HRCT of obliterative bronchiolitis and other small airways diseases

H R C T of O b l i t e r a t i v e B r o n c h i o l i t i s and O t h e r Small Airways Diseases David M. Hansell

ANY DIFFUSE lung diseases are characterized by a degree of inflammation and scarring of the small airways. The pathologic type of inflammation, extent of involvement, and underlying cause all contribute to the final clinical presentation. The "broncholitides" are a truly heterogeneous group of disorders, such that few pathologically defined types of bronchiolitis are reflected by a distinctive clinical syndrome. This has led to much confusion because of the mismatch between pathologic, imaging, and clinical classifications of diseases of the small airways. The detection of small airways disease has undergone a renaissance as a result of increased understanding of the high-resolution computed tomographic (HRCT) appearances of the various pathologic types of small airways disease. Traditionally, detection of diseases of the small airways has relied on nonspecific and often unreproducible physiologic measures. The difficulty in detecting early small airways dysfunction can be readily appreciated by considering the fact that the summed cross-sectional area of the small airways luminal diameters is much greater than that of the central airways, and so the small airways account for less than a quarter of total airflow resistance. Thus, an extraordinary number of small airways need to be affected before there is a measurable physiologic deficit. In the normal state, the small airways (generally considered to be those with an internal diameter of 2 mm or less) are invisible on HRCT. Features of small airways disease on HRCT can be broadly categorized into direct and indirect signs: considerable thickening of the bronchiolar walls by inflammatory infiltrate or luminal and surrounding exudate render affected airways directly visible. By contrast, cicatricial scarring of many bronchioles results in the indirect sign of patchy density differences of the lung parenchyma, reflecting areas of under-ventilated, and consequently under-perfused lung (the so-called mosaic attenuation pattern); the pathophysiologic mechanism of this pattern is discussed more fully below.

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PATHOLOGIC CLASSIFICATION AND CLINICAL BACKGROUND

Inflammation of the bronchioles (bronchiolitis) with or without subsequent scarfing and obliteration is a very common lesion in the lungs.l However, the number of such lesions is rarely extensive enough to cause clinical symptoms. Pathologic studies have repeatedly emphasized the frequent involvement of the bronchioles in diverse diffuse lung diseases. Because of the wide diversity of conditions that are characterized by an element of bronchiolar damage, the term "small airways disease" has much to recommend it; from the radiologist's viewpoint, this term does not attempt to define the exact size of the airways included in this generic term, but it can be taken to include all airways below the resolution of HRCT in the normal state. The specific and classical term obliterative bronchiolitis (synonymous with 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 clinicopathologic entity of BOOP, more usefully termed cryptogenic organizing pneumonitis (COP), 2 is now regarded as quite distinct from obliterative bronchiolitis. Historically, these terms have caused consternation among clinicians and radiologists, if not pathologists. There are numerous reports in the literature describing cases of "bronchiolitis obliterans" whose pathologic descriptions contain all the hallmarks of an organizing pneumonia, characterized by buds of loose granulation tissue occupying the airspaces and respiratory bronchioles, without any obliteration of the small airways. 3-5 It is now generally accepted that there is no direct connection between obliterative bronchiolitis and BOOP, 6 From the National Heart & Lung Institute and Division of Investigative Science, Imperial College School of Medicine, London; and the Department of Radiology, Royal Brompton Hospital, London, England. Address reprint requests to David M. Hansell, MD, Department of Radiology, Royal Brompton Hospital, Sydney St, London, SW3 6NP, England. Copyright 9 2001 by W.R Saunders Company 0037-198X/01/3601-0007535.00/0 doi:l O.1053/sroe.2001.20463

Seminars in Roentgenology, Vol XXXVI, No 1 (January), 2001: pp 51-65

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DAVID M. HANSELL Table 1. Classification of Small Airways Disease by Pathologic Features (After Myers and Colby)

Constrictive bronchiolitis (obliterative bronchiolitis, bronchiolitis obliterans) Cryptogenic organizing pneumonia (bronchiolitis obliterans organizing pneumonia [BOOP], proliferative bronchiolitis) Acute bronchiolitis (infectious bronchiolitis) Small airways disease (adult bronchiolitis) Respiratory bronchiolitis (smoker's bronchiolitis, respiratory bronchiolitis-associated interstitial lung disease) Mineral dust airways disease (early pneumoconiosis) Follicular bronchiolitis Diffuse panbronchiolitis

such that in the interests of clarity, it has been suggested that the bronchiolitis obliterans part of BOOP should be discarded. In those patients in whom no causative agent for the organizing pneumonia can be found, the term COP is more appropriate. Given its distinctive features, BOOP/ organizing pneumonia is not considered further in this review of small airways diseases. The various conditions included within the term small airways diseases are usually classified into pathologic 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. Although pathologists categorize small airways diseases according to their histopathologic subtypes, 7 the difficulty with this classical approach is that there are not always obvious clinical (or HRCT) correlates with these pathologic subtypes. One of the more comprehensive histopathologic schemes, described by Myers and Colby, 8 is shown in Table 1. A simpler approach relies on the fundamental difference between the indirect HRCT signs of constrictive bronchiolitis and the direct visualisation on HRCT of exudative forms of bronchiolitis (typified by diffuse panbronchiolitis). These two patterns of small airways disease account for most that are encountered in clinical practice. Other miscellaneous forms of small airways disease with more or less distinctive pathologic and imaging features, if not clinical presentations, are dealt with separately in this article. HIGH-RESOLUTION COMPUTED TOMOGRAPHIC TECHNIQUE

Standard HRCT technique is satisfactory for demonstrating the signs of advanced constrictive

bronchiolitis and, at the other end of the pathologic/imaging spectrum, diffuse panbronchiolitis: the former requiring appropriate contrast resolution to demonstrate regional density differences (mosaic attenuation pattern), the latter requiring adequate spatial resolution to depict the small branching structures that characterises panbronchiolitis (treein-bud pattern). By comparison with other CT techniques (for example spiral CT for pulmonary embolism), there are few technical parameters that can be altered when performing an HRCT examination of the lungs. Nevertheless, given an identical scanning protocol, the final appearance of the images obtained on two different CT scanners 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. A suggested protocol is thin (1 to 2 ram) collimation sections at a 10-mm interval from apices to costophrenic angles in the supine position. Whether expiratory CT sections (usually limited to approximately six sections taken between the aortic arch and right hemidiaphragm) need to be obtained in every case is controversial. In some centers, additional expiratory sections are obtained irrespective of the findings on the standard inspiratory HRCT sections. 9,~~If there is the opportunity to review the inspiratory HRCT of a patient with suspected small airways disease, the number of cases requiring additional expiratory sections will be small: in most patients with clinically significant constrictive bronchiolitis, the HRCT features will be readily apparent on the inspiratory HRCT sections. Furthermore, in patients with diffuse panbronchiolitis the presence (or absence) of obvious air-trapping on expiratory CT sections does not alter the diagnosis, which is made on the basis of the tree-in-bud pattern on inspiratory HRCT sections. Nevertheless, it is often reassuring, particularly for clinicians, to have the sometimes subtle mosaic pattern emphasised on additional expiratory sections (Fig 1). There are other maneuvers that may enhance the appearance of air-trapping. ~ Sections obtained in quick succession at a single level during forced expiration, for example, at a rate of two per second, may show areas of air-trapping that are inconspicuous or absent on sections obtained more conven-

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ing 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.~5,16 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 2), 17 but they are not routinely used in clinical practice. CONSTRICTIVE BRONCHIOLITIS

Constrictive (obliterative) broncbiolitis is, in most cases, associated with a recognized predis-

Fig 1. Post bone marrow transplant patient with clinical and functional features of constrictive bronchiolitis. (A) CT section obtained at end inspiration showing subtle regional inhomogeneity of the density of the lung parenchyma and some bronchial dilatation. (B) CT section performed at end expiration emphasizing the patchy density differences, reflecting the widespread patchy air-trapping.

tionally at "end" expirationS2; the physiologic reasons for the increased conspicuity of air-trapping on dynamic CT examinations are not fully understood. ~3 For patients who are unable to reliably suspend respiration, specifically at end-expiration, scanning in a decubitus position has been suggested~4; in this position the dependent lung is relatively restricted and so potentially mimics the state at end expiration. The density differences that characterize the mosaic attenuation pattern on HRCT may be extremely subtle and simple image processing of adjacent thin sections may improve detection. Spiral CT can be used to acquire a "slab" of anatomically contiguous thin sections (eg, 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, produc-

Fig 2. Patient with cylindrical bronchiectasis in association with ulcerative colitis. (A) On the standard HRCT section there is the suggestion of some density differences in the lung parenchyma. (B) A minimum intensity projection (MinlP) image consisting of five contiguous 1.5-mm sections increases the conspicuity of the parenchymal density differences caused by the small airways disease.

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DAVID M. HANSELL Table 2. Some Causes and Associations of Constrictive (Obliterative) Bronchiolitis Postinfectious (usually viral) Adenovirus, respiratory syncytial virus, influenza Mycoplasma pneumoniae Inhalational injury Nitrogen dioxide (silo-filler's disease), sulfur dioxide, ammonia, phosgene Hot gases Connective tissue disorders Rheumatoid arthritis Sj6gren's syndrome (Others very rarely) AIIograft recipients Bone marrow transplant Heart-lung or lung transplant Drugs Including penicillamine, Iomustine Other conditions Inflammatory bowel diseases Bronchiectasis, including cystic fibrosis Hypersensitivity pneumonitis Microcarcinoid tumorlets Sauropus androgynus ingestion

Note. Truly cryptogenic cases of constrictive bronchiolitis are exceedingly rare.

posing condition or causative agent (Table 2). Viral infections, particularly by respiratory syncytial virus and adenovirus, 18,~9 are a common cause of constrictive bronchiolitis in children (Fig 3). Nonviral agents are much less commonly implicated, although Mycoplasma pneumoniae is a particularly potent cause of constrictive bronchiolitis. 2~ Caution is needed in interpreting reports that suggest bacterial infections, for example, Nocardia asteroides and Legionella pneumophila, may be responsible for an obliterative bronchiolitis. 5,21

Fig 3. Constrictive bronchiolitis in a child caused by an adenovirus lower respiratory tract infection (standard section CT). There are striking segmental areas of low attenuation within which the pulmonary vasculature is of reduced caliber. In addition, there is widespread bronchial wall thickening; lower sections revealed mild cylindrical bronchiectasis.

Fig 4. Swyer-James (McLeod's) syndrome, The left hemithorax is of reduced volume, and the pulmonary vasculature is attenuated. Note the collapsed left lower lobe containing bronchiectatic airways in the paravertebral region. Sections below this level revealed some minor patchy density differences in the right lower lobe indicating that the disease is not strictly unilateral. Expiratory CT showed air-trapping in the left upper lobe.

The pathology described in these particular reports is of an organizing pneumonia rather than constrictive bronchiolitis (highlighting the historical confusion surrounding the terminology of "bronchiolitis obliterans"). Postinfectious constrictive obliterative bronchiolitis is largely confined to children; although repeated viral lower respiratory tract infections are a usual fact of adult life, clinically significant constrictive bronchiolitis as a consequence is fortunately rare. = Swyer-James (or MacLeod's) syndrome is a particular form of constrictive bronchiolitis that occurs following an insult, usually a viral infection, to the developing lung. The characteristic pathophysiologic feature is that the 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 the radiographic descriptions, the transradiancy is predominantly or exclusively unilateral (Fig 4). The patchy nature of lung involvement is particularly well demonstrated on CT, which shows bronchiectatic changes and bilateral features of constrictive bronchiolitis in most cases. 23-25 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 that reach the small airways. 26 It has been

HRCT OF OBLITERATIVE BRONCHIOLITIS AND OTHER SMALL AIRWAYS DISEASES

Fig 5. Patient with severe constrictive bronchiolitis (associated with rheumatoid arthritis). The lungs are of large volume with some flattening of the diaphragms. There is some peribronchial thickening in the lower zones; these appearances are nonspecific and may be encountered in other forms of chronic obstructive pulmonary disease.

most frequently described following nitrogen dioxide inhalation (silo-filler's disease). 27 Among the connective tissue diseases, constrictive bronchiolitis is most strongly associated with rheumatoid arthritis (Figs 5 and 6). 28-3~ Constrictive bronchiolitis associated with rheumatoid arthritis is often rapidly progressive with refractory airfow obstruction unresponsive to any treatment. 29 Nevertheless, minor degrees of constrictive bronchiolitis are probably present and subclinical in many patients with rheumatoid arthritis. 3~,32 Pencillamine has been incriminated as a 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. 28,33 Patients with Sjrgren's syndrome may have a combination of interstitial disease (usually lymphocytic interstitial pneumonitis) and small airways disease, but unlike rheumatoid arthritis, constrictive bronchiolitis is rarely the dominant presenting feature. 34.35 Constrictive bronchiolitis is a an important and frequent cause of morbidity and mortality in patients receiving heart and lung transplants (Fig 7). 36,37 It has a prevalence of between 25% and 50% and usually manifests itself between 9 and 15 months (range 60

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days to 5.6 years) after transplantation. 38,39 It is probable that subclinical damage to small airways epithelium occurs earlier, within the first few weeks following transplantation, and that subtle abnormalities on HRCT may predate the functional abnormalities of supervening small airways obliteration. 40 Frequent and severe episodes of acute rejection, potentiated by cytomegalovims and other infective agents, increase the risk of development of constrictive bronchiolitis. The reliable detection of acute rejection in these circumstances is difficult, but the identification of areas of ground-glass opacification on HRCT within the first few months after transplantation is suggestive although nonspecific. 4! Modification of the immunosuppressive regimen may be successful in delaying the development of constrictive bronchiolitis, but relapses are common. 39 Constrictive bronchiolitis is also a well-recognized complication of bone marrow transplantation. 38,42 The disorder develops usually within 18 months of transplantation and is also variably responsive to increased immunosuppression. Constrictive bronchiolitis is rarely truly cryptogenic. 43 Most reported cases probably have an undisclosed precipitating cause or association, such as a connective tissue disease which subsequently declares itself. 44 RADIOGRAPHIC AND HRCT FEATURES OF CONSTRICTIVE BRONCHIOLITIS

The radiographic features of constrictive bronchiolitis can be summarized as diminished pulmonary vasculature and mild overinflation of the lungs with or without bronchial wall thickening. 45 These nonspecific abnormalities, seen in any form

Fig 6. Inspiratory CT section of a patient with rheumatoid arthritis associated constrictive bronchiolitis. The margins between areas of relatively high and low attenuation of the lung parenchyma are indistinct and merge imperceptibly.

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Fig 7. Expiratory HRCT of a patient with post lung transplantation-related obliterative brenchiolitis. Note the clear geographic demarcation between air-trapping pulmonary Iobules and the adjacent relatively unaffected lung.

of chronic obstructive pulmonary disease, are prone to considerable observer variation (Fig 5). Furthermore, these features are not present in all patients finally diagnosed as having constrictive bronchiolitis.46.47 In an early CT study of constrictive bronchiolitis, 15 patients who fulfilled the criteria of Turton et a143 were examined with conventional (contiguous 10-mm sections) and thin-section computed tomography (interspaced 3-mm sections). 48 Chest radiographs were normal in 5 of 15 patients; the remaining I0 patients showed "limited vascular attenuation and hyperinflation." In 13 of 15 patients, 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 a l , 49 w e r e the first studies 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. 5~ The HRCT signs comprise patchy areas of reduced parenchymat density (the "mosaic attenuation pattern"), attenuation 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. 25,54 The individual CT signs of constrictive bronchiolitis are summarized below: 9 Areas of decreased attenuation Regions of decreased attenuation usually have poorly defined margins (Fig 6), but sometimes

DAVID M. HANSELL

have a sharp geographical outline (representing a collection of affected secondary pulmonary lobules) (Fig 7). The relatively higher attenuation regions of lung represent shunting of blood to the normally ventilated lung. When severe, the lung may be of homogeneously decreased attenuation (so that the patchy density difference, or mosaic pattern, is lost) (Fig 8). Reduction in caliber of the macroscopic pulmonary vessels In the areas of decreased attenuation, pulmonary perfusion is reduced. In acute bronchiolar obstruction this represents physiologic reflex of hypoxic vasoconstrictionY There is vascular remodeling and the reduced perfusion becomes irreversible (Fig 9). In some instances, the inflammatory process that causes bron-

Fig 8. Patient with post viral constrictive bronchiolitis. (A) A mosaic pattern is inconspicuous, but the lung parenchyma is of generally decreased attenuation. (B) Section taken at end expiration does not emphasize the mosaic pattern in this patient who had functional evidence of severe small airways disease.

HRCT OF OBLITERATIVE BRONCHIOLITIS AND OTHER SMALL AIRWAYS DISEASES

Fig 9, Constrictive bronchiolitis and arteriolar involvement. Adjacent to the obliterated bronchioles (sectioned at t w o points [arrowheads]), the accompanying arteriolar wall is abnormally thickened with muscular hyperplasia (Courtesy of T.V. Colby, MD).

chiolar scarring may synchronously affect the adjacent pulmonary artery, thus leading to vascular obliteration. Although the vessels within areas of decreased attenuation on HRCT may be of markedly reduced caliber, they are not distorted. 9 Abnormalities of the macroscopic airways The severity of bronchial dilatation and wall thickening is highly variable from one case to another: in immunologically mediated constrictive bronchiolitis (eg, post-transplant or rheumatoid arthritis associated), marked dilatation of the bronchi is a frequent finding. 56 Some degree of bronchial thickening and dilatation abnormality is the rule in most

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patients with constrictive bronchiolitis (Fig 10). 52 Air-trapping at expiratory CT The regional inhomogeneity of the lung density is accentuated on sections obtained at end, or during, expiration. Areas of decreased attenuation, not visible on inspiratory CT sections, may be detectable on end-expiratory CT sections (Fig 1 1). j~ The cross-sectional area of the affected parts of the lung do not decrease in size on expiratory CT. 54 Expiratory CT may also be helpful in differentiating between the three main causes of a mosaic pattern (infiltrative lung disease, small airways disease, and occlusive pulmonary vascular disease), which may be problematic on inspiratory CT. 9,58 An important caveat is that in patients with widespread small airways disease, end-expiratory CT sections may appear virtually identical to the standard inspiratory CT sections, simply because of the severity of the air-trapping (ie, there is no mosaic pattern

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Fig 10. Post bone marrow transplantation (3 years earlier) in a g-year-old boy with acute lymphoplastic leukemia with clinical features of chronic rejection. The dominant CT abnormality in this individual was widespread cylindrical bronchiectasis with a generalized decrease in attenuation of the lung parenchyma. The nature of the focal areas of ground glass opacification was uncertain but were thought to represent a drug-induced pneumonitis.

Fig 11. Patient with post viral constrictive bronchiolitis. (A) The inspiratory HRCT sections through the upper lobes does not reveal any obvious parenchymal abnormality. (B) A t end expiration the inhomogeneous density of the lung parenchyma, reflecting the small airways disease, is revealed.

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or change in cross-sectional area of the lungs) (Fig 8). The HRCT signs listed above are not, by themselves, specific for constrictive bronchiolitis and may be encountered in other chronic obstructive pulmonary diseases. However, in the context of a known cause or association of constrictive bronchiolitis, an HRCT showing this constellation of features can be regarded as diagnostic. Nevertheless, there are circumstances in which the distinction between constrictive bronchiolitis and other obstructive pulmonary disease, particularly in patients with advanced disease, can be difficult. Areas of decreased attenuation of the lung parenchyma on HRCT in patients with severe obstructive airways disease due to constrictive bronchiolitis may sometimes be 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 gastrapping. 59 However, the "emphysema" seen in that study was not associated with decreased gasdiffusing capacity, the functional hallmark of emphysema. 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 alphal-antitrypsin deficiency) and advanced constrictive obliterative bronchiolitis may be less straightforward on HRCT appearances alone (Fig 12). A recent study that tested the ability of observers to distinguish, on the basis of HRCT appearances, 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 was reasonable (kappa = 0.63). 6o At a more fundamental level, it may be difficult to decide whether a mosaic attenuation pattern reflects the presence of small airways disease,

DAVID M. HANSELL

Fig 12. Alphal-antitrypsin deficiency-related panacinar emphysema. The appearances through the lower lobes resemble those of severe constrictive bronchiolitis: there is generalized decrease in attenuation of the lung parenchyma and mild cylindrical bronchiectasis.

occlusive vascular disease, or infiltrative lung disease. 9.58,61,62 In a study of 70 patients in whom the mosaic attenuation pattern was the dominant HRCT abnormality, Worthy et a163 showed that infiltrative lung disease and small airways disease were readily identified, but the mosaic pattern caused by occlusive vascular disease was frequently misinterpreted. Usually the differentiation between the basic causes of a mosaic attenuation pattern is readily made if the clinical and physiologic features, particularly the gas diffusing capacity, of the patient are taken into account. DIFFUSE PANBRONCHIOLITIS Panbronchiolitis is responsible for the other basic HRCT pattern of small airways disease and is typified by diffuse panbronchiolitis. Diffuse (Japanese) panbronchiolitis is a sinobronchial disease and was initially thought to be confined to Asian countries, but sporadic cases have been reported in every continent. 64 Symptoms include cough, sputum, chronic sinusitis, and signs of progressive obstructive airways disease. Given these clinical features, it has been suggested that the inclusive term "sinobronchial syndrome" would be more appropriate65; however, the term diffuse panbronchiolitis is relatively unambiguous, and is well established. Some patients respond to long-term low-dose erythromycin with subjective and objective improvement, 66 although the mechanism of action of erythromycin is unknown (and is not simply ascribable to its bactericidal properties). The prognosis is surprisingly poor with a reported 10-year survival rate as low as 25%. 67

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progresses, an element of fibrotic bronchiolar constriction supervenes, but in the absence of longitudinal histopathologic studies, it is not clear the extent to which the basic "exudative" pathology progresses to constrictive bronchiolar obliteration. On chest radiography the dominant pattern is of numerous small (<5 mm) ill-defined nodules, such that the radiographic pattern may be interpreted as reflecting an interstitial, rather than airways-centered, disease (Fig 13). The nodules are symmetrically distributed and initially most prominent basally. Later, the radiographic features of cylindrical bronchiectasis may become evident. HRCT appearances reflect the pathologic distribution of disease: there is a nodular pattern and small branching opacities (tree-in-bud pattern) 7~ can be identified in a predominantly centrilobular distribution, corresponding to the plugged and thickened small airways. Accompanying cylindrical bronchiectasis, usually mild, is an almost invariable feature. Interestingly, although a mosaic attenuation pattern may be present in some cases (Fig 14), it is not usually a major feature; furthermore, air-trapping on expiratory CT is often surprisingly unimpressive. Nevertheless, functional studies have

Fig 13. Patient w i t h chronic sinusitis and panbronchiolitis. (A) The radiographic pattern in the right lower zone is of

numerous poorly defined nodules and inconspicuous bronchial wall thickening. (B) The HRCT section through the lower lobes demonstrates that the nodular appearances on the chest radiograph result from a widespread tree-in-bud pattern caused by the diffuse panbronchiolitis.

Most of the definitive pathologic and imaging studies originate from Japan. 68-7~ The typical histopathologic 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 lumens and the immediately adjacent alveoli, although the distal air-spaces are not involved. The bronchiolocentric lesions are visible macroscopically as yellow nodules. As the disease

Fig 14. Patient with idiopathic bronchiectasis showing coexisting pattern of small airways disease in the form of a mosaic attenuation pattern (constrictive bronchiolitis) and a tree-in-bud pattern (panbronchiolitis) in the posterior lung.

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sometimes complex abnormalities found on pulmonary function testing. 76 The HRCT features of subacute extrinsic allergic alveolitis consist of varying proportions of ground-glass opacification, poorly defined centrilobular nodules, and areas of decreased attenuation (Fig 16). 77,78 There is a strong correlation between the extent of the areas decreased attenuation (a component of the mosaic attenuation pattern) on HRCT and pulmonary function indices of air-trapping. 79,8~ The air-trapping, graphically shown on expiratory CT, is present in most patients with subacute disease and reflects the underlying component of cellular bronchiolitis. Even in patients with chronic fibrotic disease, expiratory CT may show lobular air-trapping among the reticular pattern.

Sarcoidosis By virtue of their perilymphatic distribution, sarcoid granulomas are concentrated around the airways. Functional studies using sophisticated

Fig 15. Subacute extrinsic allergic alveolitis (hypersensitivity pneumonitis), Note the intense inflammatory infiltrate surrounding the bronchiolar lumen.

shown that the peripheral zone of lung is less dense than normal because of air-trapping. 72 The HRCT features of diffuse panbronchiolitis, in the appropriate clinical setting, are virtually pathognomonic. However, other conditions may cause a similar (primarily tree-in-bud) pattern on HRCT, and these include primary pulmonary lymphoma, 73 invasive aspergillosis centered on the airways, 74 and other infections of the airways including tuberculosis. 75

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MISCELLANEOUS CONDITIONS WITH SMALL AIRWAYS INVOLVEMENT

Extrinsic" Allergic Alveolitis (Hypersensitivity Pneumonitis) In this condition, inhalation of organic dusts and deposition in the terminal and respiratory bronchioles causes an inflammatory (or cellular) bronchiolitis of variable severity in susceptible individuals (Fig 15). The potential for varying degrees of involvement of the airways and interstitium, and the coexistence of subacute and more chronic changes, explains the

Fig 16. Subacute extrinsic allergic alveolitis (hypersensitivity pneumonitis). (A) End inspiratory section through the lung bases showing a combination of ground-glass opacification (note the black bronchus sign) and more focal areas of reduced lung attenuation, (B) At end expiration the patchy air-trapping caused by the coexisting bronchiolitis becomes evident.

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Fig 17. Patient with pulmonary sarcoidosis confirmed on transbronchial biopsy. (A) There are scattered pulmonary nodules approximately 6 mm in diameter, some of which are bronchocentric. (B) A section taken at end expiration shows patchy air-trapping presumed to reflect obstructing peribronchiolar granulomas.

tests have suggested that airflow obstruction located at the level of the small airways may be an early feature of sarcoidosis. 8~2 Supportive evidence, seen as patchy air-trapping on expiratory CT, was first described in three case reports, 83 and later confirmed in larger series (Fig 17). 84,85 In some cases, the air-trapping, thought to reflect bronchiolar obstruction, foreshadows the more typical parenchymal manifestations of sarcoidosis. It seems that this phenomenon is common in patients with sarcoidosis at presentation (demonstrated in 20 of 21 patients in o n e s e r i e s ) . 84 However, the exact prevalence of this phenomenon and its clinical significance, if any, are as yet unknown. Follicular Bronchiolitis Follicular bronchiolitis is primarily a histopathologic diagnosis and is characterized by hyperplastic lymphoid follicles, ranged along bronchioles that are compressed as a consequence. There is also infiltration of the adjacent bronchiolar walls and interstitium by polyclonal lymphocytes. 86.87 The exact relationship between follicular bronchiolitis, lymphocytic interstitial pneumonitis, and constrictive obliterative bronchiolitis, particularly in patients with rheumatoid arthritis in whom these pathologies may coexist, remains controversial. Follicular bronchiolitis is most commonly encountered in patients with rheumatoid arthritis or Sj6gren's syndrome, but other associations include a familial form with immunodeficiency. 86 The prognostic implication of follicular bronchiolitis (a diagnosis made on the basis of lung biopsy) is uncertain, particularly as it may be identified on a background of other pathology, for example, usual interstitial pneumonia in association with a connective tissue disease. In some individuals, corn-

pression of the bronchioles by the hyperplastic follicles results in severe airflow limitation. 88 Peribronchiat lymphoid hyperplasia in children (termed follicular bronchitis) may represent an exaggerated immune response to a viral infection, and results in mild airflow obstruction in the long term. s9 The plain chest radiograph shows nonspecific small nodular or reticulonodular opacities, 87,9~but may be normal. In an HRCT study of 14 patients (12 with a connective tissue disease) with biopsyproven follicular bronchiolitis, the predominant abnormality was small nodules (3-mm diameter, but up to 12 m m in some cases). 91 In some cases, the nodules had a predictably centrilobular bronchocentric distribution, such that the HRCT pattern resembled sarcoidosis (Fig 18). Areas of groundglass opacification probably reflect the more generalized lymphocytic infiltration, present in just over half of patients. 91 Mild bronchial dilatation with wall thickening occurs in some cases, but

Fig 18. Follicular bronchiolitis. Curious irregular-shaped opacities, some of which are bronchocentric in distribution (in this case concentrated mainly in the upper lobes).

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whether this is directly related to the presence of follicular bronchiolitis, or is associated with the background autoimmune disease, is unclear.

Respiratory Bronchiolitis-Associated Interstitial Lung Disease The concept of damage to the small airways by cigarette smoke is not new. In an early necropsy study of the lungs of young smokers (who died from an unrelated cause), the characteristic pathologic features were respiratory bronchiolitis, an abundance of pigmented alveolar macrophages within the lumina of the respiratory bronchioles, and associated mild peribronchiolar interstitial fibrosis. 92 The term respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) has been coined to describe this reasonably distinctive lesion found in cigarette smokers. 93 It seems likely that mild pathologic changes of RB-ILD are present in most smokers' lungs, but that very few individuals develop a full clinicopathologic syndrome with symptoms ascribable to RB-ILD. The dominant pathologic abnormality is the profusion intra-alveolar macrophages, such that there is an obvious overlap between the pathologic features of RB-ILD and desquamative interstitial pneumonitis (DIp)94; this outpouring of macrophages into the airspaces may be regarded as an idiosyncratic reaction to (heavy) cigarette smoke exposure. Accompanying interstitial fibrosis is of variable severity but is usually a minor component. However, in one series the features of UIP (honeycombing) on HRCT were present in 3 of 10 patients. 95 Similarly, centrilobular emphysema, when present, is usually of surprisingly minor extent. Given the potential for considerably different proportions of each pathologic component in a given cigarette smoker 96 and the uncertainty about what constitutes "pure" RB-ILD, it has been suggested that the term "smoking-related interstitial lung disease" be used to cover the whole spectrum. 95 There is no predictable correlation between the presence of the pathologic entity of RB-ILD and clinical symptoms or functional abnormalities (the latter showing a mild restrictive defect with reduced gas transfer). 97 The radiographic and CT appearances are nonspecific. 94"98 The CT in some biopsy-proven cases may be normal. 96 The typical constellation of HRCT features include: patchy ground-glass opacification (most probably reflecting the DIP

Fig 19. Respiratory bronchiolitis interstitial lung disease. A complex pattern of ground-glass opacification, faint low attenuation nodules, and some thickening of the interlobular and intralobular septa. Superimposed on this pattern are several relatively low attenuation secondary pulmonary Iobules, reflecting the component of respiratory bronchiolitis.

component),99,100 poorly defined centrilobular nodules, 94 a limited reticular pattern with some thick-

ening of the interlobular septa (probably due to interstitial fibrosis), and minor thickening of the macroscopic airways (possibly changes of chronic bronchitis) (Fig 19). Emphysema is generally a minor feature and abnormalities centered on the small airways (ie, the respiratory bronchiolitis) are not usually present; possibly masked by the coexisting patchy interstitial and airspace pathology. To date, there are no reports about the utility of expiratory CT in patients with RB-ILD. Taking together the features listed above, the overall HRCT appearances may be reminiscent of subacute hypersensitivity pneumonitis, and thus knowledge of the patient's smoking history is important in refining the differential diagnosis.

Micro-Carcinoid Tumorlets Hyperplastic aggregates of neuroendocrine cells cause an extremely unusual form of obliterative bronchiolitis. Diffuse hyperplasia or more focal carcinoidlike tumorlets are associated with fibrosis and scarring of the bronchioles. ~~176 The functional consequences of the resulting constrictive obliterative bronchiolitis may be very severe. On HRCT, there are nodules of varying sizes reminiscent of metastatic disease (although the tumorlets are not neoplastic in behavior); close examination of the distribution of the larger nodules may show that they arise at the carinas of adjoining airways (the typical location of "conventional" solitary carcinoid tumors). The nodules are superimposed on a background mosaic attenuation pattern re-

HRCT OF OBLITERATIVE BRONCHIOLITIS AND OTHER SMALL AIRWAYS DISEASES

63

fiecting the a c c o m p a n y i n g obliterative b r o n c h i o l i tis (Fig 20). 1~ T h e s e two H R C T signs are i n d i v i d ually entirely n o n s p e c i f i c but, taken t o g e t h e r in the c o n t e x t o f a patient with d i s a b l i n g airflow limitation, they are s u g g e s t i v e o f this curious and rare condition. CONCLUSION

It is r e m a r k a b l e that H R C T h a s m a d e s u c h an i m p a c t o n t h e d e t e c t i o n a n d c h a r a c t e r i z a t i o n o f d i s e a s e s that, at first s i g h t , m i g h t b e e x p e c t e d to b e i n c o n s p i c u o u s or i n v i s i b l e o n H R C T i m a g e s . T h i s a r t i c l e has a t t e m p t e d to b r o a d l y c a t egorize the H R C T imaging of small airways disease into conditions s h o w i n g indirect signs (the m o s a i c a t t e n u a t i o n p a t t e r n o f c o n s t r i c t i v e b r o n c h i o l i t i s ) a n d t h o s e in w h i c h t h e a f f e c t e d a i r w a y s are d i r e c t l y v i s u a l i z e d (the t r e e - i n bud sign of panbronchiolitis). The strong correl a t i o n b e t w e e n the v a r i o u s H R C T s i g n s o f b r o n c h i o l a r d i s e a s e s and p h y s i o l o g i c m e a s u r e s o f s m a l l a i r w a y s d y s f u n c t i o n has l a r g e l y c o n f i r m e d

Fig 20. Microcarcinoid tumorlets. Several nodules ranging in size from a few millimeters to 1 cm scattered throughout the lungs. There is generalized decrease in attenuation of the lung parenchyma reflecting the severe accompanying obliterative bronchiolitis.

that t h e s e d i r e c t a n d i n d i r e c t H R C T s i g n s are r o b u s t . In t h e a b s e n c e o f a r e l i a b l e n o n i n v a s i v e g o l d s t a n d a r d , t h e u s e o f H R C T f o r the d i a g n o s i s o f s m a l l a i r w a y s d i s e a s e will c o n t i n u e to increase.

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