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undergone a renaissance as a result of increased understanding of the high-resolution computed tomographic (HRCT) appearance of the various pathologic types of small airways disease. In contrast to the numerous studies on HRCT-pathologic correlations in interstitial lung disease, there is relatively little similar literature on small airways diseases, probably because of the relative rarity of the individual conditions that make up this heterogeneous group, and the reluctance of clinicians to submit patients with suspected small airways disease to lung biopsy.

The greatest difficulty in reaching an understanding of diseases of the small airways is the problem of clas- sification. The apparently simple term small airways disease is defined differently by pathologists, physiolo- gists and physicians. Each of these groups has its own understanding of the term and use it variously in a morphological or functional sense. Further confusion arises when the term is used synonymously with inflammation of the distal bronchioles, that is, “bronchiolitis” [1]

The generic terms bronchiolitis and the more specific obliterative bronchiolitis (alternatively bronchiolitis obliterans) have been used to describe a variety of clinico-pathological conditions [2]. The increasing array of reported causes and associations prohibits a manage- able clinical classification. Although pathologists categ- orise small airways diseases according to their histopathologic subtypes, the difficulty with this classical approach is that there are not always obvious clinical or imaging (HRCT) correlates. One of the more compre- hensive histopathologic schemes, described by Myers and Colby, is shown in Table 1 [3]. Many other schemes are loosely based on the classification of Myers and Col- by, for example an abbreviated version by Worthy and Muller [4] includes the following five histopathological entities: 1) cellular bronchiolitis, 2) panbronchiolitis, 3) respiratory bronchiolitis, 4) constrictive bronchiolitis and 5) bronchiolitis obliterans with intraluminal polyps. A simpler approach is to divide small airways disease into “exudative” and “constrictive” types based on the fundamental difference between the indirect HRCT signs of constrictive bronchiolitis and the direct visualisation on HRCT of exudative forms of bronchio- Introduction

Abnormalities of the small airways are found in a wide variety of disorders. The pathologic type of inflammation, extent of involvement, and underlying cause all contribute to the final clinical presentation. Identifica- tion of small airways disease has been hampered by the non-specificity and insensitivity of plain chest radiography and conventional pulmonary function tests. Fur- thermore, because the small airways are a “silent zone”

of the lungs, clinical presentation is often late so that lung biopsy may not be feasible because of severe airflow obstruction. The detection of small airways has

Chapter

Contents

Introduction . . . 145

Anatomic Definition of the Bronchioles . . . 146

Pathologic Considerations in Constrictive (Obliterative) Bronchiolitis . . . 147

High-Resolution Computed Tomography of Constrictive Obliterative Bronchiolitis . . . 149

Areas of Decreased Density of the Lung Parenchyma . . . 149

Reduction in Calibre of the Macroscopic Pulmonary Vessels . . . 150

Abnormalities of the Macroscopic Airways . . . 150

Air Trapping at Expiratory CT . . . 150

Specific Forms of Small Airways Disease . . . 151

Cryptogenic Obliterative Bronchiolitis . . . 151

Exclusion Criteria for the Diagnosis of Cryptogenic Obliterative Bronchiolitis . . . 152

Post-viral Obliterative Bronchiolitis . . . 152

Small Airways Disease Associated with Connective Tissue Diseases . . . 154

Post-transplant Obliterative Bronchiolitis . . . 155

Diffuse Panbronchiolitis . . . 156

Interstitial Lung Diseases with a Component of Small Airways Disease . . . 158

Respiratory Bronchiolitis – Interstitial Lung Disease . . . 158

Extrinsic Allergic Alveolitis (Hypersensitivity Pneumonitis) . . . 160

Sarcoidosis . . . 160

References . . . 161

HRCT – Pathologic Correlations in Small Airways Diseases

Zelena Aziz, David M. Hansell

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litis (typified by diffuse panbronchiolitis). These two patterns of small airways disease account for most that are encountered in clinical practice.

The confusion surrounding the concept of bronchiolitis obliterans organising pneumonia (BOOP) is dimin- ishing with the realisation that this distinctive clinico- pathological entity is primarily a disease of the air spaces (Fig. 1) [5–7], and the term ‘organising pneumonia’

without the bronchiolitis obliterans prefix, is therefore more appropriate. Although the terms BOOP/ proliferative bronchiolitis/bronchiolitis obliterans with intraluminal polyps /organising pneumonia are encountered in the pathological literature on small airways disease, BOOP/COP will not be further considered in this review.

This review will explore some of the radiologic and pathologic features relevant to the two main types of small airways disease: ‘constrictive’ and ‘exudative’. In- dividual conditions characterised by small airways disease, including those which have components of both interstitial and small airways disease will then be dis- cussed.

Anatomic Definition of the Bronchioles

The branching pattern of airways is one of asymmetric dichotomy so that each bronchus gives rise to two daughter bronchi of differing lengths. There is a thirty- fold difference in diameter between the trachea and the terminal bronchiole (approximate diameter of 0.5 mm).

The distal airways are generically called bronchioles, one morphologic definition being all those airways that do not contain cartilage; this occurs after between six to twenty divisions. However, there is no precise distinction between bronchi and bronchioles because cartilage

may be found in some peripheral airways less than 1 mm in diameter [8]. Although there cannot be an exact division between “small airways” (those with an internal diameter of less than 2 mm) and the remainder of the bronchial tree, it may be useful to consider conditions as affecting “large” or “small” airways because of their distinctive clinical and physiological abnormalities (provided the reality of anatomical and physiological continuity of the bronchial tree is remembered) [9].

The bronchioles are classified as terminal (membranous) bronchioles or respiratory bronchioles [10]. The terminal or membranous bronchioles are considered to be the furthest reaches of the conducting airways since they are defined by a complete fibromuscular wall (that is, no alveoli arise directly from them). In man, the terminal bronchioles are found between the sixth and twenty third generations of branching [11] and have been variously estimated to number between 25,000 and 65,000 [12, 13]. The terminal bronchioles vary in length from 0.8 to 2.5 mm and have an internal luminal diameter of 0.6 mm which appears to be relatively con- stant along the length of the bronchiole [14]. Down- stream from these airways is the transitional zone that denotes a change in functional characteristics from gas Table 1.Classification of small airways disease by pathological fea-

tures

Constrictive bronchiolitis Obliterative bronchiolitis Bronchiolitis obliterans Cryptogenic organising pneumonia

Bronchiolitis obliterans organising pneumonia 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

Fig. 1 ACT through the mid-zones of a patient with organising pneumonia. There is ground glass opacification and areas of parenchymal consolidation in a predominantly peripheral distribution.BAt a pathological level there are buds of granulation tissue (immature, potentially reversible, fibrosis) occupying the air spaces

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conduction to gas exchange. The respiratory bronchioles which appear in this transitional zone have alveoli arising directly from their walls. The distinction between terminal and respiratory bronchioles at a mi- croscopic level on the basis of diameter alone is not always straightforward, because of variations in inflation pressure at the time of specimen fixation. A single terminal bronchiole supplies a gas-exchange unit – the pulmonary acinus (Fig. 2). The acinus comprises numerous alveolar sacs which communicate through alveolar ducts with the respiratory bronchioles [11].

The secondary pulmonary lobule consists of approximately ten (range 3–24) acini and is defined as the smallest portion of lung that is surrounded by a connective tissue septum [15]. An important feature of the secondary pulmonary lobule is the “core structure” com- prising the supplying bronchiole and homologous pulmonary artery. At the level at which the centrilobular bronchiole enters the lobule, the bronchiole is approxi-

mately 1 mm in diameter and has a wall thickness of less than 100 µ [16], below the limits of HRCT spatial resolution.

Pathologic Considerations in Constrictive (Obliterative) Bronchiolitis

Constrictive (obliterative) bronchiolitis represents an attempt to repair bronchiolar damage caused by a wide variety of agents [8] and the most frequently encountered are shown in Table 2. The term constrictive bronchiolitis is specific in a pathologic sense because it refers to lesions characterised by scarring leading to obliteration of the bronchiolar lumen; it has the secondary advantage of implying a functional effect, namely limitation of air flow through the bronchioles. The histopathologic findings in constrictive obliterative bronchiolitis may be patchy and in established cases only short

Fig. 2.Normal bronchial and bronchiolar anatomy and schematic representation of an acinus. Note the level (*) at which normal airways are no longer visible on HRCT

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segments of the bronchioles may be affected, necessitat- ing careful step-sectioning to ensure the obliteration is fully demonstrated [17]. Patients with obliterative bronchiolitis caused by a known insult, such as a viral infection, seem to have widely spaced or “skip” lesions with eccentric or focal damage to bronchiolar epithelium whereas in immunopathological forms of bronchiolitis, for example chronic rejection post-lung transplant, widespread circumferential epithelial damage is more usual. The cardinal feature of constrictive obliterative bronchiolitis is submucosal and peribronchiolar fibrosis, resulting in narrowing and obliteration of the bronchiolar lumen (Fig. 3).

The inflammatory process that leads to fibrosis and cicatrisation is centred mainly on the terminal and respiratory bronchioles. The initial inflammatory infiltrate is composed of polymorph neutrophils, lymphocytes and plasma cells. The polymorphs tend to traffic into the bronchiolar lumen, while the mononuclear cells re- side in the peribronchiolar interstitium [3]. In some cases, there may be necrosis and sloughing of the bronchiolar epithelium which ultimately results in mucosal scarring. There is disagreement about the degree of involvement of the epithelial lining in bronchiolitis: one authority states that fibrosis is laid down between the muscularis mucosa and an intact epithelium [18]; however, epithelial denuding is probably the rule in most cases of obliterative bronchiolitis [19]. Smooth muscle hyperplasia occurs in the bronchiolar walls and where there is submucosal fibrosis, the bronchiolar lumen nar- rows in either a concentric or irregular manner. The lumen is progressively reduced, becoming slit-like and finally totally obliterated [10]; van Gieson staining of the durable mural elastin fibres may be the only evidence of the bronchiolar remnant [17]. Elsewhere bronchioles appear distorted and ectatic and may contain mucus plugs and cellular debris. The natural history of the inflammatory process within the bronchiolar walls is unknown but persistent inflammation may be found in the specific circumstance of post-viral bronchiolitis obliterans in children [20, 21]. Because of the relative lack of pathological studies in adult constrictive bronchiolitis [22] (and because longitudinal pathologic studies are impossible), the evolution of obliterative bronchiolitis remains relatively uncharted. In adults however there appears to be temporal compartmentalisation between the inflammatory and fibrotic bronchiolar changes; the subepithelial bronchiolar lesions being either primarily fibrotic or inflammatory. It is suggested that inflammation and fibrosis occur at different time points in the course of the disease, or alternatively, that patients with 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 Sjögren’s syndrome Transplant recipients

Bone marrow transplant Heart-lung or lung transplant Drugs

Penicillamine Lomustine Other conditions

Inflammatory bowel diseases Bronchiectasis including cystic fibrosis Hypersensitivity pneumonitis Microcarcinoid tumourlets Paraneoplastic pemphigus

Fig. 3.The end stage of constrictive obliterative bronchiolitis with complete loss of the bronchiolar lumen by circumferential fibrosis. In the normal state, the lumen of the airway is approximately the same as that of the accompanying pulmonary artery (courtesy of Prof. B Corrin)

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one type of presentation usually do not show transition to another type of bronchiolar pathology [23]. The lack of clinical response by patients with constrictive bronchiolitis to immunosuppressive treatment suggests that on-going bronchiolar mural inflammation is, at most, a minor feature.

Whether there is a temporal relationship between constrictive bronchiolitis and the so-called proliferative (organising pneumonia end of the spectrum) bronchiolitis is unclear. There is little in the literature to suggest that immature intraluminal fibrosis, or granulation tissue in the membranous bronchioles is transfigured to produce the lesion of established constrictive bronchiolitis [3]. Nevertheless, in particular situations such as heart-lung transplantation [24] and silo filler’s disease [25] it is possible that intraluminal granulation tissue in the terminal bronchioles progresses over time to a pathological picture indistinguishable from constrictive bronchiolitis. This sequence should be regarded as ex- ceptional and it seems that constrictive bronchiolitis is not necessarily preceded by a proliferative phase.

In pathologic studies of constrictive bronchiolitis, reference is rarely made to the state of the larger airways. In vivo studies using high-resolution computed tomography suggest that there is often abnormality of the larger airways and sometimes frank bronchiectatic change, particularly in conditions in which a pure constrictive bronchiolitis is the dominant feature, for example, lung allograft rejection [26–28] and MacLeod’s (Swyer-James) syndrome [29]. A recent histological study of childhood constrictive obliterative bronchiolitis [20] describes bronchiectasis in 30% of open lung biopsy specimens and in a 100% of lobectomy and au- topsy specimens. Other exceedingly rare cases of coexisting inflammatory obliteration of the bronchioles and the larger cartilaginous bronchi have been reported in association with Stevens-Johnson syndrome [30] and Castleman’s disease [31]. In diffuse panbronchiolitis, ectatic dilatation of both the bronchioles and bronchi occurs, the former being filled with a combination of inflammatory exudate and foamy macrophages [3, 32, 33].

Apart from this singular entity, the relationship between large and small airways involvement is uncertain; specifically, whether obliterative bronchiolitis ultimately leads to damage of the larger airways, or vice versa, remains contentious.

High-Resolution Computed Tomography of Constrictive Obliterative Bronchiolitis

The signs of small airways disease on chest radiography are indirect [34]: widespread bronchiolar obstruction that characterises constrictive obliterative bronchiolitis results in areas of lung that are under-ventilated with at-

tenuation of the pulmonary vasculature and increased transradiancy. The sensitivity of chest radiography in detecting anything other than very severe small airways disease is low and is further diminished if there is coexisting interstitial lung disease: the visual “noise” of addi- tional parenchymal disease obscures these relatively subtle indirect signs of small airways disease. The ra- diographic features of cryptogenic constrictive obliterative bronchiolitis described by Breatnach and Kerr can be summarised as diminished pulmonary vasculature and mild over-inflation of the lungs [35]. However, even these non-specific abnormalities are not present in all patients finally diagnosed as having obliterative bronchiolitis [34, 36, 37].

In one of the first CT studies of constrictive bronchiolitis, 15 patients who fulfilled the criteria of Turton et al. [38] were examined with conventional and thin section computed tomography (contiguous 10 mm sections and interspaced 3 mm sections) [39]. Chest radio- graphs were regarded as normal in five out of the fifteen patients; the remaining ten patients showed “limited vascular attenuation and hyperinflation”. In thirteen out of fifteen patients (87%) a pattern of “patchy irregular areas of high and low attenuation in variable propor- tions, accentuated in expiration” was noted. This, and a report of two cases by Eber et al. [40] 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 signs of constrictive obliterative bronchiolitis [41–44]. The HRCT features comprise areas of reduced density of the lungs (the patchy density differences giv- ing 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 [45–47]. These individual CT signs of constrictive obliterative bronchiolitis are now considered on more detail.

Areas of Decreased Density of the Lung Parenchyma Regions of decreased attenuation (“black lung”) usually have poorly defined margins (Fig. 4a), but sometimes have a sharp geographical outline (representing a col- lection of affected secondary pulmonary lobules) (Fig. 4b). The relatively higher attenuation regions of lung represent relatively increased perfusion of the nor- mally ventilated lung. When severe, the lung may be of homogeneously decreased attenuation (so that the patchy density difference, or mosaic pattern, is lost) (Fig. 5).

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Reduction in Calibre

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 vasoconstric- tion [48] but in the chronic state there is vascular re- modelling and the reduced perfusion becomes irreversible. In some instances the inflammatory process that causes bronchiolar scarring may synchronously affect the adjacent pulmonary artery, thus leading to vascular obliteration (Fig. 6).Although the vessels within areas of decreased attenuation on HRCT may be of markedly reduced calibre they are not distorted.

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 (e.g. post- transplant or rheumatoid arthritis associated), marked dilatation of the bronchi is a frequent finding [49, 50].

Some degree of bronchial thickening and dilatation abnormality is the rule in most patients with constrictive bronchiolitis [43].

Air Trapping at Expiratory CT

The regional inhomogeneity of the lung density is accentuated and small or subtle areas of air trapping may be revealed on CT performed at end-expiration [51–54].

The cross-sectional area of the affected parts of the lung does not decrease in size on expiratory CT [47]. Expira- tory CT may 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 [55, 56]. 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 (i.e. there is no mosaic pattern or change in cross-sectional area of the lungs).

The individual HRCT signs listed above may be encountered in other conditions characterised by chronic obstructive pulmonary disease. Patients with asthma show widespread, usually minor, bronchial abnormalities and the HRCT appearances may be confused with those of obliterative bronchiolitis [57]. A mosaic attenuation pattern is also seen commonly in severe asthma, but the inspiratory and expiratory decreased attenuation demonstrated tends to be more extensive in obliterative bronchiolitis than in asthma [58]. In patients with centrilobular emphysema, the HRCT features of permeative destruction of the lung parenchyma and Fig. 4 AHRCT of patient with post-viral constrictive obliterative

bronchiolitis, predominantly affecting the right lung, showing areas of decreased attenuation with poorly defined margins. Within the areas of decreased attenuation the vessels are or reduced calibre.BHRCT of another patient with post-viral constrictive obliterative bronchiolitis. In this case the areas of decreased attenuation have a more geographical margin, representing individually affected secondary pulmonary lobules

Fig. 5.Patient with severe “end stage” constrictive obliterative bronchiolitis. The lungs are of uniformly decreased attenuation and the mosaic pattern is absent because of the widespread involvement of the small airways. The main features are decreased calibre of the pulmonary vessels and bronchiectatic changes

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distortion of the pulmonary vasculature within areas of decreased attenuation are usually sufficiently distinctive to prevent confusion with constrictive obliterative bronchiolitis. The differentiation between panacinar emphysema and advanced constrictive obliterative bronchiolitis may be less straightforward, but a recent study evaluating the use of thin-section CT in distinguishing between causes of obstructive pulmonary disease revealed surprisingly few misdiagnoses between these two groups [57].An explanation for this being that the degree of parenchymal destruction is usually great- er in patients with panlobular emphysema.

The mosaic pattern is a non-specific HRCT sign and can reflect the presence of small airways disease, occlusive vascular disease, or infiltrative lung disease [55, 56, 59, 60]. In a study of 70 patients with a mosaic pattern as the dominant HRCT abnormality, Worthy et al. showed that infiltrative lung disease and small airways disease were readily identified but the mosaic pattern caused by occlusive vascular disease was frequently misinterpret- ed [61]. A recent study by Arakawa [62] has shown that air trapping is common (seen in 60%) on expiratory scans in acute pulmonary embolism, highlighting that expiratory air trapping may not be as helpful as previ- ously thought in distinguishing a mosaic pattern caused by small airways disease and occlusive vascular disease.

In practice the differentiation between the various causes of a mosaic pattern is less problematic if the clinical and functional picture, particularly the gas diffusing ca- pacity, are taken into account.

The density differences that make up the mosaic pattern may be extremely subtle on inspiratory CT 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 (for example, a 5 mm slab consisting of five adjacent 1 mm sec-

tions); 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 [63, 64].

Specific Forms of Small Airways Disease

It has been suggested that inflammation of the bronchioles with or without subsequent obliteration is the most common lesion within the lungs [65], so that while clinically identifiable “pure” obliterative bronchiolitis may be rare in practice, milder obliterative bronchiolitis, sometimes masked by a more familiar disease, is often overlooked. Over the years pathological studies have drawn attention to frequent involvement of the small airways in a wide variety of diffuse interstitial and airway diseases [66–70]. What follows is a consideration of specific types of bronchiolitis that have been classified as clinically recognisable entities [71].

Cryptogenic Obliterative Bronchiolitis

Cryptogenic obliterative bronchiolitis (idiopathic bronchiolitis obliterans) is, by definition, applied to those patients with evidence of obliteration of the small airways, with no identifiable cause or disease known to be associated with obliterative bronchiolitis. The clinical diagnosis is thus therefore largely one of exclusion. In an early pathological study of 42,038 consecutive post mortems over forty two years, LaDue identified only one patient as having bronchiolitis obliterans of no Fig. 6.Adjacent to the two scarred bronchi-

oles the pulmonary artery shows mural fibrosis and intimal hyperplasia suggesting involvement with the initial inflammatory process that resulted in the obliterative bronchiolitis (Courtesy of Prof. T Colby)

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known cause [72]. Later, Turton et al. identified ten patients out of 2,094 individuals with chronic flow obstruction and an FEV1of less than 60% in whom the obstructive deficit was irreversible and no cause could be isolated. The rigorous exclusion criteria applied by these authors are detailed below; such patients were considered to have a distinct disease entity and were la- belled as having “cryptogenic obliterative bronchiolitis”

[38].

Exclusion Criteria for the Diagnosis

of Cryptogenic Obliterative Bronchiolitis [38]

쐌 Diurnal peak respiratory flow rate (PEFR) variability

>50L/min

쐌 Increase in PEFR of >50L/min or 20% after oral corticosteroid therapy

쐌 Rise in FEV1 or FVC of <15% after inhaled beta2- agonist therapy

쐌 History of episodic wheezing 쐌 Personal/family history of atopy

쐌 Chronic bronchitis (Medical Research Council criteria)

쐌 Emphysema

쐌 Known cause of chronic airflow obstruction Five of the ten patients reported by Turton et al. had associated rheumatoid arthritis and two had had a pre- ceding chest infection (viral?), leaving a total of three patients. Thus, using the most stringent criteria, less than 1% of cases in this series can be considered truly idiopathic, highlighting the extreme rarity of cryptogenic obliterative bronchiolitis. Nevertheless, the oblig- atory inclusion criterion of an FEV1of less than 60%

undoubtedly reduces the apparent prevalence of the disease because pathologically bona fide but less severe cases are excluded.

In a remarkable descriptive study of seventy “unse- lected” hospital patients, McLean examined 20,000 sections from blocks of lung tissue from seventy patients.

McLean found, through his painstaking analysis, that pathological evidence of bronchiolitis obliterans, although relatively slight, was extensive and increased with age; quantitative data on the profusion and severity of small airway lesions is not given but McLean states: “in all such patients aged over forty years (howev- er normal their lungs appeared to be on superficial in- spection) diffuse damage to the smaller bronchioles was regularly found” [73].

The clinical course of patients thought to have cryptogenic obliterative bronchiolitis is variable: in the series reported by Turton et al., half the patients survived for more than ten years [38] and in a smaller series of four patients there did not appear to be any disease progression over a five year follow-up period [22]. Al- though it is convenient to exclude smokers when de- scribing patients with cryptogenic obliterative bronchiolitis for study, this may is a potential source of selection bias: Kindt et al. studied sixteen patients, nine of whom were smokers, with mild chronic airflow obstruction and found that five of these individuals had an obliterative bronchiolitis [74]. The authors considered the smoking history in these patients insufficient to account for the severity of these bronchiolar lesions, suggesting that bronchiolitis in smokers may not always be due to tobacco smoke.

Post-viral Obliterative Bronchiolitis

The epidemiological and pathological consequences of lower respiratory tract viral infections are difficult to study because of the wide range of potential infective agents, the extreme variability of lung injury, and the lack of satisfactory pathological data. Given that most

Fig. 7.Natural history of viral lower respiratory tract infections: potential outcomes (modified from [9])

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individuals are likely to suffer repeated viral respiratory tract infections in a lifetime, in numerical terms post- viral bronchiolitis is by far the commonest cause of obliterative bronchiolitis. However, the severity or extent of post-viral obliterative bronchiolitis is highly variable and in the vast majority, the resulting functional deficit is slight or non-existent. Although exact figures are not available, the scheme shown in (Fig. 7) provides some idea of the likely outcome of viral infection of the airways [9].

Infectious agents known to be capable of causing an obliterative bronchiolitis are the DNA viruses such as adenovirus, cytomegalovirus and varicella; of the RNA viruses the most commonly recognised are influenza A and B, parainfluenza 2 and 3 and the respiratory syncytial virus. Occasionally a severe viral lower respiratory tract infection in childhood results in Swyer-James’ (or MacLeod’s) syndrome in which, in addition to an obliterative bronchiolitis, there is arrest of the normal increase in number of alveoli in the developing lung; involvement is often asymmetrical resulting in the char- acteristic “hyperlucent lung” [29] (Fig. 8). Mycoplasma pneumoniae, which has a particular predilection for cil- iated cells, is a potent cause of obliterative bronchiolitis [75]. In the developing world pertussis and measles remain common causes of obliterative bronchiolitis.

Many factors determine the differences in type of micro-organism responsible for lower respiratory tract infections in adults and children – most obviously preexisting immunity to specific viral agents. In children, acute viral lower respiratory tract infections may result in a lymphocytic infiltrate around the airways, so called follicular bronchiolitis (see section on small airways disease associated with connective tissue diseases) (Fig. 9). By adulthood, most lower respiratory tract infections are bacterial. However, no bacterium has defi- nitely been incriminated as a cause of obliterative bron-

chiolitis. Although some authors have listed bacteria such as Haemophilus influenzae and Nocardia aste- roides as causes of obliterative bronchiolitis [76], firm evidence for these, or other bacteria, as causative agents is scant. Nocardia asteroides and Legionella pneumophi- la have both been reported as causes of obliterative bronchiolitis [77, 78]. However, the pathology described in both reports is clearly of an organising pneumonia, rather than a constrictive obliterative bronchiolitis.

In a study of patients with bronchiectasis, Miszkiel et al. showed that patients colonised with Pseudomonas aeruginosa had features consistent with obliterative bronchiolitis on computed tomography significantly more often than non-colonised control patients [79].

However, this link does not necessarily imply that Pseu- Fig. 8. HRCT of a patient with Swyer-James’ (MacLeod’s) syndrome. The asymmetrical (if not unilateral) lung involvement is characteristic. In addition to the features of constrictive obliterative bronchiolitis, the left lung is of small volume (partly due to the collapsed bronchiectatic left lower lobe) and on higher sections the main pulmonary artery was small

Fig. 9.Low power photomicrograph of a lung biopsy taken from a child with a slow to re- solve lower respiratory tract infection. Note the inflammation and follicles of lymphocytes centred on the airways (Courtesy of Dr A Nicholson)

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domonas aeruginosa is the causative agent of oblitera- tive bronchiolitis; the relationship may merely reflect the fact that patients with severe bronchiectasis and associated obliterative bronchiolitis are more likely to have their airways colonised by Pseudomonas aerugino- sa. A similar relationship between Mycobacterium avi- um intracellulare and small airways disease has been described. Kubo et al. [80] found both radiological and physiological evidence of small airways disease in patients with MAI infection who were not known to have preexisting lung disease which suggests that infection by MAI may directly cause small airway pathology.

Although it is recognised that a variety of infective agents may result in both bronchiectasis and obliterative bronchiolitis, the relationship between the two has not been fully elucidated. In a study of the sequel of childhood infection by adenovirus type 21, Becroft showed that in addition to an obliterative bronchiolitis, bronchiectasis also occurred [81]. Whether this was the result of synchronous damage to the large and small airways, or bronchiectasis developing as a consequence of the obliterative bronchiolitis is not clear (Fig. 10). The converse idea that bronchiectasis may ultimately lead to obstruction of the small airways is sometimes implied:

“...bronchiolitis obliterans is often found beyond chron- ic suppurative bronchial disease, such as bronchiectasis or cystic fibrosis” [8] and “Longstanding obstruction may lead to deletion of small airways, which are re- placed by relatively acellular fibrotic strands” [82].

Small Airways Disease Associated with Connective Tissue Diseases

The connective tissue diseases are collectively characterised by immunologically mediated chronic inflammatory damage to a variety of tissues. Obliterative

bronchiolitis associated with rheumatoid arthritis was first reported in 1956 [83], but attention became sharp- ly focussed on small airways involvement in connective tissue diseases following the report by Geddes et al.

[17]. The pathogenesis of obliterative bronchiolitis in the connective tissue diseases remains uncertain [84];

there is no clear autoimmune basis and other possibil- ities such as an increased susceptibility to airways infections or complications of therapy have been postulated, but these remain unproven.

Small airways involvement in connective tissue diseases may be cryptic because of the panoply of other possible pathologies which have the potential to mask the functional effects of small airways disease. Despite the recognition that the multi-system connective tissue diseases are associated with various lung complications, there is little quantitative data on their prevalence, severity and natural history. Knowledge of bronchiolar involvement is largely based on anecdotal clinical descriptions of severe cases [85]. A pathological study that re- viewed forty one open lung biopsies of patients with rheumatoid arthritis [86] did not include any cases of

“pure” obliterative bronchiolitis, highlighting the variable recognition of bronchiolar involvement in rheumatoid arthritis.

A histopathological diagnosis of obliterative bronchiolitis may not be readily established even when an open lung biopsy is undertaken: small airways involvement needs to be distinguished from involvement of the airways by a background fibrosing process – this phe- nomenon is described in lone cryptogenic fibrosing alveolitis [87] and in fibrosing alveolitis associated with systemic sclerosis [88]. In one CT study of eighty four patients with rheumatoid arthritis, twenty three individuals (30%) showed features of bronchiectasis and/or bronchiolectasis [50]; again, whether these abnormalities reflect small airways disease is uncertain.

The role of penicillamine in inducing obliterative bronchiolitis in patients with rheumatoid arthritis has been widely debated. In one large study which examined this specific question, rheumatoid arthritis patients treated with penicillamine had a significantly higher prevalence of obliterative bronchiolitis (3 out of 133) than untreated patients (0 out of 380) [89]. Fur- thermore, there was a close temporal relationship between the onset of small airways disease and starting penicillamine treatment, suggesting an underlying pre- disposition to obliterative bronchiolitis, triggered by penicillamine treatment. Nevertheless, these observa- tions do not exclude the possibility of a spurious link between penicillamine and obliterative bronchiolitis:

the use of one and the development of the other both reflecting more progressive and severe rheumatoid arthritis.

A separate pathological entity termed follicular bronchiolitis is more commonly associated with rheu- Fig. 10.HRCT of a patient who had had a severe viral lower respir-

atory infection nine years earlier. In the middle lobe and both lower lobes there are features of bronchiectasis and coexisting obliterative bronchiolitis

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matoid arthritis, often accompanied by Sjögren’s syndrome, than with the other connective tissue diseases [90, 91]. Follicular bronchiolitis refers to a form of bronchiolar disease characterised histologically by the presence of abundant lymphoid tissue, frequently with prominent germinal centres, situated in the walls of bronchioles, and to some extent, bronchi. The characteristic lesion is external compression of the bronchioles by hyperplastic lymphoid follicles (Fig. 11); this external compression may be accompanied by lymphocytic infiltration of the adjacent bronchiolar wall. The most common HRCT finding in follicular bronchiolitis are small (1 to 12 mm) nodules located predominantly in a centrilobular distribution (Fig. 12). Peribronchial nodules and patchy non-segmental areas of ground glass have also been described [92]. The CT pattern of

nodular attenuation is not surprising considering the predominant histological findings of peribronchiolar inflammation with coalescent germinal centres [92]. Al- though coexisting follicular and obliterative bronchiolitis have been reported [93, 94], the link between the two is unclear. More diffuse lymphocytic infiltration of the bronchiolar walls has been reported in patients with Sjögren’s syndrome [95]. It seems likely that these specific forms of lymphocytic bronchiolitis are rare except in connective tissue diseases and thus should not be regarded as a precursor to constrictive obliterative bronchiolitis.

Interstitial fibrosis is an extremely common association of systemic sclerosis and the occurrence of inde- pendent small airways disease in systemic sclerosis is thus difficult to define.Although standard lung function tests have suggested the presence of small airways disease in up to 42% of patients with systemic sclerosis [85], this high prevalence is questionable. In another study which used sophisticated lung function tests, no evidence of small airways disease was found in non- smoking patients with systemic sclerosis [96].

Post-transplant Obliterative Bronchiolitis

Obliterative bronchiolitis is a well-recognised and seri- ous complication in patients who have received a heart- lung or lung transplant. Burke et al. first reported the frequent occurrence and grave consequences of obliterative bronchiolitis in heart-lung recipients in 1984 [97].

The pathogenesis of this specific form of obliterative bronchiolitis has been the subject of much study [24]

[98, 99]. The general consensus is that obliterative bronchiolitis reflects chronic rejection and is due to immunologically mediated injury to the pulmonary endothe- lium and bronchial epithelium with possible contribu- Fig. 11.Lung biopsy from a patient with

Sjögren’s syndrome showing hyperplastic lymphoid follicles ranged along a bronchiole causing compression of the lumen. The surrounding lung parenchyma is normal

Fig. 12.HRCT of a patient with rheumatoid arthritis and biopsy proven follicular bronchiolitis. The unusual irregular opacities appear to be centred on the airways, as would be expected from the pathology (see Fig. 11). There are also focal areas of lung destruction (pathogenesis unknown) resembling emphysema

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tions from intercurrent infection and vascular insuffi- ciency. However, there are reports suggesting that the number of early or “acute” rejection episodes correlates with the later development of obliterative bronchiolitis [100, 101].

Bronchiolitis obliterans in the post-transplant patient progresses through a sequence of lymphohistio- cytic-mediated cytotoxicity directed at the respiratory epithelium. The initial process is a lymphocytic infiltrate of the sub-mucosa of the airways with migration of lymphocytes through the basement membrane into the epithelium [102]. At this site, epithelial cell necrosis occurs with denudation of the mucosa. The subsequent secondary cascade of inflammatory mediators eventu- ally leads to the migration of fibroblasts and myofibro- blasts into the luminal exudate. Intraluminal plugs of fibrous tissue may occur and it has been postulated that this latter feature is more likely to reflect a response to infection or aspiration [24].

The diagnostic fibrous scarring can be eccentric with formation of a fibrous plaque in the wall of the airway, concentric with the interposition of a ‘donut’ of collagen tissue, or the granulation tissue may completely obliter- ate the lumen of the airway, reducing the air passages to stenotic cords of scar tissue [103]. Generally the development of obliterative bronchiolitis is thought to mirror the progression of chronic lung transplant rejection [104]. It has been estimated using a variety of diagnostic criteria, that obliterative bronchiolitis occurs in at least 40% of individuals surviving at least three months following transplantation [105]. The reported incidence of obliterative bronchiolitis after lung transplantation reflects the mean follow-up periods of the different groups of survivors, those with longer follow-up having higher rates of obliterative bronchiolitis. For example, in one large series of patients who had heart-lung transplantation for cystic fibrosis, the incidence of obliterative bronchiolitis at one, two and three years was 17%, 28% and 48% respectively [106]. Most cases are identified clinically between six and eighteen months post- transplantation.

The reported sensitivity and specificity of HRCT for the diagnosis of established constrictive bronchiolitis in post-lung transplant patients has been variable, largely due to patient selection and the HRCT feature evaluated [26, 49, 107–111]. Early studies concentrated on bronchiectasis [26, 27], but more recently attention has turned to the mosaic attenuation pattern on inspiratory CT and, more particularly, on expiratory CT. In a study by Leung et al. [108], air trapping on expiratory CT was the most sensitive sign (sensitivity 91%) of obliterative bronchiolitis in 11 patients with transbronchial biopsy confirmation. In a recent prospective study that includ- ed 111expiratory CT scans in 38 heart-lung transplant recipients, the presence of air trapping occupying more than 32% of lung parenchyma had a sensitivity of 83%

and a specificity of 89% for the diagnosis of bronchiolitis obliterans syndrome, and in some patients this preceded the spirometric criteria for BOS [111]. However Lee et al. have questioned the sensitivity and specificity of expiratory CT. In their study [109], the air trapping score in patients with biopsy proven bronchiolitis obliterans was not significantly different to biopsy negative patients with airflow limitation.

Obliterative bronchiolitis also occurs following au- tologous bone marrow transplantation [112]. In this setting, other complications (including a variety of infections, pulmonary oedema and drug toxicity) are equally problematic in these patients [106]. In general, the obliterative bronchiolitis which is a presumed manifestation of graft-versus-host disease occurs in only a small pro- portion of patients following allogenic bone marrow transplant (probably less than 10%) and is usually less severe than that seen following lung transplantation [113].

Diffuse Panbronchiolitis

Exudative bronchiolitis 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 in- itially thought to be confined to Asian countries, but sporadic cases have been reported in every continent [114]. Nevertheless, most of the definitive pathological and imaging studies originate from Japan [32, 33, 115].

The pathology is characterised by thickening of the walls of the respiratory bronchioles with infiltration by lymphocytes, plasma cells and histiocytes and bronchiolectasis, with secretions and foamy macrophages fill- ing the chronically inflamed airways and immediately adjacent alveoli (Fig. 13). The inflammatory process may extend from the centrilobular airways to involve the adjacent interstitium, but the air-spaces are not affected. The bronchiolocentric lesions are visible macro- scopically as yellow nodules. As the disease progresses, an element of fibrotic bronchiolar constriction super- venes.

In the absence of longitudinal histopathological studies, it is not clear the extent to which the basic “exudative” pathology progresses to constrictive bronchiolar obliteration.

HRCT appearances reflect the pathologic process.

There is a nodular pattern and small branching opacities (tree-in-bud pattern) can be identified in a predominantly centrilobular distribution, corresponding to the plugged small airways (Figs. 14, 15]. These features are reversible and most patients respond to erythromycin (although the mechanism for this response is unclear: there is no obvious bacterial cause). Mild cylindrical bronchiectasis is an almost invariable accompa-

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niment and progression of bronchiectasis occurs in severe cases. Even in those who respond to treatment with erythromycin, follow-up CT scans do not demonstrate any appreciable change in the severity of bronchiectasis [115]. Interestingly, although mosaic attenuation may be identified in some cases, it is not usually a major feature; furthermore, regional inhomogeneity of the density of the lung parenchyma on expiratory CT, reflecting air trapping, maybe surprisingly unimpressive. The HRCT features, in the appropriate clinical setting, are virtually pathognomonic. However, other conditions may rarely cause an identical pattern on HRCT and these include invasive aspergillosis centred on the airways [116] and primary pulmonary lymphoma [117].

Other conditions characterised by a tree-in-bud pattern are listed in Table 3.

Fig. 13.Pathology of diffuse panbronchiolitis: the bronchiolar wall is thickened by a chronic inflammatory infiltrate and the surrounding alveoli are filled with foamy macrophages (Courtesy of Prof M. Kitaichi)

Fig. 14.HRCT of a patient with diffuse panbronchiolitis showing a combination of mild cylindrical bronchiectasis and peripheral branching structures; the latter represent thickened and plugged bronchioles

Fig. 15.A patient with diffuse panbronchiolitis showing a predominantly nodular pattern in association with the tree-in-bud pattern

Table 3.Conditions characterised by tree-in-bud pattern on high- resolution computed tomography

Major feature

Diffuse panbronchiolitis

Bronchiectasis (idiopathic and known cause e.g. cystic fibrosis)

Mycobacterial infection

Aspiration and bronchopneumonia

Acute infectious bronchiolitis (e.g. Mycoplasma pneumoniae) Invasive aspergillosis centred on the airways

Occasional or rare feature

Sjögren’s syndrome (follicular bronchiolitis) Allergic bronchopulmonary aspergillosis Pneumocystis carinii pneumonia Leukaemia

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Interstitial Lung Diseases with a Component of Small Airways Disease

In contrast to the occurrence of small airways involvement in chronic obstructive airways disease [118], disease of the small airways was not considered part of the concept of “interstitial” lung disease until more recently [119]. One explanation is the stereotyping of interstitial lung disease as functionally restrictive: the heterogeneous group of conditions classically regarded as interstitial are typified by reduced lung volume and compliance (restriction) with no evidence of airflow obstruction. In contradistinction, chronic obstructive pulmonary disease is characterised by an obstructive defect with normal or increased lung volume. It is now widely recognised that diffuse lung pathology cannot always be com- partmentalised into processes that affect the small airways or alveolar interstitium exclusively.

Perhaps the earliest acknowledgement of small airways involvement as a constituent of an interstitial lung disease was by Hamman and Rich in their description of fulminant pulmonary fibrosis [66] The pathological features of the condition documented by Hamman and Rich are now thought to resemble an acute interstitial pneumonia with diffuse alveolar damage and hyaline membrane formation, rather than an accelerated usual interstitial pneumonia [120].

An early suggestion that small airways were functionally involved in interstitial pulmonary disease was made by Ostrow and Cherniack in 1973 [121]. Further morphological and physiological studies confirmed that peribronchiolar fibrosis can cause narrowing of the small airways in fibrosing alveolitis and have a measur- able effect on physiological indices of small airways function [87, 122]. These studies used dynamic compliance and maximum expiratory flow-volume curves to detect small airways obstruction; the validity of these and other esoteric tests when there is coexisting interstitial lung disease is controversial. In one study which used closing volume and upstream conductance to identify small airways obstruction in a nine patients with fibrosing alveolitis, the authors concluded that there was no evidence of narrowing of (functional) small airways in ventilated parts of the lung [123]. This study highlights the difficulty in functional evaluation of what is likely to be patchy and variable bronchiolar involvement. The prevalence of small airways disease in patients with fibrosing lung disease depends heavily whether it is sought in terms of pathological, functional or clinical terms. In summary, although bronchiolar involvement by interstitial fibrosis can occur, its prevalence and significance remain a source of debate [119].

Respiratory Bronchiolitis – Interstitial Lung Disease Respiratory bronchiolitis is a common incidental histologic finding in heavy smokers [124] but such cases were thought to be asymptomatic until Myers et al. described 6 patients, all heavy smokers, who had clinical, radiological and physiologic evidence of chronic interstitial lung disease but only respiratory bronchiolitis on open lung biopsy [125]. The term “Respiratory bronchiolitis – interstitial lung disease (RB-ILD)” was later coined in a further series that described the histologic differences between the incidental changes of smoking, RB-ILD and DIP [126]. Almost all patients with RB-ILD are cigarette smokers [127–129], although occasional patients have occupational exposure to irritant fumes [129] and a few patients are described as never smokers [128].

Histologically, respiratory bronchiolitis is characterised by an accumulation of alveolar macrophages within the respiratory bronchioles spilling into neighbour- ing alveoli. These macrophages typically have glassy eo- sinophilic cytoplasm with variably intense light brown pigmentation that most likely represent metabolites of cigarette smoke, (hence the term ‘smokers macrophages’) given that the degree of cytoplasmic pigmentation of macrophages has been shown to correlate with the number of pack-years smoked [128]. Their accumulation may be associated with peribronchiolar alveolar septal thickening by fibroblasts and collagen deposi- tion, characteristically radiating from the bronchiole and there is usually an accompanying chronic inflammatory cell infiltrate in the wall of the bronchiole and the surrounding alveolar walls (Fig. 16). Again, the presence of peribronchiolar fibrosis has been shown to correlate with the number of pack-years smoked, but no correlation was found between pulmonary function tests and pathologic findings [128]. The interstitial fibrosis is of variable severity but is usually a minor component.

The typical HRCT features include: patchy ground- glass opacification (Fig. 17) [130] [131], poorly defined centrilobular nodules (upper zone predominant) [131]

and a limited reticular pattern with some thickening of the interlobular septa (probably due to interstitial fibrosis). A recent study of 21 patients with pathologically proven RB-ILD also documented patchy areas of decreased attenuation, a mosaic attenuation pattern (most probably reflecting small airways dysfunction) in 38%

[127] (Fig. 18). Associated emphysematous changes are often present (57%) (Fig. 19) and interestingly, the majority of patients showed wall thickening of both proxi- mal and distal airways, presumably analogous to chronic bronchitis. The extent of centrilobular nodules has been found to correlate with the extent of macrophages in respiratory bronchioles and with the extent of chronic inflammation of respiratory bronchioles. Ground

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glass opacity correlates with macrophage accumulation in the alveolar space and alveolar ducts [127].

The features on HRCT of an infiltrative process in combination with small airways disease are remarkably reminiscent of the HRCT appearances of subacute hypersensitivity pneumonitis, and the differential diagnosis between these two conditions is an important one for radiologists. The constellation of HRCT features seen in RB-ILD in approximate order of frequency are summarised below:

쐌 Poorly defined centrilobular nodules 쐌 Areas of ground-glass opacity 쐌 Bronchial wall thickening

쐌 Areas of decreased attenuation reflecting small airways disease

쐌 Emphysema (paraseptal and centrilobular) – limited 쐌 Thickened interlobular septa

쐌 Features of established interstitial fibrosis Fig. 16.Pathology of respiratory bronchio-

litis–interstitial lung disease (RB-ILD). The lumen of the bronchiole in the centre of the field is full of pigmented macrophages. The bronchiolar wall is disrupted and there is some peribronchiolar fibrosis (Courtesy of Dr A Nicholson)

Fig. 17.Areas of ground glass opacification in a patient with RB- ILD

Fig. 18.Patient with RB-ILD showing a subtle mosaic attenuation pattern on HRCT

Fig. 19.HRCT of a patient with RB-ILD showing patchy areas of ground glass on a background of emphysema