The Core Curriculum: Cardiopulmonary Imaging, 1st Edition (2004)

Chapter 15. Obstructive Lung Disease

Obstructive lung diseases are characterized by progressive expiratory airway flow limitation and respiratory symptoms, including chronic cough, sputum production, and dyspnea. These diseases are common and associated with significant morbidity and mortality. Clinically, asthma is characterized by reversible airflow obstruction, chronic bronchitis by a productive cough, and emphysema by irreversible airflow obstruction, dyspnea on exertion, pulmonary hyperinflation, and destruction of alveolar walls. Pathologically, asthma is characterized by inflammation and airway remodeling, whereas chronic obstructive pulmonary disease (COPD) is categorized by emphysema, small airway inflammation and fibrosis, and mucous gland hyperplasia (1).

Although there are many similarities among the major pathophysiologic categories of disease causing chronic airflow obstruction, the advent of new therapeutic modalities and differences in patient prognosis highlight the importance of making a specific diagnosis. For example, patients with nonasthmatic airflow obstruction have a greater rate of decline in forced expiratory volume in 1 second (FEV1) and poorer survival than patients with chronic asthmatic bronchitis (2), and patients with a self-reported history of chronic bronchitis have a steeper drop in FEV1 than patients with asthma (3). By using clinical history, physical examination, and pulmonary function testing together with imaging, in particular high resolution computed tomography (HRCT), the subsets of chronic obstructive lung disease can be distinguished and therapy correctly tailored.

Clinically and radiographically, manifestations of more than one form of COPD may be present in the same patient.

Table 15.1 lists the common diseases that are traditionally considered under the heading “COPD.” COPD is currently defined as a disease state characterized by airflow obstruction that does not change markedly over months of observation. It is usually pathologically a result of chronic bronchitis or emphysema (1,4). According to a National Heart, Lung and Blood Institute Workshop on the subject, “The term ‘COPD’ is generally used in clinical discourse to describe individuals diagnosed with one or more of the following conditions: asthmatic bronchitis, chronic bronchitis, chronic obstructive bronchitis and emphysema” (5). Less common obstructive lung diseases include bronchiolitis obliterans and lymphangioleiomyomatosis. It is estimated that 14 million people in the United States have COPD, of which approximately 12.5 million have chronic bronchitis and 1.65 million have emphysema. COPD is the fourth leading cause of death in the United States (4). Asthma is also common, affecting approximately 11 million people (6). The prevalence of COPD, in particular asthma, is increasing (7,8). Given the strong association of COPD and cigarette smoking, this condition is largely preventable. Within any one patient features of emphysema, chronic bronchitis and asthma may overlap, and distinguishing between them may therefore be confounded. For example, some patients with asthma, particularly longstanding asthma, lack the reversibility of airflow obstruction that characterizes asthma, thereby mimicking COPD (7). Conversely, some patients with chronic bronchitis and emphysema have a significant component of bronchoreversibility, thereby mimicking asthma (9).

Table 15.1: Chronic Obstructive Pulmonary Diseases

Asthma
Chronic bronchitis
Emphysema
Bronchiectasis

Clinical History and Physical Examination

Cough, wheezing, and dyspnea are the common symptoms of obstructive lung disease and overlap between asthma and COPD. History can be useful to identify a specific obstructive lung disease, for example, a history of symptoms first appearing in childhood, a persistent cough after an upper respiratory tract infection, and/or a history of atopic disease or occupational exposure favor asthma (10,11). An episodic cough, perhaps brought on by exercise or allergens, also indicates an asthmatic component to obstructive lung disease. In contrast, patients with COPD generally have more constant and progressive symptoms; many patients with longstanding disease may be asymptomatic even in the face of severe disease (12). Age is an indicator of the type of obstructive lung disease. In one study, the mean age of patients with predominantly asthmatic bronchitis was 29.6 years versus 64.6 years for emphysematous COPD (2). Patients with α1-antitrypsin deficiency develop premature COPD, with a mean age of dyspnea onset at 40 years for smokers and 53 years for nonsmokers. Therefore, patients less than 50 years of age with moderate or severe chronic airflow obstruction, basilar emphysema, and a strong family history of obstructive disease, should be tested for α1-antitrypsin deficiency (4).

The most useful signs on physical examination of airflow obstruction are objective wheezing, barrel chest deformity, rhonchi, hyperresonance, subxiphoid apical impulses, and an objective measurement of prolonged expiration (11,13,14). Forced expiratory time may be useful to screen for obstructive lung disease; however, physicians are generally poor at estimating the severity of obstruction from physical examination. In one series, only 38% of physicians’ pretreatment estimates were accurate (15). The role of blood studies in the evaluation of obstructive lung disease is limited. An elevated IgE level and increased blood eosinophils may aid in identifying patients with asthmatic airflow obstruction. Patients with any history of asthma have a higher degree of eosinophilia and elevated IgE levels than patients without a history of asthma (3,16). However, patients with newly diagnosed chronic bronchitis may also have elevated IgE and eosinophil levels.

Pulmonary Function Testing

The most useful laboratory studies for the evaluation of airflow obstruction are pulmonary function tests. These tests are necessary for diagnosis, evaluating disease severity, and monitoring response to treatment (4,17). Spirometry is a simple screening test for airflow obstruction, with spirometers widely available and simple to use. American Thoracic Society guidelines provide normal standards and the framework for the interpretation of results, with values adjusted for age and gender (Table 15.2) (18). The most valuable measurements include the FEV1, forced vital capacity (FVC), and peak inspiratory/expiratory flows measured from a maximal expiratory maneuver. A decrease in the FEV1/FVC ratio from the predicted range is diagnostic of airflow obstruction (18,19). A lower initial FEV1/FVC ratio in COPD may be associated with greater declines in FEV1 over time (20). Airflow obstruction severity is judged on FEV1 expressed as a percent of the predicted value (18). A graphic representation of peak expiratory and inspiratory flow versus lung volume, known as the flow-volume loop, should be examined to exclude potential upper airway obstruction (21).

Measurement of spirometric parameters before and after administration of a short-acting β agonist may aid in establishing bronchoreversibility. A rise in FEV1 of 12% with an absolute rise of at least 200 mL indicates bronchoreversibility (18). Complete reversibility of airflow obstruction makes the diagnosis of asthma likely and strongly argues against COPD (11). However, a subset of patients with asthma develop irreversible airflow obstruction (7,22,23,24). Such patients typically have a longer duration of asthma and more symptomatic disease than asthma patients with reversible obstruction (22). Furthermore, asthma patients with irreversible airflow obstruction may have baseline FEV1, FVC, and postbronchodilator FEV1 measurements indistinguishable from COPD patients; therefore, the lack of bronchodilator reversibility cannot be used with sufficient specificity to differentiate COPD from asthma (23). Up to 30% of patients with COPD have bronchoreversibility at spirometric testing (25,26). In a series of patients with asthma (n = 287) or COPD (n = 108), the mean increase in FEV1 from baseline after inhaled albuterol was higher in asthma patients (16.5% versus 10.6%); however, there was significant overlap (9). The best specificity for the diagnosis of asthma (84%) was defined at a threshold of a 20% or greater increase in FEV1 from baseline; however, sensitivity was poor. The postbronchodilator FEV1 has been shown to be the single best predictor of survival in patients with COPD, with a value below 30% of predicted associated with marked reduction in long-term survival (25). As a result, the postbronchodilator FEV1 has become instrumental in establishing an appropriate time for considering surgical therapy in patients with advanced COPD.

Spirometry can also be performed after the administration of an agent to induce bronchial hyperreactivity, such as methacholine (19,27). Patients with asthma have greater airway hyperresponsiveness than patients with COPD (27,28,29),30), although many patients with COPD also have airway hyperreactivity (27). In the Lung Health Study of almost 6,000 current smokers with borderline to moderate airflow obstruction, nonspecific airway hyperresponsiveness (defined as a drop of at least 20% in FEV1 after inhalation of no more than 25 mg/mL methacholine) was noted in 85.1% of women and 58.9% of men (31). Baseline airway obstruction, wheeze, cough with or without sputum production, and a past history of asthma or hay fever were associated with hyperresponsiveness.

Table 15.2: Categories of Obstructive Abnormality on Pulmonary Function Testing

 

FEV1 (% Predicted)

FEV1 / FVC(% Predicted)

Mild obstructive abnormality

70%

<70%

Moderate/moderately severe obstructive abnormality

50–70%

<70%

Severe obstructive abnormality

<50%

<70%

FEV, forced expiratory volume in one second; FVC, forced vital capacity.
From American Thoracic Society. Lung function testing: selection of reference values and interpretative strategies. Am Rev Respir Dis 1991;144:1202–1218, with permission.

The measurement of lung diffusing capacity for carbon monoxide (DLCO) is a routine test in the evaluation of chronic airflow obstruction, particularly for more advanced disease. DLCO is a sensitive test for emphysema, a disease process associated with loss of alveolar surface area and pulmonary circulation (32). Decreased DLCO accompanying chronic airflow obstruction suggests at least a component of emphysema (33). The specificity of DLCO for obstructive lung disease is low, and it should be used together with clinical history and physical examination. In large epidemiologic studies, a normal DLCO is associated with asthma rather than COPD (34). DLCO may be also increased in patients with asthma (35,36). However, when asthma manifests with irreversible airway obstruction, DLCO may be low (23). In patients with emphysema, there is a strong correlation between low DLCO and greater severity of emphysema on CT (37). A decreased DLCO is associated with a more rapid decline in pulmonary function over time (20).

Peak expiratory flow is the maximal flow that can be achieved during maximal expiratory effort. This measurement has been widely accepted and advocated for the monitoring of patients with airflow obstruction, particularly asthma (17). Widespread availability of inexpensive, simple, reliable devices has made the routine measurement of peak expiratory flow rate possible (38). There is a close relationship between the FEV1 and peak expiratory flow rate; however, in general peak expiratory flow rate is consistently higher (38,39). Limitations of using peak expiratory flow rate include a reduction in peak expiratory flow rate both with obstructive lung disease and upper airway obstruction (21) and a lower sensitivity of peak expiratory flow rate than spirometry for detecting reversibility of airflow obstruction after bronchodilators or detecting bronchial response to challenge with occupational sensitizers (40,41).

Radiologic Studies

Posteroanterior and lateral chest radiographs are part of the initial evaluation of dyspnea. Many of the radiographic signs of obstructive lung disease lack specificity, such that chest radiographs are used predominantly to support a diagnosis of obstructive lung disease and not for primary diagnosis. Radiographic signs of obstructive lung disease also lack sensitivity and should not be used to exclude the diagnosis. The radiographic features of asthma, chronic bronchitis, and emphysema often overlap, similar to the overlap in clinical features. Although CT findings in the different forms of obstructive lung disease are well described and CT is the best tool to evaluate the severity of emphysemain vivo, CT has a limited role in the primary diagnosis of obstructive lung disease. In a small subset of dyspnea patients with an isolated reduction in diffusing capacity and otherwise normal pulmonary function tests and a normal chest radiograph, HRCT is useful for establishing the diagnosis of emphysema (42,43). When bronchiectasis is suspected, HRCT is the technique of choice for detecting, localizing, and characterizing bronchiectasis, having replaced bronchography. HRCT examinations can also be performed at end-expiration to add a functional component to the inspiratory HRCT technique. Expiratory CT may demonstrate air trapping in patients with small airway diseases such as asthma and bronchiolitis obliterans, often when inspiratory HRCT images are normal (44).

Asthma

Clinical Features and Definition

The diagnosis of asthma is based on clinical history and evidence of reversible airflow obstruction (17). Asthma is typically characterized by airway inflammation, airway hyperresponsiveness, and reversible airflow obstruction (7,45). Accurate diagnosis, monitoring of disease severity, and treatment response are considered the standard of care for asthma (17). Asthma is difficult to diagnose on purely clinical grounds (17,46). In one series of 60 adults with a physician diagnosis of asthma, 40% did not meet objective diagnostic criteria for asthma. Disease severity is often understated by both the patient and physician in the absence of spirometry or peak flow measurement (17).

Asthma is often thought of as a childhood illness, with many outgrowing the disease by adolescence if not adulthood. Asthma may persist into adulthood. Individuals diagnosed with asthma in childhood who ceased wheezing during adolescence have no difference in pulmonary function than normal control subjects, whereas those who continue to wheeze have abnormal pulmonary function. However, 60% of patients who stopped wheezing have evidence of bronchial hyperresponsiveness with histamine challenge (47). The outcome of childhood asthma is predominantly related to the initial level of bronchial obstruction and airway responsiveness. Lack of asthma at follow-up is associated with younger age and less severe airway obstruction when first tested, whereas the absence of bronchial hyperreactivity is associated with younger age, higher FEV1, and shorter untreated period (48). Milder disease and early intervention are important components to asthma outcome. Tobacco smoke has a deleterious effect on asthma. Asthmatics exposed to greater than 3 hours of smoke per week have greater severity of asthma scores, worse asthma-specific quality of life scores, and decreased SF-36 health status questionnaire scores and increased odds for emergency room visits, urgent doctor visits, and hospitalizations compared with non–smoke-exposed asthma control subjects (49).

The development of asthma is multifactorial and includes family history of asthma and current or former smoking (50). The odds of having a child with asthma are three times greater in a family in which one parent has asthma and six times more likely when both parents have asthma and are greater if the mother has asthma than if the father has asthma (51). In one series of 265 first-degree offspring of asthma patients, 18% of the offspring had definite asthma and 8% had probable asthma (52).

Pathophysiology

Inflammation is now recognized to have a large role in asthma (7). Even in patients with mild asthma there is collagen deposition beneath the epithelial basement membrane and extensive inflammation in bronchial biopsy specimens (53). There are increased numbers of inflammatory cells and eosinophils in the airway epithelium of asthmatics, and these cells are associated with increased bronchial reactivity. Greater subepithelial thickening correlates with lower FEV1 and greater peak flow variability, suggesting that the clinical severity of asthma is associated with both the severity of inflammation and also the degree of airway remodeling (54). Patients with COPD who demonstrate corticosteroid reversibility may have features of asthma and inflammation, with COPD responders having a larger number of eosinophils and higher levels of eosinophilic cationic protein in bronchoalveolar lavage fluid and thicker reticular basement membrane than COPD nonresponders (55).

Airway inflammation plays an important role in asthma.

Chest Radiography and Computed Tomography

The chest radiographic features of asthma include pulmonary hyperinflation with increased lung lucency and mild bronchial wall thickening (Fig. 15.1). However, the chest radiograph is often normal, particularly in the absence of acute asthma symptoms. Mild pulmonary artery enlargement may occur due to transient pulmonary hypertension (56). During acute exacerbation of asthma, atelectasis, mucous plugging, spontaneous pneumomediastinum, or pneumothorax may develop. The latter occurs due to air trapping with a ball–valve phenomenon, allowing air into the lungs with inspiration but little if any exit of air on expiration. HRCT examinations are frequently abnormal in asthma patients with normal chest radiographs. In one series 71.9% of asthmatics had an abnormal HRCT, whereas only 37.8% of these patients had an abnormal chest radiograph (57). HRCTs may be normal, particularly in mild asthma.

Radiographs are often normal in asthma patients.

HRCT may show bronchial wall thickening or air trapping in asthma not evident on chest radiographs.

Figure 15.1 Posteroanterior chest radiograph of a patient with asthma demonstrates pulmonary hyperinflation and peribronchial cuffing.

Bronchial dilatation occurs in 28% to 36% of asthma patients and bronchial wall thickening in 82% to 92% of asthma patients (58,59). Reversible findings on HRCT include mucoid impaction and lobar collapse, present in 10% to 20% of asthmatic patients (57,58). In longstanding asthma, bronchial dilatation and bronchial wall thickening on HRCT are often irreversible (23,57,58,60). Bronchial wall thickening and bronchial dilatation are more common and more severe in asthmatic patients with moderate to severe airflow obstruction and in patients with a prolonged history of asthma than in patients with mild obstruction or normal airflow (61,62,63,64).

Air trapping is commonly demonstrated on expiratory HRCT and may precede the development of airway dilatation and thickening (Fig. 15.2) (60). Patients with nonallergic asthma have more extensive airway remodeling on CT than patients with allergic asthma, with a higher frequency of bronchial dilatation, bronchial recruitment, and emphysema (63). In contrast, patients with chronic stable asthma develop a reduction in lung attenuation on HRCT that is not due to emphysema. In nonsmoking asthmatic patients, emphysema is not a feature of asthma on HRCT (65,66). This reduction in lung attenuation may represent nondestructive hyperinflation.

Figure 15.2 HRCT in a patient with asthma and irreversible airflow obstruction. A. Inspiratory image demonstrate diffuse abnormally low attenuation lung parenchyma. B. On the expiratory image the lungs remain inflated, without the usual decrease in size and increase in attenuation that is expected at expiration.

Some lung findings on HRCT in mild asthmatics can be provoked and are reversible. After bronchial provocation with methacholine chloride, a reduction in lung attenuation and reduction in the cross-sectional area of small airways (less than 5 mm2) occurs compared with baseline, accompanied by a 10% to 26% decrease in FEV1. After reversal with albuterol, these findings return to normal (67). After methacholine inhalation, the internal airway lumen diameter has been shown to decrease 17% from baseline, increasing to 18% above baseline after albuterol inhalation (68). Methacholine-induced bronchial constriction occurs in bronchi of all sizes but is most severe in the small bronchi 2 to 4 mm in diameter (69). Although in normal patients a decrease in bronchial wall thickness accompanies bronchoconstriction, bronchial wall thickness does not decrease in asthmatic patients as measured on HRCT (69).

Chronic Bronchitis

Chronic bronchitis is diagnosed clinically by the presence of chronic productive cough for 3 months in each of 2 successive years in a patient in whom other causes of chronic cough have been excluded (4). Compared with asthma and emphysema, the radiographic features of chronic bronchitis are poorly described. Findings at chest radiography include pulmonary hyperinflation and thickened bronchial walls, resulting in peribronchial thickening or cuffing, and increased “markings” due to superimposition of the thickened small bronchi and bronchiole walls (70). There is little information on the HRCT findings in chronic bronchitis. The most common HRCT finding is bronchial wall thickening, a nonspecific finding (71). In one series of 45 patients with air trapping on expiratory HRCT, 4 patients with chronic bronchitis were reported (44). All four patients had air trapping on expiratory HRCT, and one patient had a normal inspiratory HRCT. In the remaining three patients, the inspiratory HRCT demonstrated bronchial wall thickening, a tree-in-bud appearance secondary to mucoid impaction, and ground glass opacity presumed to be secondary to concomitant infection.

Emphysema

According to the American Thoracic Society, emphysema is defined as “a condition of the lung characterized by abnormal, permanent enlargement of the air spaces distal to the terminal bronchiole, accompanied by destruction of their walls” and without obvious fibrosis (4). Emphysema occurs due to an imbalance in the proteolytic activity in the lungs, resulting in destruction of alveolar tissue. This may be seen with an overabundance of proteolytic enzymes, a lack of antiproteases, or a combination of both. In smoking-related centrilobular emphysema there is excess protease, whereas in α1-antitrypsin deficiency there is a deficiency of α1-antiproteinase.

The pathologic classification of emphysema is based on the secondary pulmonary lobule. The four major categories of emphysema, as listed in Table 15.3, are centrilobular (centriacinar), panacinar (panlobular), paraseptal, and paracicatricial (Fig. 15.3) (72). Table 15.4 summarizes the differences between centrilobular and panlobular emphysema. Centrilobular emphysema is the most common form of emphysema and is usually secondary to cigarette smoking. The destruction of alveolar walls begins in the central portion of the secondary pulmonary lobule (Fig. 15.4) and is heterogeneous, affecting adjacent lobules with varying degrees of severity; it is usually most severe in the upper lobes (Fig. 15.5). The relatively greater ventilation-perfusion ratio in the upper portion of the lungs compared with the lung bases favors greater deposition of the particulate matter from cigarette smoke in the upper lungs. Activated macrophages release the proteolytic enzyme, elastase; free radicals and oxidants in cigarette smoke inactive normally protective antiproteases, leading to greater destruction of the upper lobes than the lower lobes (72).

Table 15.3: Major Categories of Emphysema

Types of Emphysema

Anatomic Distribution

Associations

Centrilobular (a.k.a. centriacinar)

Upper lung predominant

Cigarette smoking

Panlobular (a.k.a. panacinar)

Lower lung predominant

α1-Antitypsin deficiency

Paraseptal

Subpleural

Aging

Paracicatricial

Focal

Scar/fibrosis

Figure 15.3 Illustration of centrilobular, panacinar, and paraseptal emphysema at the level of the secondary pulmonary lobule. A.Enlargement of the central airspaces of a secondary pulmonary lobule in centrilobular emphysema. B. Enlargement of airspaces uniformly throughout the secondary pulmonary lobule in panlobular emphysema. C. Enlargement of airspaces along the periphery of the lobule adjacent to the interlobular septa in paraseptal emphysema. (From 

Kazerooni EA, Whyte RI, Flint A, et al. Imaging of emphysema and lung volume reduction surgery. RadioGraphics 1997;17:1023–1036

, with permission.)

Centrilobular emphysema is usually most severe in the upper lungs and is secondary to cigarette smoking.

Panlobular emphysema typically occurs in patients with α1-antitrypsin deficiency and is accelerated by superimposed cigarette smoking. The proteolytic enzyme elastase is found within neutrophils and macrophages in the lung and is kept in check by antiproteases, such as α1-antitrypsin. More circulating α1-antiprotease is usually delivered to the lower lungs than the upper lungs due to the greater distribution of blood flow to the lower lungs. When α1-antiprotease is deficient, the greatest deficiency is therefore seen at the lung bases; the lack of antiproteolytic activity results in greater destruction of lung parenchyma at the lung bases. Therefore, in contrast to centrilobular emphysema, panlobular emphysema is usually more severe in the lower lungs than the upper lungs and homogeneously affects the entire lobule as well as adjacent lobules (Fig. 15.6).

Panlobular emphysema is usually most severe in the lower lungs and is secondary to α1-antitrypsin deficiency.

Table 15.4: Centrilobular Versus Panlobular Emphysema

 

Centrilobular

Panlobular

Within a lobule

Heterogenous

Homogenous

Anatomic distribution

Upper lung predominant

Lower lung predominant

Associations

Cigarette smoking

α1-Antitrypsin deficiency

Figure 15.4 Mild centrilobular emphysema on high resolution computed tomography with small rounded areas of low attenuation adjacent to centrilobular arteries.

Paraseptal emphysema involves the peripheral or paraseptal portion of the secondary pulmonary lobules (Fig. 15.7), the apices and paramediastinal portion of the upper lobes, and may be related to aging, although it remains poorly understood. Pathologically, the most distal portion of the acinus is involved, explaining why this form of emphysema appears to be most noticeable adjacent to the pleura or interlobular septa. This form of emphysema can lead to spontaneous pneumothorax and even progressively enlarging bulla.

Paracicatricial emphysema, also known as perifocal emphysema, occurs adjacent to areas of scarring, fibrosis, and granulomas (Fig. 15.8). As an example, it may be seen in the periphery of the upper lungs in patients with silicosis and conglomerate masses. In this form of emphysema, airspace enlargement and alveolar septal destruction occur in the vicinity of focal lesions such as fibrotic granulomas. The destruction occurs gradually after the scar has formed. The lesion often has little functional significance, unless multiple foci are present.

Figure 15.5 Advanced centrilobular emphysema on high resolution computed tomography with (A) severe emphysema involving the entire upper lobes and (B) less severe emphysema involving the lower lobes, where areas of normal attenuation parenchyma can be found.

Figure 15.6 Panlobular emphysema in a patient with α1-antitrypsin deficiency on HRCT. (A) Mild emphysema involving the entire upper lobes and (B) severe emphysema involving the lower lobes.

Figure 15.7 Paraseptal emphysema on HRCT with abnormal low attenuation regions along the pleural surface and adjacent to interlobular septa.

Figure 15.8 Paracicatricial emphysema in a patient with advanced silicosis. Peripheral emphysema surrounds the central conglomerate masses.

Table 15.5: Chest Radiographic Signs of Emphysema

Pulmonary hyperinflation
   Large retrosternal clear space
   Flattened or inverted hemidiaphragms
   Saber sheath trachea
   Barrel chest (increased anteroposterior thoracic diameter)
   Tall lungs
   Decreased height of hemidiaphragms
Lung destruction
   Bulla
   Paucity of vessels

 

Chest Radiography

The chest radiographic features of emphysema include both signs of lung destruction and pulmonary hyperinflation (Table 15.5). Signs of lung destruction include irregular radiolucency of the lungs, arterial depletion, and thin-walled bullae. Signs of hyperinflation include flattening or depression of the diaphragm, enlargement of the retrosternal clear space, increased anteroposterior chest dimension (the so-called barrel chest), increased lung height, and decreased height of the right hemidiaphragm (Fig. 15.9) (56,73,74). These signs alone or in combination have variable sensitivity for emphysema detection ranging from 40% to 80% (56). Additional signs of severe emphysema are due to secondary pulmonary arterial hypertension and right heart overload, with enlargement of central pulmonary arteries and right heart chambers. Although moderate to severe emphysema is generally radiographically detectable, chest radiographs are insensitive for detecting mild emphysema.

Signs of emphysema on radiographs include both lung destruction and hyperinflation.

Radiographs are not sensitive for mild or even moderate emphysema.

Figure 15.9 Radiographic manifestations of emphysema on (A) posteroanterior and (B) lateral chest radiographs include pulmonary hyperinflation manifesting as flattened hemidiaphragms, a large retrosternal clear space, tall lungs, and a saber sheath trachea. Abnormal pulmonary vascular branching pattern is a sign of lung destruction.

Signs of hyperinflation are the most sensitive for emphysema detection but lack specificity when applied to other obstructive lung diseases. For example, Reich et al. (75) demonstrated that when the height of the right hemidiaphragm on the lateral chest radiograph was less than or equal to 2.6 cm, chest radiographs were 67.7% sensitive for detecting patients with obstructive spirometry (75). In the same series, a right lung height of 29.9 cm or more on the posteroanterior chest radiograph was 69.8% sensitive (FP [false positive] rate for both, 5%). By combining signs of both lung destruction and hyperinflation, the specificity of chest radiographs for emphysema improves but at the expense of sensitivity. Only the presence of bullae is specific for emphysema on chest radiographs. Chest radiographs provide supporting evidence of the diagnosis of emphysema and are used to evaluate for complications of emphysema, such as pneumonia or lung cancer; the insensitivity of chest radiographs for detecting mild to moderate emphysema has limited their usefulness as a diagnostic tool (74,76,77).

Computed Tomography

CT provides excellent anatomic detail for detecting, characterizing, and estimating the severity of emphysema. Not surprisingly, conventional CT is more accurate than chest radiography, and HRCT is more accurate than conventional CT (78,79,80). On CT, emphysema appears as abnormal areas of low attenuation lung without definable walls, resulting in a decrease in the mean attenuation value of the lung parenchyma (Figs. 15.415.5, and 15.6) (56). When reporting emphysema on CT, it is important to note the severity, symmetry between lungs, and distribution within the lungs as upper lobe predominant, diffuse, or lower lobe predominant. The presence of giant bullae, bronchiectasis, or nodules (Fig. 15.10) that may represent occult lung cancer in this high risk population should also be reported. Up to 5% of emphysema patients being evaluated for lung transplantation or lung reduction surgery have been found to have incidental lung cancer during their evaluations, many of which are only detected with CT (81). CT plays a major role in selecting candidates for lung volume reduction surgery. Good candidates have target areas of emphysema, usually in both upper lobes. Poor candidates have diffuse emphysema (82).

The severity of emphysema on CT correlates very well with the severity of emphysema in pathologic specimens.

Focal apical target areas of emphysema are a predictor of good outcome after lung volume reduction surgery.

Several investigators have shown that CT is accurate for quantifying emphysema, using either visual scoring methods or attenuation threshold-based quantitative analysis; both of these methods fail to detect mild emphysema (78,79,83,84,85,86,87,88,89,90,91,92,93,94,95,96). Quantitative analysis of the severity of emphysema has been referred to as the density mask technique and was initially performed on selected axial two-dimensional images (86). The same technique can be applied to three-dimensional helical CT volumetric data sets acquired during a single inspiration for evaluation of the entire lungs (Fig. 15.11) (97,98). Lung volumes, including total lung capacity and residual volume, can also be calculated using inspiratory and expiratory helical CT data, with excellent correlation to static lung volumes (99). The thinner the collimation of the images, the better the correlation of CT attenuation based measurements with the severity of emphysema (79).

Figure 15.10 One-centimeter nodule (arrow) in the left upper lobe represents a clinically and radiographically occult bronchogenic carcinoma in an emphysema patient being evaluated for lung volume reduction surgery.

Figure 15.11 A,B. Three-dimensional density mask technique for emphysema superimposes the emphysema (all voxels less than -900 Hounsfield units as shown in white) on the total lung volume (all voxels less than -700 Hounsfield units as shown in gray) in both the anterior and lateral projections. These represent target areas for resection during lung volume reduction surgery.

Visual and quantitative CT measurements of emphysema severity correlate well with diffusing capacity and pulmonary capillary blood volume in patients with emphysema but only moderately with measures of airflow obstruction, such as FEV1, FVC, and the FEV1/FVC ratio. The severity of expiratory airway obstruction may therefore not be related to the severity of alveolar wall destruction alone (33,37,96,100,101). By measuring the lung attenuation on inspiratory and expiratory CT, the ratio of CT attenuation number at expiration to inspiration can be calculated; this has been shown to correlate well with air trapping and less well with the morphologic destruction of emphysema (102).

Scintigraphy

Planar perfusion scintigraphy and single photon emission CT with technetium 99m (99m Tc) macroaggregated albumin display the perfusion to the lungs in multiple projections and planes (103). Lung perfusion can be visually estimated or quantified. Areas of emphysema or bullae are associated with reduced lung perfusion (Fig. 15.12). The perfusion that is demonstrated on perfusion scans is relative perfusion. The lack of perfusion could be related to either a large bulla or to an area of moderate to severe emphysema in lungs that are otherwise normal. Ventilation scintigraphy with 99m Tc DTPA aerosol is of limited value due to the large amount of central airway distribution that occurs in patients with obstructive lung disease (Fig. 15.13) (104). Ventilation scintigraphy with radiolabeled xenon gas during the wash-in, equilibrium, and wash-out phases may not have the same limitation and may demonstrate areas of air trapping. The extensive perfusion abnormalities seen in patients with emphysema reduce the usefulness of ventilation-perfusion scans in emphysema patients being evaluated for suspected pulmonary embolism.

Perfusion scintigraphy demonstrates relative, not absolute, perfusion within the lungs.

Figure 15.12 Perfusion scintigraphy using technetium 99m macroaggregated albumin in a patient with upper lobe predominant emphysema demonstrates absent perfusion that corresponds to areas of emphysema seen anatomically with computed tomography.

Giant Bulla

A bulla is defined pathologically as “a sharply demarcated, dilated air space that measures 1 cm or more in diameter and possesses a thin epithelialized wall, which is usually no greater than 1 mm in thickness” and on CT as “a round, focal air space 1-cm or more in diameter, demarcated by a thin wall; usually multiple or associated with signs of pulmonary emphysema” (105). Giant bulla has varying definitions, and they may be as small as 5 cm or as large as the entire hemithorax (106). They are more common in young men than women or older individuals and are more common in smokers than nonsmokers but may been seen in the latter as well. One definition is a bulla involving one-third or more of a lung. Giant bullous disease is often referred to as vanishing lung syndrome. Rarely, a giant bulla may resolve spontaneously, often due to infection (107). More recently, giant bulla has been reported to develop after lung volume reduction surgery (108).

Figure 15.13 Ventilation scintigraphy using technetium 99m DTPA aerosol in a patient with emphysema demonstrates extensive central airway deposition of the radiotracer, hindering evaluation of regional ventilation in the lung parenchyma.

Most giant bullae asymmetrically involve the lungs on both radiographs and CT; bulla predominantly involve the upper lungs (Fig. 15.14) (109). On CT, paraseptal emphysema, centrilobular emphysema, and subpleural bullae are commonly present in addition to the dominant bulla. Bullae in these patients can involve an entire lobe or seemingly an entire lung, with marked compression of adjacent normal lung; the latter is an important criterion for determining if patients will do well with surgical resection. When giant bullae impair pulmonary function and are associated with compressed lung on CT, the usual method of treatment is surgical resection (110,111).

Compressed lung next to giant bulla on CT is used to select patients suitable for bullectomy.

Bronchiectasis

Clinical Features and Definition

Patients with bronchiectasis typically have chronic respiratory symptoms, including cough, recurrent pneumonia, and abundant sputum production. Shortness of breath and hemoptysis may also occur. The causes of bronchiectasis are varied (Table 15.6) (112).

Figure 15.14 Giant left upper lobe bulla (Bu). A. Posteroanterior and (B) lateral radiographs demonstrate a large, single, air-containing, thin-walled bulla in the left upper lobe with contralateral mediastinal shift. C. Computed tomography and (D) pulmonary angiography demonstrate compression of adjacent normal lung parenchyma and crowing of pulmonary vessels.

Cystic fibrosis is the classic disease in which bronchiectasis is a major component. It is a genetic disease in which abnormally thick mucus is produced because of an abnormal cystic fibrosis transmembrane conductance regulator protein, resulting in faulty transport of sodium and chloride within cells lining the airway. Approximately 30,000 children and adults in the United States have cystic fibrosis, and 1 in 31 individuals is a carrier of the defective gene. It is diagnosed with a sweat chloride test that measures the amount of salt in the sweat; high levels indicate cystic fibrosis (113). In cystic fibrosis, bronchiectasis is usually more severe in the upper lobes than the lower lobes and is accompanied by pulmonary hyperinflation (Fig. 15.15). With new therapies for cystic fibrosis that are gene based, it is now not uncommon to see individuals in the fourth decade of life with relatively mild disease. Patients with cystic fibrosis are prone to airway colonization with bacteria, such asPseudomonas, and also to recurrent pulmonary infection. There is a 25-point radiographic scoring system for cystic fibrosis, known as the Brasfield system, that is useful for grading the severity of lung disease and evaluating progression over time; this system has good correlation with pulmonary function (114).

Table 15.6: Causes of Bronchiectasis

Infection
   Tuberculosis
   Mycobacterium avium complex
   Allergic bronchopulmonary aspergillosis
   Recurrent infection
   Human immunodeficiency virus
Bronchial obstruction with mucoid impaction
Asthma
Chronic bronchitis
Pulmonary fibrosis
Hypogammaglobulinemia
Recurrent aspiration
Mounier-Kuhn syndrome
Inherited disorders
   α1-Antitrypsin deficiency
   Cystic fibrosis
   Williams Campbell syndrome
   Dyskinetic cilia syndromes
Idiopathic

Tuberculosis is a common cause of bronchiectasis worldwide, where it is a common indication for surgical resection of lung, but less so in industrialized nations. Lady Windemere syndrome, due to mycobacterium avium complex infection, is a subacute disease, classically in older women, in which bronchiectasis is usually most severe in the middle lobe and lingula (Fig. 15.16) (115). Bronchiectasis is also commonly seen with emphysema in α1-antitrypsin deficiency and in association with human immunodeficiency virus infection (116,117,118). Traction bronchiectasis often accompanies pulmonary fibrosis and honeycombing and may be seen with nonspecific interstitial pneumonitis and usual interstitial pneumonitis (Chapter 14). In Mounier-Kuhn syndrome, bronchiectasis is associated with tracheomegaly (Chapter 16Fig. 16.16) (119). In dyskinetic ciliary syndrome, also known as primary ciliary dyskinesia, the cilia within the bronchial epithelium are dysfunctional, leading to an inability to clear mucus from the airways and bronchiectasis. When found in association with situs inversus and recurrent sinusitis, this represents Kartagener syndrome (120). When found in association with infertility and sinusitis, this represents Young syndrome (121). Williams-Campbell syndrome is a rare cause of diffuse bronchiectasis in which there is a deficiency of cartilage in the third- to fifth-order airways (Fig. 15.17) (122).

Figure 15.15 Posteroanterior radiograph of a 25-year-old woman with cystic fibrosis and a spontaneous right pneumothorax with a chest tube in place.

Figure 15.16 Mycobacterium avium complex infection with bronchiectasis that is most severe in the right middle lobe and lingula.

Focal bronchiectasis with mucoid impaction may be seen due to bronchial atresia (Fig. 16.5) or to an endobronchial lesion, such as a carcinoid tumor (Fig. 15.18) or foreign body (123). Allergic bronchopulmonary aspergillosis classically manifests as dilated bronchi radiating out from the hila of the lungs, filled with mucus, creating a finger-in-glove appearance (Fig. 5.49) (124).

Figure 15.17 Bronchiectasis in Williams-Campbell syndrome. HRCT images demonstrate extensive cystic and varicose bronchiectasis with bronchial wall thickening.

Figure 15.18 Focal bronchiectasis with mucoid impaction secondary to carcinoid tumor.

Imaging of Bronchiectasis

HRCT is the test of choice when evaluating patients for suspected bronchiectasis, having replaced the more invasive bronchogram. Conventional bronchography with Lipiodol, first introduced in 1922 (125), and later with Dionosil has not met with widespread acceptance because of patient side effects and technical difficulties, including retained inspissated contrast, respiratory compromise, and underfilling of airways (Chapter 2Fig. 2.6) (126,127). Bronchography is also prone to interobserver variation in interpretation; in one series there was disagreement of two readers as to whether or not bronchiectasis was present in 22% of the lobes studied (128). Although more recent reports of bronchoscopic bronchography using 300 mg/mL of the iso-osmolar contrast medium, iotrolan (Schering, AG, Germany) have shown that it is better tolerated by patients and safe (129), the technique remains a more invasive and more costly alternative for the evaluation of the airways than HRCT.

HRCT is the test of choice to detect and characterize bronchiectasis.

Chest radiographs are insensitive for the detection of bronchiectasis, particularly when mild (130,131). The findings of bronchiectasis on chest radiographs include tram tracking or parallel lines, tubular or ring-shaped opacities with central lucency if bronchi are air filled, and central opacity if there is mucoid impaction (132) (Figs. 15.15 and 15.19). When air–fluid levels are present in cystic bronchiectasis, it may create an appearance known as demilunes. Bronchiectasis is frequently accompanied by pulmonary hyperinflation, an indicator of obstructive airway disease. Other secondary findings are atelectasis and decreased pulmonary vascularity. The air-containing and echo-reflective nature of the lungs makes them not amenable to interrogation with ultrasound, and magnetic resonance imaging does not sufficiently visualize the lung parenchyma and small airways (133).

Figure 15.19 Tram tracking of bronchiectasis in the right upper lobe (arrow) on a posteroanterior chest radiograph.

Computed Tomography of Bronchiectasis

CT was first reported to detect bronchiectasis in 1982 (134) and is the test of choice, using HRCT technique for detecting and characterizing bronchiectasis and for surgical planning (135). HRCT has a sensitivity of 84% to 95% and a specificity of 93% to 100% for the detection of bronchiectasis (136,137,138,139,140). In addition to identifying bronchiectasis and characterizing it morphologically as cylindrical, varicose, and cystic or saccular, expiratory HRCT images allow functional study by detecting a mosaic attenuation pattern due to areas of air trapping (141). Serial HRCT examinations can also be used to monitor disease progression or the impact of new therapies noninvasively, as proposed using a scoring system for HRCT in patients with cystic fibrosis (142). Although HRCT is accurate for bronchiectasis detection, it is inaccurate at diagnosing the cause of bronchiectasis (143,144).

The HRCT manifestations of bronchiectasis are airway dilatation, specifically bronchial diameter greater than the diameter of the adjacent pulmonary artery branch, nontapering of bronchi as they extend toward the periphery of the lungs, and a reduction in the number of visible bronchial divisions (Figs. 15.16 and 15.17). The artery-to-bronchus ratio also has good interobserver performance (κ at least 0.63) (138). In a study of surgically proven cylindrical bronchiectasis, the two HRCT findings of bronchiectasis not seen in any of the healthy subjects were visualization of bronchi within 1 cm of the costal pleura and visualization of a bronchus abutting mediastinal pleura (138). These findings were seen in 81% and 53% of patients with surgically proven disease; these findings are very specific but are somewhat lacking in sensitivity when used as the sole criteria for bronchiectasis detection. Lack of bronchial tapering and artery-to-bronchus ratios greater than 1 were both identified in 95% of patients and were more sensitive but less specific. Irregular outlines and thick bronchial walls are additional criteria that have been applied; however, these signs alone should be used with caution.

A tree-in-bud pattern of bronchiolar disease commonly accompanies other findings of bronchiectasis (Fig. 15.20) (145,146). First described in 1993 as a finding of endobronchial spread of tuberculosis, it is now recognized to occur in many small airway diseases (Table 15.7) (147). The tree-in-bud pattern is due to impaction of secretions or fibrotic material in the bronchiolar lumen, radiographically manifesting as 2 to 4 mm nodular and linear branching structures in a centrilobular distribution. The “buds” represent dilated and impacted bronchioles, whereas the “tree” branches are small centrilobular arteries or bronchi. This pattern is most commonly seen with airway infection, such as tuberculosis, or with airway inflammation. Uncommon causes include laryngotracheal papillomatosis with endobronchial dissemination from the larynx and diffuse panbronchiolitis. The latter is an uncommon idiopathic condition, occurring predominantly in Asians (148). Cryptogenic constrictive bronchiolitis, also an uncommon entity, may have an appearance similar to diffuse panbronchiolitis (149).

Tree-in-bud is a pattern of bronchiolar disease.

Figure 15.20 Tree-in-bud on HRCT is a manifestation of bronchiolar disease, in this case secondary to tuberculosis.

Table 15.7: Causes of a Tree-in-Bud Pattern

Infection
Immunologic disorders
Congenital disorders
   Cystic fibrosis
   Dyskinetic cilia syndromes
Laryngotracheal papillomatosis
Aspiration
Diffuse panbronchiolitis

Adapted from Collins J, Blankenbaker D, Stern EJ. CT patterns of bronchiolar disease: what is “tree-in-bud?” AJR Am J Roentgenol 1998;171:365–370.

Impact of Imaging on Therapy

Differentiating between the various forms of obstructive lung disease aids in tailoring the choice of therapy. For example, anticholinergic agents are potentially more useful as first-line bronchodilators in patients with COPD than in patients with asthma (150), whereas long-acting β agonists are useful in both asthma (151,152) and COPD (153,154). Modulation of airway inflammation is now an important component of asthma treatment (17,155), whereas the role of antiinflammatory agents in patients with COPD is more controversial (1,156,157). Steroid therapy is beneficial in both hospitalized (158) and ambulatory patients (159) during an acute asthma exacerbation; however, in stable symptomatic disease the role of oral steroids is more limited (156). Inhaled corticosteroids are a more recent addition to the pharmacologic armamentarium (160), decreasing exacerbations and slowing the deterioration in health-related quality of life (161,162). Nonpharmacologic therapy for airflow obstruction includes a multidisciplinary program of pulmonary rehabilitation (163).

Surgical therapy for severe airflow obstruction can be performed to provide thoracic stability, minimize dynamic airway compression, and surgically decrease hyperinflation (111,164). Most recently, lung volume reduction surgery has become popular for patients with severe emphysema. Early reports demonstrate considerable improvements in lung function, dyspnea, and health-related quality of life (165). Subsequent reports question the degree of improvement, the duration of that improvement, and criteria for patient selection (111,166,167,168). CT appears to be the best study to identify patients that may potentially benefit from lung volume reduction surgery, by both identifying and quantifying emphysema; most authors consider anatomic heterogeneity of emphysema a prerequisite to patient selection for lung volume reduction surgery (Figs. 15.5 and 15.11) (167). CT can also help identify patients who may have significant airflow obstruction that is out of proportion to a relatively mild degree of emphysema; such patients have primary airway disease and are not good candidates for lung volume reduction surgery (169). Whether studied qualitatively or quantitatively with CT, a greater postoperative improvement is seen in patients with upper lobe predominant emphysema, more heterogeneous emphysema, more compressed lung, and a larger percentage of normal and mildly emphysematous lung (82,170,171). Some investigators have shown that patients with homogeneous emphysema may have improvement after lung volume reduction surgery; however, the degree of improvement is less than patients with heterogeneous emphysema (172,173). Lung volume reduction surgery can be performed through a sternotomy, bilateral thoracotomies, or bilateral thoracoscopy. In contrast, surgery for giant bullous disease is unilateral surgery for resection of a giant bulla, with compression of normal lung on CT a prerequisite to patient selection for giant bullectomy.

References

1. Senior R, Anthonisen N. Chronic obstructive pulmonary disease (COPD). Am J Respir Crit Care Med 1998;157:S139–S147.

2. Burrows B, Bloom JW, Traver GA, et al. The course and prognosis of different forms of chronic airways obstruction in a sample from the general population. N Engl J Med 1987;317:1309–1314.

3. Postma D, Lebowitz M. Persistence and new onset of asthma and chronic bronchitis evaluated longitudinally in a community population sample of adults. Arch Intern Med 1995;155:1393–1399.

4. American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995;152:S77–S121.

5. Petty TL, Weinmann GG. Building a national strategy for the prevention and management of and research in chronic obstructive pulmonary disease. National Heart, Lung and Blood Institute Workshop Summary. JAMA 1997;277:246–253.

6. Dykewicz M, Ledford D. Recent findings in asthma likely to impact patient care. Comp Ther 1998;24:187–193.

7. O’Byrne P, Postma D. The many faces of airway inflammation. Asthma and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999;159:S41–S66.

8. Vollmer W, Osborne M, Buist A. 20-Year trends in the prevalence of asthma and chronic airflow obstruction in an HMO. Am J Respir Crit Care Med 1998;157:1079–1084.

9. Kesten S, Rebuck A. Is the short-term response to inhaled B-adrenergic agonist sensitive or specific for distinguishing between asthma and COPD? Chest 1994;105:1042–1045.

10. van Shcayck C. Diagnosis of asthma and chronic obstructive pulmonary disease in general practice. Br J Gen Pract 1996;46:193–197.

11. McIvor A, Chapman K. Diagnosis of chronic obstructive pulmonary disease and differentiation from asthma. Curr Opin Pulm Med1996;2:148–154.

12. Burdon J, Pain M, Rubinfeld A, et al. Chronic lung disease and the perception of breathlessness: a clinical perspective. Eur Respir J1994;7:1342–1349.

13. Holleman D, Simel D, Goldberg J. Diagnosis of obstructive airways disease from the clinical examination. J Gen Intern Med1993;8:63–68.

14. Holleman D Jr, Simel D. Does the clinical examination predict airflow limitation? JAMA 1995;273:313–319.

15. Emerman C, Lukens T, Effron D. Physician estimation of FEV1 in acute exacerbation of COPD. Chest 1994;105:1709–1712.

16. Burrows B, Barbee R, Cline M, et al. Characteristics of asthma among elderly adults in a sample of the general population. Chest1991;100:935–942.

17. National Asthma Education Program. National Heart, Lung and Blood Institute, National Institutes of Health. Guidelines for the diagnosis and management of asthma. NIH Publications No. 97-4051, April 1997.

18. American Thoracic Society. Lung function testing: selection of reference values and interpretative strategies. Am Rev Respir Dis1991;144:1202–1218.

19. Martinez F. Pulmonary function testing. In: Khan M, Lynch III J, eds. Pulmonary disease. Diagnosis and therapy. A practical approach. Baltimore, MD: Williams & Wilkins, 1997:107–141.

20. Cauberghs M, Clement J, Van de Woestijne K. Functional alterations accompanying a rapid decline in ventilatory function. Am Rev Respir Dis 1993;147:379–384.

21. Martinez F. Pulmonary function testing in the evaluation of upper airway obstruction. In: Norton M, ed. Atlas of the difficult airway. St. Louis, MO: Mosby-Year Book, 1996:125–133.

22. Hudon C, Turcotte H, Laviolette M, et al. Characteristics of bronchial asthma with incomplete reversibility of airflow obstruction. Ann Allergy Asthma Immunol 1997;78:195–202.

23. Boulet L, Turcotte H, Hudon C, et al. Clinical, physiological and radiological features of asthma with incomplete reversibility of airflow obstruction compared with those of COPD. Can Respir J 1998;5:270–277.

24. Brown P, Greville H, Finucane K. Asthma and irreversible airflow obstruction. Thorax 1984;39:131–136.

25. Anthonisen N. Prognosis in chronic obstructive pulmonary disease: results from multicenter clinical trials. Am Rev Respir Dis1989;140:S95–99.

26. Nisar M, Earis J, Pearson M, et al. Acute bronchodilator trials in chronic obstructive pulmonary disease. Am Rev Respir Dis1992;146:555–559.

27. Sterk P. Bronchoprovocation testing. Semin Respir Crit Care Med 1998;19:317–324.

28. Woolcock A, Anderson S, Peat J, et al. Characteristics of bronchial hyperresponsiveness in chronic obstructive pulmonary disease and in asthma. Am Rev Respir Dis 1991;143:1438–1443.

29. Brand P, Postma D, Kerstjens H, et al. Relationship of airway hyperresponsiveness to respiratory symptoms and diurnal peak flow variation in patients with obstructive lung disease. Am Rev Respir Dis 1991;143:916–921.

30. Greenspon L, Gracely E. A discriminant analysis applied to methacholine bronchoprovocation testing improves classification of patients as normal, asthma, or COPD. Chest 1992;102:1419–1425.

31. Tashkin D, Altose M, Bleecker E, et al. The Lung Health Study: airway hyperresponsiveness to inhaled methacholine in smokers with mild to moderate airflow limitation. Am Rev Respir Dis 1992;145:301–310.

32. Cotton D, Soparkar G, Graham B. Diffusing capacity in the clinical assessment of chronic airflow obstruction. Med Clin North Am1996;80:549–564.

33. Morrison N, Abboud R, Ramadan F, et al. Comparison of single breath carbon monoxide diffusing capacity and pressure-volume curves in detecting emphysema. Am Rev Respir Dis 1989;139:1179–1187.

34. Knudson R, Kalternborn W, Burrows B. Single breath carbon monoxide transfer factor in different forms of chronic airflow obstruction in a general population sample. Thorax 1990;45:524–529.

35. Collard P, Njinou B, Nejadnik B, et al. Single breath diffusing capacity for carbon monoxide in stable asthma. Chest 1994;105:1426–1429.

36. Stewart R. Carbon monoxide diffusing capacity in asthmatic patients with mild airflow limitation. Chest 1988;94:332–336.

37. Gelb A, Schein M, Kuei J, et al. Limited contribution of emphysema in advanced chronic obstructive pulmonary disease. Am Rev Respir Dis 1993;147:1157–1163.

38. Jain P, Kavuru M, Emerman C, et al. Utility of peak expiratory flow monitoring. Chest 1998;114:861–876.

39. Vaughan T, Weber R, Tipton W, et al. Comparison of PEFR and FEV1 in patients with varying degrees of airway obstruction. Effect of modest altitude. Chest 1989;95:558–562.

40. Dekker F, Schrier A, Sterk P, et al. Validity of peak expiratory flow measurement in assessing reversibility of airflow obstruction.Thorax 1992;47:162–166.

41. Berube D, Cartier A, L’Archeveque J, et al. Comparison of peak expiratory flow rate and FEV1 in assessing bronchomotor tone after challenges with occupational sensitizers. Chest 1991;99:831–836.

42. Klein JS, Gamsu G, Webb WR, et al. High-resolution CT diagnosis of emphysema in symptomatic patients with normal chest radiographs and isolated low diffusing capacity. Radiology 1992;182:817–821.

43. Chin NK, Lim TK. A 39-year-old smoker with effort dyspnea, normal spirometry results, and low diffusing capacity. Chest1998;113:231–233.

44. Arakawa H, Webb WR. Air trapping on expiratory high-resolution CT scans in the absence of inspiratory scan abnormalities: correlation with pulmonary function tests and differential diagnosis. AJR Am J Roentgenol 1998;170:1349–1353.

45. Murray JF, Nadel JA. Textbook of respiratory medicine, 2nd ed. Vol. 2. Philadelphia: Saunders, 1994:27–39.

46. Linden-Smith J, Morrison D, Hernandez P, et al. Overdiagnosis of asthma? A community survey. Am J Respir Crit Care Med1999;159[Suppl 3]:A135.

47. Martin A, Landau L, Phelan P. Lung function in young adults who had asthma in childhood. Am Rev Respir Dis 1980;122:609–616.

48. Panhuysen C, Vonk J, Koeter G, et al. Adult patients may outgrow their asthma: a 25-year follow-up study. Am J Respir Crit Care Med1997;155:1267–1272.

49. Eisner M, Yelin E, Henke J, et al. Environmental tobacco smoke and adult asthma: the impact of changing exposure on health outcomes. Am J Respir Crit Care Med 1998;158:170–175.

50. Ronmark E, Lundback B, Jonsson E, et al. Incidence of asthma in adults—report from the Obstructive Lung Disease in Northern Sweden Study. Allergy 1997;52:1071–1078.

51. Litonjua A, Carey V, Burge H, et al. Parental history and the risk for childhood asthma: does the mother confer more risk than father? Am J Respir Crit Care Med 1998;158:176–181.

52. Panhuysen C, Bleecker E, Koeter G, et al. Characterization of obstructive airway disease in family members of probands with asthma.Am J Respir Crit Care Med 1998;157:1734–1742.

53. Beasley R, Roche W, Roberts J, et al. Cellular events in the bronchi in mild asthma and after bronchial provocation. Am Rev Respir Dis 1989;139:806–817.

54. Chetta A, Foresi A, Deldonno M, et al. Bronchial responsiveness to distilled water and methacholine and its relationship to inflammation and remodeling of the airways in asthma. Am Rev Respir Crit Care Med 1996;153:910–917.

55. Chanez P, Vignola A, O’Shaugnessy T, et al. Corticosteroid reversibility in COPD is related to features of asthma. Am Rev Respir Crit Care Med 1997;155:1529–1534.

56. Webb WR. Radiology of obstructive pulmonary disease. AJR Am J Roentgenol 1997;169:637–647.

57. Paganin F, Trussard V, Seneterre E, et al. Chest radiography and high resolution computed tomography of the lungs in asthma. Am Rev Respir Dis 1992;146:1084–1087.

58. Grenier P, Mourey-Gerosa I, Benali K, et al. Abnormalities of the airways and lung parenchyma in asthmatics: CT observations in 50 patients and inter- and intraobserver variability. Eur Radiol 1996;6:199–206.

59. Lynch DA, Newell JD, Tschomper BA, et al. Uncomplicated asthma in adults: comparison of CT appearance of the lungs in asthmatic and healthy subjects. Radiology 1993;188:829–833.

60. Carr DH, Hibon S, Rubens M, et al. Peripheral airways obstruction on high-resolution computed tomography in chronic severe asthma.Respir Med 1998;92:448–453.

61. Park CS, Muller NL, Worthy SA, et al. Airway obstruction in asthmatic and healthy individuals: inspiratory and expiratory thin-section CT findings. Radiology 1997;203:361–367.

62. Park JW, Hong YK, Kim CW, et al. High-resolution computed tomography in patients with bronchial asthma: correlation with clinical features, pulmonary functions and bronchial hyperresponsiveness. J Invest Allerg Clin Immunol 1997;7:186–192.

63. Paganin F, Seneterre E, Chanez P, et al. Computed tomography of the lungs in asthma: influence of disease severity and etiology. Am J Respir Crit Care Med 1996;153:110–114.

64. Awadh N, Muller NL, Park CS, et al. Airway wall thickness in patients with near fatal asthma and control groups: assessment with high resolution computed tomographic scanning. Thorax 1998;53:248–253.

65. Biernacki W, Redpath AT, Best JJ, et al. Measurement of CT lung density in patients with chronic asthma (see comments). Eur Respir J 1997;10:2455–2459.

66. Kinsella M, Müller NL, Staples C, et al. Hyperinflation in asthma and emphysema. Assessment by pulmonary function testing and computed tomography. Chest 1988;94:286–289.

67. Goldin JG, McNitt-Gray MF, Sorenson SM, et al. Airway hyperreactivity: assessment with helical thin-section CT. Radiology1998;208:321–329.

68. Kee ST, Fahy JV, Chen DR, et al. High-resolution computed tomography of airway changes after induced bronchoconstriction and bronchodilation in asthmatic volunteers. Acad Radiol 1996;3:389–394.

69. Okazawa M, Muller N, McNamara AE, et al. Human airway narrowing measured using high resolution computed tomography. Am J Respir Crit Care Med 1996;154:1557–1562.

70. Takasugi JE, Godwin JD. Radiology of chronic obstructive pulmonary disease. Radiol Clin North Am 1998;36:29–55.

71. Hartman TE, Tazelaar HD, Swensen SJ, et al. Cigarette smoking: CT and pathologic findings of associated pulmonary diseases.Radiographics 1997;17:377–390.

72. Pratt P. Emphysema and chronic airways disease. In: Dail D, Hammar S, eds. Pulmonary pathology. New York: Springer-Verlag, 1988:654–659.

73. Pratt PC. Role of conventional chest radiography in diagnosis and exclusion of emphysema. Am J Med 1987;82:998–1006.

74. Thurlbeck WM, Simon G. Radiographic appearance of the chest in emphysema. AJR Am J Roentgenol 1978;130:429–440.

75. Reich SB, Weinshelbaum A, Yee J. Correlation of radiographic measurements and pulmonary function tests in chronic obstructive pulmonary disease. AJR Am J Roentgenol 1985;144:695–699.

76. Nicklaus TM, Stowell DW, Christiansen WR, et al. The accuracy of the roentgenologic diagnosis of chronic pulmonary emphysema. Am Rev Respir Dis 1966;93:889–899.

77. Thurlbeck WM, Müller NL. Emphysema: definition, imaging, and quantification. AJR Am J Roentgenol 1994;163:1017–1025.

78. Bergin C, Müller N, Nichols DM, et al. The diagnosis of emphysema. A computed tomographic-pathologic correlation. Am Rev Respir Dis 1986;133:541–546.

79. Miller RR, Müller NL, Vedal S, et al. Limitations of computed tomography in the assessment of emphysema. Am Rev Respir Dis1989;139:980–983.

80. Tanino M, Nishimura M, Betsuyaku T, et al. A comparative study of computed tomographic techniques for the detection of emphysema in middle-aged and older patient populations. Nihon Kokyuki Gakkai Zasshi 2000;38:368–372.

81. Kazerooni EA, Chow LC, Whyte RI, et al. Preoperative examination of lung transplant candidates: value of chest CT compared with chest radiography. AJR Am J Roentgenol 1995;165:1343–1348.

82. Flaherty K, Kazerooni E, Curtis J, et al. Short-term and long-term outcomes after bilateral lung volume reduction surgery. Prediction by Quantitative CT. Chest 2001;119:1337–1346.

83. Remy-Jardin M, Remy J, Gosselin B, et al. Sliding thin slab, minimum intensity projection technique in the diagnosis of emphysema: histopathologic-CT correlation. Radiology 1996;200:665–671.

84. Hruban RH, Meziane MA, Zerhouni EA, et al. High resolution computed tomography of inflation-fixed lungs. Pathologic-radiologic correlation of centrilobular emphysema. Am Rev Respir Dis 1987;136:935–940.

85. Spouge D, Mayo JR, Cardoso W, et al. Panacinar emphysema: CT and pathologic findings. J Comput Assist Tomogr 1993;17:710–713.

86. Müller NL, Staples CA, Miller RR, et al. “Density mask.” An objective method to quantitate emphysema using computed tomography.Chest 1988;94:782–787.

87. Gevenois PA, Yernault JC. Can computed tomography quantify pulmonary emphysema? Eur Respir J 1995;8:843–848.

88. Gevenois PA, Zanen J, de Maertelaer V, et al. Macroscopic assessment of pulmonary emphysema by image analysis. J Clin Pathol1995;48:318–322.

89. Gevenois PA, de Maertelaer V, De Vuyst P, et al. Comparison of computed density and macroscopic morphometry in pulmonary emphysema. Am J Respir Crit Care Med 1995;152:653–657.

90. Gevenois PA, De Vuyst P, Sy M, et al. Pulmonary emphysema: quantitative CT during expiration. Radiology 1996;199:825–829.

91. Sakai F, Gamsu G, Im JG, et al. Pulmonary function abnormalities in patients with CT-determined emphysema. J Comput Assist Tomogr 1987;11:963–968.

92. Sakai N, Mishima M, Nishimura K, et al. An automated method to assess the distribution of low attenuation areas on chest CT scans in chronic pulmonary emphysema patients. Chest 1994;106:1319–1325.

93. Sanders C, Nath PH, Bailey WC. Detection of emphysema with computed tomography. Correlation with pulmonary function tests and chest radiography. Invest Radiol 1988;23:262–266.

94. Foster WL Jr, Pratt PC, Roggli VL, et al. Centrilobular emphysema: CT-pathologic correlation. Radiology 1986;159:27–32.

95. Nishimura K, Murata K, Yamagishi M, et al. Comparison of different computed tomography scanning methods for quantifying emphysema. J Thorac Imaging 1998;13:193–198.

96. Müller NL, Thurlbeck WM. Thin-section CT, emphysema, air trapping, and airway obstruction (editorial; comment). Radiology1996;199:621–622.

97. Kazerooni E, Martinez F, Quint L, et al. Quantitative helical CT indices of emphysema as predictors of outcome after lung volume reduction surgery. Radiology 1996;201:298.

98. Kazerooni EA, Whyte RI, Flint A, et al. Imaging of emphysema and lung volume reduction surgery. Radiographics 1997;17:1023–1036.

99. Kauczor HU, Heussel CP, Fischer B, et al. Assessment of lung volumes using helical CT at inspiration and expiration: comparison with pulmonary function tests. AJR Am J Roentgenol 1998;171:1091–1095.

100. Gelb A, Zamel N, McKenna R Jr, et al. Mechanism of short-term improvement in lung function after emphysema resection. Am J Respir Crit Care Med 1996;154:945–951.

101. Morrison NJ, Abboud RT, Müller NL, et al. Pulmonary capillary blood volume in emphysema. Am Rev Respir Dis 1990;141:53–61.

102. Eda S, Kubo K, Fujimoto K, et al. The relations between expiratory chest CT using helical CT and pulmonary function tests in emphysema. Am J Respir Crit Care Med 1997;155:1290–1294.

103. Mettler F, Guiberteau M. Essentials of nuclear medicine, 3rd ed. Philadelphia: Saunders, 1991.

104. Jamadar DA, Kazerooni EA, Martinez FJ, et al. Qualitative ventilation-perfusion scintigraphy and SPECT imaging in the evaluation of lung volume reduction surgery candidates: description and prediction of clinical outcome. Eur J Nuclear Med 1999;26.

105. Austin JH, Muller NL, Friedman PJ, et al. Glossary of terms for CT of the lungs: recommendations of the Nomenclature Committee of the Fleischner Society. Radiology 1996;200:327–331.

106. Goto H, Yuasa K, Takahashi S, et al. Giant bulla occupying the whole hemithorax. Chest 1987;92:384–385.

107. Shanthaveerappa HN, Mathai MG Jr, Fields CL, et al. Spontaneous resolution of a giant pulmonary bulla. J KY Med Assoc2001;99:533–536.

108. Iqbal M, Rossoff L, McKeon K, et al. Development of a giant bulla after lung volume reduction surgery. Chest 1999;116:1809–1811.

109. Stern EJ, Webb WR, Weinacker A, et al. Idiopathic giant bullous emphysema (vanishing lung syndrome): imaging findings in nine patients. AJR Am J Roentgenol 1994;162:279–282.

110. Laros CD, Gelissen HJ, Bergstein PG, et al. Bullectomy for giant bullae in emphysema. J Thorac Cardiovasc Surg 1986;91:63–70.

111. Martinez F. Surgical therapy for chronic obstructive pulmonary disease: conventional bullectomy and lung volume reduction surgery in the absence of giant bullae. Semin Respir Crit Care Med 1999;20:351–364.

112. Aronchick JM, Miller WT, Jr. Bronchiectasis. J Thorac Imaging 1995;10:255–267.

113. Orenstein D, Winnie G, Altman H. Cystic fibrosis: a 2002 update. J Pediatr 2002;140:156–164.

114. Brasfield D, Hicks G, Soong S, et al. Evaluation of scoring system of the chest radiograph in cystic fibrosis: a collaborative study.AJR Am J Roentgenol 1980;134:1195–1198.

115. Hartman TE, Swensen SJ, Williams DE. Mycobacterium avium-intracellulare complex: evaluation with CT. Radiology 1993;187:23–26.

116. King MA, Stone JA, Diaz PT, et al. Alpha 1-antitrypsin deficiency: evaluation of bronchiectasis with CT. Radiology 1996;199:137–141.

117. King MA, Neal DE, St. John R, et al. Bronchial dilatation in patients with HIV infection: CT assessment and correlation with pulmonary function tests and findings at bronchoalveolar lavage. AJR Am J Roentgenol 1997;168:1535–1540.

118. McGuinness G, Naidich DP, Garay S, et al. AIDS associated bronchiectasis: CT features. J Comput Assist Tomogr 1993;17:260–266.

119. Roditi GH, Weir J. The association of tracheomegaly and bronchiectasis. Clin Radiol 1994;49:608–611.

120. Kinney TB, DeLuca SA. Kartagener’s syndrome. Am Fam Physician 1991;44:133–134.

121. Handelsman DJ, Conway AJ, Boylan LM, et al. Young’s syndrome. Obstructive azoospermia and chronic sinopulmonary infections. N Engl J Med 1984;310:3–9.

122. McAdams HP, Erasmus J. Chest case of the day. Williams-Campbell syndrome. AJR Am J Roentgenol 1995;165:190–191.

123. Anonymous. Image interpretation session. Bronchial carcinoid tumor of the left lower lobe with postobstructive bronchiectasis.Radiographics 1991;11:134–136.

124. Angus RM, Davies ML, Cowan MD, et al. Computed tomographic scanning of the lung in patients with allergic bronchopulmonary aspergillosis and in asthmatic patients with a positive skin test to Aspergillus fumigatus. Thorax 1994;49:586–589.

125. Sicard JA, Forestier J. Iodized oil as contrast medium for radioscopy. Bull Mem Soc Med Hop Paris 1922;46:463.

126. Christoforidis AJ, Nelson SW, Tomashefski JF. Effects of bronchography on pulmonary function. Am Rev Respir Dis 1962;85:127.

127. Goldman JM, Currie DC, Morgan AD, et al. Arterial oxygen saturation during bronchography via the fiberoptic bronchoscope. Thorax1987;42:634–635.

128. Currie DC, Cooke JC, Morgan A, et al. Interpretation of bronchograms and chest radiographs in patients with chronic sputum production. Thorax 1987;42:278–284.

129. Morcos SK, Andersen PB, Ward P, et al. The efficacy of bronchography via the flexible bronchoscope using a water soluble non-ionic dimer (iotrolan) in diagnosing airway disease. J Bronchol 1996;3:106–111.

130. Cole P, Flower CDR, Lavender JP. Clinical and imaging aspects of bronchiectasis. In: Potchen EJ, Grainger RG, Greene R, eds.Pulmonary radiology—The Fleischner Society. Philadelphia: Saunders, 1993:242–258.

131. Cooke JC, Currie DC, Morgan AD, et al. Role of computed tomography in diagnosis of bronchiectasis. Thorax 1987;42:272–277.

132. Webb W. Radiology of obstructive pulmonary disease. AJR Am J Roentgenol 1997;169:637–647.

133. Carr DH, Oades P, Trotman-Dickenson B, et al. Magnetic resonance scanning in cystic fibrosis: comparison with computed tomography. Clin Radiol 1995;50:84–89.

134. Naidich DP, McCauley DI, Khouri NF, et al. Computed tomography of bronchiectasis. J Comput Assist Tomogr 1982;6:437–444.

135. Breatnach ES, Nath PH, McElvein RB. Preoperative evaluation of bronchiectasis by computed tomography. J Comput Assist Tomogr1985;9:949–950.

136. Engeler CE, Tashjian JH, Engeler CM, et al. Volumetric high-resolution CT in the diagnosis of interstitial lung disease and bronchiectasis: diagnostic accuracy and radiation dose. AJR Am J Roentgenol 1994;163:31–35.

137. Kang EY, Miller RR, Muller NL. Bronchiectasis: comparison of preoperative thin-section CT and pathologic findings in resected specimens. Radiology 1995;195:649–654.

138. Kim JS, Muller NL, Park CS, et al. Cylindrical bronchiectasis: diagnostic findings on thin-section CT. AJR Am J Roentgenol1997;168:751–754.

139. Grenier P, Maurice F, Musset D, et al. Bronchiectasis: assessment by thin-section CT. Radiology 1986;161:95–99.

140. Phillips MS, Williams MP, Flower CD. How useful is computed tomography in the diagnosis and assessment of bronchiectasis? Clin Radiol 1986;37:321–325.

141. Stern EJ, Muller NL, Swensen SJ, et al. CT mosaic pattern of lung attenuation: etiologies and terminology. J Thorac Imaging1995;10:294–297.

142. Bhalla M, Turcios N, Aponte V, et al. Cystic fibrosis: scoring system with thin-section CT. Radiology 1991;179:783–788.

143. Lee PH, Carr DH, Rubens MB, et al. Accuracy of CT in predicting the cause of bronchiectasis. Clin Radiol 1995;50:839–841.

144. Reiff DB, Wells AU, Carr DH, et al. CT findings in bronchiectasis: limited value in distinguishing between idiopathic and specific types. AJR Am J Roentgenol 1995;165:261–267.

145. Collins J, Blankenbaker D, Stern EJ. CT patterns of bronchiolar disease: what is “tree-in-bud?” AJR Am J Roentgenol 1998;171:365–370.

146. Hartman TE, Primack SL, Lee KS, et al. CT of bronchial and bronchiolar diseases. Radiographics 1994;14:991–1003.

147. Im JG, Itoh H, Shim YS, et al. Pulmonary tuberculosis: CT findings—early active disease and sequential change with antituberculous therapy. Radiology 1993;186:653–660.

148. Akira M, Higashihara T, Sakatani M, et al. Diffuse panbronchiolitis: follow-up CT examination. Radiology 1993;189:559–562.

149. Poletti V, Zompatori M, Boaron M, et al. Cryptogenic constrictive bronchiolitis imitating imaging features of diffuse panbronchiolitis.Monaldi Arch Chest Dis 1995;50:116–117.

150. Skorodin MS. Pharmacotherapy for asthma and chronic obstructive pulmonary disease. Current thinking, practices, and controversies. Arch Intern Med 1993;153:814–828.

151. Boyd G, Morice A, Pounsfod J, et al. An evaluation of salmeterol in the treatment of chronic obstructive pulmonary disease (COPD).Eur Respir J 1997;10:815–821.

152. Jones P, Bosh T. Quality of life in COPD patients treated with salmeterol. Am J Respir Crit Care Med 1997;155:1283–1289.

153. Verberne A, Fuller R. An overview of nine clinical trials of salmeterol in an asthmatic population. Respir Med 1998;92:777–782.

154. Vermetten F, Boermans A, Luiten W, et al. Comparison of salmeterol with beclomethasone in adult patients with mild persistent asthma who are already on low-dose inhaled steroids. J Asthma 1999;36:97–106.

155. Barnes P. Inhaled glucocorticoids for asthma. N Engl J Med 1995;332:868–875.

156. Callahan C, Dittus R, Katz B. Oral corticosteroid therapy for patients with stable chronic obstructive pulmonary disease. A meta-analysis. Ann Intern Med 1991;114:216–223.

157. van Grunsven P, van Schayck C, Derenne J, et al. Long term effects of inhaled corticosteroids in chronic obstructive pulmonary disease: a meta-analysis. Thorax 1998;54:7–14.

158. Albert R, Martine R, Lewis S. Controlled clinical trial of methylprednisolone in patients with chronic bronchitis and acute respiratory insufficiency. Ann Intern Med 1980;92:753–758.

159. Thompson W, Nielson C, Carvalho P, et al. Controlled trial of oral prednisone in outpatients with acute COPD exacerbation. Am J Respir Crit Care Med 1996;154:407–412.

160. Burge P. EUROSCOP, ISOLDE and the Copenhagen City Lung Study. Thorax 1999;54:287–288.

161. Calverley P, Burge P, Jones P, et al. Effect of 3 years treatment with fluticasone propionate in patients with moderately-severe COPD. Am J Respir Crit Care Med 1999;159[Suppl 3]:A524.

162. Spencer S, Anie K, Burge P, et al. Rate of health status decline is reduced in COPD patients treated with fluticasone compared to placebo. Am J Respir Crit Care Med 1999;159[Suppl 3]:A522.

163. American Thoracic Society. Dyspnea mechanisms, assessment, and management: a consensus statement. Am J Respir Crit Care Med1999;159:321–340.

164. Deslauriers J. Surgical management of chronic obstructive pulmonary disease. Ann Thorac Surg 1995;60:873–874.

165. Cooper JD, Trulock EP, Triantafillou AN, et al. Bilateral pneumectomy (volume reduction) for chronic obstructive pulmonary disease.J Thorac Cardiovasc Surg 1995;109:106–119.

166. Benditt JO, Albert RK. Surgical options for patients with advanced emphysema. Clin Chest Med 1997;18:577–593.

167. Utz J, Hubmayr R, Deschamps C. Lung volume reduction surgery for emphysema: out on a limb without a NETT. Mayo Clin Proc1998;73:552–556.

168. Sciurba F. Early and long-term functional outcomes following lung volume reduction surgery. Clin Chest Med 1997;18:259–276.

169. Ingenito E, Evans R, Loring S, et al. Relation between preoperative inspiratory lung resistance and the outcome of lung-volume-reduction surgery for emphysema. N Engl J Med 1998;338:1181–1185.

170. Slone R, Pilgram T, Gierada D, et al. Lung volume reduction surgery: comparison of preoperative radiologic features and clinical outcome. Radiology 1997;204:685–693.

171. Gierada D, Slone R, Bae K, et al. Pulmonary emphysema: comparison of preoperative quantitative CT and physiologic index values with clinical outcome after lung-volume reduction surgery. Radiology 1997;205:235–242.

172. Weder W, Thurnheer R, Stammberger U, et al. Radiologic emphysema morphology is associated with outcome after surgical lung volume reduction. Ann Thorac Surg 1997;64:313–319; discussion 319–320.

173. Wisser W, Klepetko W, Kontrus M, et al. Morphologic grading of the emphysematous lung and its relation to improvement after lung volume reduction surgery. Ann Thorac Surg 1998;65:793–799.