The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). The authors received no direct compensation related to the development of the manuscript. Writing assistance was provided by Ken Sutor, BSc, of GeoMed, an Ashfield company, part of UDG Healthcare plc, which was contracted and funded by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). BIPI was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations.
The authors received no direct compensation related to the development of the video. Medical writing support for the video script was provided by Leon Newman, PhD, of GeoMed, an Ashfield company, which was contracted and funded by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). BIPI was given the opportunity to review the final video for medical and scientific accuracy as well as intellectual property considerations.

1. HRCT scanning
<ol>
	<li>Perform volumetric HRCT acquisition scanning of the chest36. Contrast agents are not required36,37:</li>
	<li>Obtain the following acquisitions with parameters shown in Table 136,37.
	<ol>
		<li>Acquire a supine inspiratory scan (volumetric) from the lung apices to the lung base.</li>
		<li>Acquire a supine expiratory scan (sequential with 10&#8211;20 mm gaps) from 2 cm below the lung apices to the lung base.</li>
		<li>Acquire a prone inspiratory optional (sequential with 10&#8211;20 mm gaps) from the carina to the lung base.</li>
	</ol>
	</li>
	<li>Give breathing instructions to the patient before each acquisition36,37. For an inspiratory scan, say &#8220;Take in a deep breath&#8230;.and let it out. Take in another deep breath&#8230;.and let it out. Take in another deep breath, and hold your breath in. Keep holding your breath&#8221;37.</li>
	<li>Obtain inspiratory scans at full inspiration35,36.</li>
	<li>Use the thinnest collimation, shortest rotation time and highest pitch to ensure that motion-free images are obtained36. Suggested scanning parameters are detailed in Table 137.</li>
	<li>For optimal quality of volumetric scans, obtain thin section (&#60;2 mm) images with high-spatial resolution reconstruction35,36.</li>
	<li>Review scans immediately after acquisition and repeat if either motion artifact is present or inadequate inspiration has occurred37.</li>
</ol>
2. Reporting
<ol>
	<li>Prepare an interpretive report.</li>
	<li>Share the report and HRCT images with the patient&#8217;s care team and add them to the patient&#8217;s medical records.</li>
</ol>

Jonathan Chung declares no potential conflicts of interest with respect to the described research, authorship, and/or publication of this article; Christopher Walker declares the receipt of royalties from Amirsys (Elsevier); and Stephen Hobbs declares the receipt of royalties from Elsevier and Wolters Kluwer Health. Open Access publication of this article is sponsored by Boehringer Ingelheim Pharmaceuticals, Inc.

While HRCT is currently the definitive imaging method for diagnosing and assessing SSc-ILD, it uses ionizing radiation and is relatively expensive. Chest radiographs may be undertaken instead, although these do not facilitate differential diagnosis to the same extent as HRCT, and a normal chest radiograph does not eliminate the possibility of ILD. Perhaps the best use of chest radiographs is to monitor for progressive disease between HRCT scans and for the exclusion of complicating disease, such as infectious pneumonia, in the setting of acute worsening of symptoms.
A perceived limitation of HRCT is radiation exposure. As described earlier, new methods of conducting CT scans may enable radiation exposure to be reduced31, and furthermore, current CT scanners provide an array of advanced techniques that offer the possibility in the future to lower radiation exposure to nearly chest radiograph levels. Alternatively, imaging methods such as MRI or lung ultrasound could potentially be used to avoid exposing the patient to radiation in the future32,72,73,74. We believe that, while there are risk-benefit considerations associated with imaging utilization, the advantages of CT in diagnosis and patient management far outweigh the potential risks.
Imaging data, particularly HRCT, provide arguably the most important information to enable diagnosis of SSc-ILD. Detailed consideration of the patterns and features of HRCT scans is usually sufficient to distinguish SSc-ILD from other lung diseases, with the benefit of avoiding the need for an invasive biopsy procedure.
Visual assessment of HRCT scans introduces a degree of subjectivity and the possibility of inter-observer variability. Computer-based methods of HRCT scan interpretation have been investigated as a possible approach to improving accuracy63,75. For example, quantitative approaches to the assessment of lung fibrosis or the extent of disease may be used to assess treatment response69,71,76. However, these methods are not widely used in daily clinical practice at this time.
We hope the information presented in this manuscript will serve as a practical guide to assist physicians in using HRCT scans for diagnosing SSc-ILD and determining prognosis. Improved methods for obtaining images and for interpreting scans have the potential to reduce patients&#8217; exposure to radiation and improve diagnostic/prognostic accuracy.

Systemic sclerosis (SSc) is a complex, heterogeneous, autoimmune disease. It may be manifested as vasculopathy, Raynaud&#8217;s phenomenon and fibrosis of the skin and internal organs1. SSc is classified into subtypes as follows: limited cutaneous, diffuse cutaneous, sine scleroderma (without skin involvement), and SSc overlap syndrome1.
SSc is not inherited in Mendelian fashion, but genetic factors appear to influence susceptibility to the disease. Incidence rates differ between ethnic groups and are increased among individuals with a family history of the disease2,3. Environmental risk factors also appear to exist, with high exposure to silica or organic solvents appearing to increase the occurrence of SSc4. The global prevalence of SSc is around 1 in 10,0001. More females than males are affected by SSc, with reported female:male ratios ranging between 3:1 and 8:1, and the age group with the highest incidence of the disease is 45&#8211;54 years5.
The lung is the second most commonly affected visceral organ in patients with SSc6. There are two main pulmonary manifestations of SSc: interstitial lung disease (ILD), and pulmonary hypertension7. ILD is usually fibrotic; it occurs in approximately 80% of patients with SSc and is more common in diffuse cutaneous scleroderma than in the limited form of the disease1,8. Pulmonary hypertension may manifest as isolated pulmonary arterial hypertension (PAH, which has a prevalence of 13&#8211;35% in SSc) or pulmonary hypertension resulting from left ventricular involvement/diastolic dysfunction or ILD/hypoxemia7. Antibody profiles differ between patients with SSc-ILD and those with SSc-PAH. For example, the presence of anti-Scl-70 antibodies is associated with SSc-ILD8, while anticentromere antibodies are more common in SSc patients with PAH than in those without PAH9.
The symptoms of SSc-ILD include dyspnea, coughing, chest pain, and exercise limitation. ILD is a major contributor to morbidity in SSc10,11,12. As a consequence, annual all-cause healthcare costs have been reported to be higher in patients with SSc-ILD than in those with SSc and no ILD: $31,285&#8211;55,446 versus $18,513&#8211;23,268, respectively13.
SSc-ILD is the leading cause of mortality in patients with SSc, accounting for 30&#8211;35% of deaths in this group10,14. Median survival among patients with SSc-ILD has been reported to be 5&#8211;8 years10,15; by comparison, approximately 76% of the overall population with SSc survive for more than 10 years from disease onset16. Significant predictors of mortality in SSc-ILD include age, forced vital capacity (FVC), baseline diffusing capacity of the lung for carbon monoxide (DLCO), extent of disease on high-resolution computed tomography (HRCT), presence of pulmonary hypertension and levels of Krebs von den Lungen 6 (KL-6) antigen17,18.
Early diagnosis is important to enable treatment to be administered with minimal delay and, in patients with a progressive phenotype, disease progression may potentially be slowed. However, diagnosing SSc-ILD is challenging because non-specific symptoms of cough, dyspnea, and fatigue can be mistaken for other aspects of SSc, such as cardiac disease and musculoskeletal involvement. Evaluations for diagnosing ILDs include: clinical presentation, history, smoking status, lung function, imaging, and in some cases, lung biopsy. Affirmation of SSc-ILD diagnosis requires several investigations, which are often used in combination19. The most frequently used assessments include pulmonary function tests and HRCT20,21,22,23. Other imaging methods, such as chest radiography and radiation-sparing imaging (e.g., magnetic resonance imaging [MRI], lung ultrasound) may also be employed22. Pulmonary function tests are used to assess the severity of the ILD and monitor its course. However, the use of pulmonary function tests alone is of limited use for diagnosing SSc-ILD24,25. HRCT of the chest is viewed as the most sensitive non-invasive means of facilitating differential diagnosis of SSc-ILD19. Baseline HRCT results, as well as changes over time, can be used to predict the future course of lung disease and potential response to therapy26.
Exposure to radiation with HRCT is sometimes considered as a limiting factor for regular screening27,28; limiting the number of slices is a potential method for reducing the radiation risk, and the dose may also be reduced by decreasing either the voltage or the current29,30,31. Alternatively, different assessment methods may be considered. For example, MRI appears to have some potential for evaluation and follow-up of ILD patients22. In one study using T2-weighted MRI images with respiratory synchronization, HRCT was performed in parallel as the &#8216;gold-standard&#8217; assessment; 100% sensitivity and 60% specificity were reported with MRI for determining the presence of ILD32. Similar agreement between MRI and HRCT in the detection and categorization of ILD was reported in another study33. Despite the promising results, MRI is currently a research methodology and it is not yet ready for generalized clinical use.
Here, we provide a practical overview of the interpretation of imaging results, with a focus on HRCT, for diagnosing lung involvement in SSc, determining prognosis, and also exploring future developments that may improve imaging methods and interpretation of results. HRCT images from representative cases are included in the paper.

<table><tbody><tr><td>CT scanners</td><td>Philips</td><td>NA</td><td>Multiple</td></tr></tbody></table>

imaging features of systemic sclerosis-associated interstitial lung disease

Early diagnosis of systemic sclerosis-related interstitial lung disease (SSc-ILD) is important to enable treatment to be administered with minimal delay. However, diagnosing SSc-ILD is challenging because key symptoms are non-specific. High-resolution computed tomography (HRCT) of the chest is recognized as a sensitive imaging method for diagnosing and assessing SSc-ILD. Exposure of patients to ionizing radiation may be considered as a limitation, although methodological steps may be taken to moderate this. We present practical recommendations for performing HRCT scans and interpreting the results. Key features of SSc-ILD on HRCT include a non-specific interstitial pneumonia (NSIP) pattern with peripheral ground-glass opacities and extensive traction bronchiectasis. Despite similarities between SSc-ILD and idiopathic pulmonary fibrosis (IPF), HRCT can be used to differentiate between these conditions: in SSc-ILD compared with IPF, there is a greater proportion of ground-glass opacity and fibrosis is less coarse. A dilated, air-filled esophagus with diameter &#62;10 mm, suggestive of esophageal dysmotility is commonly seen in SSc-ILD. Pulmonary artery size greater than the adjacent ascending aorta suggests coexistent pulmonary hypertension. Nodules must be monitored due to the increased risk of lung cancer. A large extent of disease on HRCT (&#8805;20%) or a high fibrosis score suggests an increased risk of mortality. HRCT is central to diagnosing SSc-ILD, and serial assessments can be helpful in monitoring disease progression or treatment response.

Diagnosis 
Key features of SSc-ILD on HRCT commonly include a non-specific interstitial pneumonia (NSIP) pattern with peripheral ground-glass opacities and extensive traction bronchiectasis (Figure 1 and Figure 2). Ground-glass opacities have a broad etiology and are often non-specific40,41,42. Central predominance or peripheral distribution with subpleural sparing is highly suggestive of NSIP (Figure 3).
Typically, ILD patterns in HRCT images include reticulations with architectural distortion resulting in traction bronchiectasis/bronchiolectasis (consistent with a fibrotic form of NSIP). Indeed traction bronchiectasis and traction bronchiolectasis are often the predominant features of SSc-ILD (Figure 4)43. Additional findings may include honeycombing (Figure 5; more common in limited forms of SSc), interlobular septal thickening and intralobular lines, and micronodules40,44. Honeycombing refers to clustered cystic airspaces of typically consistent diameter (~3–10 mm) with thick, well defined walls31. Honeycombing and traction bronchiectasis are key features of usual interstitial pneumonia (UIP) on HRCT. Although this pattern is most commonly associated with idiopathic pulmonary fibrosis (IPF), the prototype fibrosing ILD with a progressive phenotype, it can sometimes be seen in patients with SSc-ILD10. Recently, several signs have been identified in patients with connective tissue disease-related ILD (including SSc-ILD) and the UIP pattern on HRCT, but not in those with IPF. These are the straight edge sign (i.e., isolation of fibrosis to the lung bases with sharp demarcation in the craniocaudal plane without substantial extension along the lateral margins of the lungs on coronal images), the honeycombing predominant (or exuberant) sign (&gt;70% of fibrotic portions of the lung), and the anterior upper lobe sign (i.e., concentration of fibrosis within the anterior aspect of the upper lobes, with relative sparing of the other aspects of the upper lobes, and concomitant lower lobe involvement)45. The straight edge sign has also been associated with NSIP pathology46, which is the main CT pattern in SSc-ILD10.
Dilated air-filled esophagus is frequently observed in patients with SSc (Figure 6)47,48,49 and in patients with SSc-ILD47,48. While there is no accepted upper age limit where a dilated esophagus may no longer help to differentiate SSc-ILD and IPF, a dilated esophagus may be more difficult to interpret in patients over age 65 due to increasing incidence of esophageal motility disorders. Mediastinal lymphadenopathy (usually reactive), in which the short axis of the lymph node exceeds 10 mm, is also often observed in patients with SSc-ILD47,50. Pulmonary artery size greater than the adjacent ascending aorta suggests coexistent pulmonary hypertension (Figure 6), even in patients without fibrotic lung disease51,52,53. Areas of consolidation suggest superimposed infection, aspiration, organizing pneumonia, hemorrhage or malignancy. Nodules must be monitored due to the increased risk for lung cancer in SSc-ILD7; the most common primary cancer to arise in patients with SSc-ILD is adenocarcinoma7,54.
SSc-ILD shares a number of clinical, mechanistic, and pathological similarities with IPF15,55. However, some radiologic features allow the differentiation of these two ILDs15,45. In SSc-ILD, compared with IPF, there is a greater proportion of ground-glass opacity and fibrosis is less coarse. In cases of UIP in SSc, honeycombing may be observed in more than 70% of the fibrotic-lung tissue ─ the exuberant honeycombing sign56,57. In addition, the four-corners sign (also known as the anterior upper lobe sign) is significantly more common in SSc-ILD than in IPF; this is a pattern of inflammation and/or fibrosis focally or disproportionately involving the bilateral anterolateral upper lobes and posterosuperior lower lobes58.
Chest radiographs may initially detect ILD; however, they do not offer enough contrast resolution for reliable diagnosis. In chest radiographs from patients with SSc-ILD, the most frequent pattern is basal predominant reticulation59. Further features may include visible bronchiectasis, volume loss and honeycombing. As with HRCT, the presence of a dilated air-filled esophagus may be helpful in supporting the diagnosis of SSc-ILD47.
Prognosis 
Several different imaging findings have been shown to be associated with prognosis in SSc-ILD. Mortality risk has been reported to be higher in patients with a disease extent of at least 20% on HRCT (10-year survival was 43% versus 67%, respectively, in patients with disease extent above versus below the 20% threshold)60. Similarly, a high fibrosis score on HRCT (based on the extent of reticulation and honeycombing) has been associated with increased mortality61. Large esophageal diameters are associated with increased ILD severity and decreased DLCO48. Lung density and pulmonary artery diameter may potentially be used to predict the risk of pulmonary hypertension62. Computerized, quantitative CT parameters could also be harnessed to identify patients’ risk of lung function decline or mortality. One study suggested that the extent of ILD, quantified from HRCT, could be used to predict the decline in FVC over 12 months63. In another study, quantitative chest CT parameters provided mortality risk results that were consistent with clinical prediction models64. Despite their apparent potential, imaging-based biomarkers are currently best considered at a population level as their clinical utility in individual patients has not been established.
Treatment response 
Cyclophosphamide and mycophenolate mofetil provide modest benefit in patients with SSc-ILD. In the landmark Scleroderma Lung Study I, cyclophosphamide treatment led to slower progression of fibrosis compared with placebo65. More recently, the Scleroderma Lung Study II reported similar efficacy and improved tolerability with mycophenolate mofetil in comparison with cyclophosphamide66. Based upon positive SENSCIS® trial results67, nintedanib became the first US Food and Drug Administration-approved treatment to slow the rate of decline in lung function in patients with SSc-ILD. However, there remains a need for improved treatment options for patients with SSc-ILD. Therapies currently being investigated include monoclonal antibodies (e.g. rituximab, abituzumab), antifibrotic agents (e.g., pirfenidone), the direct thrombin inhibitor dabigatran, the proteasome inhibitor bortezomib, and hematopoietic stem cell transplantation19,68.
Serial HRCT scans showing disease progression in a patient with SSc-ILD 
HRCT assessments performed at different timepoints may be used to investigate disease progression. Figure 7 shows two sets of axial and coronal chest HRCT images taken 10 years apart in a patient with SSc-ILD. The initial axial and coronal images (Figure 7A and B) from chest HRCT show basilar predominant ground-glass opacity and reticulation with mild traction bronchiectasis and subpleural sparing consistent with NSIP in this patient with SSc. The latter set of images (Figure 7C and D) taken 10 years later, show increased reticulation and traction bronchiolectasis at the lung bases with decrease in ground-glass opacity on axial and coronal (Figure 7C and D) images from chest CT consistent with mild worsening of pulmonary fibrosis. Serial HRCT scans can also be used to monitor treatment response69,70,71; this was demonstrated in the Scleroderma Lung Study II, in which computer-aided diagnosis scores based on HRCT scans were used to compare the efficacy of cyclophosphamide with mycophenolate mofetil in patients with SSc-ILD69.
<table border="1" fo:keep-together.within-page="1">
	<tbody>
		<tr>
			<td>Phase</td>
			<td>Detector 
			collimation</td>
			<td>Voltage 
			(kVp)</td>
			<td>Current (mAs)</td>
			<td>Scan 
			interval</td>
			<td>Pitch</td>
			<td>Rotation</td>
			<td>Tube current 
			modulation</td>
		</tr>
		<tr>
			<td>Supine inspiratory</td>
			<td>Helical 1.2 mm</td>
			<td>120 (may be lowered)</td>
			<td>230 (may be lowered)</td>
			<td>N/A</td>
			<td>~1.0</td>
			<td>0.5 seconds or faster</td>
			<td>On</td>
		</tr>
		<tr>
			<td>Supine expiratory</td>
			<td>Axial 2 x 1.0 mm</td>
			<td>120</td>
			<td>150</td>
			<td>20 mm</td>
			<td>N/A</td>
			<td>1.0 seconds</td>
			<td>On</td>
		</tr>
		<tr>
			<td>Prone inspiratory</td>
			<td>Axial 2 x 1.0 mm</td>
			<td>120</td>
			<td>150</td>
			<td>20 mm</td>
			<td>N/A</td>
			<td>1.0 seconds</td>
			<td>On</td>
		</tr>
	</tbody>
</table>
Table 1: Computed tomography acquisition parameters37. kVp = kilovoltage peak; N/A = not applicable.
<img alt="CT scans of chest showing lung sections, axial and coronal views, diagnostic imaging analysis." class="xfigimg" src="/files/ftp_upload/60300/60300fig1v2.jpg" data-altupdatedat="1747911167000" data-alt="Figure 1"> 
Figure 1: Systemic sclerosis with a cellular NSIP pattern of disease. Axial (A), prone (B) and coronal (C) high-resolution computed tomography images all show extensive peripheral and basal predominant ground-glass opacities; these are typical observations with NSIP. The lack of traction bronchiectasis is suggestive of a cellular NSIP pattern of disease. NSIP = non-specific interstitial pneumonia. <a href="https://www.jove.com/files/ftp_upload/60300/60300fig1v2large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="CT scan, axial view, chest anatomy, lung analysis, diagnostic imaging, medical examination" class="xfigimg" src="/files/ftp_upload/60300/60300fig2v2.jpg" data-altupdatedat="1747911167000" data-alt="Figure 2"> 
Figure 2: Systemic sclerosis with a fibrotic non-specific interstitial pneumonia pattern of disease. Axial computed tomography image shows extensive, basal-predominant ground-glass opacities with associated traction bronchiectasis. Notably, the esophagus shows marked dilation; this is typical of scleroderma. <a href="https://www.jove.com/files/ftp_upload/60300/60300fig2v2large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="CT scan showing lung fibrosis; axial views, pulmonary imaging, diagnostic radiology." class="xfigimg" src="/files/ftp_upload/60300/60300fig3v3.jpg" data-altupdatedat="1747911167000" data-alt="Figure 3"> 
Figure 3: Systemic sclerosis with a fibrotic NSIP pattern. Axial high-resolution computed tomography images (A and B) show extensive ground-glass opacities, reticulation, architectural distortion and traction bronchiectasis. Notably, subpleural sparing is apparent; this is typical of NSIP and is seen in about 50% of all cases. NSIP = non-specific interstitial pneumonia. <a href="https://www.jove.com/files/ftp_upload/60300/60300fig3v2large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="CT lung scan showing pulmonary fibrosis; cross-sectional and coronal views; diagnostic imaging." class="xfigimg" src="/files/ftp_upload/60300/60300fig4v3.jpg" data-altupdatedat="1747911167000" data-alt="Figure 4"> 
Figure 4: Systemic sclerosis with exuberant traction bronchiectasis. Axial (A) and coronal (B) high-resolution computed tomography images show extensive middle and lower lung zone predominant traction bronchiectasis. While this may be mistaken for honeycombing, the cystic areas connect with each other and spare the immediate subpleural lung; this is typical of bronchiectasis. <a href="https://www.jove.com/files/ftp_upload/60300/60300fig4v2large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="CT scan showing lung cross-sections, illustrating respiratory cysts and bronchioles in lung analysis." class="xfigimg" src="/files/ftp_upload/60300/60300fig5v3.jpg" data-altupdatedat="1747911167000" data-alt="Figure 5"> 
Figure 5: Systemic sclerosis with a UIP pattern of lung fibrosis. Axial (A) and coronal (B) computed tomography images show peripheral and basal predominant honeycombing and traction bronchiectasis in keeping with the typical UIP pattern of lung fibrosis. Note the dilated esophagus (attributable to scleroderma) and the ‘exuberant’ honeycombing (suggestive of ILD related to connective tissue disease rather than idiopathic pulmonary fibrosis). UIP = usual interstitial pneumonia. <a href="https://www.jove.com/files/ftp_upload/60300/60300fig5v2large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="CT scan showing chest cross-section, highlighting heart and lung anatomy, medical imaging analysis." class="xfigimg" src="/files/ftp_upload/60300/60300fig6v3.jpg" data-altupdatedat="1747911167000" data-alt="Figure 6"> 
Figure 6: Systemic sclerosis with pulmonary hypertension and dilated esophagus. Contrast-enhanced chest computed tomography shows marked enlargement of the pulmonary trunk, with a larger measurement than the adjacent ascending aorta that suggests underlying pulmonary hypertension. The esophagus is markedly dilated; this is attributable to scleroderma. <a href="https://www.jove.com/files/ftp_upload/60300/60300fig6v3large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Lung CT scan images; transverse and coronal views; examining pulmonary structure abnormalities." class="xfigimg" src="/files/ftp_upload/60300/60300fig7v2.jpg" data-altupdatedat="1747911167000" data-alt="Figure 7"> 
Figure 7: Serial chest HRCT images showing progression of pulmonary fibrosis in patient with SSc-ILD. Axial (A) and coronal (B) images from chest HRCT show basilar predominant ground-glass opacity and reticulation with mild traction bronchiectasis and subpleural sparing consistent with non-specific interstitial pneumonia in this patient with SSc. After 10 years, increased reticulation and traction bronchiolectasis at the lung bases with decrease in ground-glass opacity are observed on axial (C) and coronal (D) chest HRCT images, consistent with mild worsening of pulmonary fibrosis. HRCT = high-resolution computed tomography; SSc-ILD = systemic scleroderma-associated interstitial lung disease. <a href="https://www.jove.com/files/ftp_upload/60300/60300fig7v2large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

Watch this Scientific Journal Video about Imaging Features of Systemic Sclerosis-Associated Interstitial Lung Disease at JoVE.com

Imaging Features of Systemic Sclerosis-Associated Interstitial Lung Disease

Here, we present practical recommendations for performing thoracic high-resolution computed tomography for diagnosing and assessing systemic sclerosis-related interstitial lung disease.

Early diagnosis of systemic sclerosis-related interstitial lung disease (SSc-ILD) is important to enable treatment to be administered with minimal delay. ...

imaging-features-systemic-sclerosis-associated-interstitial-lung

Research

JoVE Journal

Medicine

19.7K Views.  University of Chicago Medicine. Dit HRCT-protocol is belangrijk voor het diagnosticeren van systemische sclerose gerelateerde interstitiële longziekte. En kan worden gebruikt voor eenmalige scannen of sequentiële scannen na verloop van tijd. Het kan helpen bij het begeleiden van beslissingen over de behandeling.HRCT wordt beschouwd als de meest gevoelige niet-invasieve middelen voor het vergemakkelijken van de diagnose van systemische sclerose gerelateerde interstitiële longziekte, en kan worden gebruikt om het to...

Video: Imaging Features of Systemic Sclerosis-Associated Interstitial Lung Disease

Optical Frequency Domain Imaging of Ex vivo Pulmonary Resection Specimens: Obtaining One to One Image to Histopathology Correlation

Lung cancer is the leading cause of cancer-related deaths1. Squamous cell and small cell cancers typically arise in association with the conducting airways, whereas adenocarcinomas are typically more peripheral in location. Lung malignancy detection early in the disease process may be difficult due to several limitations: radiological resolution, bronchoscopic limitations in evaluating tissue underlying the airway mucosa and identifying early pathologic changes, and small sample size and/or incomplete sampling in histology biopsies. High resolution imaging modalities, such as optical frequency domain imaging (OFDI), provide non-destructive, large area 3-dimensional views of tissue microstructure to depths approaching 2 mm in real time (Figure 1)2-6. OFDI has been utilized in a variety of applications, including evaluation of coronary artery atherosclerosis6,7 and esophageal intestinal metaplasia and dysplasia6,8-10.
Bronchoscopic OCT/OFDI has been demonstrated as a safe in vivo imaging tool for evaluating the pulmonary airways11-23 (Animation). OCT has been assessed in pulmonary airways16,23 and parenchyma17,22 of animal models and in vivo human airway14,15. OCT imaging of normal airway has demonstrated visualization of airway layering and alveolar attachments, and evaluation of dysplastic lesions has been found useful in distinguishing grades of dysplasia in the bronchial mucosa11,12,20,21. OFDI imaging of bronchial mucosa has been demonstrated in a short bronchial segment (0.8 cm)18. Additionally, volumetric OFDI spanning multiple airway generations in swine and human pulmonary airways in vivo has been described19. Endobronchial OCT/OFDI is typically performed using thin, flexible catheters, which are compatible with standard bronchoscopic access ports. Additionally, OCT and OFDI needle-based probes have recently been developed, which may be used to image regions of the lung beyond the airway wall or pleural surface17.
While OCT/OFDI has been utilized and demonstrated as feasible for in vivo pulmonary imaging, no studies with precisely matched one-to-one OFDI:histology have been performed. Therefore, specific imaging criteria for various pulmonary pathologies have yet to be developed. Histopathological counterparts obtained in vivo consist of only small biopsy fragments, which are difficult to correlate with large OFDI datasets. Additionally, they do not provide the comprehensive histology needed for registration with large volume OFDI. As a result, specific imaging features of pulmonary pathology cannot be developed in the in vivo setting. Precisely matched, one-to-one OFDI and histology correlation is vital to accurately evaluate features seen in OFDI against histology as a gold standard in order to derive specific image interpretation criteria for pulmonary neoplasms and other pulmonary pathologies. Once specific imaging criteria have been developed and validated ex vivo with matched one-to-one histology, the criteria may then be applied to in vivo imaging studies. Here, we present a method for precise, one to one correlation between high resolution optical imaging and histology in ex vivo lung resection specimens. Throughout this manuscript, we describe the techniques used to match OFDI images to histology. However, this method is not specific to OFDI and can be used to obtain histology-registered images for any optical imaging technique. We performed airway centered OFDI with a specialized custom built bronchoscopic 2.4 French (0.8 mm diameter) catheter. Tissue samples were marked with tissue dye, visible in both OFDI and histology. Careful orientation procedures were used to precisely correlate imaging and histological sampling locations. The techniques outlined in this manuscript were used to conduct the first demonstration of volumetric OFDI with precise correlation to tissue-based diagnosis for evaluating pulmonary pathology24. This straightforward, effective technique may be extended to other tissue types to provide precise imaging to histology correlation needed to determine fine imaging features of both normal and diseased tissues.

Optical Frequency Domain Imaging of Ex vivo Pulmonary Resection Specimens: Obtaining One to One Image to Histopathology Correlation

A method to image ex vivo pulmonary resection specimens with optical frequency domain imaging (OFDI) and obtain precise correlation to histology is described, which is essential to developing specific OFDI interpretation criteria for pulmonary pathology. This method is applicable to other tissue types and imaging techniques to obtain precise imaging to histology correlation for accurate image interpretation and assessment. Imaging criteria established with this technique would then be applicable to image assessment in future in vivo studies.

Lung cancer is the leading cause of cancer-related deaths1. Squamous cell and small cell cancers typically arise in association with the conducting ...

Bioengineering

A Multimodal Imaging Approach Based on Micro-CT and Fluorescence Molecular Tomography for Longitudinal Assessment of Bleomycin-Induced Lung Fibrosis in Mice

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by the progressive and irreversible destruction of lung architecture, which causes significant deterioration in lung function and subsequent death from respiratory failure.
The pathogenesis of IPF in experimental animal models has been induced by bleomycin administration. In this study, we investigate an IPF-like mouse model induced by a double intratracheal bleomycin instillation. Standard histological assessments used for studying lung fibrosis are invasive terminal procedures. The goal of this work is to monitor lung fibrosis through noninvasive imaging techniques such as Fluorescent Molecular Tomography (FMT) and Micro-CT. These two technologies validated with histology findings could represent a revolutionary functional approach for real time non-invasive monitoring of IPF disease severity and progression. The fusion of different approaches represents a step further for understanding the IPF disease, where the molecular events occurring in a pathological condition can be observed with FMT and the subsequent anatomical changes can be monitored by Micro-CT.

We describe a non-invasive multimodal imaging approach based on Micro-CT and fluorescence molecular tomography for longitudinal assessment of the mouse lung fibrosis model induced by double intratracheal instillation of bleomycin.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by the progressive and irreversible destruction of lung architecture, which ...

Immunology and Infection

Protocol and Guidelines for Point-of-Care Lung Ultrasound in Diagnosing Neonatal Pulmonary Diseases Based on International Expert Consensus

Ultrasound is a safe bedside imaging tool that obviates the use of ionizing radiation diagnostic procedures. Due to its convenience, the lung ultrasound has received increasing attention from neonatal physicians. Nevertheless, clear reference standards and guideline limits are needed for accurate application of this diagnostic modality. This document aims to summarize expert opinions and to provide precise guidance to help facilitate the use of the lung ultrasound in the diagnosis of neonatal lung diseases.

Lung ultrasound is a noninvasive and valuable tool for bedside evaluation of neonatal lung diseases. However, a relative lack of reference standards, protocols and guidelines may limit its application. Here, we aim to develop a standardized neonatal lung ultrasound diagnostic protocol to be used in clinical decision-making.

Ultrasound is a safe bedside imaging tool that obviates the use of ionizing radiation diagnostic procedures. Due to its convenience, the lung ultrasound ...

Lung CT Segmentation to Identify Consolidations and Ground Glass Areas for Quantitative Assesment of SARS-CoV Pneumonia

Segmentation is a complex task, faced by radiologists and researchers as radiomics and machine learning grow in potentiality. The process can either be automatic, semi-automatic, or manual, the first often not being sufficiently precise or easily reproducible, and the last being excessively time consuming when involving large districts with high-resolution acquisitions.
A high-resolution CT of the chest is composed of hundreds of images, and this makes the manual approach excessively time consuming. Furthermore, the parenchymal alterations require an expert evaluation to be discerned from the normal appearance; thus, a semi-automatic approach to the segmentation process is, to the best of our knowledge, the most suitable when segmenting pneumonias, especially when their features are still unknown.
For the studies conducted in our institute on the imaging of COVID-19, we adopted 3D Slicer, a freeware software produced by the Harvard University, and combined the threshold with the paint brush instruments to achieve fast and precise segmentation of aerated lung, ground glass opacities, and consolidations. When facing complex cases, this method still requires a considerable amount of time for proper manual adjustments, but provides an extremely efficient mean to define segments to use for further analysis, such as the calculation of the percentage of the affected lung parenchyma or texture analysis of the ground glass areas.

The aim of this protocol is to provide a time efficient way to segment volumes of interest on high-resolution CT scans to use for further radiomics analysis.

Segmentation is a complex task, faced by radiologists and researchers as radiomics and machine learning grow in potentiality. The process can either be ...

Point-of-Care Lung Ultrasound in Adults: Image Acquisition

Consultative ultrasound performed by radiologists has traditionally not been used for imaging the lungs, as the lungs&#39; air-filled nature normally prevents direct visualization of the lung parenchyma. When showing the lung parenchyma, ultrasound typically generates a number of non-anatomic artifacts. However, over the past several decades, these artifacts have been studied by diagnostic point-of-care ultrasound (POCUS) practitioners, who have identified findings that have value in narrowing the differential diagnoses of cardiopulmonary dysfunction. For instance, in patients presenting with dyspnea, lung POCUS is superior to chest radiography (CXR) for the diagnosis of pneumothorax, pulmonary edema, lung consolidations, and pleural effusions. Despite its known diagnostic value, the utilization of lung POCUS in clinical medicine remains variable, in part because training in this modality across hospitals remains inconsistent. To address this educational gap, this narrative review describes lung POCUS image acquisition in adults, including patient positioning, transducer selection, probe placement, acquisition sequence, and image optimization.

Point-of-care ultrasound (POCUS) of the lungs provides quick answers in rapidly changing clinical scenarios. We present an efficient and informative protocol for image acquisition for use in acute care settings.

Consultative ultrasound performed by radiologists has traditionally not been used for imaging the lungs, as the lungs&#39; air-filled nature normally ...

Transbronchial Lung Cryobiopsy for Diagnosing Interstitial Lung Diseases and Peripheral Pulmonary Lesions - A Stepwise Approach

Transbronchial lung cryobiopsy (TBLC) is an invasive procedure increasingly implemented during the last decade as an alternative to video-assisted thoracic surgery lung biopsy (SLB) for diagnosing interstitial lung diseases (ILDs). The indication for TBLC has primarily been to sub-classify a specific ILD subtype when this cannot be achieved on the basis of a preceding multidisciplinary team discussion. Although SLB is considered the gold standard for establishing a histological diagnosis, TBLC has been gradually suggested as the first-choice histological diagnostic modality in patients with unclassified ILDs due to a comparable diagnostic yield with SLB, but superior to SLB in terms of complications, including mortality. During recent years, radial endobronchial ultrasound (R-EBUS) and electromagnetic navigation bronchoscopy (ENB)-guided TBLC for peripheral pulmonary lesions have also been described as safe procedures, which may improve the diagnostic yield compared to forceps biopsies. Still, the diagnostic properties of TBLC rely on the quality of the procedure&#39;s performance. This article aims to describe the stepwise approach to conducting TBLC with a flexible bronchoscope for the different indications mentioned, which might be helpful for novice bronchoscopists performing TBLC.

Transbronchial lung cryobiopsy (TBLC) for diagnosing interstitial lung disease and peripheral pulmonary lesions is a high-yield diagnostic and safe procedure. We describe a stepwise approach to conduct TBLC for the different indications mentioned with a flexible bronchoscope, which might be helpful for novice bronchoscopists performing TBLC.

Transbronchial lung cryobiopsy (TBLC) is an invasive procedure increasingly implemented during the last decade as an alternative to video-assisted ...

Technique for Salivary Gland Ultrasound Examination of Sjogren's Syndrome

Ultrasonographic Evaluation of Salivary Glands for Sjogren's Syndrome: Diagnostic and Monitoring Insights

Sjogren's syndrome (SS) is a chronic autoimmune condition commonly affecting the exocrine glands, causing oral or ocular dryness and extraglandular manifestations including arthralgia, cytopenia, and lymphoma. The presence of autoantibodies against SSA/Ro, labial salivary gland biopsy, ocular staining, Schirmer's test, or salivary flow assessment are included in the current classification criteria of SS. However, the availability and invasiveness of these procedures limit their widespread use in clinical settings. Salivary gland ultrasonography (SGUS) is a non-invasive imaging modality for the evaluation of the salivary gland parenchyma and is increasingly utilized to aid diagnosis and monitoring in SS. 
This article presents the protocol of SGUS for image acquisition at the parotid and submandibular glands. The objective is to present a standardized, reproducible, and practical approach to diagnostic SGUS for SS in daily clinical settings. Major salivary glands are scanned in a stepwise approach, beginning at the angle of the mandible for the superficial lobe of the parotid gland, followed by the deep lobe below the ramus of the mandible. Submandibular areas are then scanned for the submandibular glands. The steps in obtaining salivary gland images at each anatomical site are explained in the accompanying video. The echogenicity and echotexture at the thyroid gland are taken as a reference. The homogeneity, the presence and distribution of hypoechoic areas within the glands, and the border of the salivary glands are examined. The sizes and features of intra-/peri-glandular lymph nodes are recorded. The most distinctive sonographic feature in SS is glandular heterogeneity with the presence of hypoechoic/hyperechoic areas within the glands. 
In summary, while SGUS cannot diagnose SS on its own, it can supplement the current classification criteria of SS and guide the clinical decision for salivary gland biopsy to support the diagnosis of SS in patients with sicca syndrome or suspicious systemic features, combined with autoantibody testing.

Author Spotlight: A Focus on Standardized Salivary Gland Ultrasound Protocol in Connective Tissue Disease Research

Salivary gland ultrasonography is a promising tool for the diagnosis and evaluation of disease activity and complications in Sjogren's syndrome (SS). The scanning technique for salivary gland ultrasound examination relevant to SS is described in the article.

Sjogren's syndrome (SS) is a chronic autoimmune condition commonly affecting the exocrine glands, causing oral or ocular dryness and extraglandular ...

Multi-modal Pulmonary Imaging: Using Complementary Information from CT and Hyperpolarized 129Xe MRI to Evaluate Lung Structure-Function

Hyperpolarized 129Xe gas MRI is an emerging technique to evaluate and measure regional lung function including pulmonary gas distribution and gas exchange. Chest computed tomography (CT) still remains the clinical gold standard for imaging of the lungs, though, in part due to the rapid CT protocols that acquire high-resolution images in seconds and the widespread availability of CT scanners. Quantitative approaches have enabled the extraction of structural lung parenchymal, airway and vascular measurements from chest CT that have been evaluated in many clinical research studies. Together, CT and 129Xe MRI provide complementary information that can be used to evaluate regional lung structure and function, resulting in new insights into lung health and disease. 129Xe MR-CT image registration can be performed to measure regional lung structure-function to better understand lung disease pathophysiology, and to perform image-guided pulmonary interventions. Here, a method for 129Xe MRI-CT registration is outlined to support implementation in research or clinical settings. Registration methods and applications that have been employed to date in the literature are also summarized, and suggestions are provided for future directions that may further overcome technical challenges related to 129Xe MR-CT image registration and facilitate broader implementation of regional lung structure-function evaluation.

Multi-modal Pulmonary Imaging: Using Complementary Information from CT and Hyperpolarized 129Xe MRI to Evaluate Lung Structure-Function

CT and 129Xe MRI provide complementary lung structure-function information that can be exploited for regional analysis using image registration. Here, we provide a protocol that builds from the existing literature for 129Xe MR to CT image registration using open-source platforms.

Hyperpolarized 129Xe gas MRI is an emerging technique to evaluate and measure regional lung function including pulmonary gas distribution and gas ...

Protocol for High-Resolution Lung Imaging Using 3T UTE MRI with Self-Gating

Pulmonary Structural MRI using Free-Breathing, Self-Gated Ultra-short Echo Time Imaging

High quality MRI of the lungs is challenged by low tissue density, fast MRI signal relaxation, and respiratory and cardiac motion. For these reasons, structural imaging of the lungs is performed almost exclusively using Computed Tomography (CT). However, CT imaging delivers ionizing radiation, and thus is less well suited for certain vulnerable populations (e.g., pediatrics) or for research applications. As an alternative, MRI using ultra-short echo times (UTE) is attracting interest. This technique can be performed during free-breathing over the course of a ~5-10 min scan. Respiratory motion information is encoded alongside images; this information can be used to "self-gate" images. Self-gating thus removes the requirement of advanced MRI pulse sequence programming or the use of respiratory bellows, which simplifies image acquisition. In this protocol, simple, robust, and computationally efficient acquisition and reconstruction methods for acquiring high quality UTE MRI of the lungs are presented. This protocol was developed for use on a 3T MRI scanner, but the same principles can be implemented at lower magnetic field strength. The protocol includes recommended parameter settings for 3D radial UTE image acquisition as well as directions for self-gated image reconstruction to generate images at distinct respiratory phases. Through the implementation of this protocol, users can generate high-resolution UTE images of the lungs with minimal to minimal-to-no motion artifacts. These images can be used to evaluate pulmonary structure, which can be implemented for research use in a variety of pulmonary conditions.

Author Spotlight: Optimized Lung MRI Protocol with Computationally Efficient Reconstruction Methods

A protocol is described for generating high-resolution structural images of the lungs using ultra-short-echo time (UTE) Magnetic Resonance Imaging (MRI). This protocol allows for images to be acquired using a simple MRI pulse sequence during free-breathing.

High quality MRI of the lungs is challenged by low tissue density, fast MRI signal relaxation, and respiratory and cardiac motion. For these reasons, ...

Key Molecular Targets Linking Primary Sjogren's Syndrome and Lung Adenocarcinoma

Primary Sjogren's Syndrome Associated with Lung Adenocarcinoma: Probing the Potential Common Pathogenic Mechanisms and Experimental Verification

This study aimed to probe the potential common pathogenic mechanisms linking primary Sjogren's syndrome (pSS) and lung adenocarcinoma (LUAD) through bioinformatics analysis and experimental verification. The relevant genes associated with pSS and LUAD were retrieved from the Gene Expression Omnibus (GEO) database and Genecard database. Subsequently, differentially expressed genes (DEGs) associated with pSS and LUAD were screened as pSS-LUAD-DEGs. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses were performed to elucidate the significant biological functions of pSS-LUAD-DEGs. Core targets were identified by constructing the protein-protein interaction (PPI) network, further assessing hub gene diagnostic accuracy through Receiver Operating Characteristic (ROC) curve analyses. In this study, NOD/Ltj mice served as pSS animal models and were stimulated with particulate matter 2.5 (PM2.5) to generate an inflammatory reaction. Quantitative real-time polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA), and western blotting were employed for relevant molecular biology experiment verification. The results revealed through KEGG and GO enrichment analyses indicate that inflammation plays a critical role in linking pSS and LUAD. IL6, CCNA2, JAK2, IL1B, ASPM, CCNB2, NUSAP1, and CEP55 were determined as key targets of pSS-LUAD. BALB/c mice and NOD/Ltj mice exhibited enhanced expression of inflammatory cytokines IL-6 and IL-1&#946; in lung tissues following 21 days of stimulation with PM2.5, activating the JAK2/STAT3 signaling pathway and up-regulating the expression of tumor-associated genes CCNA2, CCNB2, and CEP55, with NOD/Ltj mice exhibiting more pronounced changes than BALB/c mice. This protocol demonstrates that carcinogenesis induced by the pulmonary inflammatory microenvironment may be a key reason for the high incidence of LUAD in pSS patients. Additionally, blocking-related mechanisms may help prevent the occurrence of LUAD in pSS patients.

Author Spotlight: Exploring the Role of Inflammation in the Co-occurrence of Primary Sjogren's Syndrome and Lung Adenocarcinoma

This manuscript describes the operational procedures and precautions to probe the potential common pathogenic mechanisms linking primary Sjogren's syndrome and lung adenocarcinoma through bioinformatics analysis and experimental verification.

This study aimed to probe the potential common pathogenic mechanisms linking primary Sjogren's syndrome (pSS) and lung adenocarcinoma (LUAD) through ...

Imaging Features of Systemic Sclerosis-Associated Interstitial Lung Disease

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