an increase in the specific neutrophil products, collagenase, and myeloperoxidase. Most patients have a neutrophil level over 25 percent (normal for nonsmokers is under 4 percent); some have levels exceeding 90 percent. Pathological Findings Lung biopsies reveal a cellular constrictive bronchiolitis, often quite subtle, with both acute and chronic inflammatory changes, primarily in the membranous bronchioles (Fig. 526). Few cases examined have shown airway obliteration and mucus stasis. The pulmonary parenchyma is normal or shows only mild hyperinflation. Mild focal interstitial fibrosis has

Figure 52-6 Cryptogenic constrictive bronchiolitis. A. Constrictive bronchiolitis with bronchiolar smooth-muscle hyperplasia and mild submucosal and adventitial bronchiolar scarring. Alveolar parenchymal architecture is preserved; no significant interstitial inflammation or fibrosis is present (H&E stain). B . Histiocytes in the lumen of some bronchioles. While intraluminal histocytes are common in smokers, their presence in nonsmokers suggests airway pathology analogous to mucus stasis (H&E stain).

been identified in a few subjects. No vascular lesions have been described. Treatment Steroids may be of benefit in many patients with adult bronchiolitis. Early treatment may be important, since irreversible structural changes and persistent, progressive breathlessness may develop, often with recurrent bouts of respiratory infection. BAL neutrophilia returns toward normal in patients who respond to treatment. Thus, recognition of these cases and distinction from other small-airway disorders (e.g., RBILD, asthma, chronic bronchitis, emphysema, bronchiolitis associated with connective-tissue disease, and diffuse panbronchiolitis) are possible and important.

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Respiratory Bronchiolitis-Associated Interstitial Lung Disease Bronchiolitis has been demonstrated in patients exposed to cigarette smoke. The inflammation and fibrosis lead to distortion and narrowing of small airways. Because respiratory bronchiolitis was initially found at autopsy in young cigarette smokers without known disease, the lesions were considered to be clinically insignificant. Later, it was hypothesized that the lesions in respiratory bronchioles could explain the mild abnormalities in lung function seen in cigarette smokers—socalled small-airway disease (i.e., elevated airflow resistance, airway hyperresponsiveness, and subsequent airflow limitation). More recently, RB-ILD has been recognized as a distinct clinical syndrome found in current or previous cigarette smokers. This disease may be confused with chronic diffuse interstitial fibrosis, desquamating interstitial pneumonitis (DIP), and eosinophilic granuloma of the lung (pulmonary histiocytosis X). The last two disorders also develop almost exclusively in cigarette smokers.

Clinical Findings The male-to-female ratio is 1.6:1. Most are current or former smokers in the fourth or fifth decade of life. The average exposure is more than 30 pack-years of cigarette smoking. The incidence of RB-ILD is unknown. Patients commonly present with dyspnea (70 percent) and cough (58 percent). Coarse crackles are often heard (33 percent) and occur throughout inspiration; sometimes they continue into expiration. Finger clubbing has not been reported. Routine laboratory studies are usually normal. Diffuse, fine reticulonodular interstitial infiltrates are found on the chest radiograph in most patients (80 percent), usually with normal lung volumes. Bronchial wall thickening, prominence of peribronchovascular interstitium, small regular and irregular opacities, and small peripheral ring shadows are distinctive features of respiratory bronchiolitis. Diffuse or patchy ground glass opacities or fine nodules are found on HRCT (Fig. 52-7). Mild emphysema, atelectasis, or linear and reticular interstitial abnormalities are also detected. In a study correlating pathological findings with CT abnormalities, areas of ground glass attenuation were related to three main histological features: (1) accumulation of pigmented macrophages and mucus in alveolar spaces, associated with mild interstitial inflammation or fibrosis; (2) thickening of alveolar walls by inflammatory cells; and (3) presence of organizing alveolitis. The parenchymal micronodules corresponded to bronchiolectases with peribronchiolar fibrosis. Pulmonary function may be normal; however, a mixed obstructive-restrictive pattern is most commonly found. Normal total lung capacity (TLC) and functional residual capacity (FRC) are commonly present, but the residual volume (RV) is usually increased. A normal or slightly reduced diffusing capacity (DlCO ) is frequently present. Hypoxemia may be present at rest or with exercise.

Figure 52-7 Respiratory bronchiolitis-associated interstitial lung disease. High-resolution computed tomography (HRCT) in a 35-year-old woman with a heavy smoking history and progressive dyspnea with exertion. Extensive ground glass opacities are demonstrated. The plain chest film was normal. The diagnosis was confirmed by open lung biopsy. Symptoms improved after smoking cessation.

Histopathological Findings An inflammatory process in the membranous and respiratory bronchioles is the characteristic histopathological feature of RB-ILD. Tan-brown pigmented macrophages within respiratory bronchioles, neighboring alveolar ducts, and alveoli dominate the pathological findings (a “DIP-like” reaction) (Fig. 52-8). These macrophages stain strongly with diastasepredigested periodic acid–Schiff. The bronchiole may be ectatic with mucus stasis; the walls are mildly thickened. Frequently evidence of extension of the bronchiolar metaplastic epithelium into the immediately surrounding alveoli is observed. Most of the interstitium is usually normal; alternatively, it may demonstrate mild hyperinflation. The findings are sometimes so subtle as to be missed during routine evaluation. On occasion, examination of multiple-step sections may be required. Many cases of respiratory bronchiolitis have actually been misclassified as DIP. Similar pathological findings have been demonstrated in other conditions. Treatment The clinical course and prognosis of RB-ILD are unknown. Most studies suggest a favorable response to corticosteroids, with documented improvement in the chest radiograph and in lung function. Since smoking appears to play a role in pathogenesis, smoking cessation is considered to be important in management.

Cryptogenic-Organizing Pneumonia Cryptogenic-organizing pneumonia (COP), or idiopathic BOOP, is a distinct clinical entity that was described in 1901

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Figure 52-8 Respiratory bronchiolitisassociated interstitial lung disease (RB-ILD). Photomicrograph shows inflammatory process in the membranous and respiratory bronchioles. Bronchiole wall is thickened, and bronchiolar metaplastic epithelium extends into immediately surrounding alveoli. Macrophages are present within the peribronchiolar alveolar spaces (desquamating interstitial pneumonitis [‘‘DIP”]-like reaction) (H&E stain).

by Lange. However, recognition of COP increased in the early 1980s, as several investigators highlighted the characteristic clinical course and suggested that COP is a distinct entity with features of pneumonia, rather than a primary airway disorder. The true incidence and prevalence of COP are unknown; a prevalence of 6 to 7 per 100,000 admissions has been reported. Clinical Findings Disease onset is usually in the fifth or sixth decade, with a mean age of 58 years; men and women are affected equally. Almost three-fourths of patients have symptoms for less than 2 months; few have symptoms for more than 6 months before diagnosis. Cigarette smoking is not a precipitating factor, since approximately 50 percent of subjects are never-smokers, 25 percent are ex-smokers, and only 25 percent are current smokers. The clinical presentation may mimic that of community-acquired pneumonia. A persistent and usually nonproductive cough is the most common presenting symptom (72 percent of subjects). Frequently, patients experience dyspnea with exertion (66 percent). Disease onset is usually described as a flulike illness, with fever (51 percent), malaise (48 percent), fatigue, and cough. Weight loss of greater than 10 lb is a common complaint (57 percent). Physical examination reveals inspiratory crackles (74 percent); wheezing is rare and is usually present in conjunction with crackles. Clubbing is rare (fewer than 5 percent of patients). Twentyeight percent of patients in one series had normal pulmonary function. Laboratory Findings Routine laboratory studies are nonspecific. A leukocytosis is seen in approximately half of patients. The initial erythrocyte sedimentation rate is elevated, frequently reaching or exceeding 100 mm/h; a positive C-reactive protein is observed in 70

to 80 percent of patients. Autoantibodies are usually negative or only slightly positive. Chest Imaging Studies The radiographic manifestations of COP are quite distinctive: bilateral, diffuse alveolar opacities in the presence of normal lung volume (Fig. 52-9). This pattern was present in 79 percent of reported subjects for whom the radiographic appearance was detailed. A peripheral distribution of opacities, very similar to that thought to be “virtually pathognomic” for chronic eosinophilic pneumonia, is also seen. The alveolar opacities may be unilateral. In addition, recurrent and migratory pulmonary opacities are common. Fifty percent of Japanese patients with idiopathic BOOP demonstrated migration of radiographic shadows. Irregular linear or nodular interstitial infiltrates were rarely present as the sole radiographic manifestation. Honeycombing is rarely seen at presentation and is discussed only as a late manifestation in the few patients who have progressive disease. Other radiographic abnormalities—such as pleural effusion, pleural thickening, hyperinflation, and lung cavities—seldom occur. Severity of the radiographic abnormalities correlates with the extent of histological involvement of the respiratory bronchioles and alveolar ducts, but not of the larger terminal bronchioles. CT of the lung reveals patchy airspace consolidation, ground glass opacities, small nodular opacities, and bronchial wall thickening and dilation. These patchy opacities occur more frequently in the periphery of the lung and are often in the lower lung zones (Fig. 52-9). CT may reveal much more extensive disease than is expected from review of the plain chest radiograph. Physiological Findings Pulmonary function is usually impaired; a restrictive defect is the most common finding. An obstructive defect (ratio of forced expiratory volume in 1 second to the forced vital

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patients (72 percent). Widening of the resting alveolar arterial oxygen gradient (greater than 20 mmHg) and exercise-related hypoxemia are common abnormalities (83 percent).

Figure 52-9 Cryptogenic-organizing pneumonitis (COP) in a 62year-old man with a 1-month history of dyspnea with exertion, fatigue, and weight loss. A. Posteroanterior radiograph reveals bilateral patchy alveolar opacities. B . Computed tomography shows bilateral patchy airspace consolidation in the right and left lower lobes. Air bronchograms are present on the right. Corticosteroid therapy resulted in complete resolution.

capacity percent [FEV1 /FVC%] less than 70 percent) is found uncommonly (in fewer than 21 percent of cases) and is seen mostly in patients who are current or former smokers. Lung function is occasionally normal. The pressure-volume curve is shifted downward and to the right, consistent with noncompliant lungs. The maximal transpulmonary pressure and the coefficient of elastic recoil (maximal transpulmonary pressure divided by TLC) are increased. Gas exchange abnormalities are extremely common. The DlCO is reduced in most

Bronchoalveolar Lavage Cellular Findings Bronchoalveolar lavage (BAL) studies have been reported in only a few subjects with COP. The percentage of instilled fluid recovered from patients with COP is lower than that from healthy volunteers. However, the total number of cells recovered is greater in patients with COP. The proportion of macrophages is lower, while the proportion of lymphocytes, neutrophils, and eosinophils is higher in COP. Patients with COP tend to have higher lymphocyte counts than those with idiopathic pulmonary fibrosis. Other BAL abnormalities in COP include presence of foamy macrophages and, occasionally, mast cells and plasma cells; decreased ratio of CD4 to CD8 cells; normal percentage of CD57+ cells; increased activated T cells, as reflected in human HLA-DR expression; and, occasionally, interleukin-2 (IL-2) receptor (CD25) expression. The findings are similar to those in hypersensitivity pneumonitis; in hypersensitivity pneumonitis, however, CD25 expression is normal, and CD57+ cells are increased. This “mixed pattern” of increased cellularity is thought to be characteristic of COP, especially when associated with multiple alveolar opacities on the chest radiograph. Histopathological Findings The histopathological lesion characteristic of COP is an excessive proliferation of granulation tissue within small airways (i.e., proliferative bronchiolitis) and alveolar ducts, along with chronic inflammation in surrounding alveoli. This organizing pneumonia is the most important basis for the clinical and radiographic manifestations of COP. Several additional key features are notable: (1) the distribution of lesions is usually patchy and peribronchiolar; (2) the lesions are usually located predominantly within the airspace; (3) there is a uniform, recent temporal appearance to the changes in that all the lesions look similar, with an inflamed, edematous-appearing stroma with little collagen deposition; (4) the intraluminal buds of granulation tissue consist of loose, collagen-embedding fibroblasts and myofibroblasts that extend through the pores of Kohn from one alveolus to another, giving rise to the characteristic “butterfly” pattern; (5) the bronchiolar lesions are usually secondary to intraluminal plugs of granulation tissue occurring in association with plugs in the alveolar ducts and alveolar spaces; (6) severe fibrotic changes (honeycombing) are unusual at the time of diagnosis; (7) foamy macrophages are very common in alveolar spaces, presumably secondary to the bronchiolar occlusion; (8) giant cells are rare or absent, and no granuloma or vasculitis is present; and (9) the lung architecture is not severely disrupted. Diagnosis The clinical and histopathological features of COP may be present in other disorders, such as bacterial pneumonia, hypersensitivity pneumonitis, chronic eosinophilic pneumonia,

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viral infection, drug reactions, and connective-tissue disorders. Thus, the diagnosis of COP depends on both the clinical setting and characteristic pathological features, including the prominent finding of the BOOP pattern in the absence of features suggestive of an underlying process. An open or thoracoscopic lung biopsy is recommended to confirm the diagnosis. Ample lung tissue must be obtained and carefully reviewed to rule out other diseases, especially idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, chronic eosinophilic pneumonia, and diffuse alveolar damage seen in the acute respiratory distress syndrome. Transbronchial lung biopsies are generally inadequate in confirming COP and ruling out other disorders. The histopathological features of bronchiolitis obliterans associated with areas of organizing pneumonia can be seen in a number of settings; therefore, small biopsies increase the chance of missing the central diagnosis. Step-sectioning of transbronchial biopsies is useful in identifying the lesions of COP. The biopsies must be reviewed by an experienced lung pathologist who has been given adequate clinical information to guide the search for specific lesions supporting the diagnosis. Once the characteristic findings of proliferative bronchiolitis are confirmed, the clinician must ensure that a thorough search has been performed to rule out the many other diagnostic considerations. Indeed, the clinicopathological syndrome of COP is a diagnosis of exclusion.

Treatment and Clinical Course Corticosteroid therapy is the most common treatment. Complete clinical recovery, physiological improvement, and normalization of the chest film are seen in two-thirds of patients. Approximately one-third demonstrate persistent disease. In general, clinical improvement is rapid, within several days or a few weeks. Occasionally, recovery is quite dramatic. Relapses occur commonly when corticosteroids are withdrawn after 1 to 3 months. Most patients who relapse show improvement when re-treated with corticosteroids. Spontaneous improvement in a few patients appears to occur over 3 to 6 months. Patients with airspace opacities on the chest radiograph have a much better outcome than those with interstitial opacities. The overall prognosis for COP is much better than for other interstitial lung diseases (e.g., idiopathic pulmonary fibrosis). Rapidly fatal COP is uncommon. Based on our clinical experience and that of others, high-dose oral corticosteroid therapy should be used to treat COP. Therapy is usually initiated with prednisone in a dose of 1 to 1.5 mg/kg per day (using ideal body weight), not to exceed 100 mg daily. The drug is given as a single oral dose in the morning, and the dose is maintained for 4 to 8 weeks. If, after 5 to 8 weeks, the patient’s condition is stable or improved, the dose is gradually tapered to 0.5 to 1 mg/kg per day for the ensuing 4 to 6 weeks. High-dose parenteral corticosteroid therapy (e.g., methylprednisolone, 125 to 250 mg

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intravenously every 6 h for 3 to 5 days) has been recommended as initial treatment for patients with rapidly progressive COP. For the patient in stable or improved condition, the prednisone is gradually tapered off after 3 to 6 months of therapy. A chest radiograph and pulmonary function tests should probably be performed every 6 to 8 weeks during the first year, and therapy should be reinstituted aggressively with any sign of recurrence. Although therapy with corticosteroids is usually well tolerated, side effects are common; some patients develop side effects more readily than others. If the patient’s condition deteriorates despite corticosteroid therapy, a cytotoxic agent should be considered while low-dose (0.25 mg/kg per day) therapy with prednisone is continued. Cyclophosphamide and azathioprine have both been used successfully, although the optimal dose in COP is unknown.

Localized Bronchiolitis Obliterans-Organizing Pneumonia Occasionally, localized areas of BOOP are found at open lung biopsy, usually performed to rule out carcinoma. These lesions present radiographically as irregular nodules or irregular sublobar areas of airspace consolidation. Surgical resection usually resolves this problem. The origin of the lesions is unknown and may be secondary to resolving pneumonia.

CONNECTIVE-TISSUE DISEASES Pulmonary impairment is common in many of the connective-tissue disorders. In most cases, the pulmonary dysfunction is related to alveolar, rather than airway, pathology. Bronchiolitis appears to occur infrequently and varies in its manifestations among the connective-tissue diseases. Further, most of the current understanding of bronchiolar disease in this setting is based largely on anecdotal case reports or small case series. Bronchiolitis, both constrictive and follicular, is most common in patients with rheumatoid arthritis. This section reviews the characteristics of bronchiolitis in rheumatoid arthritis, Sj¨ogren’s syndrome, systemic lupus erythematosus, progressive systemic sclerosis, polymyositis, and dermatomyositis.

Rheumatoid Arthritis and Constrictive Bronchiolitis Obstructive pulmonary disease is remarkably prevalent in rheumatoid arthritis. In particular, bronchiolitis obliterans with airway obstruction is an increasingly recognized complication of this connective-tissue disorder. The basic lesion is fibrous narrowing and obliteration of the bronchioles and smallest bronchi. The role of prior penicillamine therapy as a potential etiological factor remains to be confirmed.

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Clinical Findings Most patients are middle-aged women with long-standing seropositive rheumatoid arthritis. This finding is consistent with the increased incidence of rheumatoid arthritis in women, but it is inconsistent with the increased frequency of pulmonary disease in rheumatoid arthritis reported among men. The clinical manifestations of bronchiolitis obliterans associated with rheumatoid arthritis help to distinguish it from other pulmonary processes associated with this disorder. Clinical findings include the rather abrupt onset of dyspnea and dry cough, often associated with inspiratory crackles and a mid-inspiratory “squeak.” The chest radiograph is typically normal, but it may show signs of air trapping. HRCT usually excludes the presence of bronchiectasis. Expiratory CT often shows multiple scattered areas of air trapping consistent with small-airway obstruction. Pulmonary function studies reveal airflow obstruction and normal pulmonary compliance. Arterial blood gases show moderate hypoxemia and a respiratory alkalosis. The rapid rate of progression in airflow obstruction is atypical for COPD. Histopathological Findings A “constrictive” bronchiolitis is most common. Lymphoplasmacytic infiltration of small-airway walls is noted. The lumina are gradually obliterated, and the bronchiolar wall is destroyed by granulation tissue. Lesions are usually confined to the small bronchi and bronchioles. Parenchymal involvement is generally localized to areas surrounding the bronchiolitis. Lesions may be at different stages of development or may appear uniform. Immunofluorescence studies show granular depositions of IgM and a striking linear deposition of IgG in the alveolar wall, suggesting possible direct immunemediated lung injury. Treatment and Prognosis Treatment with antibiotics and bronchodilators is ineffective. Corticosteroid therapy appears effective in some patients. The use of intravenous cyclophosphamide and oral prednisone has been suggested. One case report has described improvement of refractory rheumatoid arthritis-associated bronchiolitis in a patient treated with etanercept (tumor necrosis factor [TNF]-α inhibitor) and methotrexate. The prognosis is poor, with early deaths reported. In most patients, the disease runs a chronic course.

Rheumatoid Arthritis and Bronchiolitis Obliterans-Organizing Pneumonia Occasionally, in rheumatoid arthritis, patchy organizing pneumonia with granulation tissue plugs extending into the alveolar ducts (BOOP) is the predominant lesion. Rheumatoid arthritis with BOOP appears to have a worse prognosis than does rheumatoid arthritis with constrictive bronchiolitis. In fact, patients with rheumatoid arthritis and BOOP are

Figure 52-10 Follicular bronchiolitis. Thin-section (1.5-mmcollimation) computed tomography scan through the lower zones in a 61-year-old man with a mixed collagen vascular disease demonstrates multiple well-defined nodules. Several nodules (solid arrows) are clustered and located a few millimeters from the pleura or interlobular septa, which indicates centrilobular distribution. Mild interlobular septal thickening (open arrows) is also present. (From Howling SJ, Hansell DM, Wells AU, et al: Follicular bronchiolitis: Thin-section CT and histologic findings. Radiology 212:637–642, 1999.)

prone to development of a rapidly progressive, fatal form of pneumonia.

Rheumatoid Arthritis and Follicular Bronchiolitis Follicular bronchitis and bronchiolitis may occur in patients with rheumatoid arthritis, Sj¨ogren’s syndrome, juvenile rheumatoid arthritis, immunodeficiency syndromes, familial lung disorders, chronic infection, and hypersensitivity-type reactions. Patients with rheumatoid arthritis always present with dyspnea; fever and cough occur occasionally. A positive rheumatoid factor is present, often at high levels (rheumatoid factor titers of 1:640 to 1:2560). The chest film is abnormal, showing bilateral reticular or nodular opacities (Fig. 5210). Arterial blood gases demonstrate hypoxemia, hypocapnia, and a widened alveolar-arterial oxygen gradient. Both obstructive and restrictive patterns have been identified by spirometry, but the restrictive pattern appears to be more common. Immunofluorescence studies are negative. The lesions of follicular bronchiolitis produce obstruction by external compression of bronchioles, rather than by direct luminal occlusion, as is characteristic of proliferative bronchiolitis obliterans (Fig. 52-11). In almost all cases, a concentric inflammatory infiltrate of lymphocytes and plasma cells surrounds the bronchiole. Abundant germinal centers in the peribronchiolar regions are present and are characterized by hyperplastic follicles located between bronchioles and pulmonary arteries. The bronchiolar lumen is often compressed into a slitlike or fish-mouth shape. Some have suggested that follicular bronchiolitis may be the precursor of interstitial lymphoid pneumonia or pseudolymphoma. Treatment with

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Progressive Systemic Sclerosis Clinically significant small-airway disease is not often found in nonsmokers with progressive systemic sclerosis, even in the presence of interstitial pulmonary involvement. Focal lymphoid hyperplasia (follicular bronchiolitis) was identified in 23 percent of the open lung biopsies from patients with progressive systemic sclerosis. Interstitial lung disease is the most important pulmonary complication of this disorder.

Polymyositis and Dermatomyositis

Figure 52-11 Proliferation of lymphoid follicles with germinal centers along the airways and infiltration of the epithelium by lymphocytes (H&E stain). (Slide courtesy of Jeffrey L. Myers, M.D., Mayo Clinic, Rochester, MN.)

BOOP, usual interstitial pneumonia, and diffuse alveolar damage are the most common histological patterns identified in patients with polymyositis and dermatomyositis. BOOP may occur de novo. Patients with polymyositis or dermatomyositis and BOOP present with cough, fever, and dyspnea, in addition to the proximal muscle weakness, malaise, and rash commonly found in this disease. The pulmonary lesion is responsive to corticosteroid therapy.

corticosteroids has yielded variable results. Erythromycin may be useful for the management of this process.

¨ Sjogren’s Syndrome Obstructive airway disease has been reported in patients with Sjögren’s syndrome, often in association with other connective-tissue diseases, particularly rheumatoid arthritis. Desiccation of the tracheobronchial tree is very common in Sjögren’s syndrome and no doubt accounts for the obstructive findings. Atrophic rhinitis, xerostomia, xerotrachea (manifested by chronic, dry cough), chronic bronchitis (with cough and production of tenacious sputum), atelectasis (with frequent middle-lobe collapse), and recurrent bronchopneumonia are manifestations of the severe mucosal dryness that can occur within the tracheobronchial tree. Secondary BOOP has been reported as a rare complication of Sjögren’s syndrome. The clinical impact of the obstructive airway dysfunction in Sjögren’s syndrome is rarely severe. Most symptomatic patients complain only of a dry cough and mild dyspnea. Adequate studies addressing pulmonary function and pathology are limited. However, lung biopsy has revealed a mononuclear cell infiltration around narrowed small airways (i.e., constrictive bronchiolitis).

DRUG-INDUCED CAUSES OF BRONCHIOLITIS Bronchiolitis, usually with organizing pneumonia, has been reported in association with a number of drugs (Table 52-1). Most reports are of single cases or small case series.

Bronchiolitis Associated with Gold Compounds Several forms of pulmonary disease occur among patients treated with gold, including chronic interstitial pneumonitis, organizing pneumonia, and bronchiolitis obliterans. Pure bronchiolitis obliterans with airflow obstruction has been associated with gold therapy, especially in patients with rheumatoid arthritis. Since patients with rheumatoid arthritis are prone to develop bronchiolitis obliterans, determination of whether the cases resulted from gold-induced airway injury is difficult.

Amiodarone-Induced Bronchiolitis Systemic Lupus Erythematosus Fewer than 5 percent of patients with systemic lupus erythematosus (SLE) have airflow obstruction. A patient with SLE who developed rapidly progressive airway obstruction and demonstrated early obliterative bronchiolitis on open lung biopsy has been reported. Hence, this lesion may account for the obstructive dysfunction occasionally seen in SLE. BOOP has also been reported in two patients with SLE. Although one patient responded to corticosteroid therapy, the other died, despite treatment with corticosteroids and cyclophosphamide.

An organizing pneumonia with or without bronchiolitis obliterans (BOOP-pattern) is seen in approximately 25 percent of cases of amiodarone-induced lung disease. This presentation is acute and characterized by cough, fever, dyspnea, and patchy alveolar opacities on the chest radiograph. Findings mimic an infectious pneumonitis. Pleuritic chest pain and nonproductive cough are common. Crackles and pleural rub are typically evident on auscultation. Treatment consists primarily of stopping the drug, provided that alternative treatment options are made for potentially life-threatening arrhythmia. Corticosteroid therapy (prednisone 40 to 60 mg a day, tapering over 2 to 6 months)

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can be life-saving for severe cases and for patients in whom withdrawal of amiodarone is not advisable. Because of the drug’s accumulation in fatty tissues and its long elimination half-life (approximately 45 days), pulmonary toxicity may progress despite drug discontinuation; furthermore it may recur upon steroid withdrawal.

Sauropus Androgynus-Induced Bronchiolitis An outbreak has been reported in Taiwan of rapidly progressive respiratory distress associated with consumption of uncooked Sauropus androgynus, a vegetable claimed to be effective in weight control. Most patients were young or middleaged women who consumed the juice of uncooked Sauropus androgynus, generally mixed with guava or pineapple juice, for a mean duration of 10 weeks. Progressive dyspnea and persistent cough were the main symptoms on presentation. Pulmonary function testing uniformly revealed moderate to severe airflow obstruction. Hypoxemia was also present. The chest radiographs were essentially normal. HRCT showed bilateral bronchiectasis and patchy low attenuation of lung parenchyma with mosaic perfusion. The radiographic presence of air-trapping was better correlated with changes in pulmonary function than was bronchiectasis. Findings on ventilation-perfusion lung scans were compatible with obstructive lung disease. Open lung biopsy specimens confirmed the presence of bronchiolitis obliterans. No effective treatment has been reported; the clinical response to prednisolone is limited.

ORGAN TRANSPLANTATION Pulmonary disease is a common complication of organ transplantation and, consequently, it is a significant source of morbidity and mortality in transplant recipients. Bronchiolitis, manifested by progressive airflow obstruction, is increasingly becoming one of the most frequent noninfectious posttransplant respiratory complications. The BOOP pattern has also been reported in transplant recipients.

graft-vs.-host disease (GVHD). GVHD has been postulated to play a role in the development of this lung disease. Bronchiolitis obliterans is most prevalent in patients after allogeneic transplantation, but it has been recently reported with autologous bone marrow transplantation, as well. Clinical Findings Approximately 10 to 17 percent of long-term survivors with chronic GVHD develop severe obstructive pulmonary disease. Risk factors include older age, recurrent sinusitis, chronic GVHD, methotrexate prophylaxis for GVHD, and acquired hypogammaglobulinemia. Patients usually present with nonproductive cough (60 percent), dyspnea with exertion (51 percent), and nasal congestion. Scattered wheezes are heard in 40 percent of patients; expiratory “squeaks” are also frequently noted. Bibasilar crackles are uncommon. Radiographic Findings The chest radiograph may show diffuse interstitial infiltrates; in approximately 80 percent of cases, the lung fields are normal. Hyperinflation may also be seen. Pneumothoraces may complicate the course of advanced disease. HRCT can be helpful in supporting the diagnosis. In established bronchiolitis obliterans, the most striking CT feature is lobular or segmental areas of lung attenuation, associated with narrowing of pulmonary vessels. The attenuation is presumed to represent areas of air trapping and oligemia. Physiological Findings The finding of a new obstructive pattern on pulmonary function testing is a significant signal that bronchiolitis obliterans is developing, especially when noted in the presence of GVHD. Reduced flow, often with hyperinflation and air trapping, is the most common manifestation. Bronchial hyperreactivity also has been identified in some patients after transplantation, but most have fixed obstruction unresponsive to bronchodilators. The presence of bronchial hyperreactivity before transplantation has not been associated with the subsequent development of either clinical or pathologically proven posttransplantation bronchiolitis obliterans. The diffusing capacity is reduced, and hypoxemia is common.

Bone Marrow Transplantation Pulmonary disease is a common complication of bone marrow transplantation, occurring in 40 to 60 percent of patients. Furthermore, pulmonary complications are a significant source of morbidity and mortality in transplant recipients. The disease usually results from an infectious pneumonia (bacterial, fungal, or viral, especially cytomegalovirus) or idiopathic interstitial pneumonitis. Lymphocytic bronchitis and lymphoplasmacytic infiltrates of the trachea and large bronchi are among the earliest pulmonary problems encountered after bone marrow transplantation. Progressive airflow obstruction secondary to bronchiolitis obliterans is one of the most frequent noninfectious posttransplant respiratory complications. Cases appear after the first 100 days following transplantation, usually in the setting of chronic

Histopathological Findings Lung biopsy findings are quite variable. The major changes are in and around the bronchioles. In most patients with rapidly progressive obstruction, marked lymphocytic, plasmacytic, or neutrophilic infiltration of the walls of the terminal respiratory bronchioles and obliteration of the bronchiolar lumina with fibrous tissue and surrounding interstitial fibrosis (i.e., “pure” bronchiolitis obliterans) are found. A moderate lymphocytic infiltrate may invade the adjacent pulmonary parenchyma. Other changes characteristic of constrictive bronchiolitis are frequently noted. The BOOP pattern has also been found after bone marrow transplantation. Transbronchial lung biopsies are usually inadequate for definitive diagnosis. An open or thoracoscopic lung biopsy is

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Figure 52-12 Bronchiolitis obliterans associated with bone marrow transplantation. Curve A shows posttransplant survival of 35 patients who developed obstructive lung disease. Curve B shows posttransplant survival of 412 concurrent patients (age 16 years or over) with chronic graft-vs.-host disease who survived at least 80 days after transplantation and who had no evidence of obstructive lung disease. (Based on data from Clark JG, Crawford SW, Madtes DK, et al: Obstructive lung disease after allogeneic marrow transplantation. Clinical presentation and course. Ann Intern Med 111:368–376, 1989, with permission.)

often necessary. Since infections are frequent, they should be diagnosed and treated promptly. In this setting, BAL analysis is useful only in ruling out infections. A lymphocytic (i.e., 30 to 50 percent lymphocytes in BAL fluid) or mixed lymphocyte-neutrophil predominance is usual. Management The appropriate treatment of bronchiolitis obliterans associated with bone marrow transplantation is unclear. In most cases, bronchodilators and corticosteroids have not improved airflow limitation. Furthermore, use of immunosuppressive agents for the treatment of chronic GVHD has had no consistent beneficial effect on pulmonary function. Consequently, early recognition and management are required if treatment is to be successful. The prognosis is variable. A significant number of reported patients have had progressive or persistent disease; many have died secondary to respiratory failure (40 to 65 percent of subjects) (Fig. 52-12). Increasing recognition, early treatment, and the introduction of cyclosporine have resulted in a reduction of the incidence of posttransplantation obstructive airway disease.

Heart-Lung Transplantation The main pulmonary complication in long-term survivors of heart-lung transplantation is a life-threatening obstructive ventilatory defect—bronchiolitis obliterans. The incidence of obliterative bronchiolitis in this setting has declined in recent years from 50 percent to 10 to 23 percent. However, in a recent study, 65 percent of lung transplant recipients (including 48 heart-lung, 18 single lung, and 8 bilateral-lung recipients) who survived longer than 90 days, and who un-

Bronchiolitis

Figure 52-13 Segmented changes in flow-volume loops in bronchiolitis obliterans associated with heart-lung transplantation. Curves are from a 33-year-old woman 7, 10, 12, and 15 months after transplantation. A. Upper left figure is essentially normal curve. B . Upper right curve shows early ‘‘coving” of the expiratory flow limb over the middle 50 percent of the forced vital capacity. C and D . Progressive obstruction is present at 12 (lower left) and 15 months (lower right). Small boxes in each panel represent normal flow. Flow is expressed in L/s; volume is expressed in L. (Based on data from Theodore J, Starnes VA, Lewiston NJ: Obliterative bronchiolitis. Clin Chest Med 11:309–321, 1990, with permission.)

derwent transplantation more than 15 months before data analysis, developed bronchiolitis obliterans. Clinical Findings Bronchiolitis obliterans is noted clinically several months to several years after heart-lung transplantation. Cough productive of mucopurulent sputum is most often seen. Progressive dyspnea follows. Most patients experience repeated upper respiratory tract infections, both viral and bacterial in origin. Occasionally, disease onset is identified only from abnormalities in routine pulmonary function testing (Fig. 52-13). With advanced disease, wheezing on exertion is common. The development of bronchiolitis obliterans frequently is preceded by acute organ rejection. Often, patients have a history of prior lung infection with cytomegalovirus, Pneumocystis carinii, or Epstein-Barr virus. Chest examination reveals diffuse, coarse crackles, inspiratory squeaks, and expiratory rhonchi. The classic signs of severe airflow obstruction and hyperinflation are seen in advanced, end-stage disease. Radiographic Findings The chest radiograph may be normal in early stages of the disease, but frequently it reveals diffuse, nonspecific peribronchial and interstitial infiltrates and variable pleural thickening. Bronchography and CT reveal central bronchiectasis.

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Physiological Findings Pulmonary function tests show largely irreversible airflow obstruction; however, TLC is reduced. The DlC O is moderately depressed. Hypoxemia and hypocapnia are universally present.

remain unknown. Unsuspected rejection or infection requiring therapy may be seen in 25 percent of surveillance bronchoscopy procedures performed after lung transplantation. Most episodes (68 percent) of unsuspected rejection or infection appear in the first 6 months following transplantation.

Histopathological Findings Histopathological changes affect all areas of the lung, but they are frequently patchy. Inspissated mucus and distal obstructive airway changes are often noted. Diffuse increases in peribronchial and interstitial fibrosis are present in most biopsies. Pleural, venous, and arteriosclerotic vascular changes are common. These changes are different from those in acute pulmonary rejection, which is characterized by perivascular lymphocytic cuffing and diffuse alveolar damage. Clinical acute rejection predisposes to subsequent development of bronchiolitis obliterans. Occasionally, classic BOOP, with patchy organizing pneumonia and granulation tissue plugs extending into the alveolar ducts, is observed as the predominant lesion. The clinical and radiographic features are those seen with BOOP (discussed previously). Usually, known causes of this lesion are identifiedâ&#x20AC;&#x201D;e.g., infection, aspiration, drug reaction, etc.

Management No clearly useful treatment protocol has been established. Efforts at preventing repeated episodes of rejection seem most important. Prompt diagnosis and treatment of acute rejection and any infectious complications are paramount. Routine serial lung function testing and fiberoptic bronchoscopy with transbronchial biopsy and BAL are helpful. The best medical regimen for prevention of bronchiolitis obliterans remains to be defined. Nonetheless, experience suggests that optimal maintenance of immunosuppression requires a regimen that includes azathioprine and cyclosporine. Prednisone is also commonly included. Use of corticosteroids, bronchodilators, antibiotics, antithymocyte globulin, or OKT3 monoclonal antibody has resulted in documented stabilization or reversal of disease in some patients. Retransplantation has been successful. Spontaneous improvement does not occur.

Pathogenesis Increasing evidence suggests that the key pathogenetic factor is a form of alloreactive injury to the bronchial epithelium. Donor-specific alloreactivity of BAL lymphocytes, manifested by a proliferative response to donor spleen cells, appears to be a useful marker for this process. A number of other possible causes or associations of bronchiolitis obliterans in heart-lung transplantation have been described: (1) recurrent, persistent bacterial or viral infections; (2) immunoreaction to the transplanted lung (e.g., GVHD or transplant rejection); (3) altered mucociliary clearance and impaired ciliary function from injury to the pulmonary nerve supply or from abnormal mucus chemistry and viscosity; (4) bronchial artery ligation and resulting alteration in repair of injured bronchi and bronchioles; (5) reaction to immunosuppressive drugs (especially cyclosporine, which has been shown to have fibroproliferative properties that could cause progressive narrowing and obliteration of affected bronchioles); and (6) loss of cough reflex and aspiration, creating a milieu favorable to continued growth of infectious agents. Diagnosis Open or thoracoscopic lung biopsy is required to confirm the diagnosis of bronchiolitis obliterans and to rule out other causes of pulmonary dysfunction in patients who have undergone heart-lung transplantation. With increased recognition of this potential complication, early detection of the disorder through use of serial pulmonary function tests, BAL, and repeated transbronchial lung biopsies can be achieved and may decrease the need for surgical lung biopsy to confirm the diagnosis. The value and role of serial surveillance transbronchial lung biopsies in the absence of clinical symptoms and signs

Lung Transplantation Lung transplant recipients were initially thought not to develop bronchiolitis obliterans. However, this complication is now recognized as the major factor limiting long-term success with this procedure. The incidence of bronchiolitis obliterans among single-lung recipients is approximately 20 percent; in double or bilateral, sequential single-lung recipients, the incidence is 12 percent. Risk factors include recurrent episodes of acute rejection, severe acute rejection, inadequate or fluctuating levels of maintenance immunosuppression, recurrent infections, and ischemic airway injury occurring early after transplantation. Bronchiolitis Obliterans Syndrome Progressive airflow limitation secondary to small-airway obstruction is the hallmark of the bronchiolitis obliterans syndrome (BOS). This syndrome has a variable clinical course. Some patients experience rapid loss of lung function and respiratory failure. Others experience either slow progression or intermittent loss of function with plateaus, during which pulmonary function is stable for prolonged periods of time. BOS likely reflects more than one process. Clinical Findings

The clinical presentation is similar to that described in heartlung transplantation. Nonproductive cough, mild malaise, and fatigue are common symptoms. Eventually, all subjects develop dyspnea. Results of physical examination are usually normal, but inspiratory squeaks may be heard. Crackles are uncommon.

909 Chapter 52 Radiographic Findings

Decreased peripheral vascular markings, slight volume loss, and subsegmental atelectasis may be early changes. A common radiographic finding in long-standing disease is the gradual progression of pleural-based densities in the middle and upper lung zones. Biopsy reveals subpleural parenchymal fibrosis without active inflammation. The scarring may result from relative ischemia in areas of affected lung. HRCT shows lobular or segmental areas of lung attenuation and narrowing of pulmonary vessels, representing regions of air trapping and oligemia. Histopathological Findings

Three major kinds of airway injury may be seen in lung allografts: acute rejection, bronchiolitis obliterans, and lymphocytic bronchitis or bronchiolitis. The lesions of bronchiolitis obliterans affect the membranous and respiratory bronchioles. They are characterized by the features of constrictive bronchiolitis (see above). If a submucosal mononuclear cell infiltrate is present, the lesions are considered “active.” Their absence may indicate “inactive” disease. Vascular changes are often found and usually consist of fibrointimal thickening of arteries and veins, with or without an active inflammatory component. A BOOP pattern, with patchy organizing pneumonia and granulation tissue plugs extending into the alveolar ducts, has been reported in some lung transplant recipients. The clinical and radiographic features are progressive respiratory failure, acute or subacute alveolar opacities noted on chest radiograph, and a restrictive pattern of pulmonary function tests. Usually, known causes of this lesion are identifiable, especially infection. Patients respond well to corticosteroid therapy. Management

Several recent trials have demonstrated significant functional improvement in BOS with treatment of macrolide antibiotics. Prevention of repeated episodes of acute rejection appears important. Prompt diagnosis and treatment of acute rejection and infectious complications are important. A regimen of immunosuppression that includes azathioprine, cyclosporine, and prednisone is most commonly employed. This regimen appears to slow the rate of decline in lung function; however, the overall prognosis remains poor. Approximately 50 percent of all deaths after the first year following transplant are due to bronchiolitis obliterans. Retransplantation has been successfully employed in some patients.

DIFFUSE PANBRONCHIOLITIS Diffuse panbronchiolitis is a distinctive form of small-airway disease that is relatively common in Japan, China, and Korea; it is rare in other parts of the world. A few case reports of the disease in non-Asians have appeared in the literature. A famil-

Bronchiolitis

ial occurrence has been described, with a significant increase in HLA Bw54 (63 percent frequency). The genetic and ethnic background observed with this unique syndrome may be explained on the basis of HLA Bw54 or its related haplotype being confined primarily to some Asian races—e.g., Japanese, Chinese, and Koreans. HLA Bw54 may also be a useful marker in the differential diagnosis of diffuse panbronchiolitis, since the frequency of this haplotype in the general population is very low (11.8 percent). A similar pulmonary lesion has been demonstrated in ulcerative colitis and adult T-cell leukemia. Environmental factors also appear important, since the disorder is very uncommon in persons of Asian ancestry living abroad. Clinical Findings Diffuse panbronchiolitis is more prevalent in men, with a 2:1 male-to-female ratio. The peak incidence occurs between the fourth and seventh decades of life; mean age at presentation is 50 years. Chronic sinusitis is present in 75 to 100 percent of cases. Sinus symptoms often precede chest symptoms by years or decades. Chronic cough with expectoration of copious purulent sputum, exertional dyspnea, and wheezing are the most common clinical manifestations. Cigarette smoking or occupational exposures have not been shown to be predisposing factors. Physical examination reveals coarse crackles; clubbing is not a feature. The most characteristic laboratory abnormality is persistent, marked elevation of serum cold agglutinins; mycoplasmal antibody titers are negative. Rheumatoid factor may be elevated. Immunoglobulin levels are usually normal. BAL studies reveal marked neutrophilia. Radiographic Findings The chest radiograph often reveals small nodular opacities up to 2 mm in diameter; the opacities are seen diffusely throughout the lung fields. A reticular “airway” pattern may be evident with more advanced disease. Hyperinflation may also be present. HRCT yields more information about the location and distribution of the pulmonary disease than do conventional radiographic techniques. HRCT also better reflects the clinical stages and pathology. On HRCT, the nodular shadows are distributed in a centrilobular fashion, often extending to small, branching linear areas of attenuation. The nodular and linear densities correspond to thickened and dilated bronchiolar walls with intraluminal mucus plugs. Inhomogeneity in lung density may be apparent as a result of peripheral air trapping. Bronchiectasis may be prominent in advanced disease. Physiological Findings Pulmonary function tests reveal marked obstruction. Arterial blood gases show hypoxemia, with or without hypercapnia. In rare instances, a restrictive ventilatory defect is present. The diffusing capacity is variably reduced. In general, patients with diffuse panbronchiolitis exhibit less bronchodilator responsiveness than do patients with COPD.

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Figure 52-14 A. Scanning power microscopy shows the inflammatory process has a predilection for bronchioles (H&E stain). B . Inflammatory process characterized by mononuclear cell inflammation of the respiratory bronchioles. Acute inflammation in the lumen of the respiratory bronchiole and chronic inflammation in the wall, including numerous interstitial foam cells, are noted (H&E stain). C . Foamy macrophages in the bronchiolar lumina and adjacent alveoli (H&E stain). (Slide courtesy of Jeffrey L. Myers, M.D., Professor of Pathology, Mayo Clinic, Rochester, MN.)

Histopathological Findings Thickening of the walls of the respiratory bronchiole, infiltration with lymphocytes, plasma cells and histiocytes, and extension of the inflammatory changes into peribronchiolar tissue are noted on biopsy (Fig. 52-14). Advanced disease is manifested by secondary ectasia of proximal bronchioles.

Management and Outcome Optimal therapy for diffuse panbronchiolitis is unclear. Lowdose erythromycin (200 to 600 mg a day) is adequate for most patients. Erythromycin impairs neutrophil chemotaxis, neutrophil superoxide production, and neutrophil-derived elastolytic activity, and it decreases the number of neutrophils in BAL fluid following challenge with gram-negative bacteria. In addition, erythromycin may cause a reduction in mucus production by decreasing glycoconjugate secretion. Finally, erythromycin has been shown to reduce the circulating pool of T lymphocytes bearing HLA-DR, a marker of cellular activation. Corticosteroids are commonly used in treatment regimens, but evidence supporting their efficacy is lacking. Nonsteroidal anti-inflammatory drugs (NSAIDs) may have a role in controlling the bronchorrhea associated with this disease by altering airway epithelial ion and water transport. No controlled trials with NSAIDs have been performed. Routine use of β2 -agonists or ipratropium bromide should be encouraged to promote mucociliary clearance and bronchodilation in patients with a component of reversible airway disease and as a part of routine pulmonary toilet. In addition, treatment of coexisting sinus disease may help in control of airway disease.

Prompt treatment of bronchial infections is also important. The choice of antibiotics should be guided by results of sputum Gram’s stain and culture. The disease progresses insidiously, and the prognosis is often poor, with fatalities due to repeated respiratory infections (particularly with Pseudomonas aeruginosa) that result in respiratory failure.

PRIMARY DIFFUSE HYPERPLASIA OF PULMONARY NEUROENDOCRINE CELLS Primary diffuse hyperplasia of pulmonary neuroendocrine cells is a clinicopathological entity characterized by diffuse hyperplasia and dysplasia of neuroendocrine cells primarily affecting the distal bronchi and bronchioles. The disorder is seen primarily in women in their fifth or sixth decade. Clinical findings include nonproductive cough and long-standing dyspnea (usually of more than 10 years’ duration). All reported cases are in never-smokers. The chest examination is unrevealing. Chest radiographs show diffuse reticulonodular opacities in most; multiple nodules are seen in a few cases. HRCT demonstrates diffuse small-airway thickening, with patchy areas of hyperlucency, suggesting air trapping. The most common physiological abnormality is irreversible airflow obstruction. Open or thoracoscopic lung biopsy is required for diagnosis. The spectrum of histopathological changes includes diffuse hyperplasia and dysplasia of neuroendocrine cells, numerous neuroepithelial bodies, prominent carcinoid tumorlets, and even typical carcinoid tumors in the distal bronchi and bronchioles. Pathogenesis, treatment, and prognosis of the syndrome are unknown. Most patients have a relatively benign course characterized by many years of symptoms.

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SUGGESTED READING Akpinar-Elci M, Travis WD, Lynch DA, et al: Bronchiolitis obliterans syndrome in popcorn production plant workers. Eur Respir J 24:298–302, 2004. Alasaly K, Muller N, Ostrow D, et al: Cryptogenic organizing pneumonia. A report of 25 cases and a review of the literature. Medicine 74:201–211, 1995. Clark JG, Crawford SW, Madtes DK, et al: Obstructive lung disease after allogeneic marrow transplantation. Clinical presentation and course. Ann Intern Med 111:368–376, 1989. Cordier JF: Cryptogenic organizing pneumonitis. Clinics Chest Med 1993;14:677–692. Cortot AB, Cottin V, Miossec P, et al: Improvement of refractory rheumatoid arthritis-associated constrictive bronchiolitis with etanercept. Respir Med 99:511–514, 2005. Costabel U, Teschler H, Guzman J: Bronchiolitis obliterans organizing pneumonia (BOOP): The cytological and immunocytological profile of bronchoalveolar lavage. Eur Respir J 5:791–797, 1992. Davison AG, Heard BE, McAllister WAC, et al: Cryptogenic organizing pneumonitis. Q J Med 52:382–394, 1983. Douglas WW, Colby TV: Fume-related bronchiolitis obliterans, in Epler GR (ed), Diseases of the Bronchioles. New York, Raven Press, 1994, pp 187–213. Douglas WW, Norman G, Hepper G, et al: Silo-filler’s disease. Mayo Clin Proc 64:291–304, 1989. Epler GR, Colby TV, McLoud TC, et al: Bronchiolitis obliterans organizing pneumonia. N Engl J Med 312:152–158, 1985. Estenne M, Maurer JR, Boehler A, et al: Bronchiolitis obliterans syndrome 2001: An update of the diagnostic criteria. J Heart Lung Transplant 21:297–310, 2002. Fitzgerald JE, King TE Jr, Lynch DA, et al: Diffuse panbronchiolitis in the United States. Am J Respir Crit Care Med 154:497–503, 1996. Grinblat J, Mechlis S, Lewitus Z: Organizing pneumonialike process. An unusual observation in steroid respon-

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sive cases with features of chronic interstitial pneumonia. Chest 80:259–263, 1981. Guilinger RA, Paradis IL, Dauber JH, et al: The importance of bronchoscopy with transbronchial biopsy and bronchoalveolar lavage in the management of lung transplant recipients. Am J Respir Crit Care Med 152:2037–2043, 1995. Jensen SP, Lynch DA, Brown KK, et al: High-resolution CT features of severe asthma and bronchiolitis obliterans. Clin Radiol 57:1078–1085, 2002. Kraft M, Mortenson RL, Colby TV, et al: Cryptogenic constrictive bronchiolitis. Am Rev Respir Dis 148:1093–1101, 1993. Kreiss K. Flavoring-related bronchiolitis obliterans. Curr Opin Allergy Clin Immunol 7:162–167, 2007. Kreiss K, Gomaa A, Kullman G, et al: Clinical bronchiolitis obliterans in workers at a microwave-popcorn plant. N Engl J Med 347:330–338, 2002. Lange W: Ueber eine eigenthumliche Erkrankung der kleinen Bronchien und Bronchiolen (Bronchitis et bronchiolitis obliterans). Dtsch Arch Klin Med 70:342, 1901. Maurer JR: Lung transplantation bronchiolitis obliterans, in Epler GR (ed), Diseases of the Bronchioles. New York: Raven Press, 1994, pp 275–289. Nagai N: The value of BALF cell findings for differentiation of idiopathic UIP, BOOP, and interstitial pneumonia associated with collagen vascular disease, in Harasawa M, Fukuchi Y, Morinari H (eds), Interstitial Pneumonia of Unknown Etiology. Tokyo: University of Tokyo Press, 1989, pp 131–136. Sugiyama Y, Kudoh S, Maeda H, et al: Analysis of HLA antigens in patients with diffuse panbronchiolitis. Am Rev Respir Dis 141:1459–1462, 1990. Theodore J, Starnes VA, Lewiston NJ: Obliterative bronchiolitis. Clin Chest Med 11:309–321, 1990. Wright JL, Cagle P, Churg A, et al: Diseases of the small airways. Am Rev Respir Dis 146:240–262, 1992. Yates B, Murphy DM, Forrest IA, et al: Azithromycin reverses airflow obstruction in established bronchiolitis obliterans syndrome. Am J Respir Crit Care Med 172:772, 2005. Zwemer FL, Pratt DS, May JJ: Silo filler’s disease in New York State. Am Rev Respir Dis 146:650–653, 1992.

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53 Bullous Disease of the Lung David M. F. Murphy Alfred P. Fishman

I. DEFINITION

IV. PATHOGENESIS

IX. PATHOPHYSIOLOGY Pulmonary Function Tests Pulmonary Mechanics Exercise Testing Pulmonary Circulation

V. DISTRIBUTION OF BULLAE

X. COMPLICATIONS

VI. ATMOSPHERIC PRESSURE EFFECTS ON BULLAE

XI. TREATMENT Medical Management Surgical Management

II. ETIOLOGY OF BULLAE III. CLASSIFICATION

VII. CLINICAL FEATURES VIII. RADIOLOGIC FEATURES Fluid in Bullae Special Techniques

DEFINITION A bulla is an air-containing space within the lung parenchyma that arises from destruction, dilatation, and confluence of airspaces distal to terminal bronchioles (Fig. 53-1). By definition, a bulla is larger than 1 cm in diameter, and its walls are composed of attenuated and compressed parenchyma. Bullae occur in several different clinical contexts: (1) with emphysema (“bullous emphysema”), particularly with the acinar (paraseptal) variety; (2) with pulmonary fibrosis, as in the late stages of sarcoidosis or complicated pneumoconiosis; (3) in so-called “vanishing lung,” in which the parenchyma is rapidly replaced by multiple bullae; and (4) in lungs that are otherwise normal (“bullous lung disease”) and therefore likely secondary to a mechanism different from that of bullae occurring in conjunction with emphysema (Table 53-1). Distinctions are drawn between bullae, blebs, and cysts (Table 53-2). A bleb is an accumulation of air between the two layers of the visceral pleura that arises when the thin covering of the bleb ruptures and permits entry of air (Fig. 53-1). In contradistinction, cysts are epithelial-lined cavities that may resemble bullae on the chest radiograph. Many fall into the

category of developmental anomalies and include mixtures of mesenchymal and epithelial components that are normally present in the lung. The pathological nature of these cystic lesions is reflected in their names: “cystic adenomatoid malformations,” “peripheral bronchogenic cysts,” “congenital polycystic disease,” and “atypical bronchopulmonary sequestration.” The designation bullous disease is reserved for multiple bullae in lungs that are otherwise normal. This entity is different in etiology and pathogenesis from that in which bullae occur in conjunction with underlying chronic obstructive pulmonary disease (COPD). Confusion occasionally arises between the two entities because some pathologists are inclined to regard bullous disease as a subset of panacinar emphysema. However, this view is not useful clinically on at least three accounts: (1) panacinar emphysema tends to occur in the lower lobes, whereas bullous disease favors the upper lobes; (2) the natural history of the two disorders is quite different; and (3) panacinar emphysema has certain distinctive features not shared by bullous disease (e.g., a “winter tree” appearance on angiography). Bullae may occur not only as part of obstructive lung disease, but also as a complication of fibrotic lung disease (Table 53-1).

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Figure 53-1 Blebs and bullae. A. Development of a bleb. A bleb is an accumulation of air within the pleura that is not confined by connective-tissue septa within the lung. Air that escapes within the substance of the lungs makes its way to the surface, separating the internal from the external elastic layers on the visceral pleura. B. Different types of bullae. In contrast to a bleb, a bulla is confined by connective-tissue septa of the lung and is deep to the internal elastic layer of the visceral pleura. Three different types of bullae are shown arising from a lung that has been removed from within the chest wall. A type I bulla is shown at the apex, a type II is in the middle zone, and a type III is arising at the base. The short dark lines denote connective-tissue septa. Panacinar emphysematous parenchyma is present within the types II and III bullae. (Based on data from Reid L: The Pathology of Emphysema. Chicago, Year Book, 1967, pp 211–240, with permission.)

ETIOLOGY OF BULLAE Bulla may originate in a variety of clinical and pathogenetic settings: (1) with emphysema of distal acini (Fig. 53-2); (2) in the setting of cigarette smoking; (3) in conjunction with scar tissue formation, which “traps” areas of normal lung, enlarges airspaces by traction on surrounding intact alveoli, or produces retraction or shrinkage of intact walls of adherent alveoli; (4) in the setting of intravenous drug abuse; (5) as a result of chronic inflammation and destructive changes in terminal and first-order respiratory bronchioles, resulting in airspace distention from delayed emptying; and (6) with α 1 antitrypsin deficiency in the elderly.

CLASSIFICATION Bullae are classified anatomically into three main types (Fig. 53-1B). Type I bullae are characterized by a narrow neck that connects the bullae with the pulmonary parenchyma. This type of bulla may be caused by over-inflation of a volume of flawed lung tissue. The bullae behave like a paper bag that is extremely compliant until full, when it then becomes tense. The walls of type I bullae are thin, and their interiors are empty. Type I bullae are usually found at the lung apices and

along the edges of the lingula and middle lobes. They often occur in association with paraseptal emphysema. Scanning electron microscopy has demonstrated that the thin neck is a consistent feature and that pleural mesothelial cells on the external surface are either reduced in number or completely absent; bundles of collagen fibers lie naked and separated from one other by small pores or crevices. In contrast, type II bullae arise from the subpleural parenchyma and are characterized by a neck of panacinar emphysematous lung tissue. Also, the interior of these airspaces consists of emphysematous lung in which blood vessels are still present. In contrast to type I bullae, the outer wall is formed by pleura covered with intact mesothelial cells. Although connective-tissue septae are present within the bullae, they are not found in the wall. Type II bullae may occur anywhere in the lung, but they are most frequent in the upper lobe, at the anterior surface of the middle lobe, and over the diaphragm. Type III bullae consist of slightly hyperinflated lung connected to the rest of the lung by a broad base extending deep into the parenchyma. This type is believed to represent an atrophic form of emphysema.

PATHOGENESIS It is unclear how bullous lung disease develops. Several hypotheses have been proposed over the years, but none have

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Table 53-1 Classification of Bullae Primary Vanishing lung syndrome Single giant bulla Bullous lung disease Secondary Emphysema Paraceptal Panacinar Centriacinar Pulmonary fibrosis Sarcoidosis Idiopathic pulmonary fibrosis Progressive massive fibrosis Conglomerate silicosis Fibrotic tuberculosis Other fibrotic lung disorders Familial disorders α1 -antitrypsin deficiency Ehlers-Danlos syndrome Salla disease Marfan’s syndrome Fabry’s disease Cutex laxa

been proved. Among these are the following: (1) Weakness of the alveolar walls predisposes to the formation of bullae, particularly at the apices of the lungs, where pleural pressures are most negative. This theory underscores the proclivity of bullae for the upper lobes and stresses the influence of mechanical forces acting upon flawed tissue. (2) Inflammatory disease of a bronchiole leads to progressive air trapping and

Bullous Disease of the Lung

“tension airspaces.” (3) Disordered collateral ventilation in some way produces the findings. (4) The same mechanisms responsible for generalized emphysema are operative in the formation of bullae. (5) Underlying paraseptal emphysema produces bullous disease. Of all the hypotheses, that of underlying paraseptal emphysema is the most popular. The hypothesis envisages destruction of alveoli adjacent to connective septae or the pleura, with small “bubbles” developing along the edges of the lung. The pattern relates to the fact that capillaries in alveolar walls that abut connective-tissue septa are less numerous than elsewhere because of a sparse network of arterioles and arteries in peripheral alveoli. Consequently, these regions of the acinus have less vascularity and greater compliance. Small bullae rarely become visible on the chest radiograph, but they are usually easily visible by computed tomography (Fig. 53-3). As a rule, small bullae usually produce no symptoms, signs, or discernible alterations in pulmonary function. However, rupture of one or more bullae may lead to spontaneous pneumothorax. Dynamic computerized tomography and intra-bulla pressure measurements have raised questions about the theory that bullae are formed by positive pressure within the airspace. The lung surrounding a bulla is less compliant than the bullae itself; accordingly, the pressure necessary to inflate the surrounding lung is greater than that necessary to inflate the bulla. The pressure within a giant bulla has been found to be the same as pleural pressure. Therefore, when a bulla and its surrounding lung are exposed to the same negative pleural pressure, the bulla fills preferentially and completely like an inflated paper bag, prior to the surrounding lung inflating. Further inspiration increases the elastic recoil pressure, thereby exerting a greater retractive force on the lung parenchyma and enlarging the airspace. Nevertheless, bullae can be removed from within the lung while still maintaining their volume, indicating a positive intra-bulla pressure. Bullae within the intact chest are molded and compressed to fit adjacent anatomic configurations. However, if the lung is released from these constraints (e.g., when removed from the chest cavity), bullae project as shiny bubbles

Table 53-2 Characteristics of Blebs, Bullae, and Cysts Bleb

Bulla

Cyst

Site

Within visceral pleura

Arises within secondary lobule

Lung parenchyma or mediastinum

Size

1–2 cm

1 cm to 75% of a lung

2–10 cm

Lining

Elastic laminae of the pleura

Connective tissue septa

Epithelium

Associated condition

Spontaneous pneumothorax

Bronchogenic carcinoma

Respiratory infection

916 Part IV

Obstructive Lung Diseases

Figure 53-3 A. CT image of the lungs showing paraseptal emphysema visible beneath the visceral pleura and an associated bulla. B. CT image of the lungs showing severe bullous emphysema with hairline markings identifying the walls of several bullae. B

Figure 53-2 A. Surgically resected specimen with a bulla projecting from the lung surface. B. A bulla is shown projecting through a previous chest tube insertion site onto the surface of the skin.

at the lung surface (Fig. 53-2). Within the thoracic cavity, large bullae cause crowding of adjacent lung parenchyma, and structures such as bronchi are displaced, stretched, and narrowed over the bullae surfaces. Very large airspaces can expand across the midline or even extend into the neck. Bullae represent more than just over-expanded alveoli, because the remnants of bronchioles and their accompanying vessels sometimes persist as trabeculae within the bullae.

917 Chapter 53

Interlobular septae can become incorporated into the wall as the airspace expands from within the secondary lobule. Two important risk factors for bullous emphysema are cigarette smoking and α 1 -antitrypsin deficiency. Many patients with bullous emphysema are cigarette smokers, and most bullous lesions are associated with paraseptal or centriacinar emphysema. Although bullous emphysema is typically found in young males, elderly patients with α 1 antitrypsin deficiency who are lifelong nonsmokers may develop bullous changes in later life. A hereditary predisposition to bullous emphysema is also suggested by its association with a variety of rare familial disorders, including Fabry’s disease, Salla disease, cutix laxa, Ehlers-Danlos syndrome and Marfan’s syndrome. Giant bullous emphysema has also been reported with histological changes of placental transmogrification of the lung. The tight skin mouse, which has a dominant mutation for the elastase gene and is characterized by multiple connective-tissue abnormalities, serves as a unique model for bullous emphysema. In addition, pups, which have weakness of bronchial cartilage, may constitute a valuable model.

Bullous Disease of the Lung

high altitude) or increases (e.g., with diving) in atmospheric pressure, respectively. Boyle’s law governs the changes: at constant temperature, the volume of a given mass of gas varies inversely with its pressure. Expressed mathematically, P1 V1 = P2 V2

(1)

where V1 = initial volume V2 = final volume P1 = initial pressure P2 = final pressure Therefore, a twofold increase in pressure results in a 50 percent decrease in volume. In addition, Charles’s law, which states that at constant pressure, the volume of a gas is proportional to its absolute temperature, should be considered in predicting behavior of bullae: V1 /V2 = T1 /T2

(2)

where

DISTRIBUTION OF BULLAE As noted previously, the tendency for bullae to occur in the upper lobes is usually attributed to the greater mechanical stresses imposed on the lung apices than bases. Because intrapleural pressure near the lung apices is more negative than at the bases, apical alveoli are subjected to greater expanding stresses than are basal alveoli. Radioactive gas studies and in situ freezing techniques have demonstrated that alveoli in the upper lung zones are considerably larger than those in the lower zones. Gravity also plays a role, as the upright lung behaves like a coiled spring, which, when allowed to dangle in the upright position, shows larger gaps between coils at the top than the bottom. Engineering techniques used to study the distribution of stresses in aircraft have been applied to the analysis of stresses on the lung. These have shown that the larger expanding stresses at the apices are directed primarily in a vertical direction, and to a lesser extent, laterally. The stresses tend to increase with expansion of the lung, but they are present also when the lung volume decreases below functional residual capacity (FRC). The increase in apical stress at low lung volumes has been attributed to an increase in the rigidity of the lungs as residual volume is approached.

V1 = initial volume V2 = final volume T1 = initial temperature, absolute T2 = final temperature, absolute Combining Boyle’s and Charles’s laws results in the general gas law, which indicates the relationships among pressure, volume, and temperature for an air-filled structure: P1 V1 /T1 = P2 V2 /T2

(3)

Finally, an additional relevant consideration is that within body cavities, gas is not “dry,” but rather, it is saturated with water vapor, the partial pressure of which is related to body temperature. Since normal body temperature is fairly constant at 37◦ C, the partial pressure of water vapor is also constant at 47 mmHg. Furthermore, since water vapor is not compressible, “wet” gases respond to pressure changes differently than dry gases. Expressed mathematically, V1 (P1 − PH2 O) = V2 (P2 − PH2 O)

(4)

where V1 = initial volume V2 = final volume P1 = initial pressure of gas in the cavity, mmHg P2 = final pressure of gas in the cavity, mmHg PH2 O = water vapor pressure

ATMOSPHERIC PRESSURE EFFECTS ON BULLAE

Thus, for a given reduction in pressure, wet gas expands to a greater extent than does dry gas. The magnitude of relative gas expansion is the ratio of the final volume of the gas (V2 ) to the initial volume (V1 ), which can be expressed as:

Changes in ambient pressure have effects on bullae size that may be of clinical importance. Bullae, blebs, and cysts increase or decrease in size with decreases (e.g., with ascent to

V2 /V1 = (P1 − PH2 O)/(P2 − PH2 O) = (P1 − 47)/(P2 − 47) (5)

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Obstructive Lung Diseases

Ascent to 39,000 feet in an unpressurized cabin would result in a fivefold increase in the volume of dry air and a sevenfold increase in the volume of wet air. With reductions in ambient pressure, a pressure differential develops between the inside of a bulla and the external environment. The pressure differential is relieved if air can escape from the bulla to the external environment. If not, the volume of the bulla increases as ambient pressure declines. Normally, changes in bulla volume are limited anatomically by the magnitude of chest cavity expansion. However, with chest over-expansion, or with an inability to decompress, increases in bulla volume may lead to its rupture and air entry into the extraalveolar compartments, including the mediastinum (pneumomediastinum), soft tissues of the chest or neck (subcutaneous emphysema), pleural space (pneumothorax), or vascular system (air embolism). The magnitude of the effect is related to the ratio of pressure of the gas within the bulla to ambient pressure. To some extent, this kind of expansion occurs during commercial air travel, since airplanes are not pressurized to atmospheric pressure but rather to a cabin pressure equivalent to an altitude of 6000 to 8000 feet. However, the incidence of barotrauma in commercial flight is low, probably because bulla volume changes are small. In studies performed in subjects with blebs or bullae who are taken to altitudes of 18,500 feet (at an ascent rate of 1000 feet per minute), little increase in bulla volume is noted, probably reflecting good communication between bullae and airways and adequate pressure equalization. The fact that so little volume change occurs supports the “paper bag” hypothesis for bulla formation, rather than a “ball valve” mechanism. In contrast, with space travel, since spacecraft are maintained at atmospheric pressure, as long as decompression does not occur, no changes in the size of bullae are observed.

CLINICAL FEATURES In asymptomatic individuals, bullae may be detected in the course of routine chest radiography. However, in some patients, bullae give rise to progressive dyspnea or chest pain (Fig. 53-4). On occasion, a patient with bullous lung disease develops sudden, severe breathlessness secondary to development of a spontaneous pneumothorax (Fig. 53-5) or sudden increase in bulla size due to air trapping. Development of bullae in individuals with obstructive airways disease tends to aggravate existing breathlessness, presumably because of a further decline in expiratory flow rates (Fig. 53-6). In patients with known bullous disease, the onset of fatigue, generally accompanied by an increase in coughing and sputum production, usually heralds the presence of infection in a bulla. Occasionally, pleuritic chest pain is part of the syndrome, while fever and leukocytosis are often not prominent. A Gram’s stain of the sputum often shows only mixed flora, without a predominant organism. Radiograph-

ically, infection is usually identified by the appearance of an air-fluid level (Fig. 53-7). Alternatively, the accumulation of fluid may be attributed to impeded drainage of the contents of the bulla secondary to obstruction of microscopic communications between the airspace and pulmonary parenchyma. In some instances, infection of a bulla causes it to disappear completely. More often, the air-fluid level persists for weeks or months after the infection has cleared. The physical findings in a patient with one or more bullae usually reflect the overall state of the lungs. Only infrequently do giant bullae reach a size sufficient to cause a localized decrease in regional air entry, with absent breath sounds and increased resonance to percussion.

RADIOLOGIC FEATURES Although routine chest radiography is the most practical method for identifying the presence of bullae, the technique discloses only about 15 percent of bullae identified at autopsy. In a given patient, serial radiographs taken over years are invaluable in tracing evolution of the disease. The presence of the condition is suggested by areas of increased radiolucency which are sharply delineated by fine radiopaque lines representing the walls of the bullae. These lines, or “hairline shadows,” are composed of compressed and fused interlobular septae or pleura. Because the hairline shadows appear incomplete on the chest radiograph, they delineate only segments of the bulla wall (Fig. 53-5 A and B). Distinction between hairline shadows produced by a bulla, and thicker, sometimes irregular, walls of a cavity is usually not difficult. More troublesome is distinguishing bullae from cysts. The presence of other radiologic signs of emphysema or fibrotic lung disorders suggests that the cystic structure is a bulla. Similarly, distinguishing between a large bulla and pneumothorax may be challenging. Observation of “the double wall sign” (i.e., the presence of air on both sides of the bulla wall) may be helpful in identifying the findings as due to a bulla. The differential diagnosis of multiple, enlarged thin-walled airspaces on the chest radiograph in adults is shown in Table 53-3.

Fluid in Bullae Although a localized air-fluid level on the chest radiograph raises the possibility of infection, the differential diagnosis includes lung abscess, tuberculosis, fungal disease, cavitary lung carcinoma, pulmonary hemorrhage within a bulla, congestive heart failure, and carcinoma arising from within a bulla (Fig. 53-8). The superimposition of a chronic infiltrate and an existing bulla raises the likelihood of concomitant fungal infection or tuberculosis. The presence of a fluid level within a bulla, especially if the bulla is located subpleurally, occasionally prompts the mistaken diagnosis of a loculated hydropneumothorax. Computed tomography is helpful in separating these two conditions: when locules within the bulla fill with fluid, the

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Bullous Disease of the Lung

A B

Figure 53-4 Large bulla in a 35-year-old woman admitted because of chest pain and increasing dyspnea. A. Chest radiograph (PA view). A large translucent area in the left upper lung represents a bulla that is causing compression of adjacent lung. B. Chest radiograph (lateral view). A hairline shadow outlines a large bulla in the left upper lobe. C. Bronchogram of left lung. Compression of the bronchial tree by the large bulla is evident.

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Figure 53-6 The effects of an enlarging airspace on radial traction exerted by elastic tissue on the airways. The reduction in lumen diameter is associated with an increase in airway resistance.

bulla shows characteristic strands or septae, sometimes in a “stepladder” configuration. In contrast, a loculated hydrothorax shows no septae.

Special Techniques

Figure 53-5 Bullous disease in a 53-year-old man. A. Chest radiograph (PA view) showing upper zonal areas of increased radiolucency. B. Chest radiograph (lateral view) showing hairline borders of multiple bullae. C. Chest radiograph showing a leftsided pneumothorax with residual inflated bullae. (Courtesy of Dr. S. Flicker.)

A chest radiograph obtained after forced expiration is sometimes helpful in demonstrating the presence of bullae: air trapping during the expiratory maneuver accentuates their outline by preventing a decrease in their size as the surrounding lung empties. Large bullae sometimes displace the mediastinum contralaterally and may even compress the opposite lung. Computed Tomography Computed tomography (CT) provides valuable anatomic information about the size, number, and relationships of bullae, as well as crowding of adjacent lung and disposition of the pulmonary vasculature. Bullae are identified as areas of radiolucency that usually do not contain blood vessels and that are confined by visible walls. High-resolution computed tomography (HRCT) shows that large bullae are frequently associated not only with distal acinar (paraseptal) emphysema, but also with centri-acinar emphysema—the type of emphysema usually associated with cigarette smoking. These observations are consistent with the hypothesis that peripheral airspaces in paraseptal emphysema may coalesce to form larger bullae that may crowd normal adjacent lung. In addition, CT has shown that when bullae occur in the context of generalized emphysema, the extent of bullous emphysema correlates poorly with measurements of pulmonary function, and that the main determinant of

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Bullous Disease of the Lung

Figure 53-7 An infected bulla in a 44-year-old man with mitral stenosis. A. Chest radiograph (PA view). A translucent area is visible in the right midzone with a clearly defined air-fluid level. B. Lateral radiograph.

respiratory function is the severity of emphysema in the bullous-free parts of the lung (Fig. 53-9). In contrast, the severity of emphysema in nonbullous lung, as assessed by CT-density histograms of the lung, correlates well with measurements of air flow limitation and diffusing capacity. CT has been used to create three-dimensional reconstructions of bullae, which can then be used to calculate bullae volumes. Nuclear Medicine Techniques Lung scanning using radionuclide-based techniques may provide useful preoperative information in evaluating patients with bullous lung disease (Figs. 53-10 and 53-11). A lung

Table 53-3

perfusion scan provides a semiquantitative assessment of regional blood flow; results of ventilation scans vary with the technique: a single-breath scan using 133 xenon often fails to demonstrate ventilation of a bulla, whereas a continuous ventilation scan often shows slow filling and emptying of the structure. Complete lack of communication between the airways and bulla is reflected in the absence of filling during all phases of the continuous ventilation scan. Very occasionally, angiography may be necessary to provide additional information on the pulmonary vasculature (Fig. 53-11). Similarly, a regional bronchogram at the time of bronchoscopy is sometimes helpful in assessing the state of the airways in compressed lung.

PATHOPHYSIOLOGY

The Differential Diagnosis of Thin-Walled Enlarged Airspaces in the Lungs

Clinical evaluation of bullous lung disease is aided by assessment of pulmonary function, pulmonary mechanics, exercise performance, and the pulmonary circulation.

Cystic bronchiectasis

Pulmonary Function Tests

Pneumatoceles

Pulmonary function tests have considerable practical value in distinguishing between individuals with localized bullae in whom intervening lung is normal (bullous disease), and those in whom localized bullae are part of obstructive airways disease (bullous emphysema) (Tables 53-4 and 53-5). The distinction is important, since those with obstructive airways disease are generally poor surgical candidates because of impaired pulmonary function.

Fungal infections (coccidioidomycosis) Septic emboli Parasitic disorders

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Obstructive Lung Diseases

Figure 53-9 CT image showing a giant right upper lobe bulla compressing adjacent pulmonary parenchyma. The bulla was surgically resected with significant improvement in pulmonary function. See Table 53-7.

In individuals with bullous disease, the volume of air in the lungs can be estimated using plain radiography, CT, body plethysmography, or other pulmonary function test methods for determining lung volume, including closed circuit (helium dilution) and open circuit (nitrogen washout) techniques. The volume of air trapped in a bulla can be determined as the difference between the functional residual capacities determined plethysmographically and by open or closed circuit methods (Table 53-6). This difference is due to the relative inability of the inert gas used in the circuit methods to enter the bulla. Although the nitrogen washout curve is usually normal, the concentration of N2 in alveolar gas at the end of the testâ&#x20AC;&#x2122;s 7-minute period of breathing 100 percent O2 is often abnormal. Finally, somewhat counterintuitive is the observation that expansion of a large bulla may produce a restrictive pattern on pulmonary function testingâ&#x20AC;&#x201D;presumably as a result of the bulla compressing intervening normal lung.

Pulmonary Mechanics

Figure 53-8 Infected bullae. A. Bilateral infected bullae in a 62year-old man. B. Fluid levels in both bullae. C. Clearing of the infection revealed a bronchogenic carcinoma on the left. (Courtesy of Dr. M. Feierstein.)

Distinction between widespread obstructive airways disease with concomitant bullae and bullous lung disease has practical significance, since surgical lung resection in generalized emphysema offers a less certain therapeutic response than does resection of giant bullae in the absence of widespread obstructive lung disease. As large bullae expand, they initially cause relaxation of adjacent elastic lung tissue; with continued expansion, adjacent lung is compressed. Relaxation of the surrounding pulmonary parenchyma results in a decrease in radial traction on airways, thereby increasing air flow resistance. The effects of bullectomy on respiratory mechanics are inconsistent. In some patients, removal of a large bulla increases lung static elastic recoil and decreases airways resistance (Table 53-7); in others, bullectomy decreases elastic recoil pressure.

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Figure 53-10 Lung scans in the preoperative evaluation of patients for bullectomy. A. Preoperative ventilation lung scan (133 Xe). Ventilation is absent in the left upper zone. B. Preoperative perfusion lung scan using 131 Imacroaggregated albumin. Blood flow is absent in the left upper zone while it is maintained at the left base. (Courtesy of Dr. A. Alavi.)

As a practical matter, the diffusing capacity, rather than lung elastic recoil, is usually determined to aid in distinguishing between widespread emphysema and localized bullae; indeed, the diffusing capacity correlates better with morphologic estimates of emphysema than do most other tests. Although the combination of a decreased diffusing capacity and reduced static elastic recoil pressure favors the diagnosis of widespread emphysema rather than localized bullae, both measurements may also be decreased by bullae that compress adjacent normal lung. Respiratory muscle strength, assessed by measurements of maximal inspiratory and transdiaphragmatic pressures, improves after bullectomy in some patients with bullous emphysema.

Exercise Testing In patients with a few circumscribed bullae and otherwise normal lungs, exercise testing reveals that the alveolar-arterial difference in PaO2 , ratio of dead space to tidal volume, diffusing capacity, and arterial oxygenation remain normal or near normal with exercise. On the other hand, in patients in whom bullae are associated with panacinar emphysema, the alveolar-arterial difference in PaO2 is widened at rest and during exercise. The latter group of patients also may develop arterial hypoxemia during exercise. The PaCO2 tends to hover around the upper limit of normal at rest and during exercise, and the ratio of dead space to tidal volume is higher than in patients with normal intervening lung. The steady-state diffusing capacity is also reduced and fails to increase normally during exercise.

Patients in whom bullae are associated with chronic bronchitis also show a widened alveolar-arterial difference in PaO2 and an increase in the ratio of dead space to tidal volume at rest. However, in these patients the decrease in PaO2 during exercise is modest, even though the PaCO2 at rest is abnormally high and increases further during exercise (indicating progressive alveolar hypoventilation).

Pulmonary Circulation As a rule, resting pulmonary arterial pressure and blood flow are within normal limits in patients with bullous lung disease (i.e., the bullae act like â&#x20AC;&#x153;amputatedâ&#x20AC;? segments of lung); the volume of the vascular bed available for recruitment as cardiac output increases is limited. However, in patients in whom bullous disease has severely reduced the extent of the pulmonary vascular bed, pulmonary arterial pressure may be elevated at rest and during exercise; in a few instances, pulmonary and cor pulmonale may be observed. Exercise in bullous lung disease is generally associated with an excessive increase in pulmonary arterial pressure as increases in pulmonary blood flow are not effectively accommodated by the restricted vascular bed. Underlying pulmonary disease further exaggerates the increase in pulmonary artery pressure during exercise.

COMPLICATIONS The major complications of bullous lung disease are infection of the bulla, chest pain, hemorrhage, spontaneous pneumothorax, and lung cancer.

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Figure 53-11 Large bulla in a 38-year-old man admitted because of increasing dyspnea. A. A chest radiograph (PA view). A large translucent area in the right upper lung represents an enlarging bulla that is causing compression of adjacent lung. B. Pulmonary arteriogram, subtraction technique. The pulmonary vasculature is compressed by the large bulla. C. Lung scans in the preoperative evaluation of patients for bullectomy. The ventilation lung scan (133 Xe) shows decreased ventilation to the left upper lung zone. The perfusion lung scan using 131 I-macroagglutinated albumin shows blood flow is decreased on the left upper zone while it is maintained at the left base. Quantitative regional ventilation and perfusion obtained from the lung scans of this patient. Ventilation is markedly reduced in the right upper zone. Perfusion is absent in the right upper zone while it is present at the base. (A and B courtesy of Dr. M. Ora; C courtesy of Dr. B. Paczolt.)

925 Chapter 53

Table 53-4

Table 53-5

Pulmonary Function Tests in a 65-Year-Old Black Man with Bullous Lung Disease

Pulmonary Function Tests

Prebronchodilator Spirometry

Actual

% Pred.

Bullous Disease of the Lung

Test

Bullous Disease

Obstructive Airways Disease and Bullae

TLC, L

N↑

RV, L

↑

FRC, L

↑

FRC,∗ L

↑

RV/TLC%

↑

FEV1 , L

N↓

↓

FVC, L

N↓

↓

FEV1 /FVC%

↓

MVV, L/min

↓

Pred.

FVC, L

1.21

3.16

FEV1 , L

0.74

2.46

FEV3 , L

1.03

2.94

FEV1 /FVC%

FEV3 /FVC%

FEF25−75 , L/s

0.34

3.21

PEFR, L/s

3.05

6.57

FIF25−75 , L/s

1.30

5.67

SVC, L

1.42

3.72 ↓

1.13

2.38

DCO /Va, (ml/min/mmHg)/L

IC, L ERV, L

0.28

1.33

Raw, cmH2 O/L/s

N↑

↑

FRC, L

1.60

3.59

Cst, exp, L/cmH2 O

N↑

↑

RV, L

1.31

2.26

Pst, TLC, cmH2 O

N↓

↓

TLC, L

2.73

5.85

∗

RV/TLC%

48.11

123

39.00

DLCO , single breath, ml/min/mmHg Pulmonary vascular pressures Pulmonary artery, mmHg Mean, mmHg

10.06

60/22 27

25.18

30/16 20

True infections within bullae are rare. The presence of an air-fluid level in a bulla usually is attributable to surrounding pneumonitis. Fluid within the airspace is usually sterile, is frequently resorbed, and may be associated with shrinkage and complete resolution of the bulla. Occasionally, a fungus (usually Aspergillus species) colonizes a bulla and may go on to form a mycetoma or “fungus ball” which can lead to hemoptysis.

FRC determined by body plethysmography. Note: N = normal, ↑ = increased, ↓ decreased.

Chest pain may occur with a bulla and is attributed to over-distention of the structure. The pain is angina-like and located retrosternally. The symptom is sometimes so severe as to constitute an indication for surgical intervention. Hemoptysis, which is occasionally massive, can result from rupture of blood vessels within the walls of bullae. Pneumothorax secondary to bulla rupture into the pleural space can severely compromise a patient’s ventilatory reserve in the setting of generalized emphysema. However, bullae per se do not appear to indicate a predisposition to recurrent pneumothoraces. Recurrent spontaneous pneumothorax also may be a complication of paraseptal emphysema, particularly in patients who continue to smoke. Lung density measurements in spontaneous pneumothorax demonstrate air trapping, suggesting a ball-valve mechanism due to peripheral airway inflammation, rather than rupture of preexisting bullae. Patients with ruptured bullae also tend to have prolonged air leaks, along with pleural and parenchymal infections.

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Table 53-6 Pulmonary Function Tests in a 43-Year-Old Man with Right-Upper-Lobe Bulla (see Fig. 53–12) Prebronchodilator Pulmonary Function Tests Actual

Predicted

% Predicted

FVC (L)

4.79

4.69

102

FEV1 (L)

3.39

3.57

FEF25−75% (L/s)

2.24

3.73

PEFR (L/s)

8.74

8.92

FEV1 /FVC%

70.79

—

116.75

131

SVC (L)

4.76

4.66

102

TLC (L)

7.09

6.63

107

FRC (L)∗

2.86

2.70

106

FRC (L)†

3.83

2.70

142

RV (L)

2.34

1.90

123

32.98

28.92

114

MVV (L/min)

RV/TLC (%) Raw (cm H2 O/L/s) ∗ measured

4.30

0.5–2.0

—

by helium dilution; † measured by body plethysmography.

Primary lung cancer has been reported to be associated with bullous lung disease. In many instances, the bullae are detected only by CT. The increased incidence of lung cancer may be due to the fact that lung cancer occurs more frequently in fibrotic lungs which are, themselves, predisposed to development of bullae. Other explanations for the increased incidence of malignancy include dystrophic changes in lung parenchyma caused by bullous disease or persistence of carcinogens in poorly ventilated bullae.

TREATMENT Many patients with bullous lung disease can be managed medically. Because the natural history of a bulla is unpredictable, patients with bullous disease should be monitored by chest radiography at regular intervals to ensure that the disease is

stable. Occasionally, bullae enlarge suddenly and rapidly for no apparent reason; alternatively, they may shrink or disappear, usually as a result of infection.

Medical Management The finding of a bulla in an asymptomatic patient calls for reassurance, a recommendation for annual chest radiography, advice to stop smoking, and an alert to the need for a prompt visit to a physician should symptoms develop. Activities that promote rupture of bullae (e.g., contact sports and scuba diving) should be proscribed. Chronic bronchitis, asthma, or emphysema associated with bullae require treatment in their own right. For patients with α 1 -antitrypsin deficiency augmentation therapy with antiproteases may be appropriate. Infection of a bulla requires sputum specimens for culture and Gram’s stain. Fiberoptic bronchoscopy is usually performed if sputum samples fail to disclose the nature of the infection; sterile sheathed catheters may be helpful in obtaining noncontaminated respiratory tract secretions for culture. Direct sampling of fluid from within the bulla is rarely useful in making the diagnosis. Once the diagnosis of an infected bulla has been established, treatment with antibiotics and chest physiotherapy is begun. The choice of antibiotic depends on the findings on Gram’s stain and sputum cultures. Treatment is sometimes prolonged and may require parenteral administration, since poor drainage of the bulla inevitably slows resolution of the disease process. The course of the infection should be followed by interval chest radiographs. Most infections eventually respond to medical therapy, but radiographic evidence of an air-fluid level often persists after the infection has resolved. An infected bulla containing a very large amount of fluid may require surgical intervention in order to minimize the risk of the fluid being decanted into the adjacent or contralateral lung and airways.

Surgical Management In patients with giant bullae who are selected carefully for the presence of localized disease and well-preserved pulmonary function, surgical intervention may provide symptomatic relief, extend exercise tolerance, and improve spirometry, diffusing capacity, and ventilation-perfusion matching. In general, surgical outcome depends on the size and number of resected bullae, condition of compressed lung, status of the contralateral lung, and development of postoperative complications. Radionuclide scanning and CT are helpful in preoperative assessment of the compressed lung. Pulmonary angiography is now rarely employed for this purpose. Localized Bullae with Normal Intervening Lung (Bullous Lung Disease) In patients with localized bullae and normal intervening lung, acute complications (e.g., spontaneous pneumothorax

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Table 53-7 Preoperative and Postoperative Pulmonary Function Tests in Bullous Disease∗ Preoperative

Postoperative

Test

Actual

Predicted

Actual

Predicted

FVC (L)

1.76

3.67

2.79

3.67

FEV1 (L)

0.73

2.43

1.23

2.43

FEF25−75% (L/s)

0.26

2.36

0.44

2.36

PEFR (L/s)

3.57

7.93

4.83

7.93

FEV1 /FVC%

41.76

>70

44.04

>70

MVV (L/min)

29.09

100.3

51.80

100.3

SVC (L)

2.54

3.97

3.71

3.97

TLC (L)

7.27

9.32

5.80

9.32

FRC (L)

5.25

3.41

3.62

3.41

RV (L)

4.73

2.34

2.09

2.34

RV/TLC%

65.05

38.72

36.09

38.72

Raw (cm H2 O/L/s)

35.60

0.5–2.0

5.46

0.5–2.0

DLCO (ml/mm/mmHg)

7.20

23.2

9.78

23.2

DLCO /VA (ml/min/mmHg/L)

2.04

3.85

2.13

3.85

∗ Test

for a 74-year-old man who underwent successful bullectomy after smoking cessation. Second study performed 4 months after surgery (see Fig. 53-9).

or massive hemorrhage) may require urgent surgical intervention, even though the bullae may be small. In non-urgent circumstances, indications for surgical intervention include the following: (1) enlarging bullae that cause dyspnea; (2) enlarging bullae that compress surrounding lung tissue; (3) bullae that cause recurrent pneumothoraces; (4) bullae that become infected and fail to respond to medical treatment; (5) bullae causing acute respiratory insufficiency; (6) bullae that become acutely distended; (7) enlarging bullae that produce severe chest pain; (8) bullae associated with primary lung cancer; and (9) bullae containing very large fluid collections. The surgical approach depends on the location of the bullae. Median sternotomy, which is associated with less postoperative morbidity than standard thoracotomy, may be appropriate for bilateral upper lobe bullae. As a rule, small wedge excisions or plications of large bullae produce larger increments in expiratory flow rate than lobectomy and may be performed with using video-assisted thoracoscopy (see be-

low). Surgical techniques developed to reduce air leaks following resection of emphysematous lung include use of “buttressed stapling” and application of fibrin glues. Bullectomies are now sometimes combined with lung volume reduction surgery. The best functional improvement after surgery occurs when the bulla comprises 50 to 100 percent of the hemithorax (Fig. 53-12), where postoperative increments in forced expiratory volume in 1 second (FEV1 ) range from 50 to 200 percent. Better results may be anticipated when the involved lung contributes little to overall ventilation, when large volumes of trapped air exist, and when there is crowding and compression of normal lung parenchyma. Surgical techniques involve buttressing staple lines using bovine pericardium and use of fibrin glues and pleural tents. Attention to postoperative management is critical to good surgical outcomes and includes underwater thoracostomy suction, early and vigorous chest physiotherapy, and early ambulation. Regular postoperative chest radiographs

928 Part IV

Obstructive Lung Diseases

Video-Assisted Thoracoscopy Video-assisted thoracoscopy has become a common surgical approach in plication of bullae. Thoracoscopy requires careful general anesthetic management and introduction of a double-lumen endotracheal tube to permit collapse of one lung. Once a bulla has been identified, the lung is deflated and the bulla excised using a stapling device. Mortality and complication rates are usually lower than with other surgical approaches.

Figure 53-12 CT image showing a single right upper lobe bulla in the medial portion of the lung. See Table 53â&#x20AC;&#x201C;6.

identify residual airspaces. Prolonged air leaks may be managed using Heimlich valves following patient discharge from the hospital. Postoperative complication rates tend to be high (up to 80 percent). Not surprisingly, persistent air leaks and pleuropulmonary infections are common; atrial fibrillation, need for prolonged postoperative mechanical ventilation, massive subcutaneous emphysema, and retention of respiratory secretions also occur. Overall surgical mortality may be as high as 9 percent, but it is usually approximately 2 to 5 percent. The most common causes of death are infection and respiratory failure; sudden development of a contralateral pneumothorax and herniation of a bulla across the mediastinum are uncommon causes. Five-year survival is approximately 90 percent, and significant increments in FEV1 persist in over 80 percent of patients. Residual volume usually returns to baseline. Improvements in dyspnea also persist at 3 years in over 80 percent of patients. Localized Bullae with Abnormal Intervening Lung As a rule, bullae that complicate either obstructive or fibrotic lung disease do not require surgical intervention unless a lifethreatening complication arises. When bullae occur in conjunction with widespread panacinar emphysema, usually, but not necessarily, little improvement is seen with bullectomy. This is particularly true in COPD when the FEV1 is less than 35 percent of predicted. Elderly individuals in whom the bullae are associated with widespread emphysema frequently have a high surgical mortality. When bullae are associated with chronic bronchitis, improvement after surgery is generally shortlived (i.e., less than 6 months). A prolonged, productive cough and secondary pulmonary hypertension are associated with a poor prognosis. The outlook after surgery is better for those who stop smoking than for those who do not (Table 53-7).

Laser Surgery Current laser-based surgical techniques have evolved since 1990, when a low energy carbon dioxide laser was used to ablate pleural blebs in treatment of spontaneous pneumothorax. Subpleural bullae collapse when exposed to laser energy, as do multiple bullae occurring in the setting of widespread emphysema. Complications of the technique include postoperative air leaks, bleeding, and acute lung injury. Patients with large bullae associated with crowding of adjacent lung structures, upper lobe predominance, and minimal underlying emphysema appear to experience the greatest improvement in FVC, FEV1 , maximal voluntary ventilation (MVV), specific airway conductance, and residual volume. Both the argon beam coagulator and yttriumaluminum-garnet (YAG) laser have been used in conjunction with video-assisted thoracoscopy in ablating bullae in treatment of bullous emphysema. Procedure-related mortality in using these two devices is 0 and 10 percent, respectively.

External Drainage: Monaldi Procedure In 1938, Monaldi described a two-stage technique for the open intubation and external drainage of tuberculous cavities. The procedure was subsequently applied to treatment of pyogenic lung abscesses and bullae as a singlestage procedureâ&#x20AC;&#x201D;endocavitary aspiration with sclerosis and pleurodesis, known as the Brompton technique. The technique is sometimes useful in patients whose pulmonary function precludes thoracotomy. Data indicate a 28 percent improvement in FEV1 and 12 percent improvement in total lung capacity following the procedure. The mortality rate is approximately 7 percent. Predictors of a poor prognosis are an FEV1 less than 0.5 L and a PaCO2 greater than 49 mmHg.

Reduction Pneumoplasty and Lung Transplantation Other potential treatments for giant bullae include reduction pneumoplasty, following which both symptomatic and functional improvements have been reported. Reduction pneumoplasty is most effective when bullae are larger than onethird of a hemithorax, adjacent lung is compressed, and the FEV1 is less than 50 percent of predicted. However, the duration of improvement and the late morbidity and mortality are not well defined.

929 Chapter 53

SUGGESTED READING Aaronberg DJ, Sagel SS, Lefrak S, et al: Lung carcinoma associated with bullous lung disease in young men. AJR 134:249, 1980. Brenner M, Kayaleh RA, Milne EN, et al: Thorascopic laser ablation of pulmonary bullae. Radiographic selection and treatment response. J Thorac Cardiovasc Surg 107:883, 1994. Cooper J: Technique to reduce air leaks after resection of emphysematous lung. Ann Thorac Surg 57:1038, 1994. DesLauriers J, Leblanc P: Management of bullous disease. Chest Surg Clin N Am 4:539, 1994. Fitzgerald MX, Keelan PG, Cugell DW, et al: Long-term results of surgery for bullous emphysema. J Thorac Cardiovascular Surg 68:566, 1974. Gould GA, Redfpath AT, Ryan M, et al: Parenchymal emphysema measured by CT lung density correlated with lung function in patients with bullous disease. Eur Respir J 6:698, 1993. Greenberg JA, Singhal S, Kaiser LR: Giant bullous lung disease: Evaluation, selection, techniques, and outcomes. Chest Surg Clin N Am 13:631, 2003. Hillerdal G, Gustafsson G, Wegenius G, et al: Large emphysematous bullae: Successful treatment with thorascopic technique using fibrin glue in poor risk patients. Chest 107:1450, 1995. Kaiser LR: Video-assisted thorascopic surgery: Current state of the art. Ann Surg 56:691, 1994. Laurenzi GA, Turino GM, Fishman AP: Bullous disease of the lung. Am J Med 32:361, 1962. Lewis RJ, Caccavale RJ, Sisler GE: VATS argon beam coagulator treatment of diffuse end-stage bilateral bullous disease of the lung. Ann Thorac Surg 55:1394, 1994.

Bullous Disease of the Lung

Morgan MDL, Edwards CW, Morris J, et al: Origin and behavior of emphysematous bullae. Thorax 44:533, 1989. Reid L: The Pathology of Emphysema. Chicago, Year Book, 1967, pp 211â&#x20AC;&#x201C;240. Shah SS, Goldetraw P: Surgical treatment of bullous emphysema, experience with the Brompton technique. Ann Thorac Surg 58: 1452, 1994. Shipper PH, Meyers RF, Battafarano RJ, et al: Outcomes after resection of giant emphysematous bullae. Ann Thorac Surg 78:976, 2004. Smit HJ, Golding RP, Schrawel FM, et al: Lung density measurements in spontaneous pneumothorax demonstrate air trapping. Chest 125:2083, 2004. Smit NJ, Wienk MA, Schreurs AJ: Do bullae indicate a predisposition to recurrent pneumothorax? Br J Radiol 73:356, 2000. Snider GL: Reduction pneumoplasty for giant bullous emphysema. Chest 109:540, 1996. Stern EJ, Webb WR, Weinacker A, et al: Idiopathic giant bullous emphysema (vanishing lung syndrome) imaging findings in nine patients. J Roentgenol 162:279, 1994. Teramoto S, Fukuchi Y: Bullous emphysema. Curr Opin Pulm Med 2:90, 1996. Travaline JM, Addonizio VP, Criner GJ: Effect of bullectomy on diaphragm strength. Am J Respir Crit Care Med 152:1697, 1995. Tomashefski, JF, Feeley DR, Shillito FH: Effects of altitude on emphysematous blebs and bullae. Clin Aviation Aerospace Med 37:1158, 1966. Vishnevsky AA, Nikoladze GD: One stage operation for bilateral bullous lung disease. J Thorac Cardiovasc Surg 99:30, 1990. Waitches GM, Stern EJ, Dubinsky T: Usefulness of the doublewall sign in detecting pneumothorax in patients with giant bullous emphysema. AJR 174:1765, 2000.

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