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Imaging in Cystic Fibrosis and Non–Cystic Fibrosis Bronchiectasis Jonathan D. Dodd, MB1
Lisa P. Lavelle, MD1
Aurelie Fabre, FRCPath, PhD2
1 Department of Radiology, St. Vincent’s University Hospital, Elm Park,
Dublin, Ireland 2 Department of Pathology, St. Vincent’s University Hospital, Elm Park, Dublin, Ireland
Darragh Brady, MD1
Address for correspondence Jonathan D. Dodd, MB, Department of Radiology, St. Vincent’s University Hospital, Elm Park, Dublin 4, Ireland (e-mail: [email protected]).
Abstract
Keywords
► cystic fibrosis ► computed tomography ► X-ray ► bronchiectasis ► radiation
Bronchiectasis is defined as a permanent and progressive dilation of the airways, typically as a result of inflammation, infection, and subsequent repair. It typically presents with chronic cough, suppurative sputum production, and airway dilation. Highresolution computed tomography (HRCT) is now well established as the primary imaging tool for its investigation. Cystic fibrosis (CF) remains the most common autosomal recessive inherited disorder worldwide and its pulmonary hallmark is bronchiectasis. Although CF and non-CF bronchiectasis are different clinical entities, they are typically imaged using HRCT and share many imaging aspects, and also some differences. Several important recent CT technology developments have improved the detection and characterization of bronchiectasis and its complications. Many CT aspects of radiation exposure have also undergone important enhancements in recent years resulting in significant dose reductions. This is particularly relevant in a pulmonary disease such as bronchiectasis, which often undergoes serial HRCT surveillance in contemporary practice. Several new CT clinical applications in bronchiectasis have been recently advanced, and CT is now being increasingly incorporated into investigative algorithms to assess bronchiectasis treatment effects. In this review, we assess the latest imaging features of CF and non-CF bronchiectasis, discuss radiation dose reducing methods and technology of the latest scanners, describe recent CT clinical applications, and explore the use of CT as a treatment surrogate in CF and non-CF bronchiectasis.
Bronchiectasis is defined as a permanent and progressive dilation of the airways, typically as a result of inflammation, infection, and repair. This leads to mucociliary dysfunction and subsequent permanent dilation of the airways. Although bronchiectasis is detectable on chest radiography, computed tomography (CT) is now well established as having a significantly higher sensitivity and specificity in detection and characterization, and it has become the primary imaging tool for the investigation of bronchiectasis.1–3 Two key CT imaging findings for radiologists when attempting to diagnose bronchiectasis are (1) the internal diameter of the bronchus must be larger than its accompanying vessel and
Issue Theme Cystic Fibrosis and NonCystic Fibrosis Bronchiectasis; Guest Editor: Andrew M. Jones, MD, FRCP
(2) the bronchus does not taper in the periphery of the lungs (►Fig. 1).4 Airway wall thickening and mucus plugging, especially in active disease, often accompany these changes.5 When the internal diameter of the bronchus is larger than its accompanying vessel and is seen in cross section, this is known as the “signet ring” sign. Cystic fibrosis (CF) remains the most common autosomal recessive inherited disorder worldwide. The highest prevalence by country includes Ireland, Scotland, and the United Kingdom, but all countries in the world have recorded cases.6 Our knowledge of its pathophysiology has dramatically changed in the past decade, and so has our technology and
Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0035-1546749. ISSN 1069-3424.
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accurate assessment of the extent and severity of bronchiectasis can be made using volumetric protocols (►Fig. 3).11
Minimum intensity projections (MinIPs) are reformatted CT images based on a minimum density of a given voxel in an image. Voxels above this threshold minimum density are removed from image reconstruction. The addition of MinIP sequences to a chest CT protocol allows an improvement in airway dilation detection and in assessing for the presence of air trapping.12,13 MinIPs have been shown to improve the ability to detect bronchiectasis, mosaic attenuation, and associated obliterative bronchiolitis compared with standard reformats2,14 (►Fig. 4).
Expiratory CT Acquisitions in Bronchiectasis
Fig. 1 Axial CT image in a patient with cystic fibrosis shows a nontapering bronchus (arrowheads) in the right middle lobe, the signet ring sign (straight arrow) in the right lower lobe, and marked airway wall thickening (curved arrow)—all classical CT imaging hallmarks of bronchiectasis.
techniques for imaging the disease. In an era where radiation exposure from CT scanning is of paramount importance,7 several new techniques have reduced the radiation dose from chest CT for this patient population.8 Chest CT is growing in use as a method of assessing responses to new treatments. It is also being increasingly used, particularly in CF, as an outcome surrogate.9 This has important implications on how we monitor treatment response, particularly in the presence of evolving disease-modulating agents. In this review, we will look at four major aspects of imaging CF and non-CF bronchiectasis: (1) technical, (2) radiation dose, (3) contemporary clinical applications, and (4) treatment response.
Imaging in Bronchiectasis—Technical Aspects Volumetric versus Traditional Incremental Protocols A key development in the improved imaging detection of bronchiectasis is multidetector as opposed to single detector CT. This has allowed imaging in any image plane using “volumetric” CT protocols rather than the traditional incremental scan protocols.10 As a result, imaging of the entire lungs has become the standard approach. The major limitation of traditional incremental CT protocols is that they omit 90% of the lungs between the slice gaps. Volumetric protocols encompass the entire lung in any image plane, thus providing a much more comprehensive view of the lungs (►Fig. 2). As a result, it has been shown that bronchiectasis may be missed in between slices using incremental protocols, and a more
A further improvement in imaging bronchiectasis is the addition of volumetric expiratory sequences.15 Traditional chest CT approaches have used an incremental set of five slices, resulting in an underestimation of the extent of air trapping. A volumetric protocol performed in expiration allows a comprehensive assessment of the extent of air trapping.16,17 The routine addition of expiratory to inspiratory CT protocols illustrated that in most cases of bronchiectasis, mosaic attenuation on inspiratory CT scans corresponded to air trapping on expiratory CT scans. The question of why bronchiectasis is associated with parenchymal attenuation changes was answered in a landmark radpath study assessing the cause of mosaic attenuation in bronchiectasis. Kang et al assessed the CT scans of 22 patients with severe bronchiectasis who underwent 47 lobe resections, and compared CT to pathological findings.18 The areas of mosaic attenuation on CT corresponded pathologically to areas of bronchiolitis distal to the dilated airways. Bronchiolitis was present as an associated feature of bronchiectasis in 40 (85%) of the 47 resected lobes. These included six lobes with obliterative bronchiolitis, 18 with inflammatory bronchiolitis, and 16 with obliterative and inflammatory bronchiolitis. Many chest radiologists utilize the presence of mosaic attenuation on CT as a method of detecting areas of bronchiectasis. It is now clear that many CF patients suffer from extensive small airways bronchiolitis, and that this in fact may be a more dominant finding than large airways bronchiectasis.19 This has been shown to be true even for those patients with end-stage disease awaiting lung transplant. The extent of mosaic attenuation may vary, but a proportion of it may be reversible (►Fig. 5).
Free-Breathing Chest CT The temporal resolution of CT continues to undergo extraordinary developments. The latest dual source scanners can acquire free-breathing CT chest acquisitions without breathing artifact.20 The term “dual source” means that instead of the traditional single CT X-ray tube and detector gantry, there are instead two CT X-ray tubes and two detector gantries.21 This results in image acquisition taking half the time to acquire. This is particularly advantageous in patients who Seminars in Respiratory and Critical Care Medicine
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Minimum Intensity Projections in Bronchiectasis
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Fig. 2 Comparison of traditional incremental protocol (A) which produced 8–12 single slices through the lungs. Ninety percent of the lung is omitted using this protocol. (B) Volumetric protocols give complete visualization of the lungs with no slice gaps. This allows imaging reconstruction in axial, coronal, and sagittal image planes.
Fig. 3 The left and middle images show two slices from an incremental chest CT protocol. These images have missed a small peripheral segment of bronchiectasis (circle) in the lateral segment right middle lobe depicted on the right thumbnail which was acquired with a volumetric acquisition.
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struggle with breath holding or those with more severe disease, in whom long breath holds of 10 seconds or more can be problematic. The protocol is relative new and more studies are needed to assess its true potential, but early studies indicate minimum breathing artifact with freebreathing protocols using this type of application (►Fig. 6).
Fig. 4 Minimum intensity projection depicts multiple dilated airways in the right middle and lower lobes. Note the clear, sharp depiction of the dilated airways compared with the uninvolved left lung. Note also the “mosaic” appearance to the right lung, particularly in the periphery —a CT finding frequently found in patients with bronchiectasis.
A recent hotly debated topic in imaging has been the radiation dose incurred by CT in both non-CF and CF bronchiectasis.22,23 There has been considerable confusion in the literature surrounding this theme related to conflicting methodology, different phantoms conditions, different scanner types and parameters, and different methods for estimating the subsequent cancer burden. It is now considered that there is a definite small but significant risk of developing cancer from CT radiation.24,25 The exact risk is difficult to accurately estimate, as all current risk estimates are based on theoretical exposures and dose results from Japanese atomic bomb survivors, but it is felt to be small.26 A consistent conclusion is that the younger the patient, the higher the risk of developing subsequent cancer.27 This has particular relevance to the CF population, in whom biennial high-
Fig. 5 (A) Expiratory CT image showing multiple areas of mosaic attenuation (asterisk) in all lobes associated with areas of bronchiectasis (curved arrows). (B) Histological appearances of obliterative bronchiolitis with peribronchiolar fibroinflammatory process (arrows), which surrounds the lumen with concentric narrowing and obliteration of the bronchiolar lumen (Br) (hematoxylin and eosin stain, 10 magnification; scale bar, 100 µm). (C) Histological appearances of obliterative bronchiolitis with scar (asterisk) adjacent to pulmonary artery (PA) secondary to a completely occluded bronchiole with some residual bronchiolar wall smooth muscle (SM) (hematoxylin and eosin stain, 10 magnification; scale bar, 100 µm).
Fig. 6 (A) Axial, (B) coronal soft tissue, and (C) coronal lung reformations showing motion-free contours of the pulmonary vessels and the diaphragm in a freely breathing patient without the use of ECG synchronization (used with permission from Bauer et al 20). Seminars in Respiratory and Critical Care Medicine
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Imaging in Bronchiectasis—Radiation Dose
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resolution CT (HRCT) surveillance to detect and monitor structural changes has been advocated from an early age.28 The debate has now moved from the established association between radiation exposure and cancer risk to dose reduction, using the lowest achievable levels while maintaining diagnostic image quality. The desirable chest CT dose is now considered to be submillisievert < 1 mSv.29 Many different industry CT innovations have occurred in the last 3 to 5 years to achieve this.
Low-Dose CT-Reducing Peak Kilovoltage and Milliampere Second The most important CT development in reducing radiation dose in bronchiectasis imaging has been the recognition that the peak kilovoltage (kVp) and milliampere (mA), two parameters that impose the radiation dose to the patient, can be significantly reduced without affecting diagnostic image quality. The tube voltage, or kVp, is the most important parameter because it reduces radiation dose exponentially as its decreased. Thus, a relatively small change in voltage of 20 kVp (from 140 to 120 kVp or from 120 to 100 kVp) results in a decrease in radiation dose of 30 to 40%.30 The traditional kVp for a chest CT is 120, and most centers have now adopted a reduced kVp in CF patients to 100 kVp. Some centers have reduced the kVp further to 80, so-called ultra-low-dose protocols. This ultra-low-dose protocol works well in CF because most patients have a low body mass index and image quality is minimally affected. Less substantial, though significant, reductions can be achieved by lowering the tube current, as expressed in mAs. Tube current has a direct linear relationship to radiation dose. The traditional mAs for chest CT is between 200 and 300 mA for most scanners, and this can be reduced to 50 to 80 mA with little effect on diagnostic image quality (►Fig. 7).
Fig. 7 Axial CT image of (A) a standard chest CT at 120 kVp and 2 years later; (B) an ultra-low dose CT at 80 kVp was performed in the same patient. Note that although the ultra-low dose CT image appears more noise, there are no significant differences in diagnostic image quality.
Iterative Reconstructions—A New Radiation Dose Lowering Method of CT Image Reconstruction For many years, CT images have been reconstructed using a method called filtered back projection. This has required typical kVp and mA values of approximately 120 and 250, respectively, to generate diagnostic image quality. This results
Fig. 8 (A) Traditional standard filtered back projection image reconstruction versus (B) Iterative image reconstruction. Note the slightly more “bleached” appearance to the iterative reconstruction image, with no loss of diagnostic image quality. Note also the aspergilloma in one of the cystic dilated airways (arrow).
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final and perhaps most simple adjustment to CT protocols which should be regularly emphasized to technologists in the CT scan room is the importance of the craniocaudal scan coverage. Considerable education should be inputted into technologist education pieces regarding the importance of the scan range as a crucial way of reducing dose (►Fig. 9).
Imaging in Bronchiectasis—Contemporary Clinical Applications
Fig. 9 Keeping the scan range tight in the craniocaudal direction dramatically decreases radiation dose. A poorly planned scan range (solid horizontal lines) includes too much of the neck and below diaphragm tissues. A more strategic scan range (dotted lines) starts at the apex of the lungs and stops at the lowest costophrenic angle—this can reduce radiation dose by 20 to 25%.
in standard chest CT radiation doses in the order of 3 to 6.5 mSv in adults.31 Newer preprocessing methods of image reconstruction allow the use of lower kVp and mAs to derive similar imaging information while reducing radiation dose. These are termed iterative reconstructions, and in fact have been available for many years but have required prohibitive computational time. It is only with the advent of more powerful computing technology that they have become a reality in clinical practice. They result in an increase in image quality, a decrease in image noise, and an improvement in spatial resolution. Radiation dose reductions in the order of 30 to 40% are achieved using these reconstructions and their application is becoming widespread32,33 (►Fig. 8).
Reduced Scan Range Such ultra-low-dose HRCT approaches have gone a long way to reducing radiation exposure to the patient. But a
Many CT scoring systems have now been developed to objectify and score the severity of lung disease in both CF and non-CF bronchiectasis.34 The initial CF Bhalla score has undergone numerous modifications since its initial publication.35 The two most commonly used CF-CT scoring systems are the modified Bhalla scoring system (►Table 1)36 and the modified Brody scoring system.37 Both score the extent and severity of lung disease on CT with similar accuracy, and allow an objective and quantitative assessment of lung disease, within-patient comparisons over time, and between patient comparisons over time in different patient subgroups. Although CT scoring systems in non-CF bronchiectasis are less well validated, there is evidence that at least the extent of bronchiectasis is associated with increased morbidity and mortality. The recently developed bronchiectasis severity index (BSI) is a useful clinical predictive tool that identifies patients at risk of future mortality, hospital admissions, and exacerbations.38 Independent predictors of the BSI included prior hospital admissions, Medical Research Council dyspnea score 4, forced expiratory volume in 1 second < 30% predicted, Pseudomonas aeruginosa colonization, colonization with other pathogenic organisms, and three or more lobes with bronchiectasis on HRCT. Significant differences in exacerbation frequency and quality of life between patients classified as low, intermediate, and high risk by the score have been demonstrated.
Table 1 Modified Bhalla CT scoring system39 CT abnormality
0
1
2
3
Severity of bronchiectasis
Absent
Lumen slightly > adj. vessel
Lumen ¼ 2–3 adj. vessel
Lumen > 3 adj. vessel
Peribronchial thickening
Absent
AWT ¼ adj. vessel
AWT 2 adj. vessel
AWT > 2 adj. vessel
Extent of bronchiectasis (BPS)
Absent
1–5
6–9
>9
Extent of mucous plugging (BPS)
Absent
1–5
6–9
>9
Sacculations/abscesses (BPS)
Absent
1–5
6–9
>9
Generations of bronchial divisions
Absent
Up to 4th generation
Up to 5th generation
Up to 6th generation
No. of bullae
Absent
Unilateral
Bilateral
>4
Collapse/consolidation
Absent
Subsegmental
Segmental/lobar
Air trapping
Absent
1–5
>5
Abbreviations: adj., adjacent; AWT, airway wall thickening. Seminars in Respiratory and Critical Care Medicine
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Fig. 10 A 30-year-old woman with CF. (A) Flow–volume (F/V) loop at time 1 demonstrates FEV1 of 2.9 L (94% of predicted). (B) Transverse 1-mm HRCT image through the upper lobes demonstrates moderate bronchiectasis (straight arrow) and peribronchial wall thickening (curved arrow) and an apical bulla (arrowhead). (C) Twenty-nine months later, the F/V loop demonstrates FEV1 of 2.7 L (88% of predicted). (D) Transverse 1-mm HRCT image through the upper lobes demonstrates marked progression of disease with new and severe bilateral upper lobe collapse (note the anterior shift of the left major and right minor fissures, straight arrows) and marked progression in the extent and severity of bronchiectasis (curved arrows).
CF Lung Disease Surveillance Using HRCT A large body of work has now been published on using HRCT to survey disease changes in CF lung disease.39,40 It is well known that lung disease changes are heterogeneous in CF lung disease, and that spirometry provides a global picture of lung disease. Many centers have now incorporated surveillance HRCT every 2 to 3 years to better assess the progression of CF lung disease over time and in response to treatments. Many patients demonstrate entirely stable or mildly reduced spirometry over significant periods of time but declining HRCT scores with progressive structural changes. Individual HRCT abnormalities decline at different rates depending on the degree of lung function impairment (►Fig. 10).39,41 The reason for this is that lung function provides an indirect measure of overall lung disease, but is insensitive to small yet cumulative focal lung damage that occurs in an indolent fashion in CF patients over many years. It has become clear that some patients exhibit greater changes in CT with lesser changes in spirometry over time, while others demonstrate the opposite.40,42 As a result, multimodality assessment with both spirometry and CT has been advocated by many.43 A particularly important development has been the recognition of structural lung damage from a much early age than Seminars in Respiratory and Critical Care Medicine
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previously identified. Lung disease may be identified in infants within the first week of life,44 with abnormalities reported in lung function, pulmonary inflammation, and P. aeruginosa.45 The AREST studies have shown children with CF
Fig. 11 Kaplan–Meier plot of the proportion of patients with cystic fibrosis who were alive while awaiting lung transplant. Individuals are grouped in tertiles (tertile 1, < 25 [solid line]; 2, 26–32 (dashed line); 3, > 33 (dotted line).
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Fig. 12 Cine dynamic tracheal CT in a patient with CF taken in inspiration and during dynamic expiration. (A) A normal tracheal diameter (arrow) during full inspiration. (B) there is marked collapse of the trachea of 89% cross-sectional area (arrow) during forced expiratory maneuvers.
diagnosed by newborn screening can also have structural damage on HRCT.46 In a landmark study assessing prevalence of lung disease in 57 infants with CF, overall 80.7% demonstrated an abnormal CT; 18.6% had bronchial dilatation, 45.0% had bronchial wall thickening, and 66.7% had gas trapping. Thus, investigative and treatment strategies are undergoing more aggressive changes at earlier ages in CF.
Lung Transplantation in CF—Who Should Be Listed? Up to one-third of patients with CF awaiting lung transplant (LTX) die while waiting. Improvements to the inclusion criteria for transplantation are needed. In a prospective multicenter (17 centers) study of 411 patients with CF screened for LTx, CT scans were scored for infection/inflammation (INF), air trapping/hypoperfusion, normal/hyperperfusion, bulla/cysts, and a total lung score (LAS).19 Three hundred sixty-six (186 males) of 411 patients entered the waiting list and 67 (18%) died while waiting, 263 of 366 (72%) underwent LTx, and 36 of 366 (10%) were awaiting LTx at the census date. Multivariate Cox analysis including INF and LAS indicated that INF and LAS had significant, independent predictive value for survival. The authors concluded that CT scores for infection and total lung disease correlate with and add to the predictive value of survival in CF while awaiting transplant (►Fig. 11).
Tracheomalacia in CF—Cine Tracheal Multidetector CT There is considerable evidence that many patients with CF and non-CF bronchiectasis have tracheomalacia. Histopathologic studies have revealed reduced amounts of cartilage within the walls of bronchiectatic airways in CF.47 Others have shown destruction of cartilage in chronically colonized tracheal walls. It has also been shown that cartilage extends for a shorter distance along bronchial
walls in patients with CF compared with the cartilage extension in control subjects, and is typically preceded by a marked inflammatory infiltrate with increased numbers of macrophages and severe chondrolysis.48–50 Multidetector cine tracheal CT is being increasingly used to evaluate tracheomalacia because it is noninvasive.51,52 A cross-sectional study in patients with CF using cine tracheal CT evaluated tracheal changes in both forced expiratory maneuvers and coughing, and demonstrated dramatic reductions in tracheal luminal diameters during both procedures, worse on coughing.53 Tracheomalacia was demonstrated in 69% of patients during forced expiratory maneuvers and in 29% of patients during coughing (►Fig. 12).
Nontuberculous Mycobacterium and Non-CF Bronchiectasis—Using Chest CT to Improve Detection Several recent studies support the finding that bronchiectasis on CT together with signs of bronchiolitis, namely centrilobular and tree-in-bud nodules, are indicative of nontuberculous mycobacterium (NTM) infection.54,55 Bronchiectasis is most commonly seen in the right middle lobe and/or lingula. In a study by Koh et al of 126 patients suspected of NTM, when more than five lobes showed bronchiectasis and bronchiolitis on CT, particularly in association with consolidation or cavities, appearances were highly suggestive of NTM.54 So strong is the association between NTM and bronchiectasis that many have postulated that NTM may in fact cause bronchiectasis, although this requires further corroboration. McEvoy et al applied a similar imaging approach to patients with CF.36 In 27 NTM-positive CF patients, findings suggestive of NTM(þ) were similar but more extensive than those of Koh et al. The findings on CT of >7 Seminars in Respiratory and Critical Care Medicine
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Fig. 13 (A) HRCT image from a patient with NTM-positive sputum 3 with multifocal cavitation (arrows) and tree-in-bud nodules (arrowheads) in more than five lobes. (B) Acutely inflamed bronchiectasis (Br) (hematoxylin and eosin stain, 2 magnification; scale bar, 1 mm). (C) Higher power view of the squared area showing suppurated epithelioid and giant cell granuloma (hematoxylin and eosin stain 20 magnification; scale bar, 100 μm). Acid fast bacillus identified on Ziehl-Neelsen stain (inset: 60 magnification; scale bar, 10 μm).
bronchopulmonary segments showing CT signs of bronchiolitis, particularly when associated with consolidation and peribronchial wall thickening, were highly suggestive of NTM(þ) (►Fig. 13).
Mounier–Kuhn Syndrome and Bronchiectasis Mounier–Kuhn syndrome is characterized by tracheobronchial dilation secondary to atrophy of the muscular and elastic tissues in the trachea and main bronchial walls.56 Diagnostic imaging criteria include a tracheal width exceeding 3 cm, a right mainstem bronchial diameter > 2.5 cm, and a left mainstem bronchial diameter > 2 cm in cross section.57,58 It has a predilection for males, and typically presents with chronic cough and recurrent respiratory infections. The muscle atrophy was originally described by Katz et al and is one of the major reasons the condition is Seminars in Respiratory and Critical Care Medicine
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typically associated with numerous tracheal diverticulae.59 It is becoming increasingly recognized and reported as the realization that CXR may have underestimated its prevalence as well as the wider availability and applicability of chest CT. Dynamic cine CT may demonstrate tracheomalacia and patients often develop central obstructive physiology (►Fig. 14).
Allergic Bronchopulmonary Aspergillosis HRCT of the lungs has been used to improve the diagnosis of ABPA. Several features on CT can be used to diagnose ABPA with high accuracy.60 Early reports utilized the finding of predominantly central bronchiectasis to specifically detect the disorder, but subsequent studies have shown this finding to be less sensitive and specific, and a combination of airway wall thickening, mucus plugging, high-density mucus
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Fig. 14 (A) Axial CT of the upper trachea shows a grossly dilated trachea measuring 3.9 cm. Note the tracheal diverticulum (arrow). (B) Axial CT image of the lower lobes shows severe cystic bronchiectasis with multiple air–fluid levels.
plugging, mosaic perfusion, and atelectasis in addition to bronchiectasis improves the diagnostic accuracy of CT considerably.60–62 In general, three or more lobes are involved on CT in proven cases. CT abnormalities are included in the diagnostic criteria for ABPA (►Fig. 15).
Non-CF Bronchiectasis and Other Pulmonary Diseases It is now clear that there is a significant prevalence of bronchiectasis in patients with chronic obstructive airways disease (COPD). Several studies have suggested prevalence as high as 57%.63 It is also known that COPD patients with bronchiectasis have a higher mortality than those without bronchiectasis. This finding is supported by studies that have found that patients with both COPD and bronchiectasis have increased bronchial inflammation; longer, more severe, and more frequent exacerbations; more virulent organisms in the bronchial mucosa; and worse lung function.64 The prognostic value of the presence and severity of bronchiectasis suggests the ability to detect patients with a COPD–bronchiectasis phenotype. This carries important implications in terms of promoting earlier identification and establishment of early and more aggressive treatment against infection (►Fig. 16).
Imaging in Bronchiectasis—Treatment Responses Disease-Modulating Agents in CF
Fig. 15 Axial CT image of a 48-year-old woman with ABPA. Her CT shows central bronchiectasis (curved arrows) in the right middle and lower lobes and extensive mucoceles (straight arrows) and peripheral atelectasis (arrowhead) in the right lower lobe. Note the considerable airway wall thickening (asterisk).
Tremendous interest is being generated by the development of several disease-modifying agents in CF lung disease. The most evaluated of these is ivacaftor, a drug designed to increase the time that activated CF transmembrane conductance regulator channels at the cell surface remain open. In a randomized, double-blind, placebo-controlled trial of ivacaftor versus placebo, CF patients receiving the drug demonstrated improvements in lung function at 2 weeks that were sustained through 48 weeks.65 Improvements in HRCT abnormalities have also been documented following the use of ivacaftor.66 These include a decrease in airway wall thickening, a decrease in mucus plugging, and a decrease in ground glass opacities (►Fig. 17).
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Fig. 16 (A) Axial CT image showing multifocal areas of centrilobular emphysema in the upper lobes (arrows). (B) Diffuse bronchiectasis is seen in the right middle and lower lobes. Note airway wall thickening (arrow) and mucus plugging (arrowhead) in the right lower lobe.
Fig. 17 (A) Axial CT image pretreatment with ivacaftor. Note the diffuse airway wall thickening (arrows) and subsegmental consolidation (arrowhead). (B) Following 2 years of ivacaftor treatment, note the reduction in airway wall thickening (arrows) and consolidation (arrowhead).
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fibrosis: assessment with chest CT at chest radiography dose levels. Radiology 2014;273(2):597–605 Singh S, Kalra MK, Gilman MD, et al. Adaptive statistical iterative reconstruction technique for radiation dose reduction in chest CT: a pilot study. Radiology 2011;259(2):565–573 de Jong PA, Ottink MD, Robben SG, et al. Pulmonary disease assessment in cystic fibrosis: comparison of CT scoring systems and value of bronchial and arterial dimension measurements. Radiology 2004;231(2):434–439 Bhalla M, Turcios N, Aponte V, et al. Cystic fibrosis: scoring system with thin-section CT. Radiology 1991;179(3):783–788 McEvoy S, Lavelle L, Kilcoyne A, et al. High-resolution CT of nontuberculous mycobacterium infection in adult CF patients: diagnostic accuracy. Eur Radiol 2012;22(12):2736–2742 Brody AS, Tiddens HA, Castile RG, et al; CT Scanning in Cystic Fibrosis Special Interest Group. Computed tomography in the evaluation of cystic fibrosis lung disease. Am J Respir Crit Care Med 2005;172(10):1246–1252 Chalmers JD, Goeminne P, Aliberti S, et al. The bronchiectasis severity index. An international derivation and validation study. Am J Respir Crit Care Med 2014;189(5):576–585 Judge EP, Dodd JD, Masterson JB, Gallagher CG. Pulmonary abnormalities on high-resolution CT demonstrate more rapid decline than FEV1 in adults with cystic fibrosis. Chest 2006;130(5): 1424–1432 de Jong PA, Nakano Y, Lequin MH, et al. Progressive damage on high resolution computed tomography despite stable lung function in cystic fibrosis. Eur Respir J 2004;23(1):93–97 Owens CM, Aurora P, Stanojevic S, et al; London Cystic Fibrosis Collaboration. Lung Clearance Index and HRCT are complementary markers of lung abnormalities in young children with CF. Thorax 2011;66(6):481–488 de Jong PA, Lindblad A, Rubin L, et al. Progression of lung disease on computed tomography and pulmonary function tests in children and adults with cystic fibrosis. Thorax 2006;61(1):80–85 Tiddens HAWM, Stick SM, Davis S. Multi-modality monitoring of cystic fibrosis lung disease: the role of chest computed tomography. Paediatr Respir Rev 2014;15(1):92–97 Wagener JS, Kahn TZ, Copenhaver SC, Accurso FJ. Early inflammation and the development of pulmonary disease in cystic fibrosis. Pediatr Pulmonol Suppl 1997;16:267–268 Dakin CJ, Numa AH, Wang H, Morton JR, Vertzyas CC, Henry RL. Inflammation, infection, and pulmonary function in infants and young children with cystic fibrosis. Am J Respir Crit Care Med 2002;165(7):904–910 Pillarisetti N, Williamson E, Linnane B, et al; Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF). Infection, inflammation, and lung function decline in infants with cystic fibrosis. Am J Respir Crit Care Med 2011;184(1):75–81 Hayward J, Reid ML. The cartilage of the intrapulmonary bronchi in normal lungs, in bronchiectasis, and in massive collapse. Thorax 1952;7(1):98–110 Ogrinc G, Kampalath B, Tomashefski JFJ Jr. Destruction and loss of bronchial cartilage in cystic fibrosis. Hum Pathol 1998;29(1):65–73 Baker NR, Tao Y. A tracheal culture model of respiratory tract infection with Pseudomonas aeruginosa. In Vitro 1982;18(4): 369–376 Tsang KW, Rutman A, Tanaka E, et al. Interaction of Pseudomonas aeruginosa with human respiratory mucosa in vitro. Eur Respir J 1994;7(10):1746–1753 Boiselle PM, Lee KS, Lin S, Raptopoulos V. Cine CT during coughing for assessment of tracheomalacia: preliminary experience with 64-MDCT. AJR Am J Roentgenol 2006;187(2):W175-7 Boiselle PM, Ernst A. Tracheal morphology in patients with tracheomalacia: prevalence of inspiratory lunate and expiratory “frown” shapes. J Thorac Imaging 2006;21(3):190–196
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preliminary observations of the role of maximum and minimum intensity projection images. Radiology 1996;200(2):341–347 Remy J, Remy-Jardin M, Artaud D, Fribourg M. Multiplanar and three-dimensional reconstruction techniques in CT: impact on chest diseases. Eur Radiol 1998;8(3):335–351 Wittram C, Batt J, Rappaport DC, Hutcheon MA. Inspiratory and expiratory helical CT of normal adults: comparison of thin section scans and minimum intensity projection images. J Thorac Imaging 2002;17(1):47–52 Eda S, Kubo K, Fujimoto K, Matsuzawa Y, Sekiguchi M, Sakai F. The relations between expiratory chest CT using helical CT and pulmonary function tests in emphysema. Am J Respir Crit Care Med 1997;155(4):1290–1294 Bankier AA, Mehrain S, Kienzl D, Weber M, Estenne M, Gevenois PA. Regional heterogeneity of air trapping at expiratory thinsection CT of patients with bronchiolitis: potential implications for dose reduction and CT protocol planning. Radiology 2008; 247(3):862–870 Loeve M, Lequin MH, de Bruijne M, et al. Cystic fibrosis: are volumetric ultra-low-dose expiratory CT scans sufficient for monitoring related lung disease? Radiology 2009;253(1):223–229 Kang EY, Miller RR, Müller NL. Bronchiectasis: comparison of preoperative thin-section CT and pathologic findings in resected specimens. Radiology 1995;195(3):649–654 Loeve M, Hop WC, de Bruijne M, et al; Computed Tomography Cystic Fibrosis Survival Study Group. Chest computed tomography scores are predictive of survival in patients with cystic fibrosis awaiting lung transplantation. Am J Respir Crit Care Med 2012; 185(10):1096–1103 Bauer RW, Schell B, Beeres M, et al. High-pitch dual-source computed tomography pulmonary angiography in freely breathing patients. J Thorac Imaging 2012;27(6):376–381 Petersilka M, Bruder H, Krauss B, Stierstorfer K, Flohr TG. Technical principles of dual source CT. Eur J Radiol 2008;68(3):362–368 Brenner DJ. Radiation risks potentially associated with low-dose CT screening of adult smokers for lung cancer. Radiology 2004; 231(2):440–445 Brenner DJ, Hall EJ. Computed tomography—an increasing source of radiation exposure. N Engl J Med 2007;357(22): 2277–2284 Pearce MS, Salotti JA, Little MP, et al. Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours: a retrospective cohort study. Lancet 2012;380(9840):499–505 Mathews JD, Forsythe AV, Brady Z, et al. Cancer risk in 680,000 people exposed to computed tomography scans in childhood or adolescence: data linkage study of 11 million Australians. BMJ 2013;346:f2360 Kuo W, Ciet P, Tiddens HAWM, Zhang W, Guillerman RP, van Straten M. Monitoring cystic fibrosis lung disease by computed tomography. Radiation risk in perspective. Am J Respir Crit Care Med 2014;189(11):1328–1336 O’Connor OJ, Vandeleur M, McGarrigle AM, et al. Development of low-dose protocols for thin-section CT assessment of cystic fibrosis in pediatric patients. Radiology 2010;257(3):820–829 Mott LS, Park J, Murray CP, et al; AREST CF. Progression of early structural lung disease in young children with cystic fibrosis assessed using CT. Thorax 2012;67(6):509–516 Thrall JH. Radiation exposure in CT scanning and risk: where are we? Radiology 2012;264(2):325–328 Litmanovich DE, Tack DM, Shahrzad M, Bankier AA. Dose reduction in cardiothoracic CT: review of currently available methods. Radiographics 2014;34(6):1469–1489 Boone JM, Hendee WR, McNitt-Gray MF, Seltzer SE. Radiation exposure from CT scans: how to close our knowledge gaps, monitor and safeguard exposure—proceedings and recommendations of the Radiation Dose Summit, sponsored by NIBIB, February 24-25, 2011. Radiology 2012;265(2):544–554
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with cystic fibrosis: determination of prevalence and severity with dynamic cine CT. Radiology 2009;252(2):577–586 Koh W-J, Lee KS, Kwon OJ, Jeong YJ, Kwak S-H, Kim TS. Bilateral bronchiectasis and bronchiolitis at thin-section CT: diagnostic implications in nontuberculous mycobacterial pulmonary infection. Radiology 2005;235(1):282–288 Jeong YJ, Lee KS, Koh W-J, Han J, Kim TS, Kwon OJ. Nontuberculous mycobacterial pulmonary infection in immunocompetent patients: comparison of thin-section CT and histopathologic findings. Radiology 2004;231(3):880–886 Krustins E, Kravale Z, Buls A. Mounier-Kuhn syndrome or congenital tracheobronchomegaly: a literature review. Respir Med 2013; 107(12):1822–1828 Shin MS, Jackson RM, Ho KJ. Tracheobronchomegaly (Mounier-Kuhn syndrome): CT diagnosis. AJR Am J Roentgenol 1988;150(4):777–779 Woodring JH, Howard RS II, Rehm SR. Congenital tracheobronchomegaly (Mounier-Kuhn syndrome): a report of 10 cases and review of the literature. J Thorac Imaging 1991;6(2):1–10 Katz I, Levine M, Herman P. Tracheobronchiomegaly. The MounierKuhn syndrome. Am J Roentgenol Radium Ther Nucl Med 1962; 88:1084–1094 Ward S, Heyneman L, Lee MJ, Leung AN, Hansell DM, Müller NL. Accuracy of CT in the diagnosis of allergic bronchopulmonary
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aspergillosis in asthmatic patients. AJR Am J Roentgenol 1999; 173(4):937–942 Stevens DA, Moss RB, Kurup VP, et al; Participants in the Cystic Fibrosis Foundation Consensus Conference. Allergic bronchopulmonary aspergillosis in cystic fibrosis—state of the art: Cystic Fibrosis Foundation Consensus Conference. Clin Infect Dis 2003;37 (Suppl 3):S225–S264 Meza Brítez RL, del Río Navarro BE, Ochoa López G, Pietropaolo Cienfuegos D, del Río Chivardi JM, Rosas Vargas MA. [Allergic bronchopulmonary aspergillosis. A report of a case and literature review]. Rev Alerg Mex 2008;55(3):112–116 Martínez-García M-A, de la Rosa Carrillo D, Soler-Cataluña JJ, et al. Prognostic value of bronchiectasis in patients with moderate-tosevere chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013;187(8):823–831 Martínez-García M-A, Soler-Cataluña J-J, Donat Sanz Y, et al. Factors associated with bronchiectasis in patients with COPD. Chest 2011;140(5):1130–1137 Ramsey BW, Davies J, McElvaney NG, et al; VX08-770-102 Study Group. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011;365(18): 1663–1672 Hoare S, McEvoy S, McCarthy CJ, et al. Ivacaftor imaging response in cystic fibrosis. Am J Respir Crit Care Med 2014;189(4):484
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Imaging in Cystic Fibrosis and Non–Cystic Fibrosis Bronchiectasis Jonathan D. Dodd, MB1
Lisa P. Lavelle, MD1
Aurelie Fabre, FRCPath, PhD2
1 Department of Radiology, St. Vincent’s University Hospital, Elm Park,
Dublin, Ireland 2 Department of Pathology, St. Vincent’s University Hospital, Elm Park, Dublin, Ireland
Darragh Brady, MD1
Address for correspondence Jonathan D. Dodd, MB, Department of Radiology, St. Vincent’s University Hospital, Elm Park, Dublin 4, Ireland (e-mail: [email protected]).
Abstract
Keywords
► cystic fibrosis ► computed tomography ► X-ray ► bronchiectasis ► radiation
Bronchiectasis is defined as a permanent and progressive dilation of the airways, typically as a result of inflammation, infection, and subsequent repair. It typically presents with chronic cough, suppurative sputum production, and airway dilation. Highresolution computed tomography (HRCT) is now well established as the primary imaging tool for its investigation. Cystic fibrosis (CF) remains the most common autosomal recessive inherited disorder worldwide and its pulmonary hallmark is bronchiectasis. Although CF and non-CF bronchiectasis are different clinical entities, they are typically imaged using HRCT and share many imaging aspects, and also some differences. Several important recent CT technology developments have improved the detection and characterization of bronchiectasis and its complications. Many CT aspects of radiation exposure have also undergone important enhancements in recent years resulting in significant dose reductions. This is particularly relevant in a pulmonary disease such as bronchiectasis, which often undergoes serial HRCT surveillance in contemporary practice. Several new CT clinical applications in bronchiectasis have been recently advanced, and CT is now being increasingly incorporated into investigative algorithms to assess bronchiectasis treatment effects. In this review, we assess the latest imaging features of CF and non-CF bronchiectasis, discuss radiation dose reducing methods and technology of the latest scanners, describe recent CT clinical applications, and explore the use of CT as a treatment surrogate in CF and non-CF bronchiectasis.
Bronchiectasis is defined as a permanent and progressive dilation of the airways, typically as a result of inflammation, infection, and repair. This leads to mucociliary dysfunction and subsequent permanent dilation of the airways. Although bronchiectasis is detectable on chest radiography, computed tomography (CT) is now well established as having a significantly higher sensitivity and specificity in detection and characterization, and it has become the primary imaging tool for the investigation of bronchiectasis.1–3 Two key CT imaging findings for radiologists when attempting to diagnose bronchiectasis are (1) the internal diameter of the bronchus must be larger than its accompanying vessel and
Issue Theme Cystic Fibrosis and NonCystic Fibrosis Bronchiectasis; Guest Editor: Andrew M. Jones, MD, FRCP
(2) the bronchus does not taper in the periphery of the lungs (►Fig. 1).4 Airway wall thickening and mucus plugging, especially in active disease, often accompany these changes.5 When the internal diameter of the bronchus is larger than its accompanying vessel and is seen in cross section, this is known as the “signet ring” sign. Cystic fibrosis (CF) remains the most common autosomal recessive inherited disorder worldwide. The highest prevalence by country includes Ireland, Scotland, and the United Kingdom, but all countries in the world have recorded cases.6 Our knowledge of its pathophysiology has dramatically changed in the past decade, and so has our technology and
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DOI http://dx.doi.org/ 10.1055/s-0035-1546749. ISSN 1069-3424.
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accurate assessment of the extent and severity of bronchiectasis can be made using volumetric protocols (►Fig. 3).11
Minimum intensity projections (MinIPs) are reformatted CT images based on a minimum density of a given voxel in an image. Voxels above this threshold minimum density are removed from image reconstruction. The addition of MinIP sequences to a chest CT protocol allows an improvement in airway dilation detection and in assessing for the presence of air trapping.12,13 MinIPs have been shown to improve the ability to detect bronchiectasis, mosaic attenuation, and associated obliterative bronchiolitis compared with standard reformats2,14 (►Fig. 4).
Expiratory CT Acquisitions in Bronchiectasis
Fig. 1 Axial CT image in a patient with cystic fibrosis shows a nontapering bronchus (arrowheads) in the right middle lobe, the signet ring sign (straight arrow) in the right lower lobe, and marked airway wall thickening (curved arrow)—all classical CT imaging hallmarks of bronchiectasis.
techniques for imaging the disease. In an era where radiation exposure from CT scanning is of paramount importance,7 several new techniques have reduced the radiation dose from chest CT for this patient population.8 Chest CT is growing in use as a method of assessing responses to new treatments. It is also being increasingly used, particularly in CF, as an outcome surrogate.9 This has important implications on how we monitor treatment response, particularly in the presence of evolving disease-modulating agents. In this review, we will look at four major aspects of imaging CF and non-CF bronchiectasis: (1) technical, (2) radiation dose, (3) contemporary clinical applications, and (4) treatment response.
Imaging in Bronchiectasis—Technical Aspects Volumetric versus Traditional Incremental Protocols A key development in the improved imaging detection of bronchiectasis is multidetector as opposed to single detector CT. This has allowed imaging in any image plane using “volumetric” CT protocols rather than the traditional incremental scan protocols.10 As a result, imaging of the entire lungs has become the standard approach. The major limitation of traditional incremental CT protocols is that they omit 90% of the lungs between the slice gaps. Volumetric protocols encompass the entire lung in any image plane, thus providing a much more comprehensive view of the lungs (►Fig. 2). As a result, it has been shown that bronchiectasis may be missed in between slices using incremental protocols, and a more
A further improvement in imaging bronchiectasis is the addition of volumetric expiratory sequences.15 Traditional chest CT approaches have used an incremental set of five slices, resulting in an underestimation of the extent of air trapping. A volumetric protocol performed in expiration allows a comprehensive assessment of the extent of air trapping.16,17 The routine addition of expiratory to inspiratory CT protocols illustrated that in most cases of bronchiectasis, mosaic attenuation on inspiratory CT scans corresponded to air trapping on expiratory CT scans. The question of why bronchiectasis is associated with parenchymal attenuation changes was answered in a landmark radpath study assessing the cause of mosaic attenuation in bronchiectasis. Kang et al assessed the CT scans of 22 patients with severe bronchiectasis who underwent 47 lobe resections, and compared CT to pathological findings.18 The areas of mosaic attenuation on CT corresponded pathologically to areas of bronchiolitis distal to the dilated airways. Bronchiolitis was present as an associated feature of bronchiectasis in 40 (85%) of the 47 resected lobes. These included six lobes with obliterative bronchiolitis, 18 with inflammatory bronchiolitis, and 16 with obliterative and inflammatory bronchiolitis. Many chest radiologists utilize the presence of mosaic attenuation on CT as a method of detecting areas of bronchiectasis. It is now clear that many CF patients suffer from extensive small airways bronchiolitis, and that this in fact may be a more dominant finding than large airways bronchiectasis.19 This has been shown to be true even for those patients with end-stage disease awaiting lung transplant. The extent of mosaic attenuation may vary, but a proportion of it may be reversible (►Fig. 5).
Free-Breathing Chest CT The temporal resolution of CT continues to undergo extraordinary developments. The latest dual source scanners can acquire free-breathing CT chest acquisitions without breathing artifact.20 The term “dual source” means that instead of the traditional single CT X-ray tube and detector gantry, there are instead two CT X-ray tubes and two detector gantries.21 This results in image acquisition taking half the time to acquire. This is particularly advantageous in patients who Seminars in Respiratory and Critical Care Medicine
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Minimum Intensity Projections in Bronchiectasis
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Fig. 2 Comparison of traditional incremental protocol (A) which produced 8–12 single slices through the lungs. Ninety percent of the lung is omitted using this protocol. (B) Volumetric protocols give complete visualization of the lungs with no slice gaps. This allows imaging reconstruction in axial, coronal, and sagittal image planes.
Fig. 3 The left and middle images show two slices from an incremental chest CT protocol. These images have missed a small peripheral segment of bronchiectasis (circle) in the lateral segment right middle lobe depicted on the right thumbnail which was acquired with a volumetric acquisition.
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struggle with breath holding or those with more severe disease, in whom long breath holds of 10 seconds or more can be problematic. The protocol is relative new and more studies are needed to assess its true potential, but early studies indicate minimum breathing artifact with freebreathing protocols using this type of application (►Fig. 6).
Fig. 4 Minimum intensity projection depicts multiple dilated airways in the right middle and lower lobes. Note the clear, sharp depiction of the dilated airways compared with the uninvolved left lung. Note also the “mosaic” appearance to the right lung, particularly in the periphery —a CT finding frequently found in patients with bronchiectasis.
A recent hotly debated topic in imaging has been the radiation dose incurred by CT in both non-CF and CF bronchiectasis.22,23 There has been considerable confusion in the literature surrounding this theme related to conflicting methodology, different phantoms conditions, different scanner types and parameters, and different methods for estimating the subsequent cancer burden. It is now considered that there is a definite small but significant risk of developing cancer from CT radiation.24,25 The exact risk is difficult to accurately estimate, as all current risk estimates are based on theoretical exposures and dose results from Japanese atomic bomb survivors, but it is felt to be small.26 A consistent conclusion is that the younger the patient, the higher the risk of developing subsequent cancer.27 This has particular relevance to the CF population, in whom biennial high-
Fig. 5 (A) Expiratory CT image showing multiple areas of mosaic attenuation (asterisk) in all lobes associated with areas of bronchiectasis (curved arrows). (B) Histological appearances of obliterative bronchiolitis with peribronchiolar fibroinflammatory process (arrows), which surrounds the lumen with concentric narrowing and obliteration of the bronchiolar lumen (Br) (hematoxylin and eosin stain, 10 magnification; scale bar, 100 µm). (C) Histological appearances of obliterative bronchiolitis with scar (asterisk) adjacent to pulmonary artery (PA) secondary to a completely occluded bronchiole with some residual bronchiolar wall smooth muscle (SM) (hematoxylin and eosin stain, 10 magnification; scale bar, 100 µm).
Fig. 6 (A) Axial, (B) coronal soft tissue, and (C) coronal lung reformations showing motion-free contours of the pulmonary vessels and the diaphragm in a freely breathing patient without the use of ECG synchronization (used with permission from Bauer et al 20). Seminars in Respiratory and Critical Care Medicine
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Imaging in Bronchiectasis—Radiation Dose
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resolution CT (HRCT) surveillance to detect and monitor structural changes has been advocated from an early age.28 The debate has now moved from the established association between radiation exposure and cancer risk to dose reduction, using the lowest achievable levels while maintaining diagnostic image quality. The desirable chest CT dose is now considered to be submillisievert < 1 mSv.29 Many different industry CT innovations have occurred in the last 3 to 5 years to achieve this.
Low-Dose CT-Reducing Peak Kilovoltage and Milliampere Second The most important CT development in reducing radiation dose in bronchiectasis imaging has been the recognition that the peak kilovoltage (kVp) and milliampere (mA), two parameters that impose the radiation dose to the patient, can be significantly reduced without affecting diagnostic image quality. The tube voltage, or kVp, is the most important parameter because it reduces radiation dose exponentially as its decreased. Thus, a relatively small change in voltage of 20 kVp (from 140 to 120 kVp or from 120 to 100 kVp) results in a decrease in radiation dose of 30 to 40%.30 The traditional kVp for a chest CT is 120, and most centers have now adopted a reduced kVp in CF patients to 100 kVp. Some centers have reduced the kVp further to 80, so-called ultra-low-dose protocols. This ultra-low-dose protocol works well in CF because most patients have a low body mass index and image quality is minimally affected. Less substantial, though significant, reductions can be achieved by lowering the tube current, as expressed in mAs. Tube current has a direct linear relationship to radiation dose. The traditional mAs for chest CT is between 200 and 300 mA for most scanners, and this can be reduced to 50 to 80 mA with little effect on diagnostic image quality (►Fig. 7).
Fig. 7 Axial CT image of (A) a standard chest CT at 120 kVp and 2 years later; (B) an ultra-low dose CT at 80 kVp was performed in the same patient. Note that although the ultra-low dose CT image appears more noise, there are no significant differences in diagnostic image quality.
Iterative Reconstructions—A New Radiation Dose Lowering Method of CT Image Reconstruction For many years, CT images have been reconstructed using a method called filtered back projection. This has required typical kVp and mA values of approximately 120 and 250, respectively, to generate diagnostic image quality. This results
Fig. 8 (A) Traditional standard filtered back projection image reconstruction versus (B) Iterative image reconstruction. Note the slightly more “bleached” appearance to the iterative reconstruction image, with no loss of diagnostic image quality. Note also the aspergilloma in one of the cystic dilated airways (arrow).
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final and perhaps most simple adjustment to CT protocols which should be regularly emphasized to technologists in the CT scan room is the importance of the craniocaudal scan coverage. Considerable education should be inputted into technologist education pieces regarding the importance of the scan range as a crucial way of reducing dose (►Fig. 9).
Imaging in Bronchiectasis—Contemporary Clinical Applications
Fig. 9 Keeping the scan range tight in the craniocaudal direction dramatically decreases radiation dose. A poorly planned scan range (solid horizontal lines) includes too much of the neck and below diaphragm tissues. A more strategic scan range (dotted lines) starts at the apex of the lungs and stops at the lowest costophrenic angle—this can reduce radiation dose by 20 to 25%.
in standard chest CT radiation doses in the order of 3 to 6.5 mSv in adults.31 Newer preprocessing methods of image reconstruction allow the use of lower kVp and mAs to derive similar imaging information while reducing radiation dose. These are termed iterative reconstructions, and in fact have been available for many years but have required prohibitive computational time. It is only with the advent of more powerful computing technology that they have become a reality in clinical practice. They result in an increase in image quality, a decrease in image noise, and an improvement in spatial resolution. Radiation dose reductions in the order of 30 to 40% are achieved using these reconstructions and their application is becoming widespread32,33 (►Fig. 8).
Reduced Scan Range Such ultra-low-dose HRCT approaches have gone a long way to reducing radiation exposure to the patient. But a
Many CT scoring systems have now been developed to objectify and score the severity of lung disease in both CF and non-CF bronchiectasis.34 The initial CF Bhalla score has undergone numerous modifications since its initial publication.35 The two most commonly used CF-CT scoring systems are the modified Bhalla scoring system (►Table 1)36 and the modified Brody scoring system.37 Both score the extent and severity of lung disease on CT with similar accuracy, and allow an objective and quantitative assessment of lung disease, within-patient comparisons over time, and between patient comparisons over time in different patient subgroups. Although CT scoring systems in non-CF bronchiectasis are less well validated, there is evidence that at least the extent of bronchiectasis is associated with increased morbidity and mortality. The recently developed bronchiectasis severity index (BSI) is a useful clinical predictive tool that identifies patients at risk of future mortality, hospital admissions, and exacerbations.38 Independent predictors of the BSI included prior hospital admissions, Medical Research Council dyspnea score 4, forced expiratory volume in 1 second < 30% predicted, Pseudomonas aeruginosa colonization, colonization with other pathogenic organisms, and three or more lobes with bronchiectasis on HRCT. Significant differences in exacerbation frequency and quality of life between patients classified as low, intermediate, and high risk by the score have been demonstrated.
Table 1 Modified Bhalla CT scoring system39 CT abnormality
0
1
2
3
Severity of bronchiectasis
Absent
Lumen slightly > adj. vessel
Lumen ¼ 2–3 adj. vessel
Lumen > 3 adj. vessel
Peribronchial thickening
Absent
AWT ¼ adj. vessel
AWT 2 adj. vessel
AWT > 2 adj. vessel
Extent of bronchiectasis (BPS)
Absent
1–5
6–9
>9
Extent of mucous plugging (BPS)
Absent
1–5
6–9
>9
Sacculations/abscesses (BPS)
Absent
1–5
6–9
>9
Generations of bronchial divisions
Absent
Up to 4th generation
Up to 5th generation
Up to 6th generation
No. of bullae
Absent
Unilateral
Bilateral
>4
Collapse/consolidation
Absent
Subsegmental
Segmental/lobar
Air trapping
Absent
1–5
>5
Abbreviations: adj., adjacent; AWT, airway wall thickening. Seminars in Respiratory and Critical Care Medicine
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Fig. 10 A 30-year-old woman with CF. (A) Flow–volume (F/V) loop at time 1 demonstrates FEV1 of 2.9 L (94% of predicted). (B) Transverse 1-mm HRCT image through the upper lobes demonstrates moderate bronchiectasis (straight arrow) and peribronchial wall thickening (curved arrow) and an apical bulla (arrowhead). (C) Twenty-nine months later, the F/V loop demonstrates FEV1 of 2.7 L (88% of predicted). (D) Transverse 1-mm HRCT image through the upper lobes demonstrates marked progression of disease with new and severe bilateral upper lobe collapse (note the anterior shift of the left major and right minor fissures, straight arrows) and marked progression in the extent and severity of bronchiectasis (curved arrows).
CF Lung Disease Surveillance Using HRCT A large body of work has now been published on using HRCT to survey disease changes in CF lung disease.39,40 It is well known that lung disease changes are heterogeneous in CF lung disease, and that spirometry provides a global picture of lung disease. Many centers have now incorporated surveillance HRCT every 2 to 3 years to better assess the progression of CF lung disease over time and in response to treatments. Many patients demonstrate entirely stable or mildly reduced spirometry over significant periods of time but declining HRCT scores with progressive structural changes. Individual HRCT abnormalities decline at different rates depending on the degree of lung function impairment (►Fig. 10).39,41 The reason for this is that lung function provides an indirect measure of overall lung disease, but is insensitive to small yet cumulative focal lung damage that occurs in an indolent fashion in CF patients over many years. It has become clear that some patients exhibit greater changes in CT with lesser changes in spirometry over time, while others demonstrate the opposite.40,42 As a result, multimodality assessment with both spirometry and CT has been advocated by many.43 A particularly important development has been the recognition of structural lung damage from a much early age than Seminars in Respiratory and Critical Care Medicine
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previously identified. Lung disease may be identified in infants within the first week of life,44 with abnormalities reported in lung function, pulmonary inflammation, and P. aeruginosa.45 The AREST studies have shown children with CF
Fig. 11 Kaplan–Meier plot of the proportion of patients with cystic fibrosis who were alive while awaiting lung transplant. Individuals are grouped in tertiles (tertile 1, < 25 [solid line]; 2, 26–32 (dashed line); 3, > 33 (dotted line).
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Fig. 12 Cine dynamic tracheal CT in a patient with CF taken in inspiration and during dynamic expiration. (A) A normal tracheal diameter (arrow) during full inspiration. (B) there is marked collapse of the trachea of 89% cross-sectional area (arrow) during forced expiratory maneuvers.
diagnosed by newborn screening can also have structural damage on HRCT.46 In a landmark study assessing prevalence of lung disease in 57 infants with CF, overall 80.7% demonstrated an abnormal CT; 18.6% had bronchial dilatation, 45.0% had bronchial wall thickening, and 66.7% had gas trapping. Thus, investigative and treatment strategies are undergoing more aggressive changes at earlier ages in CF.
Lung Transplantation in CF—Who Should Be Listed? Up to one-third of patients with CF awaiting lung transplant (LTX) die while waiting. Improvements to the inclusion criteria for transplantation are needed. In a prospective multicenter (17 centers) study of 411 patients with CF screened for LTx, CT scans were scored for infection/inflammation (INF), air trapping/hypoperfusion, normal/hyperperfusion, bulla/cysts, and a total lung score (LAS).19 Three hundred sixty-six (186 males) of 411 patients entered the waiting list and 67 (18%) died while waiting, 263 of 366 (72%) underwent LTx, and 36 of 366 (10%) were awaiting LTx at the census date. Multivariate Cox analysis including INF and LAS indicated that INF and LAS had significant, independent predictive value for survival. The authors concluded that CT scores for infection and total lung disease correlate with and add to the predictive value of survival in CF while awaiting transplant (►Fig. 11).
Tracheomalacia in CF—Cine Tracheal Multidetector CT There is considerable evidence that many patients with CF and non-CF bronchiectasis have tracheomalacia. Histopathologic studies have revealed reduced amounts of cartilage within the walls of bronchiectatic airways in CF.47 Others have shown destruction of cartilage in chronically colonized tracheal walls. It has also been shown that cartilage extends for a shorter distance along bronchial
walls in patients with CF compared with the cartilage extension in control subjects, and is typically preceded by a marked inflammatory infiltrate with increased numbers of macrophages and severe chondrolysis.48–50 Multidetector cine tracheal CT is being increasingly used to evaluate tracheomalacia because it is noninvasive.51,52 A cross-sectional study in patients with CF using cine tracheal CT evaluated tracheal changes in both forced expiratory maneuvers and coughing, and demonstrated dramatic reductions in tracheal luminal diameters during both procedures, worse on coughing.53 Tracheomalacia was demonstrated in 69% of patients during forced expiratory maneuvers and in 29% of patients during coughing (►Fig. 12).
Nontuberculous Mycobacterium and Non-CF Bronchiectasis—Using Chest CT to Improve Detection Several recent studies support the finding that bronchiectasis on CT together with signs of bronchiolitis, namely centrilobular and tree-in-bud nodules, are indicative of nontuberculous mycobacterium (NTM) infection.54,55 Bronchiectasis is most commonly seen in the right middle lobe and/or lingula. In a study by Koh et al of 126 patients suspected of NTM, when more than five lobes showed bronchiectasis and bronchiolitis on CT, particularly in association with consolidation or cavities, appearances were highly suggestive of NTM.54 So strong is the association between NTM and bronchiectasis that many have postulated that NTM may in fact cause bronchiectasis, although this requires further corroboration. McEvoy et al applied a similar imaging approach to patients with CF.36 In 27 NTM-positive CF patients, findings suggestive of NTM(þ) were similar but more extensive than those of Koh et al. The findings on CT of >7 Seminars in Respiratory and Critical Care Medicine
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Fig. 13 (A) HRCT image from a patient with NTM-positive sputum 3 with multifocal cavitation (arrows) and tree-in-bud nodules (arrowheads) in more than five lobes. (B) Acutely inflamed bronchiectasis (Br) (hematoxylin and eosin stain, 2 magnification; scale bar, 1 mm). (C) Higher power view of the squared area showing suppurated epithelioid and giant cell granuloma (hematoxylin and eosin stain 20 magnification; scale bar, 100 μm). Acid fast bacillus identified on Ziehl-Neelsen stain (inset: 60 magnification; scale bar, 10 μm).
bronchopulmonary segments showing CT signs of bronchiolitis, particularly when associated with consolidation and peribronchial wall thickening, were highly suggestive of NTM(þ) (►Fig. 13).
Mounier–Kuhn Syndrome and Bronchiectasis Mounier–Kuhn syndrome is characterized by tracheobronchial dilation secondary to atrophy of the muscular and elastic tissues in the trachea and main bronchial walls.56 Diagnostic imaging criteria include a tracheal width exceeding 3 cm, a right mainstem bronchial diameter > 2.5 cm, and a left mainstem bronchial diameter > 2 cm in cross section.57,58 It has a predilection for males, and typically presents with chronic cough and recurrent respiratory infections. The muscle atrophy was originally described by Katz et al and is one of the major reasons the condition is Seminars in Respiratory and Critical Care Medicine
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typically associated with numerous tracheal diverticulae.59 It is becoming increasingly recognized and reported as the realization that CXR may have underestimated its prevalence as well as the wider availability and applicability of chest CT. Dynamic cine CT may demonstrate tracheomalacia and patients often develop central obstructive physiology (►Fig. 14).
Allergic Bronchopulmonary Aspergillosis HRCT of the lungs has been used to improve the diagnosis of ABPA. Several features on CT can be used to diagnose ABPA with high accuracy.60 Early reports utilized the finding of predominantly central bronchiectasis to specifically detect the disorder, but subsequent studies have shown this finding to be less sensitive and specific, and a combination of airway wall thickening, mucus plugging, high-density mucus
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Fig. 14 (A) Axial CT of the upper trachea shows a grossly dilated trachea measuring 3.9 cm. Note the tracheal diverticulum (arrow). (B) Axial CT image of the lower lobes shows severe cystic bronchiectasis with multiple air–fluid levels.
plugging, mosaic perfusion, and atelectasis in addition to bronchiectasis improves the diagnostic accuracy of CT considerably.60–62 In general, three or more lobes are involved on CT in proven cases. CT abnormalities are included in the diagnostic criteria for ABPA (►Fig. 15).
Non-CF Bronchiectasis and Other Pulmonary Diseases It is now clear that there is a significant prevalence of bronchiectasis in patients with chronic obstructive airways disease (COPD). Several studies have suggested prevalence as high as 57%.63 It is also known that COPD patients with bronchiectasis have a higher mortality than those without bronchiectasis. This finding is supported by studies that have found that patients with both COPD and bronchiectasis have increased bronchial inflammation; longer, more severe, and more frequent exacerbations; more virulent organisms in the bronchial mucosa; and worse lung function.64 The prognostic value of the presence and severity of bronchiectasis suggests the ability to detect patients with a COPD–bronchiectasis phenotype. This carries important implications in terms of promoting earlier identification and establishment of early and more aggressive treatment against infection (►Fig. 16).
Imaging in Bronchiectasis—Treatment Responses Disease-Modulating Agents in CF
Fig. 15 Axial CT image of a 48-year-old woman with ABPA. Her CT shows central bronchiectasis (curved arrows) in the right middle and lower lobes and extensive mucoceles (straight arrows) and peripheral atelectasis (arrowhead) in the right lower lobe. Note the considerable airway wall thickening (asterisk).
Tremendous interest is being generated by the development of several disease-modifying agents in CF lung disease. The most evaluated of these is ivacaftor, a drug designed to increase the time that activated CF transmembrane conductance regulator channels at the cell surface remain open. In a randomized, double-blind, placebo-controlled trial of ivacaftor versus placebo, CF patients receiving the drug demonstrated improvements in lung function at 2 weeks that were sustained through 48 weeks.65 Improvements in HRCT abnormalities have also been documented following the use of ivacaftor.66 These include a decrease in airway wall thickening, a decrease in mucus plugging, and a decrease in ground glass opacities (►Fig. 17).
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Fig. 16 (A) Axial CT image showing multifocal areas of centrilobular emphysema in the upper lobes (arrows). (B) Diffuse bronchiectasis is seen in the right middle and lower lobes. Note airway wall thickening (arrow) and mucus plugging (arrowhead) in the right lower lobe.
Fig. 17 (A) Axial CT image pretreatment with ivacaftor. Note the diffuse airway wall thickening (arrows) and subsegmental consolidation (arrowhead). (B) Following 2 years of ivacaftor treatment, note the reduction in airway wall thickening (arrows) and consolidation (arrowhead).
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