Small airways diseases: detection and insights with computed tomography

The detection of various forms of small airways disease has undergone a renaissance as a result of increased understanding of the high-resolution computed tomography (HRCT) appearances of the various pathological subtypes of small airways disease. Investigation of small airways dysfunction, without reference to the state of the more proximal or distal airways, characterized much of the early pathophysiological work on small airways disease. While conceptually convenient, the reality of anatomical continuity between the small and large airways, and the presence of coexisting parenchymal abnormalities in many diseases, has been starkly revealed in the detailed images of HRCT. The known spatial resolution limits of HRCT would suggest that attempts to image the normal small airways (arbitrarily considered to be those with an internal diameter of ≤2 mm) would appear to be, at first sight, a futile enterprise. It is in the diseased state that HRCT draws the veil aside. Abnormalities on HRCT that reflect small airways disease can be broadly categorized into indirect and direct signs: widespread scarring and obliteration of the bronchioles results in the indirect sign of patchy density differences of the lung parenchyma, representing areas of under-ventilated and under-perfused lung (the so-called mosaic attenuation pattern). By contrast, considerable thickening of the bronchiolar walls by inflammatory infiltrate and/or luminal and surrounding exudate render the affected small airways directly visible. This article concentrates on the HRCT imaging of the “purer” forms of bronchiolar disease, while acknowledging that there is a “small airways” component, to a greater or lesser extent, in the heterogeneous totality of chronic obstructive pulmonary disease (COPD). Some of the principles and observations contained in this review are applicable to the commoner, if less tangible, entity of COPD. Although primacy is given to HRCT in this review, some of the signs and functional correlations discussed may well be applicable to other forms of imaging, in particular the rapidly developing technique of hyperpolarized gas magnetic resonance imaging (MRI) of the lungs 1.

Pathological background and classification

Inflammation of the bronchioles with or without subsequent scarring and bronchiolar obliteration is a very common lesion in the lungs 2 and pathological studies have repeatedly emphasized the frequent bronchiolar involvement in diverse diffuse lung diseases. Because of the wide variety of conditions which are characterized by an element of bronchiolar damage, the term “small airways disease” has much to recommend it; from the imaging point of view, the term does not attempt to define the exact size of the airways included in this generic term, but it can usefully be taken to include all airways below the resolution of HRCT in the normal state.

The specific and classical term obliterative bronchiolitis (synonym: bronchiolitis obliterans) has, until recently, been the subject of confusion, primarily because of its use in the context of bronchiolitis obliterans organizing pneumonia (BOOP). The clinico-pathological entity of BOOP, more usefully termed cryptogenic organizing pneumonia (COP) 3, should be regarded as quite distinct from obliterative bronchiolitis and it has been suggested that the bronchiolitis obliterans part of BOOP should be discarded altogether 4. Given its distinctive features, BOOP/organizing pneumonia is not considered further in this review.

The various conditions included within the term small airways diseases are usually classified into pathological subtypes or by less precise clinical criteria (usually by presumed cause or association). The latter approach has become increasingly unsatisfactory because of the increasing number of new causes and associations reported in the literature. While pathologists categorize small airways diseases according to their histopathological subtypes 5, the difficulty with this traditional approach is that there are not always obvious clinical or imaging correlates with these pathological subtypes. One of the more comprehensive histopathological schemes, described by Myers and Colby 6 is shown in table 1⇓. Many other schemes are loosely based on the classification of Myers and Colby 6, for example an abbreviated version by Worthy and Müller 7 includes the following five histopathological entities: 1) cellular bronchiolitis; 2) panbronchiolitis; 3) respiratory bronchiolitis; 4) constrictive bronchiolitis; and 5) bronchiolitis obliterans with intraluminal polyps. Whereas Hwang et al. 8 categorize small airways disease as follows: 1) infectious bronchiolitis; 2) constrictive bronchiolitis; 3) proliferative bronchiolitis (i.e. BOOP); 4) respiratory bronchiolitis; 5) diffuse panbronchiolitis; and 6) mineral dust-induced bronchiolitis.

A simpler approach relies on the fundamental difference between the indirect HRCT signs of constrictive bronchiolitis and the direct visualization of the small airways on HRCT in exudative forms of bronchiolitis (typified by diffuse panbronchiolitis). These two basic HRCT patterns of small airways disease account for the majority encountered in clinical practice. Other miscellaneous forms of small airways disease with more or less distinctive pathological and imaging features, if not clinical presentations, are dealt with separately.

High-resolution computed tomographic technique

Standard HRCT technique is satisfactory for demonstrating the features of various obstructive lung diseases, particularly in advanced disease. However, some modifications are needed to enhance the sometimes subtle signs of small airways disease. The two fundamental forms of small airways disease, namely constrictive (obliterative) bronchiolitis and, at the other end of the pathological/imaging spectrum, diffuse panbronchiolitis make different demands on the technique; for the optimal imaging of patients with constrictive bronchiolitis, appropriate contrast resolution is needed to demonstrate regional density differences (mosaic attenuation pattern), whereas the imaging of patients diffuse panbronchiolitis necessitates adequate spatial resolution to depict the characteristic small branching structures (tree-in-bud pattern).

Despite the relatively few technical parameters that can be altered when performing a HRCT examination, the final appearance of the images of the lungs obtained on different computed tomography (CT) scanners, even with the use of identical window settings (the controls that determine the contrast and depth of the grey scale of the CT image), can be remarkably different. Such differences may be problematic, particularly in the context of the confident identification of a mosaic attenuation pattern or assessment of the degree of wall thickening of the macroscopic bronchi.

Window settings have a marked effect on the apparent size of structures 9 and in the context of diseases of the airways, the most obvious effect of inappropriate window settings is on the thickness of bronchial walls. Narrowing the window settings will increase apparent bronchial wall thickness and at the same time reduce the apparent internal bronchial diameter. No absolute window settings can be recommended because of variation between CT machines and individuals preferences, however for diagnostic purposes consistent window settings from patient to patient are advisable and a window level of −400–−950 Hounsfield Units (HU) and a width of 1,000–1,600 HU have been widely recommended 10–12. In a study that correlated thin-section CT with planimetric measurements of inflation-fixed lungs 13, it has been shown that wider latitude is possible; specifically, for the accurate estimation of bronchial wall thickness the authors suggest that, irrespective of the chosen window width, the window centre should be −250–−700 HU, and that within this range bronchial wall thickness is not appreciably affected (window width should be >1,000 HU, a narrower window width will cause a spurious appearance of bronchial wall thickening). A survey of thoracic radiologists indicates that for the evaluation of the lung parenchyma, the majority use a window level of −600 HU and a window width of 1,500 HU 14.

A typical HRCT protocol used in clinical practice would simply be thin (1–2 mm) collimation sections at 10 mm interval from lung apices to the costophrenic angles with the patient breath-holding at full inspiration, in a supine position. Normal lung parenchyma increases in attenuation on expiration (fig. 1⇓). Areas of air-trapping caused by small airways disease are seen as regional inhomogeneity, i.e. areas that remain relatively lucent (black) interspersed with areas of normal higher density lung (fig. 2⇓). This important sign of enhancement of the mosaic attenuation pattern on CT sections obtained at end-expiration (usually limited to approximately six sections taken between the aortic arch and right hemidiaphragm) has led some workers to suggest that they should be acquired routinely, irrespective of the findings on the standard inspiratory HRCT sections 15, 16. Whether expiratory CT sections need to be obtained in all cases of suspected small airways disease is questionable. However, there is no doubt that presymptomatic air-trapping in, for example, cigarette smokers may be detectable on expiratory CT in the face of normal inspiratory CT images 17. Furthermore, it is often reassuring to have the sometimes subtle mosaic pattern emphasized on additional expiratory sections.

Obtaining end-expiratory CT images is not always straightforward and a few patients are unable to comply, despite coaching by an experienced technologist, with the request to “breathe right out and hold it”. Determining the state of inflation of the lungs from the appearances of the inspiratory and expiratory CT scans is largely subjective, but invagination of the posterior membrane of the trachea on the expiratory CT scan implies a satisfactory effort by the patient (fig. 3⇓); the normal decrease in cross-sectional area of the lungs, at the level of the carina, by ∼55% at end-expiration is, in practice, less easy to gauge 18. Despite the theoretical attractions of spirometrically-gated CT, in which images are obtained at predetermined levels of lung inflation 19–21, relatively few clinical studies have made use of this method. For patients who are unable to reliably suspend respiration, specifically at end-expiration, scanning in a decubitus position has been suggested 22; in this position the dependent lung is relatively restricted and so mimics the state of the lungs at end-expiration.

There are other manoeuvres that may enhance the appearance of air-trapping 23. Sections obtained in quick succession during forced expiration, for example at a rate of two per second at a given level, may show areas of air-trapping that are inconspicuous or absent on sections obtained more conventionally at end-expiration 24; the physiological reasons for the increased conspicuity of air-trapping on dynamic CT examinations are not fully understood 25 but may reflect the “pendelluft” phenomenon whereby partially obstructed lung empties more slowly than normal lung during rapid expiration, so emphasizing attenuation differences 26. A recent study that compared low-dose dynamic expiratory CT with the more conventional end-expiratory CT technique demonstrated that the density changes were significantly greater with the dynamic technique 27, but artefact inherent in the low-dose dynamic method may be problematic. Nonetheless, this study provides further support for the concept that CT data obtained during, rather than following, expiration is the most sensitive mode for detecting air-trapping on CT.

The density differences that characterize the mosaic attenuation pattern on HRCT, on either inspiratory or expiratory images, may be very subtle and close to the limit of visual detection. Altering window settings may increase the conspicuity of a mosaic pattern but the subjective manipulation of window settings will spuriously affect the apparent extent of abnormal versus normal lung (fig. 4⇓). Simple image processing of CT data can be used to improve detection and decrease observer variation. Spiral CT can be used to acquire a “slab” of anatomically contiguous thin-sections (for example, a 5 mm slab consisting of five adjacent 1 mm sections); a simple image processing algorithm is applied whereby only the lowest attenuation value of the five adjacent pixels is projected on the final image, producing a so-called “minimum intensity projection (MinIP) image”. This technique improves the detection of subtle areas of low attenuation, encountered in small airways disease and emphysema 28, 29. There is no doubt that MinIP and similar postprocessing of HRCT images improves the conspicuity of the regional inhomogeneity of the lung parenchyma caused by small airways diseases (fig. 5⇓) 30, 31, and these techniques are useful in the investigation of structure/function relationships (see later) but they are not routinely used in clinical practice.

While much of the current (and probably future) work has relied on HRCT images for disease quantification, the volumetric acquisition of CT data using spiral and multidector CT holds a promise for specific applications. The basis of spiral CT scanning is continuous movement of the patient through the CT gantry while the x-ray tube and detector rotate around the long axis of the patient. In this way, there is fast, continuous and complete acquisition of data of the whole thorax. For clinical diagnostic purposes, the volumetric data is reconstructed into “conventional” cross-sectional images and in this respect, the full potential of novel analysis and presentation of volumetric data has yet to be realized 32.

Constrictive (obliterative) bronchiolitis

Constrictive bronchiolitis is associated with numerous predisposing conditions or causative agents and the most frequently encountered are shown in table 2⇓.

Viral lower respiratory tract infections are a common cause of constrictive bronchiolitis, particularly in children 33, 34. Nonviral agents are much less commonly implicated, although Mycoplasma pneumoniae 35 is an especially potent cause of constrictive bronchiolitis because of its predilection for the respiratory epithelium. There are sporadic reports in the literature suggesting that bacterial infections, for example Nocardia asteroides and Legionella pneumophila, may be responsible for an obliterative bronchiolitis 36, 37; however, the imaging and pathology described in these reports is of an organizing pneumonia rather than constrictive bronchiolitis (highlighting the historical confusion surrounding the terminology of “bronchiolitis obliterans” and “BOOP” referred to earlier). Nevertheless, infection with M. pneumoniae is one of the uncommon situations in which both constrictive bronchiolitis and “proliferative” bronchiolitis (i.e. BOOP) truly coexist 38. There is indirect evidence that in a few specific situations, bacterial colonization or infection is associated with small airways involvement; in patients with idiopathic bronchiectasis, there is a link between infection with Pseudomonas aeruginosa and the extent and severity of CT features of bronchiectasis and constrictive bronchiolitis, by comparison with nonPseudomonas infected bronchiectatic patients 39. A similar association has been reported in patients with Mycobacterium avium-intracellulare infection, but no pre-existing lung disease, who had a high prevalence of functional and CT evidence of small airways disease compared to a control group 40 (fig. 6⇓). The nature of such relationships (“cause versus effect”) has not been established.

Repeated viral lower respiratory tract infections are common in adult life, but clinically significant constrictive bronchiolitis as a consequence is fortunately rare 41; however, the incidental finding of focal areas of decreased attenuation at HRCT in otherwise healthy individuals may represent the clinically silent sequel of such episodes. Swyer-James (or MacLeod's) syndrome is a particular form of constrictive bronchiolitis that occurs following an insult, usually a viral infection sustained in childhood, to the developing lung. The characteristic pathophysiological feature is that lung served by damaged airways remains inflated by collateral air drift. Further development of the lung is arrested resulting in hypoplasia of the lung tissue, including the pulmonary arteries which are reduced in both size and number. As defined in the original radiographic descriptions, the transradiancy is predominantly or exclusively unilateral. The inhomogeneous nature of lung involvement is particularly well demonstrated on CT, which shows bronchiectatic changes and bilateral features of constrictive bronchiolitis in most cases 42–45. The key feature of air-trapping is well demonstrated on expiratory CT scans.

Constrictive bronchiolitis is a predictable consequence of the inhalation of many toxic fumes and gases which reach the small airways 46. It has been most frequently described following nitrogen dioxide inhalation (silo-filler's disease) 47. Epithelial injury, notably to ciliated cells, is almost invariable following exposure to any oxidant gas or hot smoke, so that bronchiectasis readily seen on CT usually accompanies this type of obliterative bronchiolitis 48. A wide variety of inorganic dusts, including silica, asbestos, mica, talc and iron or aluminium oxides have the potential to cause small airway obliteration, but this is often overlooked because of the apparently dominant pathology of dust-induced interstitial fibrosis 49. A problem in recognizing mineral dust-induced small airways disease is the similarity of lesions, namely mural fibrosis and pigmentation, found in both cigarette smokers and nonsmoking dust-exposed workers. However, when dust-exposed individuals are compared to matched nondust-exposed smoking control subjects, the degree of fibrosis around the terminal bronchioles is considerably greater in dust-exposed individuals 50. In the specific case of asbestos exposure, the earliest phases of asbestos-induced pulmonary damage is peribronchiolar fibrosis and this lesion can be identified on HRCT images as minute irregular centrilobular nodules 51. Whether other CT signs of constrictive bronchiolitis, notably air-trapping on expiratory CT, occur with any frequency in inorganic dust-induced pulmonary disease has not been reported.

Among the connective tissue diseases, constrictive bronchiolitis is most strongly associated with rheumatoid arthritis 52–54. Constrictive bronchiolitis associated with rheumatoid arthritis is often rapidly progressive with refractory airflow obstruction unresponsive to any treatment 53. Nevertheless, minor degrees of constrictive bronchiolitis are probably present and subclinical in many patients with rheumatoid arthritis 55, 56. In a CT study of 84 patients, 30% showed features of bronchiectasis/bronchiolectasis, presumed to reflect small airways involvement 57. In the context of rheumatoid arthritis, with the potential for coexisting interstitial pulmonary fibrosis, the question arises of whether abnormalities of the large airways are due to distortion by surrounding fibrosis (traction bronchiectasis) or are the epiphenomenon of small airways disease; there have been no HRCT-pathological correlative studies that have addressed this specific question. HRCT has revealed that both interstitial and airways disease frequently coexist in patients with rheumatoid arthritis (fig. 7⇓). Pencillamine has been incriminated as a contributory causative agent. In a study of 602 patients with rheumatoid arthritis, there was a 3% prevalence of clinically apparent constrictive bronchiolitis, and cases were confined to those patients receiving penicillamine 58, nevertheless penicillamine is not a sine qua non for the development of constrictive bronchiolitis in rheumatoid arthritis patients 52. Patients with Sjögren's syndrome may have a combination of interstitial disease (usually lymphocytic interstitial pneumonitis) and bronchiolocentric lymphocyte infiltration but, unlike rheumatoid arthritis, constrictive bronchiolitis is rarely the dominant presenting feature 59, 60.

Constrictive bronchiolitis is an important and frequent cause of morbidity and mortality in patients receiving heart and lung transplants 61, 62. It occurs in up to 50% of recipients and usually manifests itself between 9–15 months (range 60 days–5.6 yrs) after transplantation 63, 64. It is probable that subclinical damage to small airways epithelium (secondary to acute rejection and/or cytomegalovirus (CMV) infection) occurs earlier, within the first few weeks following transplantation, and that subtle HRCT abnormalities caused by, for example, CMV infection 65 may predate the functional abnormalities of supervening small airways obliteration 66. The contribution of imaging to the detection of acute rejection in these circumstances is limited, but the identification of areas of ground-glass opacification on HRCT within the first few months after transplantation is suggestive although nonspecific 67. Modification of the immunosuppressive regimen may be successful in delaying the development of constrictive bronchiolitis, but relapses are common 64. The reported sensitivity and specificity of HRCT for the diagnosis of established constrictive obliterative bronchiolitis in postlung transplant patients has been variable, largely due to differences in patient selection and the HRCT feature evaluated 66, 68, 69–72. Early studies concentrated on bronchiectasis, rather than a mosaic attenuation pattern, as the marker of obliterative bronchiolitis 73, 74, but more recently attention has turned to the mosaic attenuation pattern on inspiratory CT and, more particularly, on expiratory CT; in one series the sensitivity of 40% and specificity of 78% increased to 80% and 94% respectively, when expiratory CT sections were examined 69. In a study by Leung et al. 69, air-trapping on expiratory CT was the most sensitive sign (sensitivity 91%) of obliterative bronchiolitis in 11 patients with transbronchial biopsy confirmation 69. Nevertheless, there is considerable heterogeneity between series concerning which test (transbronchial biopsy, pulmonary function testing, expiratory HRCT) is the most accurate for the detection of obliterative bronchiolitis in post-transplant patients. A recent study suggests that air-trapping on expiratory CT is not as specific or sensitive as previously thought 71; the air-trapping score in patients with biopsy proven obliterative bronchiolitis was not significantly different to biopsy negative patients with airflow limitation. However, given the patchy nature of the disease, a negative transbronchial biopsy does not necessarily preclude obliterative bronchiolitis 75 and expiratory HRCT may show evidence of obliterative bronchiolitis in some biopsy negative cases 71.

Obliterative bronchiolitis also occurs following bone marrow transplantation 63, 76, 77. The disorder develops usually within 18 months of transplantation and is variably responsive to increased immunosuppression. At this stage, other complications (including a variety of infections, pulmonary oedema and drug toxicity) are frequent 78 and imaging characteristics are not discriminatory 63. In general, clinically obvious obliterative bronchiolitis occurs in only a small proportion of patients following allogeneic bone marrow transplant and is usually less severe than that seen following lung transplantation 77.

Constrictive bronchiolitis is rarely truly cryptogenic 79, 80; most cases probably have an undisclosed precipitating cause or association, such as a connective tissue disease which subsequently declares itself 81.

High-resolution computed tomography of individual features of constrictive bronchiolitis

The plain radiographic features of constrictive bronchiolitis are nonspecific, and absent in all but the most severe cases; the signs can be summarized as diminished pulmonary vasculature and over-inflation of the lungs with or without bronchial wall thickening 82–84. These abnormalities, seen in any form of COPD, are prone to considerable observer variation.

In one of the first CT studies of constrictive bronchiolitis, 15 patients who fulfilled the criteria of Turton et al. 79 were examined with conventional (contiguous 10 mm sections) and thin-section CT (interspaced 3 mm sections) 85. Chest radiographs were normal in five of 15 patients; the remaining 10 patients showed “limited vascular attenuation and hyperinflation”. In 13 of 15 a pattern of “patchy irregular areas of high and low attenuation in variable proportions, accentuated in expiration” was recorded. This, and a report of two cases by Eber et al. 86, were the first reports to identify regional inhomogeneity of the density of the lung parenchyma as the key CT feature of constrictive bronchiolitis.

Subsequent descriptions have confirmed and refined the HRCT features of constrictive bronchiolitis 8, 87–90. The HRCT signs comprise areas of reduced density of the lungs (the patchy density differences giving rise to the term “mosaic attenuation pattern”), constriction of the pulmonary vessels within areas of decreased lung density, bronchial abnormalities, and lack of change of cross-sectional area of affected parts of the lung on scans obtained at end-expiration 44, 91. These individual CT signs of constrictive bronchiolitis are now considered in more detail.

Accuracy of high-resolution computed tomography signs and interpretive pitfalls

The individual HRCT features of constrictive bronchiolitis are not, in isolation, specific for that disease and may be encountered in other COPDs. Conversely, the sensitivity of the individual, or combined, HRCT signs of constrictive bronchiolitis cannot be easily extracted from the current literature. However, in the context of a known cause or association of constrictive bronchiolitis, an HRCT examination showing the concatenation of mosaicism, bronchial abnormalities and air-trapping on expiratory images can be regarded as diagnostic. The frequency with which “significant” obliteration of the small airways occurs without accompanying abnormalities on HRCT is unknown, and given the lack of a reliable in vivo gold standard, this question remains open. Furthermore, there are circumstances in which the discrimination between constrictive bronchiolitis and other obstructive pulmonary diseases, particularly in advanced disease, can be difficult.

In considering the diagnostic accuracy of HRCT, it is worth reiterating the basic point that the sign of mosaic attenuation pattern is nonspecific in that it is the dominant abnormality in three completely different types of diffuse pulmonary disease: small airways disease, occlusive vascular disease, or infiltrative lung disease 15, 94–96. In a study of 70 patients in whom the mosaic attenuation pattern was the dominant HRCT abnormality, Worthy et al. 97 showed that small airways disease and infiltrative lung disease were readily and correctly identified but the mosaic attenuation pattern caused by occlusive vascular disease was frequently misinterpreted. Bronchial abnormalities and the presence of air-trapping on expiratory CT scans are the most useful discriminatory features in identifying small airways disease as the cause of mosaic attenuation. However, the phenomenon of hypoxic bronchodilatation in chronic occlusive vascular disease 98 complicates the diagnostic process. Nevertheless, the differentiation between the three basic causes of a mosaic attenuation pattern is easily made when the clinical and physiological information is taken into account.

Areas of decreased attenuation of the lung parenchyma on HRCT in patients with severe obstructive airways disease due to constrictive bronchiolitis, are sometimes interpreted as “emphysema”; in constrictive bronchiolitis, the pulmonary vessels in affected lung are attenuated, but not distorted, as is the case in centrilobular emphysema. In a study of patients with bronchiectasis, it was assumed that the widespread areas of decreased attenuation on HRCT were caused by emphysema, accounting for the functional gas-trapping 99. However, the “emphysema” seen in that study was not associated with decreased gas diffusing capacity, the functional hallmark of emphysema. Similarly, in nonsmoking asthmatic individuals, areas of decreased attenuation, scored visually on HRCT have been ascribed to emphysema 100, 101. However, several strands of evidence suggest that the areas of decreased attenuation identified on HRCT in asthmatics 102, 103, particularly on expiratory images, reflect air-trapping due to small airway obstruction, rather than emphysematous lung destruction 104: in a study of 18 asthmatics and 22 normal controls, Newman et al. 105 showed more extensive areas of low attenuation (<−900 HU) on expiratory images in asthmatics, but this difference was not found on inspiratory images (areas of low attenuation, if they were caused by emphysema, would be expected on inspiratory images). The lack of any significant difference in low attenuation areas of the lung (<−950 HU) in normal through mild-to-severe asthmatic individuals has been confirmed by Gevenois et al. 106.

In patients with centrilobular emphysema, the HRCT features of permeative destruction of the lung parenchyma and distortion of the pulmonary vasculature within poorly marginated areas of decreased attenuation are usually sufficiently distinctive to prevent confusion with constrictive obliterative bronchiolitis. However, the differentiation between panacinar emphysema (typified by patients with α₁-antitrypsin deficiency) and advanced constrictive obliterative bronchiolitis may be less straightforward on HRCT appearances alone (fig. 11⇓). A recent study that tested the ability of observers to distinguish, on the basis of HRCT appearances alone, between cases of constrictive bronchiolitis, asthma, centrilobular emphysema, panacinar emphysema and normal individuals showed that the first choice diagnosis was correct in 199 of 276 (72%) observations. Furthermore, agreement on distinguishing between cases of constrictive bronchiolitis and panacinar emphysema (potentially the most challenging diagnostic call on HRCT) was reasonable (kappa 0.63) 107.

The question of the importance, or otherwise, of focal areas of low attenuation consisting of one or more secondary pulmonary lobules has persisted since such “abnormalities” were reported on dynamic expiratory CT in four out of 10 apparently healthy volunteers with normal pulmonary function tests 108. Such areas of decreased attenuation are not usually present or conspicuous on inspiratory HRCTs of normal individuals 102 and, when identified, need to be distinguished from artefactual areas of low density caused by adjacent ribs (beam hardening artefact). The frequency with which air-trapping is identified on HRCT increases with age as does the extent, which is also influenced by cigarette smoking 17, 109. A relatively high prevalence of mosaic pattern has been reported in a study of 14 healthy subjects and 39 asthmatic individuals; a mosaic pattern was seen with equal frequency in both groups (21% and 18%) 110. In addition, trivial extents of air-trapping on expiratory CT occurred with similar frequency in both groups (54% and 49%), whereas severe air-trapping was seen much less frequently in healthy subjects than asthmatics (14% versus 50%). The extent of air-trapping did not exceed 25% of the cross-sectional area of the section in question in any of the healthy subjects. It seems improbable that, as with any other clinical test, a single arbitrary figure can be used to discriminate between normality and disease. For example, the implication of the presence of five secondary pulmonary lobules showing air-trapping on expiratory CT, not previously present on a baseline CT, of a lung transplant patient is clearly very different to the identification of moderately extensive areas of air-trapping in a patient with cigarette smoking induced respiratory bronchiolitis.

Morphological-functional correlations in constrictive bronchiolitis

In small airways diseases, there is a conceptual void between the information provided by CT and its correlation with the traditional global information derived from conventional physiological tests; relatively simple correlative studies confirm broadly that the “black lung” component of the mosaic pattern probably reflects small airways disease (rather than emphysema, in the strict pathological sense of the term), but lack of histological studies of “black lung” and limitations of global pulmonary function tests raise the perennial problem of a satisfactory gold standard for a disease as elusive as constrictive bronchiolitis.

There is considerable overlap between the capabilities of image processing techniques that seek, on one hand, to identify and on the other hand, to quantify abnormalities of the lung parenchyma; it is the accurate quantification of abnormal lung that is crucial for the investigation of structure/function relationships. A variety of simple visual scoring systems have been applied to the task of quantifying the CT features of constrictive bronchiolitis, notably the component of decreased lung density of the mosaic attenuation pattern 16, 89, 93. In a study by Lucidarme et al. 93, quantification of areas of air-trapping in individuals with chronic airways disease on expiratory CT was performed using a grid counting system. The intraclass correlation coefficient between two observers was good (r=0.86), although this may be an overstatement because the coefficient was calculated only for cases in which both observers agreed that air-trapping was present. However, this type of system tends to be labourious and time consuming. Automated objective techniques such as density thresholding 111, 112 are critically dependent upon a clear dichotomy between normal and reduced lung density; while such a difference exists in emphysema, in constrictive bronchiolitis, particularly when admixed with interstitial disease, lung density representing disease is highly heterogeneous and automation of density scoring in this context has proved elusive. Thus, subjective visual scoring systems, sometimes semi-automated, are often favoured for quantitative studies of small airways disease. The “coarseness” of such scoring systems may have a marked effect on observer agreement and thus their effectiveness; using a fine grading system, i.e. the extent of the decreased attenuation component of the mosaic pattern to the nearest 5%, quantitation by observers is relatively inaccurate as judged by the levels of inter- and intra-observer variation; however, a semi-quantitative (coarser) system yields better levels of agreement, at the cost of some loss in discriminatory power associated with the coarser scoring system 113.

In terms of ease of detection, visual quantitation of areas of decreased attenuation is most readily undertaken with expiratory, rather than inspiratory, CT images. Areas of decreased attenuation are identified and scored more confidently on expiratory CT, largely due to a generalized increase in the attenuation of normal lung parenchyma on expiratory scans, enhancing the contrast between normal and affected lung. In a range of conditions characterized by small airways dysfunction, expiratory CT demonstrated areas of decreased attenuation more frequently than inspiratory CT; and the areas of decreased attenuation were of greater extent 113. The greater extent of decreased attenuation on expiration is partially due to recruitment of new areas of air-trapping on expiration, but there is also a contribution from pre-existing areas of air-trapping seen on inspiratory scans, which necessarily occupy a greater proportion of lung on expiratory scans. Furthermore, observer confidence and agreement is substantially higher on expiratory CT than inspiratory CT in conditions including hypersensitivity pneumonitis, sarcoidosis and asthma 113.

Because the density differences between normal and abnormal areas of lung in patients with small airways disease are sometimes extremely subtle, any method of enhancing the large area low contrast differences are potentially valuable 30. However, such techniques are unlikely to be applicable to conditions in which a combination of pathological processes coexist resulting in a complex mixture of CT densities and textures. A pragmatic approach is the combination of relatively simple (objective) postprocessing for image feature enhancement and (subjective) visual estimation of the extent of abnormality (this has the advantage that observers can take account of artefacts introduced by the image processing). An example of this approach is the application of MinIP images and similar postprocessing to the quantitation of a mosaic pattern in small airways disease 29, 30.

Several studies have investigated the relationships between the reported signs of constrictive bronchiolitis (areas of decreased attenuation, bronchial abnormalities, and lack of change in cross-sectional area on expiratory CT) and indices of airflow obstruction. The identification of individual CT signs which most strongly predict airflow obstruction in constrictive bronchiolitis is of relevance to the study of other diseases characterized by more complex pathophysiology in which there are functional elements of restriction and obstruction. In an early study that sought to correlate pulmonary function abnormalities with the extent of CT features of constrictive bronchiolitis, no significant relationships were found except between the forced expiratory volume in one second (FEV₁) and the number of bronchopulmonary segments containing dilated subsegmental bronchi 90. Explanations for the apparent lack of any linkage between structure and function in this study include patient selection; nearly half had CT features of diffuse panbronchiolitis, which is characterized by a mixed restrictive and obstructive pattern on pulmonary function tests 114. Thus, any correlation between indices of airflow obstruction and the CT features representing pure constrictive bronchiolitis were lost because of the “noise” introduced by the substantial proportion of cases with diffuse panbronchiolitis. Furthermore, expiratory CT scans were not evaluated, and more general functional indices of air-trapping were used rather than specific tests of small airways function such as the maximum expiratory flow rate at 25% above residual volume (MEFF_25%) 115.

A more recent study examined which of the CT signs of constrictive bronchiolitis was most closely related to indices of airflow obstruction (specifically, expiratory flow rate at low lung volumes) 89. It was shown that while bronchial wall thickness and global change in cross-sectional area (measured difference in lung area on inspiratory versus expiratory CT) correlated with such tests, the extent of decreased attenuation on expiratory CT correlated most strongly with physiological tests of small airways function and this observation remained robust on multivariate analysis 89. Although change in global cross-sectional area of the lungs on CT may be predictive of the severity of air-trapping in obliterative bronchiolitis, this relationship is more likely to hold when there is generalized rather than patchy involvement of the small airways. The weak correlation between the change in cross-sectional area of the lungs and the MEF_25% or maximum expiratory flow rate at 50% above residual volume (MEF_50%) indicates that this feature should not be used as a specific sign of small airways disease. Abnormalities of the larger airways, particularly bronchial wall thickness, predictably result in airflow obstruction in many obstructive lung diseases, including constrictive bronchiolitis. Using bivariate analysis it has been demonstrated that the extent of decreased attenuation is independently associated with a reduction in MEF_25%, whereas bronchial wall thickening is independently related to global air-trapping (reflected by the residual volume/total lung capacity (RV/TLC) ratio) 89. The nature of the link between bronchial and bronchiolar abnormalities is unclear. It has previously been suggested that decreased airflow in the small airways may reduce the efficacy of clearance of secretions in the large airways during coughing, increasing susceptibility to bronchial infection and thus leading to damage 116. However, given the anatomical continuity of the bronchial tree, it may be that the wall thickening of macroscopic bronchi, visible on thin-section CT, is merely a surrogate for invisible bronchiolar abnormalities; the original insult to the airways having affected both the bronchi and bronchioles equally (fig. 12⇓).

It has traditionally been argued that patients with small airways disease have a relatively preserved total lung carbon dioxide diffusing capacity (D_L,CO) in contrast to patients with emphysema 117, 118. However, Gelb and coworkers. 119, 120 have shown that the diffusing capacity does not reliably distinguish between emphysema and small airways disease in patients with severe airflow obstruction particularly when the FEV₁ is <1 L 121. Nevertheless, adjusted gas transfer (K_CO) is relatively preserved in the majority of patients with severe constrictive bronchiolitis 89, 120 (by contrast to the depression of K_CO that characterises emphysema). This is an important observation because the distinction between constrictive bronchiolitis and emphysema (notably the panacinar of α₁-antitrypsin deficiency) may be difficult on the basis of CT appearances alone 83. Even when the CT abnormalities are typical of constrictive obliterative bronchiolitis, they may be erroneously interpreted as the findings of emphysema (see earlier section on Accuracy). For these reasons, assimilation of the information supplied by HRCT and adjusted gas transfer provides a powerful means of making the sometimes difficult distinction between emphysema and obliterative bronchiolitis.

Diffuse panbronchiolitis

An exudative bronchiolitis, typified by diffuse (Japanese) panbronchiolitis, results in another basic HRCT sign of small airways disease, namely the “tree-in-bud” pattern. Diffuse panbronchiolitis is a sino-bronchial disease and was initially thought to be confined to Asian countries but sporadic cases have been reported in every continent 122. Given the clinical features of cough, sputum, chronic sinusitis and progressive obstructive airways disease, it has been suggested that the inclusive term “sino-bronchial syndrome” would be more appropriate 123. However, diffuse panbronchiolitis is relatively unambiguous and well established; most of the definitive histopathological and imaging studies originate from Japan 124–126. The typical histological features of diffuse panbronchiolitis are chronic inflammatory cell infiltration resulting in bronchiolectasis and striking hyperplasia of lymphoid follicles in the walls of the respiratory bronchioles; profuse foamy macrophages fill the bronchiolar lumen and the immediately adjacent alveoli, although the distal airspaces are not involved. The bronchiolocentric lesions are visible macroscopically as yellow nodules. As the disease progresses, an element of fibrotic bronchiolar constriction supervenes but, in the absence of longitudinal histopathological studies, the extent to which the basic exudative pathology progresses to constrictive bronchiolar obliteration is unclear.

High-resolution computed tomography of diffuse panbronchiolitis

The radiographic pattern in patients with diffuse panbronchiolitis is typically one of numerous small (<5 mm) ill-defined nodules, such that the radiographic pattern may misleadingly resemble an interstitial, rather than airways-centred, disease. HRCT appearances demonstrate more readily the pathological distribution of disease; there is a nodular pattern and small branching opacities (tree-in-bud pattern 127) (fig. 13⇓). Bronchioles can be identified in a predominantly centrilobular distribution. It is the florid plugging and thickening of the small airways, with exudate in the immediately surrounding alveoli, that renders visible these otherwise invisible bronchioles. Interestingly, although a mosaic attenuation pattern may be present in some cases, it is not usually a major feature; furthermore, the degree of air-trapping on expiratory CT is often surprisingly unimpressive. Nevertheless, functional studies have shown that the peripheral zone of the lung is less dense than normal, presumably because of air-trapping 128.

The HRCT features of diffuse panbronchiolitis, in the appropriate clinical setting, are virtually pathognomonic. However, other conditions may be characterized by a tree-in-bud pattern on HRCT 127, 129 and these are listed in table 3⇓. In conditions in which tree-in-bud is the dominant feature there is usually abnormality of the macroscopic bronchi, most often manifest as cylindrical bronchiectasis. In conditions in which exudate or secretions are profuse (for example, aspiration pneumonia), there may be accompanying 5–8 mm diameter “acinar nodules” which represent filling of individual acini.

Miscellaneous conditions with small airways involvement

Conclusion

HRCT has made progress towards the characterization and detection of a group of diseases which, until relatively recently, had been regarded as being beyond the scope of radiological imaging. From the imaging viewpoint, it seems logical to categorize small airways diseases into those conditions showing indirect signs on HRCT (the mosaic attenuation pattern of constrictive bronchiolitis) and those in which the affected airways are directly visualized (the tree-in-bud sign of exudative bronchiolitis). The strong correlation between the various HRCT signs of bronchiolar diseases and physiological measures of small airways dysfunction has largely confirmed the robustness of these indirect and direct HRCT signs. With the increasing interest in teasing out differences between conditions included under the umbrella of COPD, there is further scope for HRCT to differentiate between the entities that make up this unsatisfactory and arbitrary grouping. The ready availability of a diagnostic test should not allow some caveats to be overlooked: most patients with common diseases that cause airflow limitation do not need an HRCT examination, the cost-effectiveness of HRCT and radiation implications of using HRCT to screen and categorize large populations have not been investigated, generalizable figures for the sensitivity and specificity of HRCT for the detection of “significant” small airways disease are not available and depend to a considerable extent on the type of disease being sought (vide postlung transplant obliterative bronchiolitis).

Despite these provisos, high-resolution computed tomography should be seen as an invaluable diagnostic tool for patients with unexplained obstructive lung disease and as a research tool for characterizing and quantifying morphological features of small airways disease.