imaging of small airways disease.6

Imaging of Small Airways Disease

Gerald F. Abbott, MD,* Melissa L. Rosado-de-Christenson, MD,w zySantiago E. Rossi, MD,J and Saul Suster, MDz

Abstract: Small airways disease includes a spectrum of inflammatoryand fibrotic pulmonary diseases centered on the small conductingairways. High-resolution computed tomography plays a key role inthe detection and classification of small airways disease and, whencombined with relevant clinical and pathologic findings, leads to amore accurate diagnosis. The imaging manifestations of small airwaysdisease on high-resolution computed tomography may be direct orindirect signs of small airway involvement and include centrilobularnodules and branching nodular (tree-in-bud) opacities, or thedemonstration of mosaic attenuation that is typically exaggerated onexpiratory computed tomography. This article reviews the normalanatomy and histology of bronchioles and the clinical, pathologic, andimaging features of small airways diseases.

Key Words: small airways disease, bronchioles, bronchiolitis,

constrictive bronchiolitis

(J Thorac Imaging 2009;24:285–298)

The term bronchiolitis has been used to refer to a broadspectrum of inflammatory and fibrotic pulmonary

diseases centered on the small conducting airways.1 Severalclassification schemes of bronchiolitis have been proposed.Some of these are based on clinical features and take intoconsideration the clinical setting and the etiologic factorsassociated with bronchiolitis. Others are based on histo-logic features and others on high-resolution computedtomography (HRCT) findings of small airways disease.HRCT plays a key role in the detection and classificationof small airways disease and, when combined with relevantclinical and pathologic findings, leads to a more accuratediagnosis. This article will review the normal anatomy andhistology of bronchioles and the clinical, pathologic, andimaging features of small airways diseases.

NORMAL ANATOMYThe designation ‘‘small airways’’ refers to the membra-

nous and respiratory bronchioles. In addition to their small size(r2mm internal diameter), the small airways are also dis-tinguished by their lack of cartilage and submucosal glands.2,3

The terms bronchioles and small airways are used hereinterchangeably, although they are not strictly synonymous.

SECONDARY PULMONARY LOBULEThe secondary pulmonary lobule (SPL) is a key

structure in the lung anatomy and is distinguished as thesmallest functioning subunit of lung that is bound byconnective tissue septa, supplied by a lobular bronchioleand arteriole, and drained by veins and lymphatics in theinterlobular septa. Each SPL measures 1 to 2.5 cm andcontains 3 to 12 acini. The SPL are better formed and moreeasily recognized in the peripheral subpleural lung andare smaller and less regular in the central lung. The SPL arenot normally visible on radiography or computed tomo-graphy (CT)/HRCT (Fig. 1). The small airways are arrayedwithin the SPL, branching successively from a central,lobular bronchiole (1mm diameter) that in turn supplies3 to 12 terminal bronchioles, respiratory bronchioles, andalveolar ducts.3,4

BRONCHIOLESThe axial pathway of human conducting airways

extends from the main bronchus of each lung to theterminal bronchiole and may contain as many as 25 air-way generations or as few as 5. The number of generationsmay vary among different pulmonary lobes and seg-ments according to their proximity or distance from thepulmonary hilum. Small bronchi give rise to membranousbronchioles, so-called because cartilage disappears from theairway wall at that level, and the airway diameter decreasesto approximately 1mm. The last conducting membranousbronchiole, the terminal bronchiole, leads into the pulmo-nary acinus, a structural unit of lung distal to the terminalbronchiole, supplied by first-order respiratory bronchioles,which in turn supply alveolar ducts, alveolar sacs, andalveoli. The acinus is the largest unit of lung in which allairways participate in the gas exchange.

The membranous bronchioles, including the termimalbronchiole, are lined by epithelial cells consisting of ciliatedcolumnar cells and nonciliated Clara cells (Fig. 2). Elasticfibers attached to the adventitia of bronchioles fromadjacent alveoli provide mechanical support and preventsmall airway collapse in the final phase of expiration.3,4

Respiratory bronchioles arise from the distal aspectsof terminal bronchioles or as branches of other respiratorybronchioles; they are partially alveolated, transitionalairways—both conductive and respiratory—and measurein the range of 0.5mm in diameter. The respiratorybronchioles branch into multiple alveolar ducts, character-ized by walls that are totally alveolated and terminatein a semicircular blind end called the alveolar sac, eachsurrounded by 4 or more alveoli.

The canals of Lambert are direct, epithelial-linedchannels between membranous bronchioles and adjacentalveoli that provide an alternate route for collateralventilation and allow passage of macrophages from theCopyright r 2009 by Lippincott Williams & Wilkins

From the *Department of Radiology, Massachusetts General Hospital,Boston, MA; yDepartment of Radiology and Nuclear Medicine,Uniformed Services University of the Health Sciences, Bethesda,MD; wDepartment of Radiology, Saint Luke’s Hospital of KansasCity; zDepartment of Radiology, University of Missouri-KansasCity, Kansas City, MO; JDepartment of Radiology, Centro deDiagnostico Dr. Enrique Rossi, Buenos Aires, Argentina; andzDepartment of Pathology and Laboratory Medicine, MedicalCollege of Wisconsin, Milwaukee, WI.

Reprints: Gerald F. Abbott, MD, Department of Radiology, Massa-chusetts General Hospital, Thoracic Radiology-FND 202, 55 FruitStreet, Boston, MA 02114-2696 (e-mail: [email protected]).

SYMPOSIA

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alveolus to the respiratory and terminal bronchioles whereciliated cells can clear them from the lungs.4

RELATIONSHIP WITH VASCULAR ANDLYMPHATIC STRUCTURES

Throughout its course, each bronchiole is paired witha homologous arteriole of equivalent size to form abronchovascular bundle that is further supplied byaccompanying lymphatic vessels until reaching the alveo-lar-capillary network. In chronic inflammatory processes,lymphoid follicles along small airways form the mucosa-

associated lymphoid tissue reaction, designated as chronicbronchiolitis. When germinal centers are also present, thecondition is termed follicular bronchiolitis (FB).2,3

IMAGING OF SMALL AIRWAYS DISEASESmall airways disease is difficult to detect by conven-

tional radiographic imaging and physiologic testing untilwidespread involvement has occurred. In recent decades,the utilization of thin-section and high-resolution CT hasadvanced our understanding of small airways diseases and,when correlated with clinical features and pathologic

FIGURE 1. Normal anatomy. A, Illustration depicts normal CT anatomy showing polyhedral secondary pulmonary lobules that arebetter defined peripherally and less regular centrally. Gray lines outline the boundaries of the secondary pulmonary lobules, theinterlobular septa. The small airways are not visible. B, Illustration depicts the typical findings on normal chest CT. Note that theinterlobular septa are not normally visible.

FIGURE 2. Microscopic anatomy of normal small airways. A, Intermediate power photomicrograph (hematoxylin and eosin stain) showsa normal membranous bronchiole lined by a single layer of low-cuboidal epithelium with a circumferential layer of smooth muscle andno cartilage in the airway wall. B, High-power photomicrograph (hematoxylin and eosin stain) shows a terminal bronchiole withsurrounding normal alveoli. The bronchiole is partially lined by a single layer of low-columnar epithelium in continuity with the alveolarwalls. Note the absence of smooth muscle surrounding the bronchiole and its communication with adjacent respiratory bronchioles.

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findings, has greatly enhanced diagnostic accuracy in theevaluation of patients suspected of having small airwaysdisease.

The imaging evaluation of patients suspected ofhaving small airways disease should include inspiratoryand expiratory HRCT obtained using thin collimation(1.25mm or less) acquired as either noncontiguous imagesat 1 cm or 2 cm intervals, or reconstructed from a spiral/helical volumetric acquisition. Volumetric image acquisi-tion requires a higher radiation dose, but allows forevaluation of larger airways for the presence of bronch-iectasis and optimizes the detection and characterization ofairway abnormalities by utilization of reconstructed multi-planar or postprocessed images.5

Multidetector row CT of the chest enables produc-tion of multiplanar volume reconstructions that may bemanipulated to encode the minimum-intensity or max-imum-intensity voxels of a scanned volume of tissueonto a 2-dimensional image. Minimum-intensity projection(MinIP) techniques project voxels with the lowest attenua-tion value, improving the detection of subtle areas of lowattenuation and the conspicuity of regional heterogeneity(mosaic attenuation) of lung parenchyma that may bemanifestations of small airways disease. Projection ofvoxels with the highest attenuation values produces maxi-mum-intensity projection (MIP) images that facilitate therecognition of small centrilobular nodules, tree-in-budopacities, and poorly defined centrilobular nodules.6–8

DIRECT AND INDIRECT CT SIGNSOF SMALL AIRWAYS DISEASE

Centrilobular Nodules and Tree-in-bud OpacitiesThe small airways are not normally visible on HRCT.

Their location may be inferred from visualization of theiraccompanying small lobular arteries. They may become

visible at the center of the SPL when there is abnormalincreased soft-tissue density in or around the bronchioleand thickening of the bronchiolar wall. The soft tissuedensity may form direct CT signs of small airways diseaseas centrilobular nodules and/or V-shaped or Y-shapedbranching linear opacities that resemble the early seasonalappearance of a budding tree in spring time (‘‘tree-in-bud’’pattern) (Fig. 3). Poorly defined centrilobular nodules,often of a CT attenuation less than that of soft tissue, mayoccur when inflammatory cellular infiltrates involve theperibronchiolar alveoli [eg, hypersensitivity pneumonitis(HP) or respiratory bronchiolitis (RB)].9 A less commondirect sign of bronchiolitis is the presence of bronchiolec-tasis, representing dilated bronchioles that are usuallyassociated with a chronic, fibrotic process and are mosteasily recognized in the subpleural lung.

Air Trapping and Mosaic AttenuationThe CT findings of mosaic attenuation and/or air

trapping may be indirect signs of small airways disease. Theterm mosaic attenuation refers to a patchwork of regions ofdiffering attenuation detected on inspiratory CT images,and may represent obliterative small airways disease,patchy interstitial disease, or occlusive vascular disease.Air trapping is seen on end-expiration CT scans asparenchymal areas with less than the normal increase inattenuation and a lack of volume reduction and manifestson expiratory HRCT as sharply defined geographic areas oflow attenuation with contours that follow the outlinesof the underlying polyhedral SPLs (Fig. 4).6,10 Subtle ordiffuse areas of air trapping may be more easily differ-entiated by comparison between inspiratory and expiratoryCT scans and thus it is important to include expiratoryimaging in the CT evaluation of individuals suspected ofhaving small airways disease.5

FIGURE 3. Direct signs of small airways disease. A, Illustration depicts some of the direct signs of small airways disease includingcentrilobular ground-glass nodules (A), solidnodules (B), and branching and tree-in-bud opacities (C) in the center of secondarypulmonary lobules, outlined by gray lines that correspond to the anatomic location of the interlobular septa. B, Because interlobularsepta are not normally visible on HRCT, the location of centrilobular nodules and tree-in-bud opacities is inferred by their distance fromadjacent pleural surfaces (0.5 to 1.0 cm) and occasionally by their separation from lobular boundaries.

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SMALL AIRWAYS DISEASE

DefinitionThe term small airways disease refers to pathologic

conditions that involve the bronchioles primarily, or ascomponents of interstitial or alveolar lung disease. Bronch-iolitis occurs in a heterogeneous group of lesions that varyin their etiology, clinical settings, and pathologic featuresbut are centered on small conducting airways.1

Historic PerspectiveThe term ‘‘small airway disease’’ was first used by

Hogg and colleagues11 in 1968, in a study, that showed thatthe main site of airflow resistance in patients with chronicairflow obstruction was in airways less than 2mm indiameter. They also confirmed in humans what Macklemand Mead had shown in dogs—that the peripheral airwaysnormally contribute only 10% to 20% of total airwayresistance because the total cross-sectional area of the smallairways is much greater than the total cross-sectional areaof the central airways. When diseased, however, the smallairways contribute disproportionately to increased airwayresistance.11 As a consequence, measurement of airwayresistance might be normal in the setting of considerableobstruction in the peripheral airways. For this reason, thesmall airways have been described as the ‘‘silent zone’’ ofthe lungs, and diseases affecting these structures may not beevident on pulmonary function tests until late in theircourse.11

Classification of Small Airways DiseaseSmall airways disease (bronchiolitis) may be classified

according to its clinical setting, its histologic pattern, or onthe basis of HRCT imaging findings. The clinical classifica-tion is on the basis of the proven or presumed etiology, oron associated systemic conditions. Histologic classificationinto proliferative (cellular) or fibrotic (constrictive) bronch-

iolitis correlates most directly with the imaging features ofsmall airways disease.9,12 This article will emphasize theimaging appearances of bronchiolitis and review thoselesions that produce direct and indirect imaging features ofsmall airways disease.

Cellular bronchiolitis refers to bronchiolitis in whichinflammatory cells (acute, chronic, or acute and chronic)are the predominant histopathologic finding and is acommon pattern found in many clinicopathologic settings.Bronchioles are not visible on normal HRCT but maybecome visible at the center of the SPL as a direct sign ofbronchiolitis when their walls are thickened by inflamma-tory cell infiltrates. Cellular infiltrates in the peribronchio-lar alveoli may manifest as poorly defined centrilobularnodules that may be of soft tissue or ground glassattenuation.2,9,13

Constrictive bronchiolitis (syn. bronchiolitis obliter-ans) is a purely bronchiolar lesion with luminal narrowingby collagenous fibrosis and scarring that may be subtleor result in complete luminal obliteration. Constrictivebronchiolitis can be seen in a variety of disorders and insome specific clinical settings.2

CELLULAR BRONCHIOLITIS

Infectious Bronchiolitis

General FeaturesThe imaging features of bronchiolitis are relatively

common on chest CT but are often nonspecific, typicallymanifesting as centrilobular nodules and branching nodular(tree-in-bud) opacities, and have been described in viralinfection, bacterial pneumonia, tuberculosis, nontuber-culous mycobacterial infection, and aspergillosis. Somedisease entities, however, have associated findings thatprovide clues to the diagnosis. Detection of associatedcavitary lesions, for instance, suggests the diagnosis of

FIGURE 4. Indirect signs of small airways disease. A, Illustration depicts mosaic attenuation/air trapping characterized by sharply definedgeographic areas of low attenuation (darker lung) with contours that follow the polyhedral outlines of the underlying secondary pulmonarylobules, depicted by gray lines. B, Illustration depicts the same findings as in A without the underlying pulmonary architecture and, thereforemore closely approximates the findings seen on CT and HRCT.



Mycobacterium tuberculosis, atypical mycobacterial, orfungal infection,14 whereas findings of bronchiolitis asso-ciated with bronchiectasis, particularly with involvementof the middle lobe and lingula, suggest the diagnosis ofatypical mycobacterial infection.15 The combination ofcentrilobular nodules and lobular areas of ground-glassopacity on chest CT is suggestive of Mycoplasma pneumo-niae pneumonia.16

Acute infectious bronchiolitis most commonly affectschildren and is most often caused by viruses (respiratorysyncytial virus, adenoviruses, parainfluenza virus, influenzavirus, and human metapneumovirus) and M. pneumoniaepneumonia. Less common etiologies include chlamydia,bacteria, and fungi (eg, aspergillus in immunocompromisedindividuals).8,17

Clinical PresentationThe clinical presentation of adults with infectious

bronchiolitis is typically less severe than that of affectedinfants and children, but may sometimes be severe andfatal.17 Children affected by infectious bronchiolitis oftenpresent with symptoms of an upper respiratory tractinfection followed 2 to 3 days later by the abrupt onset ofdyspnea, tachypnea, and fever.1,8

PathologyHistologically, infectious bronchiolitis is characterized

by the presence of inflammatory cells, mainly neutrophils,in the walls of airways and inflammatory exudates inthe airway lumens (Fig. 5).2 In some instances, specifichistologic or microbiologic findings may indicate a specificdiagnosis (eg, hyphae in aspergillus infection, observationof acid-fast bacilli in M. tuberculosis infection).

Imaging Findings

RadiographyChest radiographs may reveal bilateral, often subtle,

nodular, or reticulonodular opacities. In children, airwaywall thickening and peribronchial consolidations arecommon. Partial small airway obstruction may manifest

as hyperinflation; patchy bilateral consolidation oftenindicates the presence of bronchopneumonia.

CT/HRCT FeaturesIn adults, infectious bronchiolitis typically manifests

on HRCT as well-defined centrilobular nodules and tree-in-bud opacities that may be patchy and unilateral or bilateraland asymmetric. The presence of tree-in-bud nodules ishighly suggestive of infectious bronchiolitis but may be amanifestation of noninfectious conditions (eg, aspiration,cystic fibrosis) (Figs. 6–9).17

Hypersensitivity PneumonitisCellular bronchiolitis is a prominent feature of

hypersensitivity pneumonitis (HP) (syn. extrinsic allergicalveolitis), an allergic lung disease caused by the inhalationof organic or inorganic agents and of some chemicals. Inaffected individuals, the small organism or protein complexlodges in the terminal and respiratory bronchioles and

FIGURE 5. Microscopic features of cellular bronchiolitis. A, Intermediate power photomicrograph (hematoxylin and eosin stain) showsdilated branching bronchioles surrounded by a dense acute and chronic inflammatory cellular infiltrate. B, High-powerphotomicrograph (hematoxylin and eosin stain) shows the inflammatory cellular infiltrate involving the bronchiolar epithelium and wall.

FIGURE 6. Purulent bronchiolitis. Unenhanced axial thin-sectionchest CT (lung window) demonstrates diffuse bilateral centrilob-ular nodules and tree-in-bud opacities consistent with the cellularbronchiolitis characteristically seen in bacterial infections. Notethe centrilobular nodules do not abut the pleural surfaces.



alveoli, and induces an alveolitis and inflammatorygranulomatous bronchiolitis of variable severity.18–21

Patients with subacute HP may experience an insidiousonset of symptoms over a period of weeks or months andmay present with cough and dyspnea on exertion, orexperience loss of appetite, weight loss, and fatigue.22

Acute HP manifests as pulmonary edema and diffuseairspace consolidation. Subacute HP manifests as bilateralground-glass opacities and poorly defined centrilobularnodules that correlate, respectively, with the histologicpresence of alveoilitis and bronchiolitis. The findings areoften diffuse, or predominantly involve the middle andlower lung zones. Lobular areas of decreased attenuationand perfusion manifest as air trapping on expiratory CTimaging. (Figs. 10, 11).8,9,21 HP is discussed in detailelsewhere in this issue (see Sirajuddin and Kanne).

Aspiration Bronchiolitis

General FeaturesDiffuse aspiration bronchiolitis (DAB) is a recently

described clinical entity characterized by chronic inflamma-tion of bronchioles as a result of recurrent aspiration offoreign material.23

Clinical PresentationHalf of all the patients affected with DAB have

oropharyngeal dysphagia; many are elderly or bedriddenpatients, or individuals with neurologic disorders ordementia. Many present with bronchorrhea, bronchos-pasm, wheezing, and dyspnea—signs and symptoms thatare often associated with oral food intake. Patients withDAB often present with a persistent respiratory illness andradiographic findings of diffuse small nodular opacities.23,24

PathologyDAB is characterized histologically by chronic mural

inflammation of bronchioles with foreign body reaction.Evidence of cryptogenic organizing pneumonia or broncho-pneumonia may be seen within associated patchy areas ofconsolidation.24

Imaging Findings

RadiographyChest radiographs demonstrate diffuse small (<5mm)

nodular opacities that may be unilateral or bilateral, andmild-to-moderate hyperinflation.23 The small nodularpattern on radiography may be misleading and resemblean interstitial, rather than an airways-related disease.6

CT/HRCT FeaturesDAB manifests on HRCT as disseminated small

centrilobular branching linear opacities (tree-in-bud pat-tern), often associated with adjacent areas of lobularconsolidation. The distribution of abnormalities revealedon HRCT is usually associated with the patient’s bodyposition at the times of recurrent aspiration and maypredominantly involve the lower lungs in individuals whoremain mostly in the supine position while awake or asleep,or be predominantly right or left-sided abnormalities inpatients who sleep or spend extended time on their right orleft side, respectively (Fig. 12).8,24

Respiratory Bronchiolitis (RB) and RespiratoryBronchiolitis-associated Interstitial Lung Disease(RB-ILD)

RB and RB-associated interstitial lung disease (RB-ILD) occur in patients who smoke and are characterizedhistologically by submucosal inflammation and fibrosis ofthe respiratory bronchioles and the presence of pigmentedmacrophages in bronchiolar lumens, alveolar ducts, andalveolar spaces. On HRCT, RB, and RB-ILD manifest aspoorly defined centrilobular nodules that resemble thoseseen in HP and are frequently accompanied by patchy areasof ground-glass opacity. The abnormalities may predomi-nantly involve the upper lobes.25 RB and RB-ILD arediscussed in detail elsewhere in this issue (see Galvin andFranks).

FIGURE 7. Viral bronchiolitis. Unenhanced coronal chest CT MIPimage (lung window) of a 45-year-old man with cough and feverdemonstrates profuse bilateral centrilobular ground-glass nodu-lar and tree-in-bud opacities surrounded by uninvolved normallung within each secondary pulmonary lobule.

FIGURE 8. Bronchiolitis in atypical mycobacterial infection.Contrast-enhanced thin-section chest CT (lung window) of a67-year-old woman with chronic dyspnea demonstrates bilateralbronchiolitis characterized by centrilobular nodules and tree-in-bud opacities affecting all lobes. Note bronchiectasis andbronchial wall thickening involving the middle lobe and lingula.



Follicular Bronchiolitis

General FeaturesFollicular bronchiolitis (FB) (syn. pulmonary lymphoid

hyperplasia, hyperplasia of the bronchus-associated lym-phoid tissue, or hyperplasia of the mucosa-associatedlymphoid tissue) is a cellular bronchiolitis characterizedhistologically by peribronchial and peribronchiolar lymphoidfollicles. The detection of FB in lung-biopsy specimenssuggests the possibility of congenital or acquired immuno-deficiency syndromes, including HIV infection and acquired

immunoglobulin deficiencies. However, FB may also befound in patients with collagen vascular disease (ie, rheuma-toid arthritis, Sjogren syndrome), systemic hypersensitivityreactions, infection, lymphoproliferative disease, and diffusepanbronchiolitis (DBP), and as a reactive process distal tobronchiectasis or in association with middle-lobe syndrome(Fig. 13).2,17,26

Clinical PresentationFB occurs most commonly in middle-aged adults but

may occasionally be found in children. Affected patientstypically present with progressive shortness of breath andcough. Fever, recurrent pneumonia, and weight loss are lesscommon clinical manifestations of FB. Pulmonary functiontests may reveal obstruction, restriction, or a mixed patternof functional abnormalities.26,27

Clinical conditions associated with FB are similar tothose associated with lymphoid interstitial pneumonia and

FIGURE 9. Bronchiolitis in Mycobacterium tuberculosis infection. A, Contrast-enhanced thin-section chest CT (lung window) of a 39-year-old man with cough demonstrates a cavitary lesion in the superior segment of the left lower lobe, patchy consolidation in the leftupper lobe, and centrilobular nodular and tree-in-bud opacities in the left upper and lower lobes. B, Contrast-enhanced coronal chestCT MIP image (lung window) of the same patient shows bilateral pulmonary involvement with two cavitary lesions in the right upperlobe, bilateral upper lobe consolidations, and centrilobular nodular and tree-in-bud opacities affecting both upper lobes and thesuperior segments of both lower lobes.

FIGURE 11. Subacute hypersensitivity pneumonitis. Contrast-enhanced thin-section chest CT (lung window) of a 49-year-oldman with dyspnea demonstrates bilateral centrilobular nodulesof soft tissue and ground-glass attenuation diffusely involvingboth upper-lung zones, and a focal geographic area of lowattenuation (air trapping) in the left upper lobe.

FIGURE 10. Subacute hypersensitivity pneumonitis. Unenhancedcoronal chest CT MinIP image (lung window) of a 54-year-oldwoman with pet birds demonstrates bilateral patchy and geo-graphic areas of low attenuation (air trapping) in both upper lobes,and diffuse centrilobular ground-glass nodules and patchy areas ofground-glass attenuation involving both lungs.



include: (1) immunological disorders (Sjogren syndrome,Hashimoto thyroiditis, pernicious anemia, autoimmunehemolytic anemia, chronic active hepatitis, primary biliary

cirrhosis, and myasthenia gravis), (2) immunodeficiency(HIV, AIDS), (3) allergy, including asthma, and (4)allogeneic bone-marrow transplantation.27

PathologyHistologically, FB is characterized by abundant

lymphoid follicles with abundant germinal centers in thewalls of bronchioles and, less extensively, along bronchi,interlobular septa, and the pleura.17,27 Obstructive pneu-monia may be seen as a result of airway compression.27

Imaging Findings

RadiographyFB manifests on chest radiography as bilateral

reticular or reticulonodular opacities. However, the findingsmay be subtle and in some cases the radiograph may beinterpreted as normal.8,26

CT/HRCT FeaturesCT/HRCT demonstrates small, poorly defined centri-

lobular nodules that are diffusely distributed. Additionalbut variable findings include peribronchial and subpleuralnodules, patchy areas of ground-glass attenuation, bron-chial wall thickening, and patchy areas of low attenua-tion.8,28 In 1 study of 12 patients with FB, HRCT findingsincluded bilateral centrilobular nodules (100%), patchyground-glass opacities (75%), peribronchial nodules (42%),and subpleural nodules (25%) (Fig. 14).28

Diffuse Panbronchiolitis

General FeaturesDiffuse panbronchiolitis (DPB) is a progressive form of

cellular bronchiolitis that occurs almost exclusively in adults ofJapanese heritage and is associated with chronic inflammationof the paranasal sinuses. The imaging features of DPB mayhave considerable overlap with those of other inflammatoryairway diseases, including cystic fibrosis, inflammatory boweldisease, idiopathic bronchiectasis, constrictive bronchiolitis(CB), and FB.2

FIGURE 12. Bronchiolitis in aspiration. Unenhanced thin-sectionchest CT (lung window) of a 79-year-old woman with neurologicdeficits demonstrates secretions in the lumen of the left lowerlobe bronchus, multifocal consolidation in the lingula and leftlower lobe, and scattered centrilobular nodules and tree-in-budopacities affecting both lungs.

FIGURE 13. Microscopic features of follicular bronchiolitis.Intermediate power photomicrograph (hematoxylin and eosinstain) shows interstitial chronic inflammation and a hyperplasticlymphoid follicle with prominent germinal center adjacent tosmall bronchioles.

FIGURE 14. Follicular bronchiolitis. Contrast-enhanced thin-section chest CT (lung window) of a 42-year-old HIV-positiveman with immunodeficiency demonstrates numerous smallbilateral centrilobular nodules and tree-in-bud opacities.



Clinical PresentationPatients with DPB typically present with cough

and dyspnea on exertion and may have symptoms ofsinusitis. Pseudomonas aeruginosa frequently colonizes therespiratory tract of affected patients. Pulmonary functiontests reveal marked obstruction and mild restrictive disease.8

PathologyThe gross pathologic features of DPB are yellow 1 to

3mm nodules. Histologically, there is transmural infiltrationof the bronchiolar interstitium and peribronchiolar tissue byfoamy macrophages, lymphocytes, and plasma cells. Theinvolved small airways may include respiratory bronchioles,terminal (membranous) bronchioles, and alveolar ducts.Terminal bronchioles may be ectatic. Follicular bronchiolitismay be present, and acute inflammation may occur inbronchiolar lumens. Superimposed acute or organizingpneumonia and bronchiectasis may also occur.2,13

Imaging Findings

RadiographyChest radiography reveals diffuse nodules (<5mm)

that predominantly involve the lower lungs, and mild-to-moderate hyperinflation.8

CT/HRCT FeaturesCT/HRCT demonstrates small centrilobular nodules

and branching linear opacities (tree-in-bud pattern),bronchiolectasis, cylindrical bronchiectasis, and areas ofmosaic attenuation. In the early stages of DPB, the tree-in-bud pattern is the predominant finding, followed bythick-walled centrilobular lucencies. In later stages, HRCTreveals large, cystic spaces, bullae, air trapping, andperipheral areas of decreased attenuation (Fig. 15).8

CONSTRICTIVE BRONCHIOLITIS

General FeaturesThe published terminology regarding CB can at times

be confusing and inconsistent. For example, the term‘‘bronchiolitis obliterans’’ has been used to refer to both CBand bronchiolitis obliterans organizing pneumonia (moreusefully designated as cryptogenic organizing pneumonia ororganizing pneumonia).1,6 The former is a relatively rarecondition characterized by collagen deposition extrinsic tothe airway lumen and is considered irreversible, whereasthe latter is a more frequently diagnosed often multifocalcellular process characterized by active fibroblast prolifera-tion within the airspace lumens that typically responds totherapy.1,29 Some advocate the use of the term ‘‘obliterativebronchiolitis’’ to refer to the clinical syndrome of airflowobstruction associated with CT or HRCT findings of smallairways disease with or without pathologic confirmationof CB.30 In addition, the term bronchiolitis obliteranssyndrome (BOS) has been proposed for the clinical syndromeof chronic rejection that can follow lung transplantation andmay be associated with HRCT abnormalities.

Clinical Features and EtiologyPatients with CB typically present with dyspnea and

chronic cough. In some cases, the symptoms follow a lowerrespiratory tract infection. Characteristic findings on aus-cultation include mid-inspiratory squeaks, wheezes, andcrackles. The disease typically follows a chronic and slowlyprogressive course; although rapidly progressive disease is

also described.1 Pulmonary function typically demonstratesairflow obstruction with mixed restrictive and obstructiveabnormalities.

There are many pulmonary and systemic conditionsthat have been associated with CB. Thus, some employ a‘‘clinical’’ classification of CB based on etiologic factors.CB may rarely be idiopathic. Affected patients are usuallyolder women with a variable history of cigarette smokingwho often experience a rapid progression of clinicalsymptoms with eventual respiratory failure.9,29 A seriesof etiologic factors has also been described that include

FIGURE 15. Diffuse panbronchiolitis. A, Contrast-enhanced coronalinspiratory chest CT MIP image (lung window) of a 55-year-oldJapanese man demonstrates diffuse bilateral centrilobular nodulesand tree-in-bud opacities on a background of parenchymalheterogeneity. B, Contrast-enhanced coronal inspiratory chest CTMinIP image (lung window) of the same patient several years laterdemonstrates progression to mosaic attenuation, with geographicareas of low attenuation demarcated from areas of normal lungparenchyma.



infection, transplantation, collagen vascular disorders,inhalational lung injury, and ingested toxins.

InfectionChildhood infection is a rare cause of CB. The causa-

tive infection typically occurs in children under 8 years ofage.31 Typical infections are viral (respiratory syncytialvirus, parainfluenza virus, adenovirus), but M. pneumoniaehas also been implicated.30 Some affected patients may goon to exhibit imaging features of the Swyer-Jamessyndrome or MacLeod syndrome as adults. It is postulatedthat viral bronchiolitis of childhood may interfere with thenormal development of the affected lung with resultant CB.These patients may be asymptomatic or may present withcough, recurrent infection, or hemoptysis.32 CB may alsobe seen in cases of cystic fibrosis and is felt to representthe sequela of recurrent episodes of pulmonary infection(Figs. 16, 17).32

Transplantation

Lung TransplantationCB is a known complication of lung and heart-lung

transplantation that impacts the morbidity and limits thesurvival of affected patients.33 CB is considered a manifes-tation of chronic allograft dysfunction or chronic rejec-tion.29,34 The major risk factor for CB is acute rejection,particularly when severe or recurrent.29,33 Severe infection,particularly cytomegalovirus pneumonia is also associatedwith the development of CB.33 CB is a late complication oftransplantation that occurs at least 3 months (median 16 to20mo) after the transplant.29,30 The onset of symptomsmay be insidious or rapid. The mechanism of rejection is

related to the activity of the recipient immune systemagainst the transplanted lung tissue.29

The International Society of Heart Lung Transplantationhas defined the BOS based on deterioration of pulmonaryfunction, specifically, the forced expiratory volume in onesecond (FEV1) when compared with baseline. A clinicaldiagnosis of BOS is based on documentation of a decline inFEV1 of more than 20% during the posttransplantationperiod, after exclusion of other causes of allograft dysfunc-tion.35 The category of ‘‘potential’’ BOS or stage BOS 0-p isbased on a decrease in forced expiratory flow in the mid-expiratory phase (forced expiratory flows between 25% and75% of forced vital capacity), but its prognostic usefulness isunder debate.34,36 Although air trapping found on expiratorythin section CT is considered the most sensitive and accu-rate imaging indicator of CB in lung transplant recipients(Fig. 18),37,38 some investigators have found a weak correlationbetween the BOS stage and the severity of bronchial dilatation,bronchial wall thickening, air trapping and mosaic attenuationseen on CT, particularly in single lung transplant recipients.35

In addition, CT may be insensitive to the diagnosis of early CBand to the detection of early stage BOS.36,39 The prevalenceof CB in lung transplant recipients surviving at 5 years isapproximately 50% with a 5-year survival after the onset ofdisease of approximately 30% to 40%.30

Hematopoietic Stem Cell TransplantationCB is a known complication of hematopoietic stem cell

(HSC) transplantation with a prevalence of approximately5%. It is one of the late pulmonary complications of HSC

FIGURE 16. Postinfectious constrictive bronchiolitis. Contrast-enhanced coronal chest CT MIP image (lung window) of a 56-year-old man with a history of recent lower respiratory tractinfection shows bilateral geographic areas of mosaic attenuationand air trapping in the right lung with hyperinflation of the rightlower lobe and multiple centrilobular nodules and small foci ofconsolidation in both upper lobes.

FIGURE 17. Constrictive bronchiolitis in cystic fibrosis. Unenhancedcoronal chest CT MIP image (lung window) of a 25-year-oldwoman with cystic fibrosis demonstrates airway wall thickening,bronchiectasis, nodular, and tubular areas of mucoid impaction,and patchy areas of mosaic attenuation (air trapping) that diffuselyinvolve both lungs but predominantly involve the upper lungzones.



transplantation and typically develops more than 100 days(median 400 to 450d) after the transplant.29,30 It is thoughtto result from graft-versus-host disease induced by thedonor cells.30 However, although it is typically describedin patients undergoing allogeneic transplants, it is alsoreported in those undergoing autologous transplants. Riskfactors for the development of CB include older age, chronicgraft-versus-host disease and methotrexate therapy. Thehistologic diagnosis may be difficult to make on transbron-chial lung biopsy due to the patchy nature of the disease.29

The prevalence of CB in allogeneic HSC transplantrecipients is estimated at approximately 9% with a range ofup to 48%.29 The mortality of affected patients reported inthe literature is variable with reports of 12% to 27% 5-yearmortalities in one series and survival of only 10% ofpatients with CB at 5 years in another.29

Connective Tissue DiseaseCB may occur in the setting of rheumatoid arthritis

with or without penicillamine treatment. Affected patientsare typically women in the fifth or sixth decades of life, andmost have long-standing disease. The small airways diseasemay rarely antedate the rheumatologic manifestationsof the disease.40 It should be noted that FB (a cellularbronchiolitis) has also been described in patients withrheumatoid arthritis. CB has also been described in a fewpatients with systemic lupus erythematosus.29

Inhalational Lung DiseaseAlthough several chemicals have been implicated, the

best understood diseases are those related to inhalation ofoxides of nitrogen. Silo filler’s disease is related to nitrogendioxide (NO2) and nitric oxide (NO), which are producedduring the anaerobic fermentation of silage. Nitrous acidsand nitric oxides produce severe injury to tissues. Thepresentation of exposed individuals will vary with thedegree of exposure. Clinical presentation may be accom-panied by mild symptoms that may progress to pulmonaryedema and acute respiratory distress syndrome. Thosepatients who recover may become asymptomatic for a shortperiod of time, and subsequently present with progressivecough, dyspnea, and hypoxemia, secondary to the devel-

opment of CB of variable severity.29 Inhalation of firefumes (Fig. 19) and the butter-flavoring ingredient acetyl inpopcorn plant workers have also been associated with thedevelopment of CB.30,41

FIGURE 18. Constrictive bronchiolitis after lung transplantation. A, Unenhanced inspiratory thin-section chest CT (lung window) of a52-year-old woman after left lung transplantation demonstrates subtle heterogeneity (mosaic attenuation) of the left lung parenchyma.B, Expiratory thin-section chest CT (lung window) of the same patient shows patchy areas of air trapping.

FIGURE 19. Constrictive bronchiolitis after smoke inhalation.A, Unenhanced inspiratory thin-section chest CT (lung window)of a 45-year-old woman after smoke inhalation in a house firedemonstrates mild mosaic attenuation and patchy ground-glassopacity in the left upper lobe. B, Expiratory thin-section CTdemonstrates bilateral scattered areas of air trapping.



Diffuse Idiopathic Pulmonary NeuroendocrineCell Hyperplasia

Proliferation of pulmonary neuroendocrine cells istypically confined to the bronchial and bronchiolarepithelium. These proliferations may take the form oftumorlets, which can be diffusely distributed through-out the lung. Nodular neuroendocrine cell prolifera-tions measuring more than 5mm in diameter are usuallyclassified as carcinoid tumors. Affected patients aretypically women who may exhibit obstructive and/orrestrictive lung function or may be asymptomatic. Thesepatients may exhibit HRCT evidence of small airwaysdisease in which multifocal pulmonary nodules may beassociated with mosaic lung attenuation and air trapping(Fig. 20).42

Miscellaneous ConditionsCB has been reported in association with ingestion of

Sauropus androgynous, a weight control preparation usedin Asia. Other associations include inflammatory boweldisease,43 paraneoplastic pemphygus and gold and penicil-lamine therapy.40

PathologyCB is characterized by fibrosing bronchiolitis of

membranous and respiratory bronchioles with submucosaland peribronchiolar concentric fibrosis and little activeinflammation or granulation tissue (Fig. 21). Early diseaseis characterized by a predominantly lymphocytic inflam-matory cellular infiltrate affecting the lumen, mucosa,submucosa, and the tissues surrounding the bronchioles.This progresses to concentric peribronchiolar fibrosis with-out associated fibroblastic proliferation.29 The airwayinvolvement tends to be circumferential and results inbronchiolar luminal narrowing and obstruction. Advanceddisease may be difficult to diagnose histologically as thebronchioles may become completely obliterated and may beinconspicuous due to the absence of surrounding inflam-mation.1 In these cases, elastic stains may be helpful for theidentification of affected small airways.29 Furthermore, thepatchy nature of the disease may result in sampling errorson transbronchial biopsy.29 Thus, there may be subtlepathologic abnormalities in spite of severe symptoms andextensive imaging abnormalities.

Imaging Findings

RadiographyPatients with CB typically have normal or near normal

chest radiographs. Previously reported radiographic ab-normalities include hyperinflation, air trapping, and per-ipheral attenuation of pulmonary vascular markings.29,32

Nodular and reticular pulmonary opacities have also beendescribed.32

Patients with Swyer-James syndrome or MacLeodsyndrome may exhibit a unilateral hyperlucent lung with

FIGURE 20. Small airways disease in diffuse idiopathic pulmo-nary neuroendocrine cell hyperplasia. Unenhanced expiratorythin-section chest CT (lung window) of a 49-year old womanwith diffuse idiopathic pulmonary neuroendocrine cell hyperpla-sia demonstrates small bilateral pulmonary nodules and patchygeographic areas of air trapping.

FIGURE 21. Microscopic features of constrictive bronchiolitis. A, Intermediate power photomicrograph (hematoxylin and eosin stain)shows a small terminal bronchiole surrounded by concentric fibrosis. B, High-power photomicrograph (hematoxylin and eosin stain)shows luminal narrowing of a small terminal bronchiole surrounded by concentric fibrosis.



decreased pulmonary vascularity and a small ipsilateralhilum. The affected lung parenchyma may exhibit normalor decreased lung volume during inspiration and expiratoryair trapping (Fig. 22).32

CT/HRCT FeaturesThe classically described CT feature of CB is a pattern

of mosaic pulmonary attenuation characterized by geo-graphic clusters of lung lobules that exhibit alternatingincreased and decreased lung attenuation (Fig. 4). Themosaic attenuation is typically accentuated on expiratoryimaging where air trapping manifests as areas of persistenthyperlucency highlighted by increased pulmonary attenua-tion in surrounding normal lung. Within low-attenuationareas of air trapping there is often a decrease in the caliberof vascular structures that is likely secondary to hypoxicvasoconstriction. In addition, there is no decrease in thecross-sectional area of the affected hyperlucent lung onexpiration.6 The areas of increased attenuation typicallyreflect normal lung parenchyma, which exhibits a relativeincrease in vessel caliber and blood flow. Expiratory thin-section CT facilitates detection of areas of air trapping. Thepatchy distribution of airway involvement gives rise tomosaic lung attenuation and perfusion. The areas ofabnormal attenuation may exhibit well or poorly definedcontours.44 It should be noted that mild-mosaic attenuationand air trapping on expiratory CT has also been describedin healthy subjects.45–47 In addition, mosaic attenuationmay occur in patients with occlusive vascular disease andin association with infiltrative lung disease. Patients withdiffuse severe disease may exhibit diffuse decreased lungattenuation that may be subtle.6,48,49

Associated findings include bronchial dilatation,bronchiectasis, and bronchial wall thickening.9,29 Otherfindings include centrilobular nodules. If pulmonary no-dules are seen, diffuse idiopathic neuroendocrine cell hyper-plasia should be considered.

Swyer-James syndrome or MacLeod syndrome refersto predominant involvement of one lobe or lung withfindings of CB.9 Affected patients typically have radio-graphic evidence of focal lung hyperlucency and decreasedvascularity with normal or decreased volume of the affectedlung. Expiratory HRCT typically demonstrates air trappingof the affected lung lobe. However, affected patients

typically exhibit air trapping and hyperlucency in otherlobes and in the contralateral lung, which is not readilyappreciated at radiography.43,50 Bronchiectasis and bron-chial wall thickening may also be observed.9

SUMMARYSmall airways disease includes a spectrum of inflam-

matory and fibrotic pulmonary diseases centered onthe small conducting airways. The imaging manifestationsof small airways disease on CT/HRCT may be direct orindirect signs of small airway involvement and includecentrilobular nodules and branching nodular (tree-in-bud)opacities, or the demonstration of mosaic attenuation thatis typically exaggerated on expiratory CT. Some diseaseentities have distinguishing clinical, pathologic, and/orimaging features that facilitate a more accurate diagnosis.

REFERENCES

1. Visscher DW, Myers JL. Bronchiolitis: the pathologist’sperspective. Proc Am Thorac Soc. 2006;3:41–47.

2. Couture C, Colby TV. Histopathology of bronchiolar dis-orders. Semin Respir Crit Care Med. 2003;24:489–498.

3. Abbott G. Airway structure. In: Federle MP, Rosado-de-Christenson ML, Woodward PJ, et al. Diagnostic and SurgicalImaging Anatomy: Chest, Abdomen, Pelvis. Salt Lake City:Amirsys; 2006:64–87.

4. Tomashefski JF, Farver CF. Anatomy and histology of thelung. In: Tomashefski JF, ed. Dail and Hammar’s PulmonaryPathology. 3rd ed. New York: Springer; 2008:20–48.

5. Lynch DA. Imaging of small airways disease and chronicobstructive pulmonary disease. Clin Chest Med. 2008;29:165–179.

6. Hansell DM. Small airways disease: detection and insights withcomputed tomography. Eur Respir J. 2001;17:1294–1313.

7. Biegelman-Aubry C, Hill C, Guibal A, et al. Multi-detectorrow CT and postprocessing techniques in the assessment ofdiffuse lung disease. Radiographics. 2005;25:1639–1652.

8. Naidich DP, Webb WR, Grenier PA, et al. Small airwaydisease. In: Naidich DP, Webb WR, Grenier PA, et al. Imagingof the Airways. Philadelphia: Lippincott Williams & Wilkins;2005:146–176.

9. Pipavath SJ, Lynch DA, Cool C, et al. Radiologic andpathologic features of bronchiolitis. Am J Roentgenol. 2005;185:354–363.

FIGURE 22. Constrictive bronchiolitis in Swyer-James syndrome or MacLeod syndrome. A, PA chest radiograph of a 33-year-old manwith Swyer-James syndrome or MacLeod syndrome demonstrates subtle hyperlucency in the right upper lobe. B. Unenhancedexpiratory thin-section chest CT (lung window) of the same patient shows bilateral areas of geographic air trapping that are mostevident in the right upper lobe. C, Unenhanced coronal expiratory chest CT (lung window) of the same patient shows bilateral areas ofair trapping that are most evident in the right upper lobe but also affect the left upper and left lower lobes. Note central bronchiectasisand bronchial wall thickening in the left lung.



10. Hansell DM, Bankier AA, MacMahon H, et al. FleischnerSociety: glossary of terms for thoracic imaging. Radiology.2008;246:697–722.

11. Hogg J, Macklem P, Thurlbeck W. Site and nature of airwayobstruction in chronic obstructive lung disease. N Engl J Med.1968;278:1355–1360.

12. Poletti V, Costtable U. Bronchiolar disorders: classification and di-agnostic approach. Semin Respir Crit Care Med. 2003;24:457–464.

13. Cagle PT, Roggli VL. Pathology of small airways. In:Tomashefski JF, ed. Dail and Hammar’s Pulmonary Pathology.3rd ed. New York: Springer; 2008:886–910.

14. Leung AN. Pulmonary tuberculosis: the essentials. Radiology.1999;210:307–322.

15. Aquino SL, Gamsu G, Webb WR, et al. Tree-in-bud pattern:frequency and significance on thin section CT. J Comput AssistTomogr. 1996;20:594–599.

16. Reittner P, Muller NL, Heyneman L, et al. Mycoplasmapneumoniae pneumonia: radiographic and high-resolution CTfeatures in 28 patients. Am J Roentgenol. 2000;174:37–41.

17. Silva CIS, Muller NL. Bronchiolitis. In: Silva CIS, Muller NL,Hansell DM. Imaging of the Chest. Philadelphia: Saunders;2008:1071–1095.

18. Hansell DM, Wells AU, Padley SPG. Hypersensitivitypneumonitis: correlation of individual CT patterns withfunctional abnormalities. Radiology. 1996;199:123–128.

19. Lacasse Y, Selman M, Costabel U, et al. Clinical diagnosisof hypersensitivity pneumonitis. Am J Respir Crit Care Med.2003;168:952–958.

20. Matar LD, McAdams HP, Sporn TA. Hypersensitivitypneumonitis. Am J Roentgenol. 2000;174:1061–1066.

21. Silva CIS, Churg A, Muller NL. Hypersensitivity pneumonitis:spectrum of high-resolution CT and pathologic findings. AmJ Roentgenol. 2007;188:334–344.

22. Morris DG, Gotway MB, Homer RJ, et al. Diffuse parench-ymal and alveolar lung disease. In: George RB, Light RW,Matthay MA, et al. Chest Medicine. Essentials of Pulmonaryand Critical Care Medicine. 5th ed. Philadelphia: LippincottWilliams & Wilkins; 2005:234–288.

23. Matsuse T, Fukuchi Y, Oka T, et al. Importance of diffuseaspiration bronchiolitis caused by chronic occult aspiration inthe elderly. Chest. 1996;110:1289–1293.

24. Barnes TW, Vassallo R, Tazelaar HD, et al. Diffusebronchiolar disease due to chronic occult aspiration. MayoClin Proc. 2006;81:172–176.

25. Heyneman LE, Ward S, Lynch DA, et al. Respiratorybronchiolitis, respiratory bronchiolitis-associated interstitiallung disease, and desquamative interstitial pneumonia: differ-ent entities or part of the spectrum of the same disease process?Am J Roentgenol. 1999;173:1617–1622.

26. Travis WD, Galvin JR. Non-neoplastic pulmonary lymphoidlesions. Thorax. 2001;56:964–971.

27. Corrin B, Nicholson AG, Burke MM. Diseases of the airways.In: Corrin B, Nicholson AG, eds. Pathology of the Lungs. 2nded. Philadelphia: Churchill Livingstone; 2006:87–130.

28. Howling SJ, Hansell DM, Wells AU, et al. Follicularbronchiolitis: thin-section CT and histologic findings. Radio-logy. 1999;212:637–642.

29. Angel LA, Homma A, Levine S. Bronchiolitis obliterans.Semin Respir Crit Care Med. 2000;21:123–134.

30. Cordier JF. Challenges in pulmonary fibrosis. 2: Bronchiolo-centric fibrosis. Thorax. 2007;62:638–649.

31. Chiu CY, Wong KS, Huang YC, et al. Bronchiolitis obliteransin children: clinical presentation, therapy and long-termfollow-up. J Paediatr Child Health. 2008;44:129–133.

32. Muller NL, Miller RR. Diseases of the bronchioles: CT andhistopathologic findings. Radiology. 1995;196:3–12.

33. Collins J. Imaging of the chest after lung transplantation.J Thorac Imaging. 2002;17:102–112.

34. de Jong PA, Dodd JD, Coxson HO, et al. Bronchiolitisobliterans following lung transplantation: early detectionusing computed tomographic scanning. Thorax. 2006;61:799–804.

35. Choi YW, Rossi SE, Palmer SM, et al. Bronchiolitis obliteranssyndrome in lung transplant recipients: correlation of com-puted tomography findings with bronchiolitis obliteranssyndrome stage. J Thorac Imaging. 2003;18:72–79.

36. Konen E, Gutierrez C, Chaparro C, et al. Bronchiolitisobliterans syndrome in lung transplant recipients: can thin-section CT findings predict disease before its clinical appear-ance? Radiology. 2004;231:467–473.

37. Leung AN, Fisher K, Valentine V, et al. Bronchiolitisobliterans after lung transplantation: detection using expira-tory HRCT. Chest. 1998;113:365–370.

38. Worthy SA, Park CS, Kim JS, et al. Bronchiolitis obliteransafter lung transplantation: high-resolution CT findings in 15patients. Am J Roentgenol. 1997;169:673–677.

39. Lee ES, Gotway MB, Reddy GP, et al. Early bronchiolitisobliterans following lung transplantation: accuracy of expira-tory thin-section CT for diagnosis. Radiology. 2000;216:472–477.

40. Ryu JH, Myers JL, Swensen SJ. Bronchiolar disorders. AmJ Respir Crit Care Med. 2003;168:1277–1292.

41. Lockey JE, Hilbert TJ, Levin LP, et al. Airway obstructionrelated to diacetyl exposure at microwave popcorn productionfacilities. Eur Respir J. 2009;34:63–71.

42. Davies SJ, Gosney JR, Hansell DM, et al. Diffuse idio-pathic pulmonary neuroendocrine cell hyperplasia: anunder-recognized spectrum of disease. Thorax. 2007;62:248–252.

43. Waitches GM, Stern EJ. High-resolution CT of peripheralairways diseases. Radiol Clin North Am. 2002;40:21–29.

44. Worthy SA, Muller NL. Small airway diseases. Radiol ClinNorth Am. 1998;38:163–173.

45. Bankier AA, van Muylem A, Knoop C, et al. Bronchio-litis obliterans syndrome in heart-lung transplant reci-pients: diagnosis with expiratory CT. Radiology. 2001;218:533–539.

46. Tanaka N, Matsumoto T, Miura G, et al. Air trapping at CT:high prevalence in asymptomatic subjects with normalpulmonary function. Radiology. 2003;227:776–785.

47. Arakawa H, Kurihara Y, Sasaka K, et al. Air trapping on CTof patients with pulmonary embolism. Am J Roentgenol.2002;178:1201–1207.

48. Sherrick AD, Swensen SJ, Hartman TE. Mosaic pattern oflung attenuation on CT scans: frequency among patientswith pulmonary artery hypertension of different causes. Am JRoentgenol. 1997;169:79–82.

49. Teel GS, Engeler CE, Tashijian JH, et al. Imaging of smallairways disease. Radiographics. 1996;16:27–41.

50. Moore ADA, Goodwin JD, Dietrich PA, et al. Swyer-Jamessyndrome: CT findings in eight patients. Am J Roentgenol.1992;158:1211–1215.



imaging of small airways disease.6

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