CT Imaging of Interstitial Lung Diseases
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Until today, computed tomography (CT) is the most important and valuable radiological modality to detect, analyze, and diagnose diffuse interstitial lung diseases (DILD), based on the unsurpassed morphological detail provided by high-resolution CT technique.
In the past decade, there has been a shift from an isolated histopathological diagnosis to a multidisciplinary acquired diagnosis consensus that is nowadays regarded to provide the highest level of diagnostic accuracy in patients with diffuse interstitial lung diseases. The 2002 ATS/ERS statement on classification of idiopathic interstitial pneumonias assigned a central role to high-resolution CT (HRCT) in the diagnostic workup of idiopathic interstitial pneumonias (ATS/ERS consensus classification 2002). The more recent 2013 ERS/ATS statement reinforced that combined clinical data (presentation, exposures, smoking status, associated diseases, lung function, and laboratory findings) and radiological findings are essential for a multidisciplinary diagnosis (Travis et al., Am J Respir Crit Care Med 188(6):733–748, 2013).
The traditional HRCT consisted of discontinuous 1 mm high-resolution axial slices. The primary focus was on visual pattern analysis demanding for the highest possible spatial resolution. Because of the intrinsic high structural contrast of the lung, it has been possible to substantially reduce dose without losing diagnostic information. This development has been supported by new detection and reconstruction techniques. Not only detection of subtle disease and visual comparison of disease stage but also disease classification and quantification nowadays take advantage of continuous volumetric data acquisition provided by multidetector row (MD) CT technique. The following book chapter will focus on acquisition technique with special emphasis on dose and reconstruction, advantages, and new diagnostic options of volumetric MDCT technique for interstitial lung diseases. Based on evidence from the literature, certain diseases will be covered more specifically, but it has to be noted that for the pattern analysis of the various interstitial lung diseases, the plethora of other publications and books is recommended.
KeywordsIdiopathic Pulmonary Fibrosis Interstitial Lung Disease Interstitial Pneumonia Maximum Intensity Projection Usual Interstitial Pneumonia
Until today, computed tomography (CT) is the most important and valuable radiological modality to detect, analyze, and diagnose diffuse interstitial lung diseases (DILD), based on the unsurpassed morphological detail provided by high-resolution CT technique.
In the past decade, there has been a shift from an isolated histopathological diagnosis to a multidisciplinary acquired diagnosis consensus, that is nowadays regarded to provide the highest level of diagnostic accuracy in patients with diffuse interstitial lung diseases. The 2002 ATS/ERS statement on classification of idiopathic interstitial pneumonias assigned a central role to high-resolution CT (HRCT) in the diagnostic workup of idiopathic interstitial pneumonias (ATS/ERS consensus classification 2002). The more recent 2013 ERS/ATS statement reinforced that combined clinical data (presentation, exposures, smoking status, associated diseases, lung function, and laboratory findings) and radiological findings are essential for a multidisciplinary diagnosis (Travis et al. 2013).
The traditional HRCT consisted of discontinuous 1 mm high-resolution axial slices. The primary focus was on visual pattern analysis demanding for the highest possible spatial resolution. Because of the intrinsic high structural contrast of the lung, it has been possible to substantially reduce dose without losing diagnostic information. This development has been supported by new detection and reconstruction techniques. Not only detection of subtle disease and visual comparison of disease stage but also disease classification and quantification nowadays take advantage of continuous volumetric data acquisition provided by multidetector row (MD) CT technique.
The following book chapter will focus on acquisition technique with special emphasis on dose and reconstruction, advantages, and new diagnostic options of volumetric MDCT technique for interstitial lung diseases. Based on evidence from the literature, certain diseases will be covered more specifically, but it has to be noted that for the pattern analysis of the various interstitial lung diseases, the plethora of other publications and books is recommended.
2 Acquisition Technique
Traditionally CT and HRCT were strongly differentiated with the latter being defined by a section thickness of <1.5 mm and the use of an edge-enhancing high-resolution reconstruction kernel. Since the advent of MDCT technique, which allows for covering the whole chest in thin section technique within one breath-hold, essentially each chest CT is a HRCT.
Reconstruction of 1, 3, or 5 mm thick slices determines the number of axial images to be evaluated. Besides for a given acquisition dose, a 3 mm thick slice has a better signal-to-noise ratio than a 1 mm thick slice. A 1 mm thick slice, however, offers a higher spatial resolution and thus superior morphological detail. These trade-offs therefore determine the choice of reconstruction depending on the clinical indication: analysis of an (advanced) tumor stage is mostly done with thicker slices, while analysis of diffuse interstitial lung disease or focal nodular disease requires maximum detail resolution and therefore thin slices.
Before the advent of MDCT, HRCT consisted of a thin section CT obtained with 1 mm slice thickness at 10 or even 20 mm gaps. The rationale behind such a protocol was that analysis of a diffuse parenchymal process does not require continuous coverage. Secondly, discontinuous scanning warranted the relatively high-dose use to achieve the excellent signal-to-noise, image quality, and thus detail resolution.
Modern MDCT scanners allow for acquisition of volumetric HRCT with high image quality at acceptable dose levels, which furthermore have been continuously decreasing over the last decades due to improved detector technology and advanced reconstruction algorithms (see also “iterative noise reconstruction”).
Modern scanners perform faster, allowing for a single continuous scan in deep breath-hold instead of acquiring discontinuous slices with multiple scans that require repetitive breath-hold maneuvers.
Volumetric 2D and 3D display techniques such as multiplanar reconstructions (MPR), maximum and minimum intensity projections (MIP and MinIP), as well as advanced volumetric quantification techniques became only possible with continuous volumetric data acquisition.
Volumetric scans allow for an easier and also more precise comparison of disease development over time in follow-up studies because slices exactly matching to each other can be compared.
Volumetric scans will also capture subtle and focal disease, potentially missed when data are acquired with large gaps in between.
Nevertheless a questionnaire among members of the European Society of Thoracic Imaging carried out in 2013 revealed that a subgroup of radiologists (15 %) still uses discontinuous HRCTs for analysis of interstitial lung diseases (Prosch et al. 2013). To which extent various aspects such as the scanner technology availability, expected image quality, or unwillingness to give up the old, but familiar techniques play a role in this remains unclear.
2.1 Scan Collimation and Slice Reconstruction
Whether the whole lung can be covered within one breath-hold with 1 mm collimation width depends on the speed of data acquisition. While a four-slice CT scanner still needed more than 25 s to cover a chest length of 30 cm, a 16-slice scanner provided already the technical base to cover the thorax (30 cm length) in less than 15 s when a table feed of 1.5 mm was used. A 64-slice scanner allowed for a scan time below 10 s. The most modern scanners (128-slice scanners and beyond) allow for coverage of the chest in less than 3 s while acquiring data with isotropic submillimeter resolution. Thus, speed of data acquisition within one breath-hold does not represent a limitation anymore.
Spatial resolution is increased by the application of a high-spatial-frequency reconstruction algorithm (Mayo et al. 1987). Standard algorithms lead to smoothening of the image in respect that visible image noise is reduced and contrast resolution increased. Sharp, high-spatial-frequency, or high-resolution algorithms, on the other hand, reduce image smoothening and increase spatial resolution. Anatomic margins and tissue interfaces, such as the fissure, pleura, or septa, appear sharper. Small vessels and bronchi are seen superiorly compared to a standard algorithm.
Reducing the field of view results in smaller pixel sizes and thus increases spatial resolution. In general, the field of view should be adjusted to the size of the lungs, usually resulting in a spatial resolution of 0.5–0.3 mm. To ensure that the field of view does not cut off any parts of the lung, it is usually limited by the diameter of the external cortex of the ribs.
To further increase spatial resolution, targeting of the field of view to a single lung or particular lobes or regions can be performed. Such an approach may be used for minute evaluation of the parenchyma or peripheral bronchi beyond the regular evaluation of images demonstrating both lungs. However, with this approach, the spatial resolution will be limited by the intrinsic resolution of the detectors and whether it will gain diagnostic information will largely depend on personal preferences. There is no literature reference that generally recommends this approach, not even for certain indications. In addition, it requires additional reconstruction time, the raw data scan must be saved until targeting is performed, and it precludes the ability to compare both lungs on the same image.
2.2 Dose Aspects
One of the major arguments not to change from discontinuous HRCT (10 or 20 mm gap) to continuous volumetric data acquisition was the associated increase in dose. Since 1 mm thin sections need to have a certain signal-to-noise level to provide acceptable diagnostic image quality, it was inevitable that volumetric data acquisition would deliver a higher dose to the patient.
Dose ranges of HRCT techniques demonstrating the potential of modern dose-reduction techniques
Effective radiation dose (mSv)
Yearly background radiation
PA chest radiograph
Discontinuous HRCT (10 mm gap)
Volumetric HRCT with xyz-modulation
Volumetric HRCT with iterative noise reconstruction
There is a multitude of publications evaluating low-dose protocols (40–60 mAs), most of them for the detection of nodules or within a screening setting. Those results cannot be directly transferred to the diagnostic workup of DILD, in which detection of ground-glass opacities and fine septal thickenings is required. Christe A et al. systematically evaluated the efficiency of a low-dose protocol for the detection of common patterns of pulmonary diseases evaluating 1 mm slices, reconstructed with filtered back projection (FBP) and a high reconstruction kernel. They concluded that a 120 kVp/40 mAs protocol was feasible for detecting solid nodules, air space consolidations, and airway and pleural diseases; however, pathologies consisting of ground-glass opacities and interstitial opacities required higher tube current or iterative noise reconstruction (Christe et al. 2013).
Some studies evaluated the visualization of certain elements of lung infiltration and diffuse lung disease: an improved detection of ground-glass opacities, pulmonary nodules, and emphysema had already been reported with first-generation IR in vivo (Pontana 2011) and by experimental studies (Christe et al. 2012). Similarly an excellent inter-method agreement comparing IR and FBP images for the detection of emphysema, GGO, bronchiectasis, honeycombing, and nodules has been described (Ohno et al. 2012). No study evaluating the impact on the diagnostic evaluation of diffuse interstitial lung disease has been published yet, but nevertheless it can be anticipated that modern IR allows for substantial (around 50 %) dose reduction of volumetric HRCT for DILD, which represents an important step forward in terms of radiation protection, especially for young patients and patients with multiple follow-up studies.
2.3 Prone Position
In the normal lung with the patient supine, there is a gradual increase in attenuation and vessel size from ventral to dorsal lung regions. This attenuation gradient is caused by the effect of gravity on blood flow and gas volume as well as some non-gravity-dependent effects. This density gradient is accentuated on expiration (Verschakelen et al. 1998). Hypoventilation and atelectasis in the dependent lung can cause areas of dependent density or subpleural lines, which can mimic early lung fibrosis.
With the patient in prone position, these hydrostatic densities will immediately disappear, while abnormalities caused by real pathology will remain. Therefore, in some cases it may be necessary to obtain images in prone position to differentiate actual disease from physiologically dependent densities or atelectasis. This is especially true when the detection of ground-glass opacities or curvilinear subpleural lines are of diagnostic relevance (e.g., in patients with subtle disease or in patients with asbestosis).
Publications dating from more than 15 years ago – thus obtained with slower scanners and discontinuous HRCT technique – found that prone scanning was useful in almost 20 % of patients (Volpe et al. 1997). This proportion is certainly too high, given the fast scanning technique available today. Prone scanning is not indicated routinely anymore. Some colleagues may prefer it in selected cases, e.g., patients with questionable, subtle disease exclusively in the dorsobasal area of the lung which would be decisive for the presence or absence of disease.
A questionnaire obtained in 2013 did not reveal a real consensus about the use of additional CT acquisitions in the prone position, though it was recommended to be performed on demand only (Prosch et al. 2013). This, however, requires the scans to be closely monitored or that the patient is called back for additional scanning. In patients with emphysema, airway disease, or diffuse obstructive lung disease, prone scans are usually not needed.
2.4 Expiratory Scans
Scans are routinely obtained in full inspiration with the lungs fully expanded, which optimizes the contrast between low-attenuation aerated air space and high-attenuation lung structures and various abnormalities. At the same time, full inspiration minimizes the frequency of confounding densities due to transient atelectasis.
Additional expiratory HRCT scans have proved useful in the evaluation of patients with a variety of obstructive lung diseases. Focal or diffuse air trapping may be detected and can be essential in the differentiation of large or small airway disease and emphysema (Kauczor et al. 2011).
The guidelines of the British Thoracic Society recommend the routine use of expiratory scans in patient’s initial HRCT evaluation (Wells and Hirani 2008). The rationale behind this is the potential value of air trapping for the differential diagnosis that can be appreciated on an expiratory scan, even in the absence of inspiratory scan abnormalities and the fact that the functional cause of respiratory disability is not always known, especially during the initial diagnostic phase. Within the context of management of interstitial lung disease, the British Thoracic Society suggest that after a diagnosis has been set, additional expiratory CT acquisitions should only be performed to evaluate inconclusive findings on inspiratory CT.
Because of dose considerations, most investigators obtain some expiratory scans on predetermined levels or discontinuous clusters (Prosch et al. 2013). There are various ways how to plan these scans: either in areas of pathology seen in inspiration or on specific predefined levels following anatomic landmarks (e.g., carina, aortic arch) in order to facilitate reproducibility in follow-up scans. How many levels need to be covered is unclear and ranges from 2 to 5. Alternatively also the expiratory scan can be obtained with volumetric data acquisition. It has the advantage of decreasing the risk of motion artifacts frequently seen in discontinuous expiratory scans, allows for quantification on a 3D basis, and allows for more precise, level-matched follow-up. Since the only purpose of these scans is the detection, localization, and quantification of air trapping, these scans can be obtained with a drastically reduced dose. Multiple studies have shown that tube current levels as low as 40 mAs are sufficient for the diagnostic purpose intended. Bankier et al. carried out a systematic comparison of expiratory CT scans obtained with 120 kV, 80 mAs, and simulated 60, 40, and 20 mAs scans and found that – though diagnostic confidence went down with decreasing acquisition dose and interreader variability went up – diagnostic accuracy was not affected (Bankier et al. 2007). Similar results had been published also by other authors (Nishino et al. 2004).
Sharply demarcated areas of air trapping need to be differentiated from ill-defined areas of varying parenchymal density in expiration. The latter is seen frequently and has been interpreted as “inhomogeneous emptying” of the lung in expiration. Correlation of scans during inspiration and expiration illustrating the unaltered volume and density in lobuli with air trapping represents the diagnostic clue.
Expiratory CT scans are also used for interpretation of a mosaic pattern seen in inspiration. Mosaic pattern is defined as areas of varying density, sharply demarcated by interlobular septa. To differentiate whether the area of increased attenuation represents ground glass, e.g., caused by an acute alveolar or interstitial process, or that the area with hypoattenuation represents air trapping caused by bronchiolitis, expiratory CT scans are very helpful.
An increased contrast between hypo- and hyperattenuated areas in expiration demarcates air trapping as pathology and bronchiolitis as underlying disease. There are less vascular structures visible in the “black” areas of hypoattenuation due to the Euler-Liljestrand reflex, causing vascular constriction in areas of lower ventilation. Importantly there are no signs of pulmonary hypertension.
A decreased contrast between hypo- and hyperattenuated areas in expiration demarcates ground glass as pathology and an acute alveolar/interstitial process as underlying disease. There is no difference in vascular calibers in the areas of different attenuation.
Thirdly, pronounced differences in vascular diameter between the areas of different attenuation indicate true mosaic perfusion. Additional signs of pulmonary hypertension, such as dilated central pulmonary arteries and pathological arterio-bronchial ratio, may be present. The underlying disease is recurrent pulmonary emboli. Though discrimination of the different underlying diseases is also possible by analyzing the vascular diameters only, many radiologists consider the information of increased contrast differences caused by air trapping the most valuable and reassuring.
Instead of acquiring the CT scans after full expiration in suspended respiration, other authors have proposed to acquire the data during forced expiration, more specifically to perform data acquisition during the dynamic process of forced expiration. While especially end-expiratory air trapping might be seen with higher sensitivity, the risk for considerable breathing artifacts hampering image quality has to be outweighed against the potentially increased diagnostic information. Dynamic scans were firstly introduced using an electron beam CT; however, it can also be performed with any MDCT scanner with a gantry rotation time of 1 s or less. Because images can be reconstructed at any time point during the scan, the temporal resolution is even higher than with the electron beam CT. Mostly continuous imaging is performed on a single axial level for 6–8 s as the patient expires rapidly. Acquisition dose is drastically reduced (usually 40 mAs). Lucidarme et al. (2000) found a significantly higher density difference between the different areas of attenuation and a higher extent of air trapping in dynamic scans as opposed to static scans, but the number of patients for which dynamic scan acquisition changed the diagnosis has been found to be small (Gotway et al. 2000).
A detailed instruction of the patient is important to avoid motion artifacts and to assure that the scan acquisition takes part in the desired respiratory status. A visual qualitative control for the inspired or expired state is possible by analyzing the shape of the trachea: in full inspiration the trachea demonstrates a round shape, while in expiration there is bulging of the dorsal membranous part of the trachea ventrally and intraluminally to a various extent. A too strong deformation producing a considerable reduction of the tracheal area and demonstrating a moon-like (luna) shape is associated with tracheomalacia which can be a hint toward severe obstructive lung disease (O’Donnell et al. 2014).
2.5 Motion Artifacts and ECG Gating
Motion artifacts caused by non-suspended respiration are common and can severely hamper a meaningful interpretation of the images. Respiratory motion leads to blurring of normally sharp details, pseudo-ground-glass opacities, and linear streaks or star artifacts from edges of vessels and other high-density structures.
On lung window setting, gross respiratory motion artifacts are normally easily recognizable, and while they degrade image quality, they will not cause misinterpretation because of their obviousness. Subtle motion-related unsharpness and ground-glass opacities, however, may mimic an interstitial process; doubling of vascular structures can mimic thickened interlobular septa or walls of a dilated bronchus.
A dedicated and detailed instruction of the patient how to deeply breathe in and out and especially to hold the breath before data acquisition is therefore an important step toward high image quality (Vikgren et al. 2008).
Cardiac pulsation artifacts typically affect the paracardiac regions of the left lower lobe and to a lower extent of the lingula and middle lobe. Aortic pulsation may affect lung areas adjacent to the aortic arch or the descending thoracic aorta, being the segments six and ten of the left lower lobe. In selected cases these pulsation artifacts may be misleading and can cause false positive findings. Typical artifacts are double contours of the bronchial walls mimicking bronchiectasis and hyperlucencies close to arteries mimicking emphysema. Usually they do not cause diagnostic problems if correlated to the blurred heart contour.
Options to reduce pulsation artifacts are reduced gantry rotation time, segmented reconstruction, or ECG triggering of scan acquisition. Reduced gantry rotation time and segmented reconstruction are means to increase scanning speed, but they go along with decreased dose delivery and thus increase of image noise. Prospective ECG triggering leads to a significant prolongation of measurement time, which interferes with the breath-hold capabilities of many patients. Retrospective cardiac gating would therefore be the method of choice to avoid disturbing pulsation artifacts at the expense of a markedly increased acquisition dose. In principal, techniques for coronary CT imaging can be used, without contrast administration, adaptation of the FOV to cover both lungs, and adaptation of acquisition dose. Similarly to motion-free imaging of the coronaries, motion-free imaging of the lung parenchyma would be achieved.
Nevertheless, the few studies that compared image quality with and without ECG triggering – carried out with relatively small groups of patients – found a significantly increased image quality based on artifact reduction, however, without relevant impact on diagnostic performance or confidence (Boehm et al. 2003). With the fast rotation time of most scanners used today, cardiac pulsation artifacts are significantly reduced and there appears no indication for ECG triggering for diagnostic workup of interstitial lung diseases.
3 Image Display and Processing
There is no single correct or ideal window setting for evaluating the lung parenchyma. Window settings have to be optimized with regard to the settings of scanners and monitors. Several combinations of window level and window width may be appropriate, and individual modifications based on personal preferences play a role.
Nevertheless, it is advisable to use a chosen lung window setting consistently in all patients to optimize comparison between different patients and between sequential examinations of the same patient. It is also very important to use window settings constantly to develop a visual default and thus understanding of normal and abnormal findings. Additional window settings may be useful in specific cases, depending on what abnormality is in question.
For the assessment of a routine lung examination, window level settings ranging from −600 to −700 HU and window widths of 1000–1500 HU are recommended. Wider window width (i.e., 2000 HU) may be applied for the evaluation of overall lung attenuation and high-contrast interfaces, especially of peripheral parenchymal abnormalities along the pleural interfaces. For example, wide windows are therefore advised for the assessment of asbestosis.
Low window level settings (e.g., −800 to −900) and narrow window width (500 HU) facilitate the detection of subtle attenuation differences and are therefore suited for the detection of emphysema, air trapping, or air-filled cystic lesions.
As a result, it might be necessary to use different window settings for identifying pathological changes of the parenchyma or the pleura on one side and for the measurement of bronchial diameter and wall thickness on the other side. Window level settings of 40–50 HU and window width settings of 350–450 HU are generally recommended for evaluation of the mediastinum, the hili, and the pleura.
3.2 Multiplanar Reformations
Multidetector-HRCT produces an isotropic dataset that allows for contiguous visualization of the lung parenchyma in three dimensions and to create multiplanar two-dimensional (2D) reconstructions in any arbitrary plane. Mostly planar coronal and sagittal reconstructions are routinely performed and considered standard for reconstructed series of any HRCT dataset (Prosch et al. 2013; Beigelman-Aubry et al. 2005; Walsh et al. 2013) (Fig. 2).
Coronal reformations facilitate the display of disease distribution, e.g., the craniocaudal gradient representing a key finding in idiopathic pulmonary fibrosis (IPF) or the upper lobe predominance in sarcoidosis or Langerhans cell histiocytosis (LCH). Coronal MPRs are also preferred by many clinicians because they facilitate anatomic orientation (Eibel et al. 2001a) and produce images more easily comparable to chest radiographs. Advantages of sagittal MPR include the sharper delineation of the interlobar fissures and thus an improved anatomic localization of lesions close to the lobar border or for lesions with transfissural extent (Eibel et al. 2001a, b). Sagittal images also ease the evaluation of the thoracic spine and the dorsal costophrenic angle.
For the dedicated evaluation of the relationship between parenchymal lesions and airways, curved MPR can be useful following the course of the branching tubular airways (Lee and Boiselle 2010). Both coronal and sagittal MPR are superior to the axial scans alone to illustrate the location and extent of abnormalities situated in the central tracheobronchial system.
Though there is a high level of concordance between reading coronal and axial slices with regard to the identification of parenchymal disease, there is a general agreement that coronal or sagittal MPRs have a complimentary role, but are not regarded as the principle scan plane used for diagnostic evaluation.
3.3 Maximum Intensity Projection
In one study 103 patients with suspicion or evidence of pulmonary nodules underwent MDCT with a collimation of 1 mm. MIP and MPR were reconstructed in all three planes. The MIP were superior in the depiction of pulmonary nodules at a statistically significant level. Additional lesions were identified with MIP that were missed with transaxial slices and MPR. The improvement by MIP was based on the identification of nodules smaller than 5 mm in diameter. The improvement by MIP also led to an increase in diagnostic confidence (Eibel et al. 2001b). In a different study, MIPs led to the detection of additional findings in 27 % of patients with nodular disease (Gavelli et al. 1998).
Finally, MIP sections of variable thickness allow assessing the size and location of pulmonary vessels. Recognizing enlarged pulmonary veins is useful in differentiating the diagnosis of pulmonary edema from other causes of diffuse ground-glass attenuation. In case of a mosaic attenuation pattern, MIP contributes to the differentiation of ground-glass attenuation (normal vascular diameter) and mosaic perfusion (altered vascular diameter). Eventually, MIP can help to differentiate between constrictive bronchiolitis and mixed emphysema (Beigelman-Aubry et al. 2005).
3.4 Minimum Intensity Projection
3.5 Quantitative CT as Imaging Biomarker
CT is increasingly being used to stage and quantify the extent of DILD both in clinical practice and in treatment trials. The continuous data acquisition of CT with high isotropic resolution provides unique options for computer-supported quantification of diffuse lung disease. There has been a history in quantifying emphysema and airway disease in COPD patients with the ultimate goal to identify different phenotypes in the spectrum of COPD. Recently, these efforts of computer-based analysis have been expanded to DILD.
Mostly, DILD often consists of a mix of various patterns that show a considerable overlap between different DILD, rendering it difficult to clearly distinguish one from the other.
The characterization of the pattern is influenced by inspiration depth, motion artifacts, and overlying other diseases such as infection.
The extent of architectural distortions in all three spatial dimensions and within the lobular anatomy is difficult to assess.
Multiple studies have shown that type and extent of parenchymal changes, including accompanying airways pathology, correlate with lung function, disease progression, response to therapy, and last but not least, disease prognosis. It has to be stated however that the extent of correlation is very variable for the different diseases and highly dependent on the type of pathology and thus the appreciated HRCT pattern.
Goh and colleagues proposed an interesting concept of combining a relatively simple visual quantification with pulmonary function (Goh et al. 2008). Firstly, the disease extent was differentiated into minimal or severe (less or more than 20 % involved lung area). For the subgroup of patients in which the disease extent was not readily classifiable on HRCT (so-called indeterminate), the distinction between limited and extensive was based on FVC threshold values below or beyond 70 % predicted (FVC = forced expiratory vital capacity). Using this relatively simple two-step approach, the authors were able to discriminate two groups of patients with significantly different outcomes and thus prognosis.
A similar approach of combining extent of disease on HRCT with pulmonary function tests has been successfully applied to patients with sarcoidosis and connective tissue diseases. For example, severity of traction bronchiectasis, extent of honeycombing, and DLco were found to be strongly associated with mortality in connective tissue disease related fibrotic lung disease (Walsh et al. 2014a, b). Similarly an extent of fibrosis exceeding 20 %, the diameter ratio between the aorta and main pulmonary artery, and a composite score of pulmonary function tests formed a significantly more effective prediction for mortality in sarcoidosis patients than any of the factors individually (Walsh et al. 2014a).
There has been an increasing interest for the use of automatic CT quantification as imaging biomarker to document disease response to treatment, disease progression, and eventually prognosis. Such a biomarker should be measurable but also reproducible and linked to relevant clinical outcome parameters (Goldin 2013). To meet the first two demands, rigorous standardization of imaging protocols over several sites and time points is needed, including centralized scanner and image quality checks. The underlying technique of automatic, texture analysis-based CT quantification is beyond the scope of this book chapter. There has been a number of studies evaluating the use of a computer-derived quantitative lung fibrosis score (QLF) for assessment of baseline disease extent and changes over time in patients with IPF (Kim 2015) and scleroderma patients treated with cyclophosphamide (Kim 2011). While this algorithm focuses solely on fibrotic changes, a different approach is used by the so-called CALIPER software (computer-aided lung informatics for pathology evaluation and rating), which associates a certain group of neighboring voxels to one of the basic patterns (normal, emphysema, ground glass, honeycombing, and reticular) for the complete lung volume (Bartholmai 2013). A recently published position paper by the Fleischner society (Hansell et al. 2015) acknowledges that CT has not only the potential to select the most appropriate patients to be included in treatment trials but also to represent a study end point in conjunction with other markers. This recent development has been fueled by the increasing precision with which image-processing software can quantify diffuse lung diseases.
4 Image Analysis
A widely accepted approach for analysis of HRCT in the context of DILD is based on the four patterns of pathological findings. It provides a structured and in certain ways standardized HRCT analysis and provides, together with distribution of the parenchymal changes, clinical history (acute versus chronic), and associated clinical (e.g., bronchoalveolar lavage) and imaging findings (e.g., lymphadenopathy, pleural effusion), the base for a differential diagnosis.
Nodular opacities (I)
Septal/reticular changes with parenchymal distortion (II)
Diseases with increased density (III), including ground glass and consolidations
Diseases with decreased density, mosaic pattern, and cysts (IV)
For communication with clinicians, it is important to use a cohesive terminology of signs and patterns describing the findings, so that they will know how a specific differential diagnosis has been made and what the confidence level of this diagnosis is. It has to be noted again that the final diagnosis in patients with DILD should be made within a multidisciplinary conference involving clinicians, radiologists, and pathologists and should thus be the result of a multidisciplinary approach.
A number of interstitial lung diseases are associated with such a characteristic pattern on HRCT, that diagnosis is strongly promoted by image findings, e.g., Langerhans cell histiocytosis, lymphangioleiomyomatosis, end-stage lung disease of usual interstitial pneumonia (UIP), and certain stages of sarcoidosis. Other diseases show a combination of findings that considerably overlap with a number of possible diagnoses, which is often the case in advanced disease with considerable parenchymal destruction. For example, there can be considerable overlap between sarcoidosis stage IV, UIP/IPF, and chronic exogenous allergic alveolitis.
4.1 Normal Anatomy
Localization and extent of parenchymal abnormalities are described in relation to readily appreciable anatomical structures, such as lobes and segments. The secondary lobule is the smallest anatomic unit bordered by connective tissue in the lung and represents one of the key anatomic structures in HRCT analysis that can be analyzed in its three-dimensional architecture.
In general, the secondary lobule measures between 1 and 2.5 cm in diameter, being bigger and rectangular in the periphery and smaller and more hexa- or polygonal in the central lung. The centrilobular core structures are formed by the pulmonary artery branch, the bronchiolus terminalis, lymphatics, and some connective tissue. It is important to note that under normal conditions, only the central pulmonary artery is visible on HRCT. The bronchiolus terminalis is below the spatial resolution and not visible under normal circumstances. Interlobular or perilobular septa represent the outer margin of the secondary lobule. They contain lung veins and lymphatics. In the peripheral subpleural 2 cm of lung parenchyma, only pulmonary arteries and some septal boundaries in an irregular distribution are visible. As soon as interlobular septa are regularly spaced or small airways become visible, these findings represent pathology. It is readily understandable that especially subtle pathological findings, such as an increased number of septal lines, is more easily appreciated in continuously scanned parenchyma that can be evaluated in all three projections as warranted.
4.2 Nodular Pattern
Pulmonary nodules are spherical or ovoid. They are categorized according to size, attenuation, margination, and localization. A general categorization of size results in micronodules (<3 mm), nodules (3–30 mm), and masses (>30 mm). Measurements of attenuation are problematic, but the appearance can be distinguished in being solid or of ground-glass opacity. Solid nodules may be sharply or poorly marginated, whereas ground-glass nodules are often poorly marginated. Values higher than 150 HU are typical for calcifications and indicate benign, postinflammatory granulomata. A surrounding area with increased ground-glass density is called “halo.” The halo sign may be caused by acute inflammation or hemorrhage.
Perilymphatic nodules occur predominantly in relation to the lymphatic pathways within the lung, both histologically and on HRCT. They appear along the bronchovascular bundles, the interlobar fissures, the interlobular septa, and the subpleural regions. Central, perihilar nodules along the bronchovascular bundle, individually or clustered, are most typical for granuloma in sarcoidosis. The nodules usually measure less than 5 mm, are well defined, and regularly marginated. They have a predominance for the perihilar regions and the upper lobes, which is particularly well depicted on coronal reformations. Confluence of granuloma may result in larger irregularly marginated nodules, ground-glass opacities, or consolidations (Criado et al. 2010).
There might be an overlap between irregularly thickened interlobular septa caused by lymphangitis carcinomatosa and a perilobular sarcoidosis with predominantly nodules along the interlobular septa. While lymphangitis carcinomatosa is frequently associated with pleural effusion and strong thickening of the central bronchovascular interstitium, it is never characterized by lung distortion. Sarcoidosis on the other hand can show heavy distortion and usually no pleural effusion.
Typical for a random distribution is its uniformity throughout the lung without a preference for certain anatomical structures. The involvement tends to be bilateral and symmetrical. A nodular pattern with a random distribution in relation to leading structures of the secondary lobule is indicative for a disease process with hematogenous spread as seen in hematogenous spread of malignant disease, miliary tuberculosis, fungal infections, cytomegaly, or herpes virus infections.
Centrilobular nodules are limited to the centrilobular regions and are never in contact with fissures or the pleura. They either originate from the respiratory bronchioles or bronchioli terminales or from the peripheral pulmonary artery branches. The nodules have a distance of at least several millimeters from interlobular septa and fissures and 5–10 mm from the pleural surface and pleura resulting in the characteristic subpleural sparing. They present as ill-defined, centrilobular ground-glass opacities in exogenous allergic alveolitis or respiratory bronchiolitis. A bit larger nodules, mostly ill-defined or consisting of solid components with a small halo around, are caused by bronchiolitis or small foci of bronchopneumonia. In silicosis, nodules can have a centrilobular as well as subpleural distribution pattern with a predominance in the posterior aspect of the upper lobes. Typically, they are smoothly marginated. The nodules range between 2 and 5 mm in diameter and can be calcified.
A tree-in-bud pattern– representing small-branching opacities with nodular endings – also show a centrilobular distribution; they represent small airway disease with wall thickened and/or secretion-filled small airways.
As described earlier, maximum intensity projections are most helpful in analyzing the distribution of nodules (see Sect. 3.3).
4.3 Septal/Reticular Pattern With or Without Signs of Parenchymal Distortion
Thickening of the lung interstitium caused by fluid, fibrous tissue, or cellular infiltration usually results in an increase in reticular or linear opacities on HRCT. Interlobular septal thickening is differentiated from intralobular septal thickening, although mostly seen together.
Any diseases causing alveolar filling-in and subsequent filling of intralobular and interlobular lymphatics will cause a pattern of crazy paving which describes the combination of ground-glass and reticular densities. Such conditions are seen in edema, bleeding, and pneumonic infiltrations, but also in alveolar proteinosis, storage diseases, or lymphoproliferative disorders.
When caused by fibrosis, intralobular interstitial thickening results in traction bronchiectasis and bronchiolectasis, as well as displacement of fissures. This reticular pattern of thickened intra- and interlobular septa, as well as irregular thickening of the bronchovascular interstitium (interface sign) is an important diagnostic finding in the heterogeneous group of interstitial lung diseases (ILD). The most recent 2013 classification of the American Thoracic Society (ATS) and European Respiratory Society (ERS) distinguishes usual interstitial pneumonia (UIP), the specific histopathological pattern seen in idiopathic pulmonary fibrosis (IPF), from six non-IPF subtypes: acute interstitial pneumonia (AIP), respiratory bronchiolitis interstitial lung disease (RB-ILD), desquamative interstitial pneumonia (DIP), organizing pneumonia (OP), lymphoid interstitial pneumonia (LIP), and nonspecific interstitial pneumonia (NSIP) (Walsh and Hansell 2010).
A UIP pattern on HRCT is highly accurate for the presence of UIP pattern on surgical lung biopsy. In the absence of honeycombing, but imaging features otherwise meeting the criteria for UIP, the HRCT findings are regarded as representing a “possible UIP,” and surgical lung biopsy is necessary if a definitive diagnosis is required (Raghu et al. 2011).
It has to be noted that UIP is not specific for IPF. UIP is also seen in a number of other DILD, such as asbestosis (pleural plaques and calcifications), sarcoidosis (upper lobe disease, heavy parenchymal distortion, associated nodular disease in perilymphatic distribution), or exogenic allergic alveolitis (bronchovascular-centered fibrosis, air trapping, relative sparing of the posterior costophrenic recesses).
4.4 Increased Density
Acute interstitial pneumonia (AIP) is histologically characterized by hyaline membranes within the alveoli and diffuse, active interstitial fibrosis also described as “diffuse alveolar damage” (DAD). There is clinical, pathological, and radiological overlap with ARDS, and patients often present with respiratory failure developing over days or weeks. Typical HRCT features are bilateral ground-glass opacities (patchy or diffuse) and consolidations. Focal sparing of lung lobules frequently result in a geographic distribution. In later stages architectural distortion with traction bronchiectasis, reticulation, and even honeycombing develops.
Respiratory bronchiolitis interstitial lung disease (RB-ILD), desquamative interstitial pneumonia (DIP), and, last but not least, nonspecific interstitial lung disease (NSIP) belong to the spectrum of smoking-induced lung changes. RB-ILDs consist of centrilobular acinar ground-glass nodules that may be confluent to areas of ground-glass opacities and thickening of the bronchial walls. A small percentage has a mild reticular pattern mainly in the lower lung zones. Desquamative interstitial pneumonia (DIP) is uncommon in its idiopathic form and mostly associated with smoking. HRCT features are similar to those encountered in RB-ILD, although the distribution is diffuse in DIP and more bronchiolocentric in RB-ILD. The typical HRCT feature of DIP is diffuse ground-glass opacity, sometimes in a geographic distribution; reticulation is uncommon.
4.5 Decreased Density/Cysts
A cystic pattern results from a heterogeneous group of diseases, all having in common the presence of focal, multifocal, or diffuse parenchymal lucencies and lung destruction. For the differential diagnosis, the presence of walls around the lucencies and the form of the lucencies (bizarre shaped or uniform round) is important.
The term “cyst” by itself is nonspecific and refers to a well-circumscribed round or irregular lesion with a visible wall. The wall is usually thin (<2–3 mm), but can have a uniform or variable thickness. Most cysts are filled with air, but can also contain liquid, semisolid, or solid material. Cysts can be very small and diffuse, but also large and confluent resulting in polygonal bizarre shapes. The presence of a definable wall demonstrated on CT differentiates cysts from emphysema.
Incidental lung cyst without other HRCT abnormalities and without a history of lung disease or signs of architectural distortion have been reported as a normal finding in elderly patients, ranging from 5 to 22 mm and located in all lobes.
In the early phase, Langerhans cell histiocytosis (LCH) has a typical nodular pattern with multiple, <10 mm small centrilobular nodules with irregular margins. Later these nodules increase in size and have a tendency to cavitate and to develop into cystic lesions with a diameter of up to 2 cm. The cysts are often confluent, have bizarre or irregular shapes, and are usually thin walled, but may be thick walled. LCH is predominantly located in the upper lobes, with sparing of the costophrenic sinus, which is better depicted on coronal reformations than on cross-sectional images. The thin walls of the cysts are prone to rupture, with an increased risk of pneumothorax. Concomitant nodules are usually irregular, measure 1–5 mm, and often have a centrilobular distribution. The interspersed pulmonary parenchyma is typically normal, without evidence of fibrosis or septal thickening.
Lymphoid interstitial pneumonia (LIP) is uncommon and considered as part of a spectrum of pulmonary lymphoproliferative disorders, ranging from benign accumulation to malignant lymphomas. Mostly it is associated with Sjögren’s disease, HIV infection, or other immunological disorders. On HRCT, typical findings are sharply demarcated cysts in a subpleural distribution with intraluminal septae associated with diffuse ground glass of the lung parenchyma. Poorly defined centrilobular nodules, thickening of the bronchovascular bundles, patchy ground-glass opacities, and focal consolidations also belong to the spectrum. In cases with consolidations, a lymphoma needs to be excluded.
Lymphangioleiomyomatosis (LAM) usually occurs in young women and is frequently associated with recurrent pneumothorax and pleural effusion. The cysts are distributed bilateral diffusely throughout the lung, involving both upper and lower lobes, with also involvement of the lung bases. They are thin walled, round, and measure 0.2–5 cm. Their wall is thin, ranging from barely visible to 4 mm in thickness. Since the thin walls of the cysts are prone to rupture, there is an increased risk of pneumothorax. Pleural effusion may also be seen. The surrounding parenchyma is typically normal. Nodules are uncommon, but may be associated with the cysts.
Sometimes it may be difficult to distinguish lymphangioleiomyomatosis and Langerhans cell histiocytosis from emphysema. A helpful finding is that the cystic spaces in LAM and LCH do not have any central nodular opacities, whereas the cystic spaces seen with centrilobular emphysema contain a small central nodular opacity representing the centrilobular artery.
Honeycomb cysts constitute the irreversible final stage of parenchymal destruction in patients with interstitial fibrosis (end-stage lung) of UIP. It is seen in IPF but also in collagen vascular diseases, asbestosis, hypersensitivity pneumonitis, or drug-related fibrosis. The cystic spaces are usually round or ovoid and measure between several millimeters and 1 cm in diameter, although more rarely they can be several centimeters in size. Within one individual, however, they are mostly uniform. They have clearly definable walls which are 1–3 mm thick. Honeycomb cysts seem to develop from alveolar disruption and massively dilated alveolar ducts and bronchioles. Honeycombing is associated with other findings of lung fibrosis, such as septal and reticular pattern, architectural distortion, and traction bronchiectasis. Most patients demonstrate several layers of irregular cystic spaces (honeycombs), which are separated from each other by irregular thick walls and intralobular septa and lines. However, note that also a singular layer of cystic spaces with thickened wall are described as honeycombing and fulfill the criteria for a definite UIP under appropriate conditions.
Though the definition of honeycombing is quite straightforward, a substantial interreader variability has been described for the diagnosis of honeycombing, which needs attention given the importance of honeycombing for the diagnosis of UIP. Even on HRCT it is not always possible to securely separate the walls of the honeycomb cysts from the thickened intralobular fibrous bands. Secondly, it is important to differentiate honeycombing from tubular bronchiectasis reaching all the way to the pleura. MinIPs have been described as helpful to differentiate between tubular bronchiectasis and focal cysts (see Sect. 3.3).
Continuous volumetric HRCT offers a number of advantages over discontinuous axial thin section CT slices, of which the most important ones refer to improved detection of subtle disease, better and more accurate comparability, and superior quantitative measures. A number of processing options such as MIP and MinIP ease analysis of HRCT patterns. Most recent developments of detector and reconstruction technology have made up for the disadvantage of continuous versus discontinuous data acquisition of the past, allowing for substantial dose savings. All these arguments have led to the fact that HRCT is routinely based on volumetric data acquisition. Today basically each chest CT offers the spatial resolution of a HRCT in all three dimensions, and it depends on the indication of the examination (e.g., malignancy versus diffuse parenchymal disease) whether contrast media is injected and which slice thickness and reconstruction techniques (e.g., MIP and MinIP) are applied.
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