Chapter 5

Radiological featuresof bronchiectasisP.L. Perera* and N.J. Screaton#

Summary

Imaging plays a crucial role in the diagnosis and monitoring ofbronchiectasis and the management of complications. Chestradiography is useful as an initial screening tool and duringacute exacerbations, but has limited sensitivity and specificity.High-resolution computed tomography (HRCT) is the refer-ence standard for diagnosis and quantification of bronchiecta-sis, providing detailed morphological information. Computedtomography (CT) is also valuable in diagnosing and managingcomplications. Routine surveillance using HRCT has beenmooted, particularly in cystic fibrosis (CF), where advances intreatment have increased life expectancy considerably, butcumulative radiation dose remains a concern.

Pulmonary magnetic resonance imaging is an evolvingtechnique that provides both structural and functional infor-mation. Its advantage is the lack of ionising radiation. Limita-tions include cost, availability and its inferior spatial resolutioncompared to CT. The technique requires further evaluation, buthas potential benefits where serial follow-up imaging is beingconsidered, such as in CF. Evaluation of mucociliary clearanceusing radionuclide scintigraphy may be of value, particularly indrug development.

Keywords: Bronchiectasis, cystic fibrosis, diagnostic imaging,magnetic resonance imaging, mucociliary clearance, spiralcomputed tomography

*Dept of Radiology, Norfolk andNorwich University Hospital,Norwich, and#Diagnostic Imaging Dept, PapworthHospital, Papworth Everard, UK.

Correspondence: N.J. Screaton,Diagnostic Imaging Dept, PapworthHospital, Papworth Everard, CB233RE, UK, Emailnicholas.screaton@papworth.nhs.uk

Eur Respir Mon 2011. 52, 44–67.Printed in UK – all rights reserved.Copyright ERS 2011.European Respiratory Monograph;ISSN: 1025-448x.DOI: 10.1183/1025448x.10003510

Bronchiectasis is characterised by irreversible dilation of bronchi, which may be focal or diffuse,and usually occurs with associated inflammation. Its pathogenesis is complex and often

multifactorial, with bronchial wall inflammation, bronchial wall weakness and infection oftenoccurring in parallel and with numerous aetiological factors. Since it was first described byLAENNEC [1] in 1819, there have been considerable advances in the understanding, diagnosis andtreatment of bronchiectasis. Imaging now forms the cornerstone of diagnosis of bronchiectasis andits complications and plays an increasing role in disease monitoring and therapeutic planning. Thepresent review focuses on imaging features in bronchiectasis and their role in diagnosis andmonitoring of disease. Several imaging modalities are available, with varying strengths and

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limitations, which are outlined below. The choice of diagnostic/monitoring strategy shows somevariation depending on access to each modality and interpretive expertise. Image-guidedintervention, such as percutaneous pleural aspiration/drainage and angiography with embolisationplay important roles in treating complications, but are beyond the scope of the present review.

Chest radiography

Chest radiography (CXR) is usually the initial study performed in both suspected bronchiectasisand the evaluation of nonspecific respiratory symptoms, such as dyspnoea and haemoptysis, whenbronchiectasis may be identified incidentally. Signs on CXR include the identification of parallellinear densities, tram-track opacities, or ring shadows reflecting thickened and abnormally dilatedbronchial walls. These bronchial abnormalities form a spectrum from subtle or barely perceptible5-mm ring shadows to obvious cysts. Tubular branching opacities conforming to the expectedbronchial branching pattern may result from fluid or mucous filling of bronchi. Peribronchialfibrosis results in a loss of definition of vessel walls (fig. 1) [2–5].

Signs of complications/exacerbations, such as patchy densities due to mucoid impaction andconsolidation, volume loss secondary to bronchial mucoid obstruction or chronic cicatrisation,are also seen. In the more diffuse forms of bronchiectasis, such as cystic fibrosis (CF), generalisedhyperinflation and oligaemia are often present, consistent with severe small airways obstruction.

The radiograph may raise the initial suspicion of bronchiectasis, triggering more definitive imaging.However, its projectional nature and limited contrast resolution lead to limited sensitivity andspecificity, particularly in mild disease. CXR also plays a role in the follow-up of bronchiectasis andmanagement of exacerbations, although, again, the relative insensitivity to change is highlighted byproponents of computed tomography (CT) and magnetic resonance (MR) imaging (MRI) [2–5].

The reported accuracy of CXR has changed over the years as the management emphasis has shiftedfrom being reactive to complications to one of early detection and proactive management, and as thediagnostic reference standard has shifted from bronchography to CT. In 1955, GUDJBERG [6]reported only 7.1% of 114 bronchiectatic patients having a normal CXR, perhaps reflecting the moreflorid nature of the condition during this period. In 1987, CURRIE et al. [7] reported an overallsensitivity of 47%, and only 13% on a lobar basis, in 19 patients with bronchographically provenbronchiectasis. The same study confirmed significant interobserver variation in CXR interpretation,with two experienced readers disagreeing on the diagnosis of bronchiectasis in 22% of cases [7].

In comparison to CXR, CT is both more sensitive and provides more specific information. BHALLA

et al. [8] showed that, out of a total of 162 bronchopulmonary segments reviewed, bronchiectasiswas detected in 124 on high-resolution CT (HRCT) and only 71 on CXR.

Radiographic scoring systems, such as those of CHRISPIN and NORMAN [9] and BRASFIELD et al. [10],have been developed and subsequently modified for patients with CF. These can be useful clinically,but are more commonly used for comparison in research. CLEVELAND et al. [11] showed that a scorebased on the scoring system of BRASFIELD et al. [10] could be used to assess the longitudinalprogression of lung disease in CF, and was at least as effective as spirometry in this regard.

Although CXR has limitations in specificity in diagnosing bronchiectasis and in detecting early orsubtle changes, it is useful for assessing more florid cases of bronchiectasis, in CF and in follow-upof bronchiectatic patients.

Computed tomography

The CT signs of bronchiectasis were first described by NAIDICH et al. [12] in 1982. Although initialstudies using 8–10-mm slice thickness showed low sensitivity [13–15], the advent of HRCT led tomarkedly improved sensitivity, resulting in HRCT replacing bronchography as the diagnosticreference standard. GRENIER et al. [16] showed that HRCT with 1.5-mm collimation at 10-mm

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intervals was accurate in the recogni-tion of bronchiectasis using broncho-graphy as the gold standard in 36patients.

Multidetector CT (MDCT) with vol-umetric acquisition further increasesthe sensitivity in detection of subtlenontapering airways. DODD et al. [17]compared contiguous 1-mm MDCTwith 1-mm incremental HRCT with10-mm interspaces in 61 bronchiec-tatic patients and 19 normal controls.Using MDCT as the gold standard,the sensitivity, specificity and positiveand negative predictive values of in-cremental HRCT in detecting bron-chiectasis were 71, 93, 88 and 81%,respectively. Interobserver agreementfor the presence, extent and severityof bronchiectasis was also better forMDCT (kappa 0.64, 0.5 and 0.48,respectively) than for incrementalHRCT (kappa 0.65, 046 and 0.25,respectively).

Optimal HRCT technique is impor-tant for maximising diagnostic accu-racy. Importantly, thin slices of1–2 mm and a high-resolution lungreconstruction algorithm are usedto optimise spatial resolution. Incre-mental imaging with 10-mm sliceinterspace reduces radiation dose,but helical MDCT permits volu-metric acquisition in a single breath-hold, which is often the preferredtechnique. Electronic images shouldbe viewed in stack/cine mode us-ing the appropriate window set-tings (centred -400– -950 HU; width1,000–1,600 HU). Difficulties in diag-nosing bronchiectasis can arise fromcardiorespiratory motion artefact, useof inappropriate window widths andlevels, and the relatively thick-walledappearance of bronchial walls on

expiratory scans. Tractional airway dilation associated with pulmonary fibrosis has a characteristiccorkscrew appearance and should be differentiated from pathological bronchiectasis.

CT signs of bronchiectasis

Bronchial dilation, the cardinal sign of bronchiectasis, is characterised on HRCT by abronchoarterial ratio (BAR) of .1, lack of bronchial tapering, and visibility of airways within1 cm of the pleural surface or abutting the mediastinal pleural surface [2, 12, 16, 18, 19].

a)

b)

Figure 1. Chest radiography showing a) cystic bronchiectasis withmultiple cystic airspaces and b) cylindrical bronchiectasis and tram-track opacities in a cystic fibrosis patient.

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The different morphological types of bronchiectasiscorresponding to the bronchographic classification ofREID [20] show differing radiological features [16, 21],but this is of little relevance in terms of aetiology andrather reflects varying severity of the disease. Although,in cylindrical bronchiectasis, there is uniform dilationof airways with nontapering walls, in varicose bronch-iectasis, dilated bronchi have a beaded appearance and,in cystic bronchiectasis, grosser bronchial dilation givesthe appearance of cysts (fig. 2).

The BAR refers to the ratio of the internal bronchialdiameter to the diameter of the accompanying pul-monary artery at an equivalent branching level. A BARof .1 is considered abnormal [14, 15, 19] and is other-wise known as the signet-ring sign (fig. 3).

The accuracy of the BAR can be limited by a number of factors, including physiologicalvariation and orientation of the bronchovascular bundle with respect to the imaging plane[16, 22, 23]. Comparison is best performed on perpendicularly orientated airways. Whenoblique to the acquisition plane, airways and vessels appear ovoid and their short axis shouldbe compared.

Physiological influence on BAR was highlighted by LYNCH et al. [23], who showed that 59% of 27normal volunteers living in Colorado, USA (1,600 m above sea level) had at least one bronchusthat had an internal diameter larger than its accompanying artery. KIM et al. [18] confirmed thisenvironmental influence on BAR by demonstrating that residents living at 1,600 m exhibitedsignificantly higher BARs than those living at sea level (0.76 and 0.62, respectively; p,0.001).Physiological variation can also occur due to regional hypoxia, and so secondary vasoconstrictioncausing apparent bronchial dilation must be recognised in order to prevent a spurious diagnosisof bronchiectasis. Conversely, if there is arterial dilation (e.g. due to pulmonary arterialhypertension), bronchiectasis could be missed. A practical problem in assessing BAR is the need toidentify the accompanying artery, which may be difficult in the presence of other lung pathology,such as consolidation. In the setting of consolidation, the presence of bronchial dilation may be areversible phenomenon and so caution should be observed when interpreting CT data during anacute illness.

Although objective measurement may be performed, visual inspection is the usual method of assessingbronchial dilation. DIEDERICH et al. [24] showed this tohave good interobserver agreement for detection (kappa0.78) and severity assessment (kappa 0.68).

Lack of bronchial tapering or tram-track appearance ofthe parallel bronchial walls is a sensitive feature ofbronchiectasis often identified in more horizontallyorientated airways in the mid-zones. KANG et al. [25]showed that lack of tapering on HRCT was moresensitive than bronchial dilation in bronchiectasis (79and 60%, respectively) using pathology as the referencestandard. However, the sign can be difficult tointerpret in nonvolumetric CT studies. KIM et al. [18]demonstrated lack of tapering on HRCT in 95% ofpatients with bronchiectasis, but also in 10% of normalsubjects. It has been suggested that bronchial diametershould remain unchanged for at least 2 cm distal to abranching point for this sign to be robust (fig. 4) [26].

Figure 2. High-resolution computed tomo-graphy image showing cystic bronchiectasis(same patient as in fig. 1a).

Figure 3. High-resolution computed tomo-graphy image demonstrating signs ofbronchiectasis, the signet-ring sign (shortarrow) and peripheral airway visible within1 cm of the pleural surface (long arrow).

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Visibility of peripheral airways is another importantdirect sign of bronchiectasis [17]. Current HRCTtechniques permit visualisation of airways of up to2 mm in diameter and walls of around 0.2 mm inthickness. KIM et al. [18] showed that normal bronchi arenot visualised within 1 cm of the costal pleura, but maybe seen within 1 cm of the mediastinal pleura. Visiblebronchi within 1 cm of the costal pleura or abutting themediastinal surface were seen in 81 and 53% of HRCTimages of known bronchiectatic patients (fig. 4).

Ancillary signs commonly identified in bronchiectaticpatients include bronchial wall thickening, mucoidimpaction and air-trapping. Minor volume loss can beseen in the early stages of bronchiectasis. Larger areas of

collapse secondary to mucous plugging may be seen in more advanced disease. Patchyconsolidation is sometimes seen reflecting superimposed infection.

Bronchial wall thickening is often seen in the presence of bronchiectasis [25], but is a variablenondiagnostic feature. It may result from reversible airway wall inflammation [27] or smoothmuscle hypertrophy and fibroblastic proliferation. Minor bronchial wall thickening has, however,also been described in normal individuals, asthmatics, asymptomatic smokers and during lowerrespiratory tract infections [23, 28].

Identification of bronchial wall thickening on HRCT is often made subjectively and is associatedwith significant interobserver variation, with no universally agreed definition. REMY-JARDIN andREMY [28] defined a thickened bronchus as being twice as thick as a normal bronchus; however,this definition is difficult in diffuse disease DIEDERICH et al. [24] defined a thick-walled bronchusby an internal diameter of ,80% of its external diameter and showed good interobserveragreement (kappa 0.66). However, this can lead to overdiagnosis of thickening in the presence ofbronchoconstriction and underestimation with marked bronchodilation. An alternative approach,used by BHALLA et al. [8] in CF and subsequently modified by REIFF et al. [29], is to comparebronchial wall thickness to the diameter of the adjacent artery. As with assessment of BAR,peribronchial fibrosis and consolidation pose practical difficulties in identifying accompanyingvessels (fig. 5).

Mucous plugging of dilated bronchi is readily identified, causing either complete or partialluminal filling (fig. 5). Plugging of the smaller peripheral airways and peribronchiolar in-flammation are characterised by a tree-in-bud appearance, with V- and Y-shaped branching

nodular opacities [30]. Mucous plugging was scored interms of number and generation of involved bronch-opulonary segments using the scoring system of BHALLA

et al. [8], and may be reversible.

Air-trapping results either from mucous plugging andabnormal bronchial compliance [31] or inflammation/fibrosis of the small airways [2]. On HRCT, air-trapping is characterised by patchy lobular areas oflow attenuation with regional vasoconstriction, whichcauses a mosaic attenuation pattern, accentuated onexpiratory images, although inspiratory images areusually characteristic (fig. 6). Air-trapping and bron-chiectasis coexist in the same lobe in approximatelyhalf of cases [25]. Whether it is the bronchiectasis andrecurrent infections driving obliterative bronchiolitis(OB) or primary small airways disease that precedes the

Figure 4. High-resolution computedtomography image showing nontaperingbronchi, in keeping with bronchiectasis.

*

Figure 5. High-resolution computed tomo-graphy image demonstrating bronchiectasiswith bronchial wall thickening (asterisk) andmucous plugging (arrow) in the right lowerlobe.

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onset of bronchiectasis is debated, and may vary [31].The latter is supported both by the observation that, inpatients with CT-proven bronchiectasis, expiratoryHRCT identifies air-trapping in 17% of lobes with nobronchiectatic features and that, in patients withrheumatoid arthritis (RA)-associated OB, the onset ofsymptoms and obstructive function may predate theonset of bronchiectasis by several years [32].

Imaging and aetiology of bronchiectasis

There are many aetiologies associated with bronch-iectasis, but a specific underlying cause is found in,40% of patients [33]. In some cases, the distributionand pattern of bronchiectasis on HRCT may suggestthe aetiology. Allergic bronchopulmonary aspergillosis(ABPA) typically demonstrates an upper zone and central predominance [34–37], hypogamma-globulinaemia may be associated with bronchiectasis with disproportionate bronchial wallthickening, middle lobe predominance is common in immotile cilia syndrome [38] and idiopathicbronchiectasis often has a lower lobe distribution [39].

However, in a large study comparing HRCT features in bronchiectasis of defined aetiology withidiopathic bronchiectasis, REIFF et al. [29] concluded that, although some HRCT features weremore common in some aetiological groups, the differences were not sufficient to be diagnostic. LEE

et al. [40] reinforced this observation in a study of 108 bronchiectatic patients in whom the correctcause was identified on CT in only 45% of cases. A confident diagnosis was asserted in a minority(9%) and was correct in only 35%. Interobserver agreement in likely aetiology was also poor(kappa 0.2) [40]. However, more recently, CARTIER et al. [41] obtained accurate diagnoses on thebasis of HRCT in 61% of 82 patients with bronchiectasis of known cause, with moderately goodagreement (kappa 0.53). Confident and accurate diagnosis was made in 44% of patients (kappa0.53). Accuracy was highest in CF (68%), previous tuberculosis (67%) and ABPA (56%). Part ofthe reason for the higher number of accurate diagnoses was attributed to the exclusion of patientsin whom the aetiology of bronchiectasis was not known. They concluded that the combination ofradiological pattern and clinical scenario would have improved the accuracy of the evaluation.

HRCT is important in the assessment of mycobacterial infection. This is particularly true ofnontuberculous mycobacteria (NTM), where the diagnosis is often first suggested on HRCT. CTsigns of NTM include bronchiectasis, nodules, tree-in-bud opacity, patchy consolidation andcavities, often affecting the upper lobes and superior segments of lower lobes in the classic subtypeand middle lobe/lingula in the nonclassic subtype [42]. The presence of this combination offeatures with a middle lobe and lingual predominance, especially in the setting of elderly femaleswith no underlying malignancy or immunocompromise, is particularly suggestive of nonclassicNTM [43, 44]. Bronchiectasis is more common in NTM infection, being seen in up to 94% ofpatients with Mycobacterium avium complex and 27% of patients with M. tuberculosis [45].

Bronchiectasis in CF usually has a bilateral, proximal, parahilar and upper lobe predominance.Other findings include bronchial wall thickening, peribronchial interstitial thickening, mucousplugging, tree-in-bud opacification, superadded consolidation and mosaic attenuation. SHAH et al.[27] assessed the CT changes in 19 symptomatic adult CF patients before and after 2 weeks oftherapy and identified air–fluid levels in bronchiectatic airways, mucous plugging, centrilobularnodules and peribronchial thickening as potentially reversible signs.

Bronchiectasis with a central or proximal predominance is the characteristic finding in ABPA(fig. 7a). REIFF et al. [29] showed that the prevalence of central bronchiectasis was higher in ABPA(11 out of 30) than in idiopathic bronchiectasis (26 out of 179) (p,0.005). However, the sensi-tivity of the observation of central bronchiectasis in diagnosing ABPA was only 37%. PANCHAL et al. [46]

Figure 6. Inspiratory high-resolution com-puted tomography image showing bronch-iectasis and widespread areas of lowattenuation, representing air-trapping.

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demonstrated central bronchiectasis in 85% of lobesand 52% of lung segments in a series of 23 patientswith ABPA. Other common findings in ABPA includemucous plugging, high-attenuation mucus, tree-in-bud opacities, atelectasis, peripheral consolidation orground-glass opacification, mosaic perfusion and air-trapping. The bronchiectasis is often cystic or varicose.WARD et al. [47] assessed CT images from 44asthmatic patients with ABPA and 38 without andfound much higher levels of bronchiectasis, centri-lobular nodules and mucous impaction in ABPA.They concluded that randomly distributed predomi-nantly central moderate-to-severe bronchiectasisaffecting three or more lobes, bronchial wall thicken-ing and centrilobular nodules in asthmatics is highlysuggestive of ABPA (fig. 7b).

High-attenuation mucous plugs are reported to occurin 18–28% of patients with ABPA, and, if observed, arethought to be characteristic [48–50]. In a study of 155patients with ABPA, AGARWAL et al. [48] found thissign in 29 patients, and that it correlated with greaterseverity and greater likelihood of relapse.

In summary, there are some recognised clinicalconditions in which assessment of bronchiectasis formsan important part of management. CT images inbronchiectatic patients should be examined for featuressuggesting ABPA, CF, immotile cilia, opportunist

mycobacteria and tracheobronchomegaly, but these observation need to be correlated withclinical and laboratory findings.

CT scoring of bronchiectasis

Although the extent, severity and distribution of bronchiectasis may be evaluated subjectively,more-robust objective scoring systems have been developed particularly for use in the researcharena. With the development of novel software tools, it is now possible to objectively quantifyparameters, such as airway wall area and volume, in a semi-automatic manner. Both subjectiveand objective quantification permit correlations between structure and function to be evaluated.

CT scoring systems are based on collective scores for the extent and distribution of a rangeof morphological abnormalities, including bronchial dilation, bronchial thickening, abscesses,mucous plugging, emphysema, collapse and consolidation.

The HRCT score of BHALLA et al. [8] was devised to evaluate the severity of CF in an objectivemanner. Severity of bronchial dilation and thickening were defined relative to the adjacentpulmonary artery, and other parameters were scored according to the number of bronchopul-monary segments involved, as shown in table 1.

This scoring system has been modified many times, and has also been adapted for use in MRIassessment of CF. Modifications have included incorporation of additional findings, such as air-trapping/mosaic attenuation, ground-glass opacification, acinar nodules and septal thickening,with some scores being per segment and others based on lobar scoring. Each scoring systemattempts to produce both a total score, by combining features, and specific morphological scores.These have been demonstrated to be more sensitive to disease and show better correlation withboth clinical features and lung function than the CXR-based scoring systems. OIKONOMOU et al. [51]

a)

b)

Figure 7. High-resolution computed tomo-graphy showing a) proximal bronchiectasisaffecting segmental airways and b) high-attenuation mucous plugs in patients withallergic bronchopulmonary aspergillosis. Nointravenous contrast medium was used in (b).

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suggested a simplified scoring system evaluating severity of bronchiectasis, bronchial wall thickeningand atelectasis consolidation. They found strong correlation between the simplified scores and thecomplete scores.

SHAH et al. [27] used a modified Bhalla score in bronchiectatic patients undergoing HRCT atbaseline and 2 weeks after exacerbation in order to identify reversible findings, and showed thatair–fluid levels, centrilobular nodules, mucous plugging and peribronchial thickening improvedfollowing treatment in 100, 36, 33 and 11% of cases, respectively.

DE JONG et al. [52] compared the original scoring system of BHALLA et al. [8] and four modifiedBhalla systems [53–56]. Three observers reviewed thin-slice CT images of 25 children with CFusing the various scoring systems. Interobserver variability was analysed using kappa coefficientsand found to be generally good (kappa .0.76; p,0.05). However, inter- and intra-observeragreement was less for mild disease, as well as for parameters such as mosaic perfusion, acinarnodules and airspace disease. All five scoring systems correlated strongly with forced expiratoryvolume in 1 second (FEV1), forced vital capacity (FVC), forced expiratory flow between 25 and75% of vital capacity (FEF25–75), FEV1/FVC ratio and each other.

Quantitative computerised evaluation of the airways presents a number of challenges, includingobtaining a plane perpendicular to the airway, exclusion of the adjacent artery, determining theborders of the bronchus, artefacts and partial volume averaging. Three different methods havebeen used to obtain airway measurements, full width at half maximum, model fitting approachesand boundary fitting approaches [19]. A detailed description of these techniques is beyond thescope of the present chapter.

GORIS et al. [57] looked at automated evaluation of the extent of air-trapping in 25 patients withmild CF compared to 10 controls; six anatomically matched CT slices were obtained during

Table 1. Summary of computed tomography scoring system

Category Score

0 1 2 3

Severity of bronchiectasis Absent Mild (luminaldiameter slightlygreater than that

of adjacentblood vessel)

Moderate (luminaldiameter 2–3 times

that of adjacentblood vessel)

Severe (luminaldiameter .3 times

that of adjacentblood vessel)

Peribronchial thickening Absent Mild (wallthickness equalto diameter of

adjacent vessel)

Moderate (wallthickness greaterthan and up to

twice the diameterof adjacent vessel)

Severe (wallthickness .2 times

the diameter ofadjacent vessel)

Extent of bronchiectasis Absent Present Present PresentBP segments n 1–5 6–9 .9

Extent of mucous plugging Absent Present Present PresentBP segments n 1–5 6–9 .9

Sacculations or abscesses Absent Present Present PresentBP segments n 1–5 6–9 .9

Bronchial divisionsinvolved (bronchiectasis/plugging) generations

Absent Up to 4th Up to 5th Up to 6th and distal

Bullae Absent Unilateral Bilateral PresentBullae n not .4 not .4 .4

Emphysema Absent Present PresentBP segments n 1–5 .5

Collapse/consolidation Absent Subsegmental Segmental/lobar

BP: bronchopulmonary. Reproduced from [8] with permission from the publisher.

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inspiration and expiration. Computerised lung segmentation was performed and automatedsoftware used to quantify air-trapping, using analysis of a histogram of the distribution of densitiesin the lung, and assessing contiguous low-attenuation voxel regions. In mild CF, air-trapping didnot correlate with global pulmonary function test (PFT) results, except for the ratio of residualvolume (RV) to total lung capacity (TLC); however, the size of the air-trapping defects was thebest discriminator between patients and control subjects (p,0.005).

KIRALY et al. [58] looked at fully automated methods of obtaining three-dimensional (3D) imagesand quantification of airway abnormalities. Working from thin-slice image acquisition and usingcomputerised segmentation techniques, they obtained 3D images of the airways with colour-codedmaps showing BAR, wall thickness and mucous plugging. These have, however, not been fullyclinically validated.

Although these objective tools are interesting, further studies are required to evaluate thevarious computerised imaging parameters and their relation to functional and clinical findingsin bronchiectasis. A note of caution was raised by MATSUOKA et al. [59], who used semi-automatic image processing to assess the airways of 52 asymptomatic patients with nocardiopulmonary disease. They found that luminal area and wall area increased in 10 and 29%of subjects, respectively, suggesting caution in over-reliance on changes in airway calibre indisease monitoring.

Structure–function relationships

Relationships between HRCT data and functional and clinical characteristics have been widelyexplored. WONG-YOU-CHEONG et al. [60] showed a clear negative correlation between FEV1 andextent of bronchiectasis on HRCT (p,0.002; r5 -0.43). SMITH et al. [61] showed correlationbetween extent of bronchiectasis on HRCT and both dyspnoea (p,0.01; r50.38) and FEV1

(p,0.01; r5 -0.43). More recently, DE JONG et al. [52] showed strong correlations between fivescoring systems [8, 53–56] and FEV1 (r5 -0.69– -0.73), FEF25–75 (r5 -0.76– -0.82) and FEV1/FVC ratio (r5-0.72– -0.78). Correlation with FVC was moderate (r5 -0.54– -0.58).

Authors have investigated which morphological abnormalities are most strongly associated with afunctional deficit. LYNCH et al. [62], in a study of 261 bronchiectatic patients, found significantcorrelation between severity of bronchiectasis, FEV1 (r5 -0.362) and FVC (r5 -0.362), andbetween bronchial wall thickening and FEV1 (r5 -0.367) and FVC (r5 -0.239). Cystic bron-chiectasis was found to show worse PFT results than cylindrical or varicose disease.

In a study of 100 patients with bronchiectasis, ROBERTS et al. [63] found good correlation betweenFEV1 and bronchial wall thickening (r5 -0.51; p50.00005) and extent of decreased attenuation onexpiratory HRCT (r5 -0.55, p50.00005) on univariate analysis. These were the only factors thatindependently correlated with degree of airflow limitation on multivariate analysis. In this study,obstructive lung function was not strongly associated with severity of bronchiectasis,bronchodilation, or retained sections in bronchiectasis (r5 -0.42, -0.35 and -0.19, respectively,on univariate analysis). Bronchial dilation as an independent factor was positively associated withairflow obstruction on regression analysis (r250.42). The authors concluded that airflowlimitation in bronchiectasis occurred mainly due to inflammatory or obstructive/constrictivebronchiolitis. They also suggested that areas of low attenuation attributed to emphysema inbronchiectatic patients in previous studies (e.g. [64]) should be interpreted with caution,suggesting that the emphysema demonstrated was often due to air-trapping related to intrinsicsmall airways disease rather than emphysema, as evidenced by preserved gas transfer in the both ofthese studies.

HRCT scoring can also be correlated with clinical parameters. In a study of 61 CF children,baseline and follow-up PFT and HRCT scores were compared to the number of respiratoryexacerbations over 2 years. Only the HRCT score (r50.91; p50.001) and bronchiectatic score(r50.083; p50.01) correlated significantly with exacerbation frequency. All HRCT parameters

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progressed over this time period except for bronchial wall thickening and mucous plugging,suggesting that these are reversible features [65]. OOI et al. [66] studied 60 patients with stablebronchiectasis with HRCT. They showed good correlation between the extents of bronchiecta-sis, bronchial wall thickening and mosaic attenuation and FEV1 (r5 -0.43– -0.60), FVC(r5 -0.36– -0.46), FEF25–50 (r5 -0.38– -0.57) and FEV1/FVC (r5 -0.31– -0.49). Regressionanalysis showed that extent of bronchiectasis and wall thickening were the most significantdeterminants of airflow obstruction, correlating with all PFT parameters This study alsodemonstrated associations between bronchial wall thickening and clinical factors, such asexacerbation frequency and 24-hour sputum production (r5 -0.32 and -0.30). ALZEER [67] foundthat the HRCT score correlated well with FEV1 (r5 -0.51), as well as with systolic pulmonaryartery pressure (Ppa,sys) (r50.23), in a study of 94 bronchiectatic patients.

Studies on the utility of HRCT in the follow-up of non-CF bronchiectatic patients have beenlimited. In a study of 48 patients, SHEEHAN et al. [68] compared serial CT studies with PFTs,showing correlation of changes in PFT results with air-trapping due to mucous plugging. Greaterseverity of mucous plugging, bronchiectasis and bronchial wall thickening were predictive ofdecreased FEV1. In a study evaluating morphological features in bronchiectasis at baseline and2 weeks after exacerbation, SHAH et al. [27] showed that changes in HRCT score duringexacerbation of bronchiectasis also correlate with improvement in FEV1/FVC (r50.39;p50.049). Severity of bronchiectasis was the component most strongly associated with PFTresults (r50.4 for FEV1 and r50.5 for FVC), whereas tree in bud and mucous plugging were notstrongly correlated.

The validity of the use of PFTs as the gold standard in evaluating HRCT has been questioned byseveral authors. BRODY et al. [69] and HELBICH et al. [53] have shown that early HRCT changes,including mosaic attenuation and bronchial dilation, can be seen early in disease in the presenceof normal PFT results. LONG et al. [70] showed HRCT changes, including wall thickening andbronchial dilation in CF infants with a mean age of 2 years, further emphasising the sensitivityof HRCT.

Regular low-dose HRCT for the surveillance of CF has been adopted by several centres sincethe late 1990s [71]. This was initially in the form of 1-mm slice incremental HRCT (with 10-mm interspaces), but, more recently, of full-lung volumetric HRCT. CT is performed as earlyas an age of 2 years, when it is performed as controlled-ventilation CT (CVCT), requiringsedation or general anaesthesia. The rationale for using this imaging-intensive approach is thatPFT results may lag behind structural CT changes, difficulty in reliably performing PFTs inyoung children and the ability of imaging to follow relevant objective structural markers, suchas bronchiectasis, bronchial wall thickening, air-trapping and mucous plugging. Furthermore,in the modern era, improved therapy has slowed the annual decline in PFT results such thatindividual variability and changes due to other factors, such as technique, puberty andinfections, have made PFTs even less reliable for disease monitoring. However, the benefit hasto be viewed in the setting of radiation risk. DE JONG et al. [72] used a computational model toestimate mortality effects of regular CTs. The mean radiation dose for the published CTprotocol was 1 mSv. Survival reduction associated with annual scans from the age of 2 yearsuntil death for CF patients with a median survival of 26 and 50 years, were approximately1 month and 2 years, respectively. Cumulative cancer mortality was approximately 2 and 13%at age 40 and 65 years, respectively. Biannual CTs exhibit half the risk. This highlights theincreasing reduction in survival with increasing age, an important point given the increasinglife expectancy of CF patients.

DE JONG et al. [73] studied 48 young patients with CF using serial low-dose HRCT and PFTs2 years apart. In all children, there was progressive structural HRCT change with deterioration inHRCT scores by 2.2–3.5% overall, but particularly with peripheral extension of bronchiectasis andmucous plugging, despite stable (or, in some cases, improved) lung function. This may reflectpoor PFT technique in young CF children, the use of predicted FEV1 (with reference to a globalpopulation) and/or the greater sensitivity of HRCT for detection of early and regional changes.

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JUDGE et al. [74] assessed serial HRCT performed 18 months apart in 39 consecutive CF patientsand found that the modified HRCT score declined faster (2.7% per year; p,0.001) than did FEV1

(2.3% per year). Six patients demonstrated worsening HRCT score with no change in PFT result.DE JONG et al. [75], in a study of 119 children and adults with CF, showed that PFT results,component and CT scores deteriorated over 2 years. The CT score (and its components) and PFTresults showed similar rates of deterioration in adults and children (p.0.09). Peripheralbronchiectasis worsened by 1.7% per year in children (p,0.0001) and by 1.5% per year in adults(p,0.0001).

In view of the potential for discordance between morphology and function and the com-plementary nature of these variables, authors have attempted to create more-robust clinicallyuseful composite scoring systems combining PFT results and HRCT findings [76].

Studies on assessment following therapy have been limited. ROBINSON et al. [76] used a compositescoring system using many of the HRCT parameters described above and combining them withPFT measures of obstructive function (FEV1 and FEF25–75). They showed the compositemeasurement to be more sensitive for assessing response to treatment in 25 CF children who wererandomised to a treatment arm and a nebulised saline arm; FEF25–50 showed 13% improvement,global HRCT 5% and composite score 30%. Small studies have shown some HRCT features to beuseful in post-treatment evaluation. NASR et al. [77] showed a significant improvement in totalHRCT score following recombinant human (rh) deoxyribonuclease (DNAse) therapy compared toplacebo. GORIS et al. [57] compared 25 CF patients with 10 age-matched controls using PFTs andautomated quantitative assessment of lung density. No significant difference was seen in PFTresults, but significant differences in air-trapping were seen, with the size of defects being the bestdiscriminator. There was a significant decrease in mean HRCT score from 25 to 22 (p50.014),with improvement in peribronchial thickening (p50.007), mucous plugging (p50.002) andoverall appearance (p50.025).

There have been some differences in the degree of correlation between PFT results and HRCTfindings of bronchiectasis in the various studies, which could be attributed to several causes,including the scoring system used, radiological interpretation, parameters assessed, populationstudied, reliability of PFTs and data analysis (multivariate versus univariate). However, the linkbetween measures of obstructive lung function (FEV1 and FEF25–50) and bronchial wall thickness/total HRCT score has been consistently shown.

Role of HRCT in bronchiectasis

CT is invaluable in the diagnosis of bronchiectasis, but also plays an important role in theevaluation of complications and assessment and monitoring of disease severity. HRCT providesgood clinical correlation, and the use of scoring systems holds promise for monitoring ofbronchiectasis. The more robust CT scoring systems have been formulated in CF patients. HRCTis sometimes of value in identifying the aetiology of bronchiectasis. Advantages of HRCT overPFTs include its ability to identify focal changes as well as provide a global score, in addition toassessing multiple parameters, some of which are reversible and others irreversible (fig. 8).

Current British Thoracic Society guidelines recommend HRCT at diagnosis and during exacerbations,but not for routine follow-up. An exception is in bronchiectasis secondary to humoral immuno-deficiency, where follow-up HRCT may be beneficial [78].

HRCT is now widely regarded as part of the standard clinical evaluation of patients with CF. Theability to quantify extent and severity of disease and to serve as a useful outcome marker, and thepotential for assessing treatment response, make this a particularly valuable investigation.However, although HRCT provides valuable information on initial assessment, the role andperiodicity of serial imaging in CF remains controversial in view of increasing life expectancy andcumulative radiation exposure. Some authors suggest that HRCT should form part of the routinemonitoring of CF, but with due consideration to the excess radiation [71]. With appropriate

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scanning technique, it is estimated that a chest CTevery other year from birth to age 30 years wouldinvolve an effective dose of 15 mSv compared to themean background radiation dose over this period of90 mSv [79].

Thus HRCT forms an important part of the investiga-tion and diagnosis of bronchiectasis and exacerbations.It is particularly useful in CF, where it has been shownto be a good marker of outcome and has demonstratedthe ability to pick up subtle and early changes withgreater sensitivity than PFTs.

Magnetic resonance imaging

Interest in the use of MRI for lung imaging arose inthe mid-1980s. The inherent difficulties in pulmonaryMRI are well documented. Lungs have an intrinsicallylow proton density, which results in poor signalgeneration. This low signal is further degraded by susceptibility artefact resulting from theinnumerable air–tissue interfaces and cardiac and respiratory motion. However, the advent ofparallel imaging and new rapid imaging sequences have permitted marked improvement intemporal and spatial resolution. Although spatial resolution using conventional proton MRI isless than that using CT, MRI offers significant morphological information and has advantages inenabling improved tissue characterisation and providing functional imaging, including vascularflow and respiratory mechanics. The use of novel imaging techniques, such as oxygen-enhancedMRI and hyperpolarised helium-3 MRI, potentially permits derivation of further functionalparameters, including regional ventilation, regional oxygen concentration and evaluation of lungmicrostructure using the apparent diffusion coefficient (ADC).

Although application of this technique currently lies largely in the research arena, a significantadvantage of MRI is the lack of radiation, which is particularly important in patients who requirerecurrent imaging and the younger population group. This is pertinent when considering thepotential cumulative lifetime radiation dose from annual/biannual low-dose CT examination in theCF population that are currently advocated by some groups [71], especially in view of the rapidimprovement in life expectancy in this patient group, which is projected to continue. Thus it isunsurprising that much of the work on thoracic MRI imaging has been focused on patients with CF.

Conventional proton MRI features

Owing to the limited spatial resolution of MRI, assessment of bronchial wall thickness andbronchiectasis are dependent upon bronchial level, wall thickness and wall signal. Third-generation bronchi and beyond are poorly visualised on MRI, except in pathological states, whenthe wall and luminal signal are raised due to wall thickening, inflammation and mucus [80].Inflammation and oedema contribute to wall thickening. Gadolinium-enhanced images may beuseful in demonstrating inflammatory change.

Mucous plugging on MRI results in homogeneous high T2-signal intensity in proximal airways or anabnormal branching grape-like pattern more peripherally, equivalent to the tree-in-bud opacitiesseen on HRCT. In contrast to CT, the improved tissue characterisation of MRI can also differentiatebetween mucus, haemorrhage and bronchial wall thickening [81]. Air–fluid levels may be identifiedon MRI, particularly in cystic or varicose bronchiectasis. Unlike CT, using contrast-enhanced MRIsequences, thickened airway walls can be differentiated from mucous plugging. Consolidation mayalso be identified as high T2-signal inflammatory fluid contrasts with the low airway signal,equivalent to the classical air bronchogram. Air-trapping and mosaic perfusion are not readily seenon conventional proton MRI in the absence of gadolinium (figs 9 and 10).

Figure 8. Coronal reconstruction fromhigh-resolution computed tomographyshowing a bronchial collateral vessel.

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An early study of 17 CF patients (aged 7–30 years) in 1995 [82] found MRI to be inferior to CT inthe assessment of bronchiectasis. Correlations between CT and MRI (r for each observer) weregood for bronchial dilation (r50.81 and 0.50), bronchial thickening (r50.82 and 0.60) andmucous plugging (r50.93 and 0.70). Progress in MRI technique in recent years has led to markedimprovement in its accuracy. In a study of six paediatric patients with CF, HEBESTREIT et al. [83]found that CXR and MRI provided equal information, and considered MRI suitable for follow-up.In a more recent study in 2007, PUDERBACH et al. [84] evaluated 31 patients with CF using CXR,MDCT and MRI. MRI and MDCT were assessed using a modified Helbich score, whereas CXRwas evaluated using a modified Chrispin–Norman score. Mosaic perfusion was excluded from theoriginal scoring system as this cannot be quantified on MRI. They concluded that morphological

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Figure 9. a) Transverse magnetic resonance (T2-weighted half-Fourier acquisition single-shot turbo spin-echo (HASTE)) image and b) corresponding computed tomography image in a 14-year-old female with cysticfibrosis. In both images, bronchial wall thickening, bronchiectasis, peripheral mucous plugging and dorsalconsolidations are demonstrated, as shown by the arrows. Reproduced from [81] with permission from thepublisher.

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Figure 10. T1-weighted magnetic resonance imaging showing appearance a) before and b) after contrastmedium in a 43-year-old cystic fibrosis patient. The post-contrast images demonstrate extensive bronchialwall enhancement and permit differentiation of a thickened wall from intrabronchial secretions, withintrabronchial fluid having an air–fluid level (arrow). Reproduced from [81] with permission from the publisher.

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MRI showed comparable results to MDCT and CXR. Median extent scores for MRI, MDCT andCXR scores were 13, 13.5 and 14, and correlation between modalities ranged 0.63–0.80 (MRI/CT0.80, p,0.0001; MRI/CXR 0.63, p,0.0018; CXR/CT 0.75, p,0.0001). The median lobe-relatedconcordance was 80% for bronchiectasis, 77% for mucous plugging, 93% for sacculation/abscessesand 100% for collapse/consolidation.

MONTELLA et al. [85] evaluated patients with primary ciliary dyskinesia using HRCT and MRI.They used a modified Helbich score for both HRCT and morphological MRI assessment, showingmean scores of 12 for both, good-to-excellent agreement between HRCT and MRI scores (r.0.8),and good correlation between both CT and MRI scores and FEV1 and FVC.

Functional MRI

A significant advantage of MRI over CT is its superior ability to assess function. Within the lungsthis mainly involves evaluation of haemodynamic function and perfusion and ventilation studies.

Perfusion imaging

In the presence of small airways obstruction, regional ventilation defects lead to impaired gasexchange and reflex hypoxic vasoconstriction [86]. Perfusion imaging can thus serve as a markerof airway obstruction. ITTI et al. [87] used radionuclide imaging to show that the degree ofabnormal lung perfusion correlates well with disease severity in CF, as measured by PFTs and theShwachman radiographic score. Contrast-enhanced pulmonary MRI imaging can be used toacquire a 3D data set in just 1.5 seconds [88, 89]. This also has advantages over scintigraphy interms of radiation dose and provides regional information.

EICHINGER et al. [90] performed morphological and contrast-enhanced MRI sequences on 11patients with CF; 198 lung segments were scored for morphological (3 point score of none,moderate or severe) and perfusion defects (0 normal; 1 impaired perfusion). In 86% of segmentsconsidered morphologically normal, homogenous perfusion was demonstrated, whereas 97% ofsegments with severe morphological changes were associated with perfusion defects. Of segmentswith moderate morphological changes, 53%showed normal and 47% impaired perfusion. Thuscontrast-enhanced MRI appears to be a feasible method of assessing regional perfusion defects as asurrogate for small airways disease, although further work is required in order to improvesensitivity in moderately affected areas of lung.

In bronchiectasis, increased blood flow though bronchial and nonbronchial systemic collateralvessels results in a systemic arterial to pulmonary venous shunt. Using conventional proton MRIand phase-contrast flow-sensitive sequences, aortic and pulmonary arterial flow can be readilyquantified. In a study of 10 patients with CF and 15 healthy volunteers, LEY et al. [91] found asignificantly increased shunt in CF patients (1.3 L?min-1) compared to healthy volunteers(0.1 L?min-1).

Oxygen-enhanced MRI exploits the weak paramagnetic properties of oxygen, which cause ashortening of T1 at high concentration and can be used as a gaseous contrast agent. The solubilityof oxygen means that images represent a combination of ventilation and perfusion. A limitation isthe low signal-to-noise ratio [81]. JAKOB et al. [92] studied five CF patients and five healthyvolunteers using oxygen-enhanced MRI, showing inhomogeneity of the lung parenchyma in theCF patients.

Hyperpolarised noble-gas-enhanced MRI

Imaging of hyperpolarised noble gases using MRI is a relatively new imaging technique that showspromise in the research arena in the evaluation of several ventilatory functional parameters.Hyperpolarised helium-3 and hyperpolarised xenon-129 are gaseous contrast agents that provide avery high MR signal [35]. Since oxygen promotes depolarisation, the polarised helium-3 is mixed

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with nitrogen rather than air before being administered by active inhalation via a device such as aplastic Tedlar bag or respirator-driven gas delivery system. The bag method uses a mixture of300 mL helium-3 and 700 mL nitrogen and requires a single anoxic breathhold. The respirator-driven system provides an accurate single dose followed by an air chaser and hence no anoxicbreathhold is required.

Polarisation is not renewable and has to be used carefully during the scan, with use of sequences tomaximise use of finite magnetisation [93]. Dedicated receiver coils for the relevant resonancefrequency of helium-3 and xenon-129 are also required.

The different physical properties of helium-3 and xenon-129 present different opportunities.Although helium-3 provides a better signal and greater polarisation levels have been obtained, itslarger diffusion coefficient results in signal loss. In addition, although helium-3 is virtuallyinsoluble in water, xenon-129 is highly soluble and hence has potential for use in assessingperfusion [93]. On a purely practical basis, the limited supply of helium-3, estimated at 200 kgglobally [94], compared to that of xenon-129 is likely to lead to xenon-129 eventually emerging asagent of choice [95].

The main techniques used in hyperpolarised noble gas imaging are static ventilation imaging anddynamic ventilation imaging, as well as assessment of lung microstructure using ADC and regionaloxygen tension imaging.

MCMAHON et al. [96] showed that static helium-3 MRI ventilation in CF correlated stronglywith HRCT assessment of structural abnormalities (R5¡0.89; p,0.001), and that thecorrelation was higher between helium-3 MRI and PFT results than helium-3 MRI and HRCT.In a further observational study of 18 patients aged 5–17 years with CF undergoinghyperpolarised helium-2 MRI, VAN BEEK et al. [97] confirmed moderate correlation between avisual score of ventilation on MRI and global assessment of pulmonary function (FEV1 r5 -0.41and FVC r5 -0.42).

In a study comparing healthy volunteers and CF patients, MENTORE et al. [98] performedspirometry and hyperpolarised helium-3 imaging at baseline in all cases, and following variousinterventions in the eight CF patients. Treatments in the CF group included bronchodilators,DNAse and chest physiotherapy. The number of ventilation defects was scored. The helium-3ventilation score correlated moderately with spirometry, and was higher in CF patients thancontrols (mean 8.2 and 1.6, respectively). The helium-3 ventilation score was raised in comparisonto controls even in CF patients with normal spirometric results. Defects in the eight treatedpatients decreased in response to bronchodilator therapy (p50.025). WOODHOUSE et al. [99]demonstrated reproducibility of regional and total lung volume measurements using hyper-polarised helium-3 MR in two examinations performed 30 minutes apart in a group of five youngCF sufferers.

The ADC of helium-3 or xenon-129 in the lung and the paramagnetic effect of oxygen are twonovel methods with the potential for extracting clinically relevant data. The ADC provides ameasure of the diffusion of gas and thus an assessment of the degree to which free diffusion isrestricted. Helium-3 has a very high self-diffusion coefficient, but, in the lung, diffusion becomesrestricted by the boundaries of the airspaces, and thus the ADC can be used to interrogate themicrostructure of the lung [93].

The oxygen-induced depolarisation of helium-3 or xenon-129 results in signal decay proportionalto the concentration of oxygen [100], permitting estimation of regional oxygen concentration anduptake and regional pulmonary perfusion, and providing a regional ventilation/perfusion (V/Q)map at a much higher resolution than that of radionuclide imaging [101]. PATZ et al. [95]measured regional oxygen concentrations using xenon-129, and, although this is inherently morecomplex than with helium-3 due to diffusion into septal tissue and vasculature, an oxygen tension(PO2) equivalent can be calculated, which can provide valuable functional information.

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A limitation of hyperpolarised noble gas MRI is that the signal is also influenced by factors otherthan ventilation, including the sensitivity of the MR coil and local oxygen concentration in thelung. The need for noble gas isotopes and both polarisation hardware and additional MRIhardware, together with considerable physical and technical support, mean that hyperpolarisednoble gas imaging remains expensive and limited to the research environment. However, thepotential to perform noninvasive evaluation of regional ventilation, diffusion, regional oxygenconcentration, lung microstructure and perfusion without the use of ionising radiation haspotential, especially in the research setting.

Summary

MRI has potential in the imaging of bronchiectasis, particularly in conditions such as CF, in whichyoung patients may require serial imaging for disease monitoring and assessment of response totreatment. Compared to HRCT, the ability of MR to provide functional imaging and lack ofradiation could compensate for its limited spatial resolution. With improvement in MRItechniques, recent studies have shown good reproducibility and good correlation with PFT results.Further work is required to improve spatial resolution, develop robust validated scoring systemsand evaluate correlations with clinical outcomes.

Currently cost, limited availability and limited spatial resolution limit the use of MRI inbronchiectasis largely to the research arena. Although hyperpolarised noble gas imaging has greatpotential in terms of provision of functional data, technical issues and set-up and ongoing costssuggest its role will be limited to research for the foreseeable future.

Scintigraphy

Prior to the advent of HRCT, ventilation (with or without perfusion) scintigraphy was used to aiddisease evaluation in bronchiectasis. DOLLERY and HUGH-JONES [102] studied the physiologicalimplications of bronchiectasis and found reduced blood flow and impaired ventilation in bronchiectaticareas. V/Q scintigraphy typically demonstrates matched ventilation and perfusion defects, reflectingabnormal ventilation secondary to bronchiectasis and associated small airways obstruction [103].

PIFFERI et al. [104] studied 16 children aged 4–18 years with clinical and CXR evidence ofbronchiectasis, performing HRCT and V/Q scintigraphy. The extent of bronchiectasis, degree ofair-trapping on expiratory HRCT and ventilation and perfusion scores from V/Q scintigraphywere assessed. HRCT scores for bronchiectasis and air-trapping showed a strong correlation withperfusion (r50.82; p,0.001) and ventilation scores (r50.72; p,0.01). There was a moderatenegative correlation between FEV1 and HRCT bronchiectatic scores (r5 -0.53; p50.02), air-trapping (r5 -0.64; p50.007) and atelectatic score (r5 -0.54; p50.03).

The authors concluded that HRCT provides a comprehensive assessment of children withbronchiectasis, and V/Q scintigraphy and lung function are additive tools to aid diagnosis andguide therapeutic management. The ongoing issue of radiation dose and absence of usefulanatomical information, however, limit the value of V/Q scintigraphy in routine practice.

Mucociliary clearance

The interaction between the cilia on respiratory epithelium and the periciliary mucous layer(periciliary liquid (PCL))/overlying mucous layer, together known as the airway surface liquid(ASL) layer, has been widely investigated. Coordinated function is responsible for the constantclearance of foreign material, including microorganisms and other debris, towards the pharynxand ultimate expectoration or swallowing. Impaired mucociliary function has been implicated inmany disease processes, but particularly bronchiectasis. Techniques to objectively measuremucociliary clearance (MCC) in vivo have been sought in order to improve understanding of thedisease processes and evaluate therapeutic response.

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Techniques for measuring MCC

In vivo assessment of MCC relies on the inhalation of radiolabelled particulate material thatbecomes trapped in the mucous layer and can be imaged scintigraphically. Data acquired from thegamma camera over time can be presented either as a series of images for visual inspection or,more commonly, as time–activity curves (fig. 11).

Technetium-99m-labelled human albumin, iron oxide and technetium-99–sulfur colloid are someof the aerosols used. Sulfur colloid is nondiffusible, remains extravascular and is expelled by MCC/swallowing. Deposition of particles is affected by many factors. Some, such as particle size andbreathing pattern, can be controlled for, whereas others reflect the underlying lung condition (e.g.obstruction and lung size). Thus, in order to make comparisons, it is important to standardise thenature of the aerosolised particles (size and distribution) and provide a consistent nebulised flowin order to produce a reproducible deposition rate [105].

In order to define the margins of the lung and differentiate central (C) and peripheral (P) lungregions, an initial ventilation study utilising a xenon-133 or krypton-81 scan [106] can beperformed immediately prior to administration of particulate material. Following this, the patient

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Figure 11. Measurement of mucociliary clearance (MCC). a) A xenon-133 equilibrium scan was used to identifythe left (L) and right (R) lung boundaries in a normal subject, and assign central (C) and peripheral (P) regions ofinterest (b). c) Deposition image obtained immediately after inhalation of technetium–sulfur colloid in the samesubject. d) Mean rate of clearance of technetium–sulfur colloid from 12 subjects with cystic fibrosis at baseline(&) and immediately after inhalation of hypertonic saline ($) [16]. The fast phase (approximately 0–20 minutes;– – – – –), reflecting clearance from large airways, and slow phase (from 40 minutes to start of cough clearancemeasurement; --------), reflecting smaller airway clearance, are highlighted. e) Effect of ratio of radioactive countsmeasured in the C and P regions on rate of MCC, as denoted by particle retention at 120 minutes, in a cohort ofnormal study subjects. VC: voluntary cough. Reproduced from [105] with permission from the publisher.

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inhales nebulised radiolabelled aerosol. Various adjuncts are used during nebulisation in order toprovide consistent reproducible dosing, including pneumotachographic devices with visualfeedback to control inhalation flow rate and tidal volume within specific ranges, metronomes toguide the timing of inhalation and exhalation, and aerosol dosimetric equipment to pulse aerosoldelivery during specific portions of the breathing cycle [105].

Following inhalation, the patient is positioned in front of the gamma camera and the gammaradiation emitted is detected and recorded. The results are analysed graphically with reference tothe zones defined on the initial ventilation scan. At this stage of analysis, it is important to accountfor decay of radioisotope and background radiation level. Given the variability of deposition ofradiolabelled aerosol in various parts of the airways, it is important to measure the initialdeposition pattern. The deposition pattern is usually presented as a ratio between C and P or as thepenetration index (PI), which is the ratio of radioactive counts per pixel in P to counts per pixel inC [107]. A high initial C/P deposition ratio or low PI is associated with a higher clearance rate inthe central airways, making this a potential confounding factor in analysing final clearance data.

The rate of clearance from central airways is up to 100–1,000 times faster than that fromperipheral airways [108, 109]. A two-phase MCC pattern is typically seen, with an initial rapidphase lasting approximately 30 minutes and reflecting clearance from the central airways and aprolonged slower phase. The latter occurs over 1–2 hours and is thought to represent movementof particles to compartments that are more difficult to clear (e.g. absorption of PCL) or slowclearance from peripheral airway/alveolar deposition. 24-hour measurement of clearance has alsobeen used to assess the pattern of clearance during the slower phase, which could also be of valuein assessing response to treatment. This, however, requires a higher administered radiation dosedue to the 6-hour half-life of technetium. A static measurement at 24 hours can be used as amarker of deposition in the nonciliate airways or alveoli [110]. The relative contributions to the24-hour measurement of slow clearance from peripheral airways, alveolar deposition and mixingin a poorly cleared part of the ASL, are not fully understood [105]. The static 24-hourmeasurement is useful in aiding calculation of other parameters, such as the tracheobronchialretention (TBR) curve, which is derived by subtracting the 24-hour retention from the correctedlung retention (LR) curve.

A potentially more accurate means of assessing peripheral clearance is inhaling particles ofdifferent sizes, smaller (4 mm) particles being deposited more peripherally than larger (7.5 mm)ones [111]. YEATES et al. [108] proposed labelling the differently sized aerosolised particles withdifferent radioisotopes to permit simultaneous measurement of central and peripheral regionalclearance. This method is not widely used due to practical difficulties.

Some authors [106] advocate measurement of activity solely in the lung periphery, where uptakeis more homogenous. This avoids the potential errors caused by differential uptake in central andperipheral airways and confounding by variability of initial deposition. It is, however, limited bya low signal-to-noise ratio due to lower deposition peripherally and intrinsically slower clearancein these regions. It is also not possible to assess response to therapy in the central airways usingthis method.

Additional imaging following various interventions, such as cough clearance (CC) assessed aftera standardised pattern of coughing, can also be performed. This has some limitations, asperforming this late in the study makes it less sensitive as the central airways would have beenlargely cleared of radioisotope. A further normalisation measurement of C/P ratio must beperformed prior to CC.

Clinical applications

Measurement of MCC has important research applications in both understanding diseaseprocesses and assessing therapeutic response. To date, the technique has not been broadly adoptedclinically, being cumbersome to establish.

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Disorders that impair MCC can seriously affect respiratory function, with build-up ofthick mucus in the airways/lungs and inability to expel harmful material. This can predis-pose to complications, such as infection and structural lung disease. Other factors may influenceMCC, which is faster in nonsmokers and enhanced by b2-agonists, particularly in non-smokers [112].

CF is a prominent example of a condition in which measurement of MCC could prove useful.Scintigraphic evaluation has also been used to demonstrate impaired MCC in primary ciliarydyskinesia [110] and following lung transplantation [113]. There have been limited studies inidiopathic bronchiectasis [114].

In CF, disordered ion transport leads to dehydration of the ASL layer [115], impaired ciliarymotion and decreased mucus clearance, ultimately leading to degradation of cilia [105],exacerbating the cycle of frequent infections. Ongoing research is focused on the earliest stages ofdisease pathogenesis and therapeutic interventions to target defective mucus clearance.Biomarkers objectively measuring MCC have the potential to assess response to treatment atan early stage in contrast to longer-term end-points, such as clinical or functional parameters,and thus to expedite drug development.

In a study of 24 patients with CF, DONALDSON et al. [116] showed improved MCC, measured usingtechnetium-99-labelled iron oxide, at both 1 and 24 hours after inhalation of hypertonic saline,and that pretreatment with amiloride reduced the magnitude of this improvement. Usingradiolabelled iron oxide BENNETT et al. [106] demonstrated significantly reduced baseline MCC at40 minutes in CF patients compared to healthy volunteers. In the CF group, treatment withuridine 5’-triphosphate and amiloride in combination improved peripheral MCC to near-normallevels. Similar studies have used technetium–sulfur colloid to demonstrate improved MCC and CCfollowing inhaled hypertonic saline and mannitol in CF patients [117].

In summary, MCC can be measured using radiolabelled particulate materials, such as technetium-99–sulfur colloid. In the research setting, this provides a potential biomarker for evaluation ofmucociliary dysfunction and, in particular, assessment of the impact of targeted therapies. This isespecially true in conditions such as CF, in which impaired MCC plays a significant part in thepathophysiology of the disease and where treatment is targeted at improving this.

Conclusions

Imaging plays a central role in the diagnosis, characterisation and quantification of disease severityin bronchiectasis, as well as the evaluation of complications. Currently CXR and CT are the mainmodalities. CXR is the initial screening tool, but has well-documented limitations in sensitivityand specificity, particularly in early disease. Radiography also plays an important role in thediagnosis of complications. HRCT is the reference standard in identifying airway dilation,permitting detection of disease and quantification of extent. Routine surveillance CT has potentialfor the diagnosis of structural disease at an early stage and impact on patient care, particularlywhere these is discordance with functional parameters. Radiation dose, however, remains anarea of concern requiring further elucidation, particularly in the cohort of CF patients given theirever-increasing life expectancy and the potentially large cumulative radiation dose. Although thepresent review concentrates on the monitoring of disease, CT is an excellent problem-solving tool,permitting the diagnosis of both infective complications, such as abscess, empyema andaspergilloma, as well as identification of small pneumothoraces or enlarged systemic collateralvessels (fig. 11) and aiding relevant image-guided intervention.

MRI offers opportunities to image the lung structure and its function without the use of ionisingradiation. The spatial resolution is inferior to that of CT but has improved substantially overrecent years. An increasing role for structural (proton) MRI is anticipated, but widespreadadoption will require further evidence to support its effectiveness. Although hyperpolarised noblegases permit interrogation of a range of physiological parameters, the set-up costs of this technique

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are likely to ensure it remains a predominantly research tool for at least the foreseeable future.Evaluation of MCC using scintigraphy is another area in which there is great potential, particularlyin order to expedite and reduce costs of drug development.

Statement of interest

None declared.

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