Lung Imaging: Selected Techniques
Number: 0581
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
Scope of Policy
This Clinical Policy Bulletin addresses selected techniques for lung imaging.
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Medical Necessity
Aetna considers lung imaging fluorescence endoscopy (LIFE) medically necessary to enhance the physician's ability to detect and biopsy abnormal bronchial tissue suspicious for pre-cancerous lesions, carcinomas in-situ, and early bronchogenic carcinomas in any of the following groups:
- Members with known or previously diagnosed lung cancer; or
- Members with suspected lung cancer including:
- Members suspected of having lung cancer because of clinical symptoms such as positive sputum cytology, hemoptysis, infiltrates or clinical signs/symptoms of pneumonia that do not resolve within 30 days of treatment, persistent cough or positive X-ray; or
- Members with a previously resected Stage I lung cancer, with no evidence of metastatic disease, who are at risk for secondary disease.
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Experimental, Investigational, or Unproven
Aetna considers the following lung imaging modalities experimental, investigational, or unproven because the effectiveness of these approaches has not been established:
- Computer-aided lung informatics for pathology evaluation and rating (CALIPER) program for the evaluation of interstitial lung disease;
- Contrast-enhanced ultrasonography for diagnosis of lung cancer;
- LIFE for all other indications not listed in Section I;
- Three-dimensional (3D) lung CT for evaluation of bronchial anatomy (Note: 3D reconstruction is considered incidental to the CT and is not separately reimbursed);
- Use of point laser Raman spectroscopy to a combined white light bronchoscopy and auto-fluorescence bronchoscopy for detection of pre-neoplastic lesions;
- Use of XV LVAS pulmonary tissue ventilation analysis for quantification of pulmonary tissue ventilation;
- Xenon Xe-129 hyper-polarized gas (Xenoview) for the evaluation of lung ventilation (Note: Contrast agents are considered part of the underlying radiology imaging service and are not separately reimbursed).
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Related Policies
Background
In the treatment of lung cancer, the best outcome is achieved when the lesion is detected and localized in the pre-invasive stage. To date, conventional white-light bronchoscopy has been inadequate for the identification and localization of many early bronchogenic carcinomas, carcinomas in situ (CIS), and pre-cancerous dysplasias because these lesions may exhibit little visual difference from normal tissue when examined with white light.
Lung imaging fluorescence endoscopy, also referred to as light‑induced or laser‑induced fluorescence endoscopy (LIFE), is an adjunct bronchoscopic imaging technique used to enhance detection of pre‑invasive and early malignant lesions of the tracheobronchial tree. Conventional white‑light bronchoscopy has limited sensitivity for identifying early bronchogenic carcinomas, carcinoma in situ, and dysplastic lesions, as these abnormalities may exhibit minimal visual differences from normal mucosa. LIFE addresses this limitation by utilizing tissue autofluorescence, in which endogenous fluorophores within the bronchial mucosa emit light when exposed to a specific wavelength.
During the procedure, blue laser light is delivered through a flexible bronchoscope to excite autofluorescence, and the emitted signal is processed to generate real‑time images. Normal bronchial mucosa typically appears green, whereas dysplastic or malignant tissue demonstrates reduced fluorescence and appears reddish‑brown. This contrast allows for improved visualization of suspicious lesions and facilitates targeted biopsy when used in conjunction with standard white‑light bronchoscopy (O’Neil, 1998; Kusunoki, 2000).
In 1996, the Xillix LIFE-Lung Fluorescence Endoscopy system received U.S. Food and Drug Administration (FDA) Premarket Approval (PMA) for use as an adjunct to white‑light bronchoscopy to identify abnormal bronchial tissue in individuals with suspected or known lung cancer (O’Neil, 1998; Takehana et al., 1999). Clinical studies have demonstrated that the addition of fluorescence imaging to conventional bronchoscopy increases the sensitivity for detection of pre‑invasive lesions, including moderate to severe dysplasia and carcinoma in situ (Kusunoki, 2000). Although fluorescence bronchoscopy is associated with lower specificity compared with white‑light bronchoscopy alone, its increased sensitivity for detecting early mucosal abnormalities supports its use as an adjunctive technique to guide biopsy in selected high‑risk individuals, particularly those with suspected or known lung cancer.
NoteLIFE is only indicated for use in conjunction with white-light bronchoscopy using an Olympus BF-20D flexible fiber optic bronchoscope and should not be used in combination with photosensitizing agents. LIFE is restricted by Federal law to be used only by physicians who have completed appropriate training in flexible fiber optic bronchoscopy and who have been trained in the use of the LIFE device.
In a prospective, multi-center, comparative, single-arm trial, Edell et al. (2009) evaluated the benefit of using a new fluorescence-reflectance imaging system, Onco-LIFE, for the detection and localization of intraepithelial neoplasia and early invasive squamous cell carcinoma. A secondary objective was to evaluate the potential use of quantitative image analysis with this device for objective classification of abnormal sites. Subjects for this study were aged 45 to 75 years and either current or past smokers of more than 20 pack-years with airflow obstruction, forced expiratory volume in 1 second/forced vital capacity less than 75%, suspected to have lung cancer based on either sputum atypia, abnormal chest roentgenogram/chest computed tomography, or patients with previous curatively treated lung or head and neck cancer within 2 years. The primary endpoint of the study was to determine the relative sensitivity of white light bronchoscopy (WLB) plus autofluorescence-reflectance bronchoscopy compared with WLB alone. Bronchoscopy with Onco-LIFE was carried out in 2 stages. The first stage was performed under white light and mucosal lesions were visually classified. Mucosal lesions were classified using the same scheme in the second stage when viewed with Onco-LIFE in the fluorescence-reflectance mode. All regions classified as suspicious for moderate dysplasia or worse were biopsied, plus at least 1 non-suspicious region for control. Specimens were evaluated by the site pathologist and then sent to a reference pathologist, each blinded to the endoscopic findings. Positive lesions were defined as those with moderate/severe dysplasia, CIS, or invasive carcinoma. A positive patient was defined as having at least 1 lesion of moderate/severe dysplasia, CIS, or invasive carcinoma. Onco-LIFE was also used to quantify the fluorescence-reflectance response (based on the proportion of reflected red light to green fluorescence) for each suspected lesion before biopsy. There were 115 men and 55 women with median age of 62 years. A total of 776 biopsy specimens were included; 76 were classified as positive (moderate dysplasia or worse) by pathology. The relative sensitivity on a per-lesion basis of WLB + FLB versus WLB was 1.50 (95% confidence interval [CI]: 1.26 to 1.89). The relative sensitivity on a per-patient basis was 1.33 (95% CI: 1.13 to 1.70). The relative sensitivity to detect intra-epithelial neoplasia (moderate/severe dysplasia or CIS) was 4.29 (95% CI: 2.00 to 16.00) and 3.50 (95% CI: 1.63 to 12.00) on a per-lesion and per-patient basis, respectively. For a quantified fluorescence reflectance response value of more than or equal to 0.40, a sensitivity and specificity of 51% and 80%, respectively, could be achieved for detection of moderate/severe dysplasia, CIS, and micro-invasive cancer. The authors concluded that using autofluorescence-reflectance bronchoscopy as an adjunct to WLB with the Onco-LIFE system improves the detection and localization of intra-epitheal neoplasia and invasive carcinoma compared with WLB alone. The use of quantitative image analysis to minimize inter-observer variation in grading of abnormal sites should be explored further in future prospective clinical trial.
According to available literature, LIFE is considered medically inappropriate for any of the following groups:
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Persons in whom white light bronchoscopic examination is contraindicated including:
- Persons with known bleeding disorder or members on anticoagulant therapy;
- Persons with uncontrolled hypertension (systolic pressure greater than 200 mm Hg, diastolic pressure greater than 120 mm Hg);
- Persons with unstable angina;
- Persons with white blood count less than 2,000 cells/microliter (ul) or greater than 20,000 cells/ul and/or platelet count less than 50,000/mm3.
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Persons in whom fluorescence examination is contraindicated including:
- Persons who are on, or have received chemo-preventive drugs (e.g., retinoic acid) within 3 months prior to the procedure;
- Persons who have received cytotoxic chemotherapy agents systemically within 6 months prior to the procedure;
- Persons who have received fluorescent photosensitizing agents (hemato-porphoryn derivatives) within 3 months prior to the procedure;
- Persons who have received ionizing radiation treatment to the chest within 6 months prior to the procedure.
Short and colleagues (2011) stated that pre-neoplastic lesions of the bronchial tree have a high probability of developing into malignant tumors. Currently, the best method for localizing them for further treatment is a combined WLB and auto-fluorescence bronchoscopy (AFB) (WLB + AFB). The average specificity from large clinical trials for this combined detection method is approximately 60%, leading to many false-positives. In a pilot study, these researchers examined if adding point laser Raman spectroscopy (LRS) to a WLB + AFB has the potential to improve the specificity of pre-neoplastic lesion detection and what the implication is to the detection sensitivity. An LRS system was developed to collect real-time, in-vivo lung spectra with a fiber optic catheter passed down the instrument channel of a bronchoscope. WLB + AFB imaging modalities were used to identify lesions from 26 subjects, from which 129 Raman spectra were measured. Multi-variate statistical analyses were performed on the spectra with a leave-one-out cross-validation. Clear in-vivo Raman spectra were obtained in 1 second. The location of individual Raman peaks in the spectra correlated well with the known positions of Raman peaks generated by lipids, proteins, and water molecules. Pre-neoplastic lesions were detected with a sensitivity of 96% and a specificity of 91%. The authors concluded that adding point LRS analysis to WLB + AFB imaging has the ability to detect pre-neoplastic lesions in real time with high sensitivity and specificity. They stated that the use of LRS has great potential for substantially reducing the number of false-positive biopsies associated with WLB + AFB with very little reduction in the detection sensitivity. These preliminary findings need to be validated by well-designed studies.
Computer Aided Lung Informatics for Pathology Evaluation and Rating (CALIPER) Program
In a retrospective study, Ungprasert et al. (2017) examined the correlation between measurements from quantitative thoracic HRCT analysis with the computer-aided lung informatics for pathology evaluation and rating (CALIPER) program and measurements from pulmonary function tests (PFTs) in patients with idiopathic inflammatory myopathies (IIM)-associated interstitial lung disease (ILD). A cohort of patients with IIM-associated ILD seen at Mayo Clinic was identified from medical record review. Retrospective analysis of HRCT data and PFTs at baseline and 1 year was performed. The abnormalities in HRCT were quantified using the CALIPER program. A total of 110 patients were identified. At baseline, total interstitial abnormalities as measured by CALIPER, both by absolute volume and by percentage of total lung volume, had a significant negative correlation with DLCO, total lung capacity (TLC), and oxygen saturation. Analysis by subtype of interstitial abnormality revealed significant negative correlations between ground glass opacities (GGO) and reticular density (RD) with DLCO and TLC. At 1 year, changes in total interstitial abnormalities compared with baseline had a significant negative correlation with changes in TLC and oxygen saturation. A negative correlation between changes in total interstitial abnormalities and DLCO was also observed; however, it was not statistically significant. Analysis by subtype of interstitial abnormality showed negative correlations between changes in GGO and RD and changes in DLCO, TLC, and oxygen saturation; however, most of the correlations did not achieve statistical significance. The authors concluded that CALIPER measurements correlated well with functional measurements in patients with IIM-associated ILD, which might suggest their role in the clinical care of this selected group of patients.
The authors stated that the main drawbacks of this trial were inherent to the retrospective design. HRCTs and PFTs were carried out at the discretion of clinicians who saw the patients without a standardized protocol, which could introduce an element of selection bias. Furthermore, less than 50% of patients underwent HRCTs and PFTs at 1 year due to the lack of a standardized protocol, resulting in a small number of eligible patients for the 1-year change analyses.
Jacob et al. (2019) compared radiology-based prediction models in rheumatoid arthritis-related ILD (RAILD) to identify patients with a progressive fibrosis phenotype. RAILD patients had CT scans scored visually and using CALIPER and FVC measurements. Outcomes were evaluated using three techniques, as follows: first, the scleroderma system evaluating visual ILD extent and FVC values; second, the Fleischner Society idiopathic pulmonary fibrosis (IPF) diagnostic guidelines applied to RAILD; and third, CALIPER scores of vessel-related structures (VRS). Outcomes were compared to IPF patients. On uni-variable Cox analysis, all three staging systems strongly predicted outcomes (scleroderma system hazard ratio (HR) 3.78, p = 9 × 10^-5; Fleischner system HR 1.98, p = 2 × 10^-3; and 4.4% VRS threshold HR 3.10, p = 4 × 10^-4). When the scleroderma and Fleischner systems were combined, termed the progressive fibrotic system (C-statistic 0.71), they identified a patient subset (n = 36) with a progressive fibrotic phenotype and similar 4-year survival to IPF. On multi-variable analysis, with adjustment for patient age, sex, and smoking status, when analyzed alongside the progressive fibrotic system, the VRS threshold of 4.4% independently predicted outcomes (model C-statistic 0.77). The combination of two visual CT-based staging systems identified 23% of an RAILD cohort with an IPF-like progressive fibrotic phenotype. The authors concluded that the addition of a computer-derived VRS threshold further improved outcome prediction and model fit, beyond that encompassed by RAILD measures of disease severity and extent.
The authors stated that this study had several drawbacks. First, while the obvious benefits of automated analysis include its objectivity and reproducibility, extremely edge-enhancing CT algorithms can result in misclassification of patterns such as honeycombing. For this reason, in the present study, CTs from three patients with RAILD CTs reconstructed with a Siemens B60f algorithm were not analyzed. To avoid the exclusion of such cases, the routine acquisition of computer-friendly reconstruction algorithms should be encouraged and will become increasingly important as quantitative CT analysis becomes more widespread. Second, the standardization of algorithms will improve the likelihood of identifying subtle changes in pattern extents across serial CT examinations. The RAILD patients in the two study centers had differing disease severities, with more advanced disease observed in the Royal Brompton Hospital population. However, these researchers believed that this heterogeneity was a potential strength rather than a major limitation, as it better reflected a real-world cohort of RAILD patients, rather than a selection of advanced, complex RAILD patients referred to a single tertiary London center. It was for this reason that these researchers also chose to compare the RAILD patients to IPF patients originating from two tertiary centers, instead of a single, homogeneous, potentially biased IPF cohort.
In a retrospective study, Crews et al. (2020) examined diagnostic and prognostic differences in major forms of ILD using quantitative CT imaging. This trial included 225 subjects with a multi-disciplinary diagnosis of IPF, interstitial pneumonia with autoimmune features (IPAF), connective tissue disease (CTD), or chronic hypersensitivity pneumonitis (cHP). Non-contrast CT scans were analyzed using the CALIPER program. Resulting data were analyzed statistically using ANOVA and Student’s t-test. Uni-variate, multi-variable, and ROC analyses were performed on patient mortality data. CALIPER analysis of axial distribution on CT scans in those with IPF showed greater peripheral volumes of reticulation than either CTD (p = 0.033) or cHP (p = 0.007). CTD showed lower peripheral ground-glass opacity than IPF (p = 0.005) and IPAF (p = 0.004). Statistical analysis of zonal distributions showed reduced lower zone ground-glass opacity in cHP than IPF (p = 0.044) or IPAF (p = 0.018). Analysis of pulmonary VRS volume by diagnosis indicated greater VRS volume in IPF compared to CTD (p = 0.003) and cHP (p = 0.003), as well as in IPAF compared to CTD (p = 0.007) and cHP (p = 0.007). Increased reticulation (p = 0.043) and ground-glass opacity (p = 0.032) were predictive of mortality on uni-variate analysis. Increased pulmonary VRS volume was predictive of mortality (p < 0.001) even after multi-variate analysis (p = 0.041). The authors concluded that the findings of this study indicated that, on a cohort-wide scale, IPF revealed greater peripheral reticulation than CTD or cHP, IPAF displayed greater peripheral reticulation than cHP, and CTD showed lower peripheral volumes of ground-glass opacity than IPF or IPAF. These investigators stated that these findings represented significant differences in axial distribution, suggesting that perhaps axial distributions should be strongly considered when making diagnoses between various forms of ILD. Moreover, these researchers stated that the implications of pulmonary VRS volume findings should be further examined regarding diagnosis as well as survival, given growing evidence that VRS has prognostic and diagnostic ramifications.
The authors stated that this trial was limited by its comparatively small number of subjects (n = 225), although it represented a relatively large study population in the context of other studies of CT imaging in ILDs. This power limitation might contribute to some of the findings—notably, the lack of significant associations between global parenchymal pattern volumes and diagnosis. Furthermore, much of the signal was lost when the data were corrected for CALIPER-derived patient total lung volumes, and the data in this trial were thus considered in absolute terms. This signal loss was possibly due to the small parenchymal pattern volumes relative to total lung volumes. While considering the data in absolute terms allowed for the observation of more granular findings, it may also permit patient anatomy and size to play a role. The exploratory nature of and large number of variables involved in this trial also limited the implementation of a correction for multiple testing in the statistical analysis. Moreover, this trial was limited in its retrospective nature. Lastly, this study was carried out at a tertiary referral center for ILD management; thus, the findings of this study may not be generalized to the community setting.
In a retrospective study, Romei et al. (2020) examined the role of CALIPER in identifying HRCT thresholds predicting IPF patients' survival and lung function decline and its role in detecting changes in HRCT abnormalities related to treatment and their correlation with FVC. This trial included 105 patients with a multi-disciplinary diagnosis of IPF for whom one HRCT at baseline and concomitant FVC were available. HRCTs were evaluated with CALIPER, and the correlation between FVC and radiological features was assessed. Radiological thresholds for survival prediction and functional decline were calculated for all patients. A total of 59 patients with at least two serial HRCTs were classified into two groups based on treatment. For patients for whom an FVC within 3 months of the HRCT was available (n = 44), the correlation of radiological and clinical progression was evaluated. The correlation between FVC and CALIPER-derived features at baseline was significant and strong. A baseline CALIPER-derived ILD extent (ILD%) higher than 20% and pulmonary VRS (PVRS%) score greater than 5% defined a worse prognosis. A significant progression of CALIPER-derived features in all patients was found, with a faster increase in untreated patients. ILD% and PVRS% changes during follow-up showed strong correlations with FVC changes. The authors concluded that the findings of this study opened up the possibility to use CALIPER to assess disease severity and progression in patients with IPF and as a reproducible and objective endpoint in future clinical trials. Moreover, these researchers stated that further investigations of a larger, well-characterized cohort with consistent HRCT data or prospective analysis with a set of intervention/control subjects are needed to validate these exciting preliminary findings.
The authors stated that this trial had several drawbacks. First, it was retrospective and thus could have some unforeseen selection bias. The sample size was relatively small (n = 105). Technical parameters among the different CT studies were not perfectly homogeneous (slice thickness and exposure parameters); however, these minimal dissimilarities were not strong enough to alter the results. The selection of HRCTs for CALIPER evaluation during the follow-up was limited to 59 patients since these investigators were careful to only include patients for whom each scan was carried out with the same brand scanner and kernel, in order to avoid bias due to image acquisition or reconstruction characteristics. These limits will be avoided in a prospective clinical trial but are a concern in real-world applications to use quantitative analysis software longitudinally. Within the follow-up group, there was an even smaller number of patients with more than a single usable HRCT during the follow-up, and a great deal of temporal inhomogeneity in the timing of the radiological and functional follow-up.
Ferrazza et al. (2020) stated that ILD remains a major cause of morbidity and mortality in systemic sclerosis (SSc). In a prospective study, these investigators characterized and quantified SSc-ILD by means of the CALIPER program. They also examined which radiological pattern is predictive of lung function decline at 12-month follow-up. This trial included 66 SSc patients who underwent HRCT at baseline. HRCT was carried out according to standard protocol using a CT 64GE light speed VCT power scanner. CALIPER classified lung parenchyma on volume units. Every volume unit was classified into radiological parenchymal patterns (honeycombing, reticular, and ground glass); PFTs were performed at baseline and after 12 months of follow-up. Cigarette smoking and other lung diseases unrelated to SSc were exclusion criteria. CALIPER analysis showed normal lung parenchyma 87.4 ± 9.8%, ground glass 2.8 ± 5.3%, reticular 4 ± 5.7%, and honeycombing 1 ± 1%. In multiple regression analysis, FEV1 (p < 0.0001), FVC (p = 0.001), and DLCO (p < 0.0001) measurements at baseline showed a negative correlation with the reticular pattern percentage. At follow-up, DLCO reduction showed a positive correlation (p < 0.001) with the percentage of ground glass pattern (r = 0.33, beta coefficient = 0.51). In the ROC curve analysis, ground glass score is a good predictor (0.75, p = 0.009; 95% CI: 0.59 to 0.91) of DLCO worsening, defined as a decrease of more than 10% of DLCO. Using a cut-off of 4.5 or higher for ground glass score, the RR for DLCO worsening was 6.8 (p < 0.01; 95% CI: 1.6 to 29.2). The authors concluded that the findings of this study showed that CALIPER was useful not only for quantifying lung damage but also for assessing worsening PFTs; however, larger studies are needed to confirm these preliminary findings.
Jiao et al. (2023) stated that HRCT, as the main tool for monitoring IPF, is characterized by subjective variability among radiologists and insensitivity to subtle changes. Recently, a few studies have aimed to decrease subjective bias by assessing the severity of IPF using computer software, i.e., CALIPER. However, these studies had diverse research directions. In a systematic review, these investigators examined the effect of CALIPER in the management of IPF. They carried out a literature search of published studies in PubMed, Web of Science, Cochrane, Embase, Scopus, and CNKI databases from database inception through February 28, 2022. The methodological quality was evaluated by using the Methodological Index for Non-Randomized Studies (MINORS). Narrative synthesis summarized findings by participant characteristics, study design, and associations with outcomes; a total of 10 studies were included. These researchers evaluated the relationship between CALIPER-derived parameters and PFT and mortality. CALIPER-derived parameters showed a significant correlation with PFT and mortality; two studies reported that CALIPER could be used to stratify outcomes. The authors concluded that CALIPER-derived parameters could be used to evaluate prognosis and mortality. CALIPER-derived parameters combined with composite physiologic index (CPI) or gender-age-physiology (GAP) could aid clinicians in implementing targeted management by refining prognostic stratification. However, research has been constrained by a small number of retrospective investigations and sample sizes; thus, it is important to design prospective, controlled trials and establish the staging system by CALIPER-derived parameters and combine them with CPI, FVC, or GAP.
Furthermore, an UpToDate review on “Interstitial lung disease in rheumatoid arthritis” (Lake, 2024) states that “The optimal method for using CT scans to identify the underlying histopathology and monitor for progression of RA-ILD has not been determined. One method may be to combine scoring systems used in other forms of ILD. In one combined case series, 157 patients with RA-ILD were characterized using: 1) a visual scoring system for systemic sclerosis ILD; 2) the Fleischner Society guidelines for idiopathic pulmonary fibrosis (IPF); and 3) an automated computer-based CT analysis (CALIPER) and followed for approximately 3 years. The combination of the two visual CT-based scoring systems identified a progressive fibrotic subset of the original cohort with poor prognosis similar to that of IPF (c-statistic of 0.71); the automated CT analysis further improved the predictive accuracy. Automated scoring systems are currently a research tool but have promise for the future.”
Contrast-Enhanced Ultrasound for Diagnosis of Lung Cancer
Huang et al. (2025) stated that lung cancer (LC) remains one of the leading causes of cancer-related mortality globally, emphasizing the need for innovative diagnostic tools to improve early detection and patient outcomes. Contrast-enhanced ultrasonography (CEUS) has emerged as a promising complement to conventional imaging modalities, offering distinct advantages such as real-time dynamic imaging, cost-effectiveness, and the absence of ionizing radiation. By enhancing the visualization of tumor vascularization, CEUS allows differentiation between benign and malignant pulmonary nodules while providing valuable insights into tumor angiogenesis, a hallmark of malignancy, and therapeutic response. Furthermore, CEUS shows utility in evaluating regional lymph nodes, detecting distant metastases, as well as analyzing blood flow dynamics via quantitative methods such as time-intensity curve analysis. Moreover, these researchers stated that despite these benefits, certain limitations persist, including reduced effectiveness in imaging deep-seated lesions, variability due to patient-specific physiological factors, and dependency on operator expertise. However, advancements in targeted contrast agents, integration with multi-modal imaging techniques, and the use of artificial intelligence (AI) technology hold significant potential to address these challenges. These investigators examined the clinical applications, advantages, and limitations of CEUS in LC diagnosis, providing a comprehensive understanding of its role in modern precision oncology. In addition, they highlighted future research directions aimed at enhancing diagnostic accuracy, improving clinical workflows, as well as expanding the adoption of CEUS in routine practice.
These researchers stated that despite its numerous advantages, CEUS faces certain limitations and challenges that need to be addressed to enhance its clinical utility. First, CEUS has limited effectiveness in imaging deep-seated lesions. The attenuation of ultrasound (US) signals in deep tissues lowers the quality of imaging for lesions located in the deeper regions of the lungs or in larger patients. Furthermore, studies have reported that approximately 20% to 30% of pulmonary lesions may not be assessed as a consequence of interference from air-tissue interfaces in the lungs, especially in cases where lesions were located near the central airways or in areas with significant air content. The bony structures of the chest wall can further hinder imaging quality. These constraints make CEUS less effective than CT or MRI for diagnosing deep or complex pulmonary lesions. Second, the safety and applicability of contrast agents require further evaluation. While micro-bubble contrast agents used in CEUS are generally safe, there are contraindications for certain patient populations, such as those with severe cardiopulmonary conditions or allergies to the contrast agent components. In addition, the diagnostic performance of CEUS may be affected by hemodynamic abnormalities in patients, potentially increasing diagnostic uncertainty in specific clinical scenarios. Third, CEUS relies heavily on operator expertise and lacks standardized protocols. The accuracy and reliability of CEUS examinations depend significantly on the skill level of the operator, including selecting the appropriate probe, adjusting imaging parameters, and interpreting dynamic images. This dependency on operator proficiency may result in variability in diagnostic outcomes. In addition, the absence of comprehensive standardized guidelines and diagnostic criteria limits the widespread adoption of CEUS across different healthcare centers and settings.
Three-Dimensional (3D) Lung CT for Evaluation of Bronchial Anatomy
In a retrospective study, Zhao et al. (2025) examined the anatomical types and variations of lung segments and subsegment bronchi based on three-dimensional (3D)-CT reconstruction technology, and provided anatomical theoretical support for thoracic surgeons in terms of surgical techniques. The 3D-CT reconstructed images of 541 patients were analyzed. These investigators examined the anatomical structure of the bronchi in the middle lobe of the right lung, sorted out the variations, and classified them in detail according to different bronchial types. In the CT 3D reconstruction of 541 patients, the bronchial anatomical types of the right middle lobe were divided into 2 types. There were 530 cases (98.0%) of 2-branched type and 11 cases (2.0%) of 3-branched type, and no 4-branched type was found in the data of this study. Furthermore, the spatial relationship between B4 and B5, and the spatial relationship between sub-segmental bronchi B4a, B4b, B5a, and B5b were analyzed. The most common anatomical type and spatial relationship of the right middle lobe bronchi in the 2-branched type were B4 and B5 in the external-internal relationship, B4a and B4b in the external-internal relationship, and B5a and B5b in the upper and lower relationship, and this subtype was 416 cases (76.9%). Furthermore, 23 cases (3.9%) were found to have a spatial relationship between B4 and B5 in the right middle lobe similar to the lingual bronchial subtype in the left upper lobe. The authors used a large number of CT 3D reconstructed images to investigate the anatomical types and variations of the bronchi in the middle lobe of the right lung. Thoracic surgeons can use these findings to guide lobectomy and segmentectomy. Moreover, these researchers stated that this trial had several drawbacks including its retrospective design, and the relatively small sample size.
Xenon Xe-129 Hyper-Polarized Gas for the Evaluation of Lung Ventilation
In December 2022, the FDA approved Xenon-129 gas (Xe-129) for the evaluation of lung ventilation in patients aged 12 years or older. Several disease states are being examined for potential use of this novel technique. This indication was expanded to include patients as young as 6 years of age in 2025. The most common uses appear to be cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). The advantages include the lack of radiation exposure and the stability of Xenon Xe-129, which is a non-radioactive isotope. There are limited data correlating this FDA-approved pulmonary ventilation modality with lung function testing, and additional measurements are needed to obtain complete lung function data. Furthermore, there are several disadvantages to this technique. It requires specialized equipment to process the inhaled gas mixture; gas must be inhaled within 5 minutes of being hyper-polarized, and the magnetic resonance imaging (MRI) must start immediately following a single-breath hold. Available evidence suggests that the information obtained from these scans might provide more useful insight into disease states. This technique may allow earlier detection of disease progression and response to therapy compared to current typical evaluations using chest CT, pulmonary function tests (PFTs), and 6-minute walk tests.
Thomen et al. (2017) investigated the use of hyperpolarized xenon-129 (129Xe) MRI to detect ventilation defects in pediatric patients with mild cystic fibrosis (CF) lung disease. The key finding was that 129Xe MRI identified significantly higher ventilation defect percentages (VDP) in children with mild CF compared to healthy controls, even when forced expiratory volume in 1 second (FEV1) was normal. Specifically, CF patients with normal FEV1 (>85% predicted) still had elevated VDP, indicating that 129Xe MRI is more sensitive than spirometry for detecting early or mild ventilation abnormalities in CF. This supports the use of 129Xe MRI as a sensitive, noninvasive tool for early detection and monitoring of regional lung function in pediatric CF. The main drawbacks of this study include the small sample size, as the study included only 11 pediatric patients with mild cystic fibrosis and 11 healthy controls. The study population was also limited to children with mild disease (FEV1 >70%), so the results may not be applicable to those with more advanced CF or to other pediatric lung diseases. The single-center design further limits generalizability, as technical factors, patient selection, and imaging protocols may differ across institutions. Additionally, the cross-sectional nature of the study precludes assessment of the utility of hyperpolarized xenon-129 MRI for longitudinal monitoring or response to therapy. Lack of comparison to other sensitive functional or structural measures, such as lung clearance index (LCI) or low-dose CT, is another limitation, as these modalities are also used to detect early CF lung disease and could provide context for the sensitivity and specificity of xenon-129 MRI. The study also did not address the reproducibility of ventilation defect percentage (VDP) measurements or inter-operator variability, which are important for clinical adoption and multi-center trials. Finally, practical limitations such as the need for specialized equipment, regulatory approval, and the feasibility of performing hyperpolarized gas MRI in routine clinical practice, especially in young children, were not addressed. These factors may impact the broader implementation of this imaging modality in pediatric CF care.
Ebner et al. (2017) prospectively evaluated the use of hyperpolarized xenon-129 (129Xe) MRI to quantify regional ventilation in patients with mild to moderate asthma, comparing a semiautomated ventilation defect percentage (VDP) calculation to traditional pulmonary function tests (PFTs) such as FEV1, FEV1/FVC, and FEF25–75%. Thirty subjects (20 asthmatics, 10 healthy controls) underwent repeated PFTs and two 129Xe MRI scans. VDP was derived using a linear binning algorithm, and its reproducibility and correlation with PFTs were assessed. 129Xe MRI detected significantly higher VDP in young asthmatic patients compared to age-matched healthy controls, even when spirometry was normal. VDP increased with age in both healthy and asthmatic groups. The semiautomated VDP was highly reproducible (intraclass correlation coefficient 0.977) and showed significant correlations with FEV1% (r = –0.42), FEF25–75% (r = –0.45), FEV1/FVC (r = –0.71), FeNO (r = 0.69), and RV/TLC (r = 0.51), indicating that regional ventilation abnormalities measured by MRI are associated with both airflow limitation and air trapping. This study had a number of drawbacks. The study included only 30 subjects (20 with asthma, 10 healthy controls), which limits statistical power and generalizability to the broader asthma population. The single-center nature may introduce site-specific biases and limit external validity. The study divided asthmatic patients into young and older subgroups, but the sample size within each subgroup was small, reducing the robustness of subgroup comparisons. The lack of significant difference in ventilation defect percentage (VDP) between older asthmatics and controls may reflect insufficient power rather than true absence of effect. The cross-sectional study assessed subjects at a single time point, precluding evaluation of the utility of hyperpolarized 129Xe MRI for longitudinal monitoring, disease progression, or response to therapy. While VDP was compared to pulmonary function tests, there was no comparison to other sensitive measures of ventilation heterogeneity (e.g., lung clearance index) or to clinical outcomes such as symptom burden, exacerbation frequency, or quality of life.
Doganay et al. (2019) evaluated the use of time-series hyperpolarized xenon-129 (129Xe) MRI to assess lobar lung ventilation in patients with chronic obstructive pulmonary disease (COPD) and compared its findings to those from ventilation/perfusion single-photon emission computed tomography/computed tomography (V/Q-SPECT/CT) and high-resolution computed tomography (CT). Twelve COPD patients (GOLD stages I–IV) underwent all three imaging modalities and pulmonary function tests (PFTs). 129Xe MRI-derived lobar ventilation showed strong correlation with both SPECT-derived lobar ventilation (r = 0.644, p < 0.001) and perfusion (r = 0.767, p < 0.001). The absolute percentage ventilation from 129Xe MRI also correlated significantly with CT-derived emphysema scores (r = 0.695, p < 0.001). Importantly, whole-lung 129Xe MRI ventilation correlated more strongly with PFTs (FEV1: r = –0.886; FEV1/FVC: r = –0.861) than CT emphysema scores did. The study concluded that 129Xe MRI provides a robust, non-ionizing, and high-resolution method for regional and lobar ventilation assessment in COPD, with performance comparable to or better than SPECT/CT and CT for functional evaluation. Drawbacks of this study include small sample size, as only twelve COPD patients (GOLD I–IV) were included, which limits statistical power and generalizability to the broader COPD population, especially for subgroup analyses by disease severity. The study was conducted at a single institution, which may introduce site-specific biases and limit external validity. This cross-sectional study assessed patients at a single time point, precluding evaluation of the utility of time-series hyperpolarized xenon-129 MRI for longitudinal monitoring, disease progression, or response to therapy. Additionally, the study did not assess relationships with clinical outcomes such as symptoms, exacerbation rates, or quality of life.
Mata et al. (2021) noted that IPF, a pattern of interstitial lung disease (ILD), is often clinically unpredictable in its progression. These researchers presented hyperpolarized Xenon-129 chemical shift imaging as a non-invasive, non-radioactive method of probing lung physiology as well as anatomy to monitor subtle changes in subjects with IPF. A total of 20 subjects (9 healthy controls and 11 IPF) underwent HP Xe-129 ventilation MRI and three-dimensional single-breath chemical shift imaging (3D-SBCSI). Spirometry was carried out on all subjects before imaging, and diffusing capacity of the lung for carbon monoxide (DLCO) and hematocrit (Hct) were measured in IPF subjects after imaging. Images were post-processed in MATLAB and segmented using ANTs. IPF subjects exhibited, on average, higher tissue/gas ratios and lower red blood cell (RBC)/gas ratios compared with healthy subjects, and quantitative maps were more heterogeneous in IPF subjects. The higher ratios were likely due to fibrosis and thickening of the pulmonary interstitium. T2* relaxation was longer in IPF subjects and corresponded with Hct scores, although the mechanism is not well understood. A lower chemical shift in the RBC spectroscopic peak correlated well with a higher tissue/RBC ratio and may be explained by reduced blood oxygenation. Tissue/RBC also correlated well, spatially, with areas of fibrosis in HRCT images. The authors concluded that these findings may aid in understanding the underlying mechanism behind gas exchange impairment and disease progression. Moreover, these researchers stated that future work is needed to attain a better understanding of the physiological implications of these parameters. Longitudinal studies with a larger population of subjects with different types of IPF are also needed to validate the findings of this study. Nevertheless, having this novel regional physiological information from 3D-SBCSI in addition to high-resolution computed tomography (HRCT) could allow for a potentially earlier diagnosis of IPF and the stratification of IPF patient types, leading to improved treatments and clinical outcomes.
The authors stated that this study had two main drawbacks. First, the total number of subjects that underwent HP Xe-129 MR imaging in this study was relatively small and may not be representative of the larger population of subjects with IPF. Second, the IPF and healthy subjects were not age-matched, and some of the differences observed may be confounded by age.
Mummy et al. (2021) noted that recent studies showed that anti-fibrotic drugs previously reserved for IPF may slow progression in other interstitial lung diseases (ILDs), creating an urgent need for tools that can sensitively evaluate disease activity, progression, and therapy response across ILDs. Hyperpolarized 129Xe MRI and spectroscopy have provided non-invasive measurements of regional gas-exchange abnormalities in IPF. In a prospective study, these researchers examined gas exchange function using 129Xe MRI in a group of subjects with non-specific interstitial pneumonia (NSIP) compared with healthy controls (HCs). Participants with NSIP and HCs were enrolled between November 2017 and February 2020 and underwent 129Xe MRI and spectroscopy. Quantitative imaging provided 3D maps of ventilation, interstitial barrier uptake, and transfer into the red blood cell (RBC) compartment. Spectroscopy provided parameters of the static RBC and barrier uptake compartments, as well as cardiogenic oscillations in RBC signal amplitude and chemical shift. Differences between NSIP and HCs were assessed using the Wilcoxon rank-sum test. A total of 36 participants with NSIP (mean age of 57 years ± 11 [standard deviation]; 27 women) and 15 HCs (mean age of 39 years ± 18; 2 women) were evaluated. Participants with NSIP had no difference in ventilation compared with HCs (median, 4.4% [1st quartile, 1.5%; 3rd quartile, 8.7%] versus 6.0% [1st quartile, 2.8%; 3rd quartile, 6.9%]; p = 0.91); however, they had a higher barrier uptake (median of 6.2% [1st quartile, 1.8%; 3rd quartile, 23.9%] versus 0.53% [1st quartile, 0.33%; 3rd quartile, 2.9%]; p = 0.003) and an increased RBC transfer defect (median of 20.6% [1st quartile, 11.6%; 3rd quartile, 27.8%] versus 2.8% [1st quartile, 2.3%; 3rd quartile, 4.9%]; p < 0.001). NSIP participants also had a reduced ratio of RBC-to-barrier peaks (median of 0.24 [1st quartile, 0.19; 3rd quartile, 0.31] versus 0.57 [1st quartile, 0.52; 3rd quartile, 0.67]; p < 0.001) and a reduced RBC chemical shift (median of 217.5 ppm [1st quartile, 217.0 ppm; 3rd quartile, 218.0 ppm] versus 218.2 ppm [1st quartile, 217.9 ppm; 3rd quartile, 218.6 ppm]; p = 0.001). The authors concluded that these preliminary results suggested that hyperpolarized 129Xe MRI and spectroscopy may illuminate the fundamental abnormalities and regional severity of gas exchange that occur in patients with non-specific interstitial pneumonia and in those with potentially other non-IPF interstitial lung diseases. These researchers stated that future studies focused on 129Xe MRI characteristics early in the disease course and in response to therapies will advance this work and will further examine its potential clinical impact. This new modality may serve to identify “treatable traits,” monitor therapy response, and personalize treatment in this disorder.
The authors stated that this study had several drawbacks. First, the confounding effect of therapy. Given the availability of effective treatment for patients with NSIP, it was not possible to recruit a treatment-naive population. Although participants with NSIP who were above the 95th-percentile value in HCs (H95%) for both the high barrier uptake percentage and RBC defect percentage (RDP) were uniformly receiving advanced therapy, some participants below one or both of these H95% values were also undergoing advanced therapy. Although this was consistent with the hypothesis that effective treatment may reduce abnormalities detected using 129Xe MRI, these investigators could not assess any causal relationship between therapy and 129Xe MRI findings. Second, the group of HCs was younger than the group with NSIP and was predominantly composed of men. Because more women show NSIP patterns and are known to have an altered immune response, and age is a factor in lung function decline, these researchers acknowledged that an age- and sex-matched control population would result in a more specific comparison. However, this did not affect the variation in measurements between individual ILD patients. Furthermore, the observed differences in gas-exchange function between HCs and participants with NSIP were far starker in pattern and degree than would be expected of ordinary age and/or sex differences. Third, although preliminary studies have shown that dissolved-phase MRI has good repeatability in a cohort of healthy patients, neither the repeatability nor the minimal clinically important difference of these measurements in fibrotic lung disease have been characterized. Fourth, the average time between the screening CT examination and the 129Xe MRI examination was almost 2 years. To ensure the availability of contemporaneous clinical findings, it would be preferable to recruit patients immediately after they undergo clinical CT and are examined by a pulmonologist. Fifth, this study did not attempt to establish correlations between 129Xe MRI and other aspects of a multi-disciplinary ILD diagnosis, such as pathologic findings and CT. Nonetheless, these findings were a necessary first step for characterizing the presentation of patients with NSIP assessed with 129Xe gas-exchange MRI and for determining possible markers of therapy response in patients with ILD in a broader way.
Lin et al. (2021) evaluated whether hyperpolarized xenon‑129 MRI could feasibly quantify regional ventilation abnormalities and predict clinical severity in children with asthma. The study hypothesized that ventilation defect percentage (VDP) and MRI-derived defect metrics would correlate with conventional measures of asthma severity and future clinical outcomes in a pediatric population. The investigators conducted a cross-sectional imaging study with longitudinal clinical follow-up in 37 children aged 6–17 years, including 13 with severe asthma, 8 with mild/moderate asthma, and 16 healthy controls. All participants underwent hyperpolarized 129Xe MRI, with quantitative analysis of VDP and expert reader scoring (number and characteristics of ventilation defects). These imaging findings were compared with baseline spirometry (FEV₁, FEV₁/FVC), patient-reported outcomes, and healthcare utilization (hospitalizations, emergency visits, and oral corticosteroid use), with additional follow-up data collected for up to 12 months. Results showed that children with asthma had significantly greater ventilation abnormalities than healthy controls, with higher VDP and more defects per slice, particularly in those with severe disease. Ventilation defects increased progressively across the severity spectrum and strongly correlated with each other (r≈0.72). Importantly, imaging metrics correlated with clinical severity: VDP was inversely associated with spirometry (FEV₁ and FEV₁/FVC), and defect burden correlated with healthcare utilization and oral corticosteroid use. Even when spirometry was normal, MRI detected regional abnormalities, highlighting its sensitivity to subclinical disease. Predictive analyses demonstrated that both VDP and especially the number of defects per slice could discriminate asthma presence, severity, and risk of increased healthcare utilization (AUC up to ~0.86). During follow-up, defect burden also correlated with subsequent corticosteroid use and asthma control, suggesting prognostic value. The study concludes that 129Xe MRI is safe, feasible, and provides a sensitive, regional biomarker of pediatric asthma severity that may outperform traditional measures in identifying high-risk patients and predicting exacerbations. Clinically, this technique may help guide risk stratification, monitor treatment response, and support personalized management in pediatric asthma. However, important limitations include the small sample size and single-center design, which limit generalizability and statistical power. The cohort was enriched for more severe asthma (quaternary-care setting), introducing potential selection bias. Asthma severity classification and outcomes relied on electronic medical record data, which may not fully account for adherence or other confounders. Incomplete follow-up data (due in part to the COVID-19 pandemic) further limited longitudinal analyses. Finally, variability in MRI analysis methods and partial reliance on reader scoring introduce potential measurement variability. Despite these limitations, the study provides early evidence supporting 129Xe MRI as a promising imaging biomarker for pediatric asthma severity and outcomes.
Guan et al. (2022) stated that 3D-SBCSI is a hybrid MR-spectroscopic imaging modality that uses hyperpolarized Xe-129 to differentiate lung diseases by probing functional characteristics. These researchers tested the effectiveness of 3D-SBCSI in differentiating physiology among pulmonary diseases. A total of 45 subjects—16 healthy, 11 IPF, 13 CF, and 5 COPD—were given 1/3 forced vital capacity (FVC) of hyperpolarized Xe-129, inhaled for approximately 7 seconds during MRI acquisition. Proton, Xe-129 ventilation, and 3D-SBCSI images were acquired with separate breath-holds using a radiofrequency (RF) chest coil tuned to Xe-129. The Xe-129 spectrum was analyzed in each lung voxel for ratios of spectroscopic peaks, chemical shifts, and T2* relaxation. CF and COPD subjects had significantly more ventilation defects than IPF and healthy subjects, which correlated with FEV1 predicted (r = -0.74). FEV1 predicted correlated well with RBC/gas ratio (r = 0.67). COPD and IPF had significantly higher tissue/RBC ratios than other subjects, longer RBC T2* relaxation times, and greater RBC chemical shifts. CF subjects had more ventilation defects than healthy subjects, elevated tissue/RBC ratio, shorter tissue T2* relaxation, and greater RBC chemical shift. The authors concluded that findings of this study indicated that 3D-SBCSI was sensitive to the physiology of lung diseases and could therefore be used to help differentiate among healthy, IPF, CF, and COPD lung disease types. This method also provides additional MRI-based markers that may reflect the underlying lung physiology, like voxel-based full Xe-129 gas spectra, multiple lung compartment T2*, and chemical shift, which no other current techniques can offer. These researchers stated that all this regional information combined may be useful for monitoring disease progression on a regional level as well as for characterizing disease phenotypes and comorbidities in the future.
The authors stated that drawbacks of this study included small sample size and no differentiation by severity within IPF and COPD subjects. The healthy volunteers tended to be closer to the age range of CF participants. While a limitation, this was also consistent with previous xenon MRI literature. Healthy and CF subjects were much younger than IPF and COPD subjects due to the differing disease populations, as CF tends to be a pediatric disease while COPD and IPF only manifest later in life.
Matheson et al. (2022) noted that in patients with post-acute COVID-19 syndrome (PACS), abnormal gas transfer and pulmonary vascular density have been reported; however, such findings have not been related to each other or to symptoms and exercise limitation. The pathophysiologic drivers of PACS in patients previously infected with COVID-19 who were admitted to inpatient treatment in hospital (or ever-hospitalized patients) and never-hospitalized patients are not well understood. In a prospective study, these researchers examined the relationship of persistent symptoms and exercise limitation with 129Xe MRI and CT pulmonary vascular measurements in individuals with PACS. This trial included patients with PACS aged 18 to 80 years with a positive polymerase chain reaction COVID-19 test; they were recruited from a quaternary-care COVID-19 clinic between April and October 2021. Subjects with PACS underwent spirometry, DLCO, 129Xe MRI, and chest CT. Healthy controls had no history of COVID-19 and underwent spirometry, DLCO, and 129Xe MRI. The 129Xe MRI RBC to alveolar-barrier signal ratio, RBC area under the receiver operating characteristic curve (AUC), CT volume of pulmonary vessels with cross-sectional area of 5 mm² or smaller (BV5), and total blood volume were quantified. St George’s Respiratory Questionnaire, International Physical Activity Questionnaire, and modified Borg Dyspnea Scale measured quality of life (QOL), exercise limitation, and dyspnea. Differences between groups were compared with Welch t-tests or Welch analysis of variance. Relationships were evaluated using Pearson (r) and Spearman (ρ) correlations. A total of 40 subjects were evaluated, including 6 controls (mean age ± SD, 35 ± 15 years, 3 women) and 34 subjects with PACS (mean age, 53 ± 13 years, 18 women), of whom 22 were never hospitalized. The 129Xe MRI RBC:barrier ratio was lower in ever-hospitalized participants (p = 0.04) compared to controls. BV5 correlated with RBC AUC (ρ = 0.44, p = 0.03). The 129Xe MRI RBC:barrier ratio was related to DLCO (r = 0.57, p = 0.002) and forced expiratory volume in 1 second (FEV1; ρ = 0.35, p = 0.03); RBC AUC was related to dyspnea (ρ = -0.35, p = 0.04) and International Physical Activity Questionnaire score (ρ = 0.45, p = 0.02). The authors concluded that Xenon 129 (129Xe) MRI measurements were lower in subjects previously infected with COVID-19 who were admitted to inpatient treatment in hospital with post-acute COVID-19 syndrome, 34 ± 25 weeks after infection compared to controls. The 129Xe MRI measures were associated with CT pulmonary vascular density, diffusing capacity of the lung for carbon monoxide, exercise capacity, and dyspnea.
The authors stated that this study had several drawbacks. First, the relatively small sample size of the control and PACS subgroups certainly limited the generalizability of these findings. This trial was not powered based on 129Xe MRI spectroscopy measurements; thus, these findings must be considered exploratory and hypothesis-generating. To provide a transparent snapshot of these results with the COVID-19 research community, these researchers provided data without statistical tests so that other centers may use their results to help generate sample sizes for long-term follow-up studies. Second, CT was not carried out in the control subgroup, which prevented CT comparisons across all three subgroups. Third, all subjects were referred from a COVID-19 clinic focusing on long-haul symptoms; thus, recruitment was likely biased toward symptomatic individuals seeking some form of explanation or intervention. Fourth, subjects with PACS were older than the controls (53 years ± 13 versus 35 years ± 15). To the authors’ knowledge, the effect of age on 129Xe gas-exchange biomarkers has not been reported. However, it is possible that, similar to age-related changes observed for DLCO, age may also influence MRI gas-transfer measurements. Fifth, COVID-19 antibody testing was not carried out to verify COVID-19 infection status in the never–COVID-19 volunteers, so while unlikely, it was possible that some may have previously experienced an asymptomatic infection before the study. Sixth, the mean RBC:barrier ratio estimated for the control subgroup was lower than previous reports, and this meant that the differences detected for patients with COVID-19 may be conservative underestimates. Seventh, the 129Xe gas-exchange MRI scan was conducted on either Visit 1, 2, or 3, which broadened the time after COVID-19 infection to 35 ± 25 weeks. Eighth, MRI scan heterogeneity was not evaluated quantitatively in this trial, and these researchers noted that previous 129Xe MRI COVID-19 investigations also reported the RBC:barrier ratio, which made comparisons with this study possible. Unfortunately, gas-exchange imaging was not technically implemented at the authors’ center until their COVID-19 study was already underway for one year, and in these subjects, MR spectroscopy was implemented first for this study.
Hahn et al. (2022) noted that IPF is a temporally and spatially heterogeneous lung disease. Identifying whether IPF in a patient is progressive or stable is crucial for therapeutic regimens. In a prospective study, these investigators examined the role of hyperpolarized (HP) 129Xe MRI measures of ventilation and gas transfer in IPF generally and as an early signature of future IPF progression. Healthy volunteers and patients with IPF were consecutively recruited between December 2015 and August 2019 and underwent baseline HP 129Xe MRI and chest CT. Patients with IPF were followed up with forced vital capacity percent predicted (FVC%p), DLCO percent predicted (DLCO%p), and clinical outcomes at 1 year. IPF progression was defined as a reduction in FVC%p by at least 10%, a reduction in DLCO%p by at least 15%, or admission to hospice care. CT and MRI were spatially co-registered, and a measure of pulmonary gas transfer (RBC-to-barrier ratio) and high-ventilation percentage of lung volume were compared across groups and across fibrotic versus normal-appearing regions at CT by using Wilcoxon signed rank tests. A total of 16 healthy volunteers (mean age of 57 years ± 14 [SD]; 10 women) and 22 patients with IPF (mean age of 71 years ± 9; 15 men) were evaluated, as follows: 9 IPF progressors (mean age of 72 years ± 7; 5 women) and 13 non-progressors (mean age of 70 years ± 10; 11 men). Reduction of high-ventilation percent (13% ± 6.1 versus 8.2% ± 5.9; p = 0.03) and RBC-to-barrier ratio (0.26 ± 0.06 versus 0.20 ± 0.06; p = 0.03) at baseline were associated with progression of IPF. Patients with progressive disease had reduced RBC-to-barrier ratio in structurally normal-appearing lung at CT (0.21 ± 0.07 versus 0.28 ± 0.05; p = 0.01) but not in fibrotic regions of the lung (0.15 ± 0.09 versus 0.14 ± 0.04; p = 0.62) relative to the non-progressive group. The authors concluded that in this preliminary study, functional measures of gas transfer and ventilation measured with 129Xe MRI and the extent of fibrotic structure at CT were associated with IPF disease progression. Differences in gas transfer were found in regions of non-fibrotic lung.
Kooner, et al. (2022) provided a comprehensive narrative review of pulmonary functional magnetic resonance imaging (PfMRI) using hyperpolarized noble gases (³He and ¹²⁹Xe) to characterize regional lung function and its relationship to asthma pathophysiology and clinical outcomes. The objective was to synthesize existing evidence on how PfMRI can identify the structural and functional abnormalities underlying asthma symptoms, disease progression, and treatment response, and to evaluate its potential role in clinical care and precision medicine. The review describes PfMRI methods, including ventilation imaging, diffusion-weighted imaging for alveolar microstructure, and dissolved-phase imaging to assess gas transfer across the alveolar-capillary interface. These techniques allow high-resolution, radiation-free visualization of lung function, including ventilation defect percent (VDP), ventilation heterogeneity, airway microstructure (via apparent diffusion coefficient), and gas exchange between alveoli and red blood cells.The evidence reviewed demonstrates that PfMRI detects spatially heterogeneous ventilation defects that correlate with asthma severity, symptoms, airflow limitation, exacerbation risk, and quality of life. Notably, ventilation abnormalities are frequently present even in patients with normal spirometry, highlighting superior sensitivity to small airway disease. PfMRI also provides mechanistic insight, linking ventilation defects to airway inflammation, mucus plugging, remodeling, and airway narrowing, with strong structure–function relationships when combined with CT imaging. The technique reveals persistent, regionally localized defects over time, suggesting nonrandom, airway-specific pathology driving disease progression. Clinically, PfMRI is shown to be sensitive to treatment response, detecting improvements in ventilation after bronchodilators, biologic therapies (e.g., anti–type 2 inflammation agents), corticosteroids, and bronchial thermoplasty—often earlier or more clearly than spirometry. Serial imaging demonstrates both reversible and persistent ventilation defects, enabling monitoring of disease trajectory and therapeutic impact. Examples of therapy-related improvements in regional ventilation are shown in . The review further highlights the potential of PfMRI for precision medicine, including phenotyping patients based on imaging-defined “treatable traits,” predicting exacerbations, guiding targeted interventions, and optimizing procedures such as image-guided bronchial thermoplasty. Beyond ventilation, diffusion imaging reveals increased apparent diffusion coefficient values in asthma, reflecting air-trapping and alveolar distension, while dissolved-phase ¹²⁹Xe imaging provides early data suggesting altered gas transfer and pulmonary microvascular function in asthma. These capabilities expand PfMRI beyond airway assessment to include distal airway and gas exchange abnormalities, offering a more complete understanding of disease mechanisms. Key limitations include the narrative (non-systematic) design, which introduces potential selection bias and does not provide quantitative synthesis. Technical barriers such as the need for specialized equipment (polarizers, multinuclear MRI scanners), lack of standardized acquisition and analysis protocols, limited availability, and complex image processing constrain widespread adoption. Additionally, normative reference values and longitudinal outcome validation remain incomplete, and evidence linking PfMRI use to improved clinical outcomes is still evolving. The static imaging approach also represents a snapshot in time, although reproducibility mitigates this limitation. Overall, this review concludes that PfMRI provides a highly sensitive, mechanistically informative biomarker of regional lung dysfunction in asthma, with strong potential to improve disease phenotyping, guide personalized treatment, and enhance monitoring of therapeutic response—pending further validation and clinical integration.
Willmering et al. (2022) conducted a prospective exploratory study to evaluate whether hyperpolarized xenon‑129 gas-transfer MRI can be feasibly and meaningfully applied in pediatric populations, and whether it can detect abnormalities across different childhood lung diseases. The study included 77 participants (including children and adults for comparison), with pediatric cohorts comprising healthy subjects and four disease groups (bone marrow transplant, bronchopulmonary dysplasia, cystic fibrosis, and childhood interstitial lung disease). Imaging was performed using 3T MRI with a breath-hold xenon inhalation protocol to generate quantitative maps of ventilation, barrier uptake (interstitial/plasma), and red blood cell transfer. The study demonstrated that pediatric 129Xe gas-transfer MRI is feasible, with 80% of children successfully completing the protocol and good overall safety, as transient oxygen desaturation during breath-holds was mild and rapidly resolved. However, compliance challenges, especially in younger children, were evident, with failures due to incomplete breath-holds or low signal-to-noise imaging data. Importantly, the results showed that gas-transfer metrics differ significantly between children and adults and are strongly age-dependent. For example, ventilation decreased and RBC-to-barrier ratios increased with age, indicating that lung physiology and gas exchange evolve throughout childhood. This finding has major implications: pediatric reference values must be age-specific, as using adult benchmarks could reduce sensitivity and specificity. In terms of clinical applicability, the study demonstrated that 129Xe MRI could detect disease-specific abnormalities across multiple pediatric lung conditions, even when conventional pulmonary function tests were often normal. For example, bone marrow transplant patients showed impaired ventilation and increased heterogeneity suggestive of inflammatory or vascular injury; bronchopulmonary dysplasia was associated with reduced barrier uptake consistent with alveolar simplification; cystic fibrosis showed ventilation impairment with increased RBC transfer suggesting inflammatory or compensatory changes; and interstitial lung disease demonstrated marked ventilation heterogeneity. Using defined limits-of-normal, the technique identified a significantly higher proportion of abnormal findings in disease cohorts compared with healthy children, supporting its sensitivity for detecting early or subclinical pathology. The study also highlights the added value of gas-transfer MRI over ventilation imaging alone, as it captures regional gas exchange abnormalities (barrier uptake and RBC transfer) that reflect underlying pathophysiology such as inflammation, fibrosis, or vascular dysfunction. This provides mechanistic insights not readily available from standard tests like spirometry or DLCO, particularly in younger children where such tests are often difficult or insensitive. Several limitations are noted. The sample size within each disease subgroup was small, limiting statistical power and generalizability. There was heterogeneity within disease cohorts (especially bone marrow transplant and interstitial lung disease), complicating interpretation of group-level results. Breath-hold dependence introduced variability and potential artifacts, particularly in younger or less compliant patients. Additionally, the study was single-center and lacked comprehensive correlation with clinical gold standards such as DLCO, and did not include structural imaging comparisons.Overall, the study demonstrates that 129Xe gas-transfer MRI is safe, feasible, and capable of providing sensitive, region-specific insights into pulmonary function and disease in children, while also emphasizing the need for age-specific reference standards and further validation in larger cohorts.
Garrison et al. (2023) presented a methodological study aimed at standardizing and operationalizing an end‑to‑end workflow for hyperpolarized xenon‑129 (¹²⁹Xe) MRI ventilation imaging, motivated by recent FDA approval and growing clinical adoption. The objective was not to test a clinical hypothesis, but to provide detailed, consensus-based best practices (developed by the ¹²⁹Xe MRI Clinical Trials Consortium) covering all phases of imaging, from gas preparation and delivery to image acquisition, safety monitoring, and quantitative analysis, so that results can be reproducible and comparable across institutions. The methods consist of a comprehensive, stepwise protocol describing equipment setup, patient screening, gas polarization and dosing, imaging acquisition, and post-processing. The authors outline preparation of hyperpolarized xenon gas using spin-exchange optical pumping, calculation of dose-equivalent volumes tailored to lung capacity, and safe administration via monitored breath-holds. Imaging is performed using standardized pulse sequences (primarily 2D RF‑spoiled gradient-echo for ventilation imaging and proton MRI for anatomical reference), with calibration steps to optimize frequency and flip angle. The workflow includes subject coaching for breath-holds, physiologic monitoring (e.g., oxygen saturation, heart rate), and post-scan recovery procedures. Quantitative analysis focuses on ventilation defect percentage (VDP), calculated from segmented ventilation and anatomical images, with discussion of more advanced segmentation and classification approaches. Representative results demonstrate the capability of ¹²⁹Xe MRI to visualize regional ventilation patterns, distinguishing normal lungs from those with various diseases. In healthy individuals, ventilation images show homogeneous signal throughout the lungs, indicating normal airflow distribution. In contrast, diseased lungs show regionally heterogeneous or absent ventilation signal. For example, severe ventilation impairment appears as patchy or absent signal in conditions like alpha‑1 antitrypsin deficiency and cystic fibrosis. The method also detects more subtle abnormalities, such as mild ventilation defects in chronic obstructive pulmonary disease. Additionally, the study highlights technical pitfalls, such as coil positioning errors or hardware defects, that can significantly affect image quality and must be controlled to ensure valid results. Quantitative analysis (e.g., VDP) further enables objective assessment of disease severity. The study concludes that hyperpolarized ¹²⁹Xe MRI provides a reproducible, noninvasive, and highly sensitive method for regional lung function assessment and that standardized protocols are essential for broader clinical and research adoption. The proposed workflow supports consistent implementation across sites, which is particularly important for multicenter trials and longitudinal monitoring of chronic lung disease. Key limitations include the procedural, not clinical, nature of the study, meaning it does not provide outcome validation or comparative effectiveness against other diagnostic modalities. The workflow primarily reflects consensus best practices rather than evidence-based optimization across all parameters, and some steps (e.g., gas polarization and advanced pulse sequence design) require specialized equipment and expertise, limiting immediate scalability. Technical constraints of the 2D imaging approach, such as signal variation across slices and separate breath-holds for ventilation and anatomical imaging, may introduce artifacts or variability. Finally, quantitative analysis methods (e.g., VDP thresholding) remain evolving, with no single universally accepted standard, which may affect cross-study comparability.
Radadia et al. (2024) compared the quantification of ventilation defects using Technegas SPECT and hyperpolarized xenon-129 (129Xe) MRI in adults scheduled for lung cancer resection, both with and without pre-existing obstructive lung disease. Forty-one participants underwent same-day Technegas SPECT, 129Xe MRI, spirometry, and DLCO testing. Ventilation defect percent (VDP) was calculated using two methods (adaptive thresholding and k-means clustering) for both imaging modalities. The study found that VDP measured by Technegas SPECT and 129Xe MRI were significantly correlated (r = 0.48–0.63, p ≤ 0.001), with a small bias toward higher VDP values on SPECT. Both modalities showed that higher VDP correlated with lower FEV1/FVC and DLCO, indicating that greater ventilation defects are associated with worse lung function. Subgroup analysis demonstrated that patients with COPD had significantly higher VDPs than those with asthma or no obstructive lung disease, regardless of imaging modality. The authors concluded that quantitative assessment of ventilation defects by Technegas SPECT and hyperpolarized 129Xe MRI is comparable, and both modalities effectively differentiate between obstructive and non-obstructive lung disease.
The study had a number of drawbacks. First, the sample size was relatively small (n = 41), with even smaller subgroups for asthma (n = 6) and COPD (n = 13), which limits statistical power and the ability to generalize findings to broader populations with obstructive lung disease or lung cancer. Second, the study population consisted exclusively of adults scheduled for lung cancer resection, which may not reflect the spectrum of disease severity or comorbidities seen in general clinical practice. Additionally, ventilation defect percent (VDP) quantification was performed using two different methods (adaptive thresholding and k-means clustering), but there is no universally accepted standard for VDP calculation, and results may vary depending on the chosen algorithm. The study also reported a small but consistent bias toward higher VDP values with Technegas SPECT compared to 129Xe MRI, suggesting that the modalities are not directly interchangeable and that systematic differences may exist between techniques. Another limitation is the lack of direct comparison to clinical outcomes such as post-operative pulmonary function or surgical morbidity, which would be necessary to establish the prognostic value of each imaging modality. Finally, the study did not address the logistical and technical challenges associated with hyperpolarized 129Xe MRI, such as limited availability, the need for specialized equipment, and regulatory considerations, which may impact clinical implementation.
Radadia et al. (2025) conducted a prospective observational study to evaluate whether preoperative ventilation abnormalities measured using advanced imaging modalities predict postoperative outcomes in patients undergoing lung cancer resection. The study enrolled 107 adults at a single center who underwent preoperative Technegas-SPECT and hyperpolarized xenon‑129 MRI to quantify ventilation defect percent (VDP), alongside conventional pulmonary function testing, and followed patients for 4 weeks after surgery to assess pulmonary complications and hospital length of stay. Results demonstrated that abnormal ventilation was highly prevalent before surgery, detected in 58% of patients using SPECT and 73% using MRI, including many patients with otherwise normal spirometry measures. Importantly, preoperative VDP was significantly higher in patients who developed postoperative complications compared with those who did not, and this relationship persisted even among patients with normal FEV₁ and DLCO. VDP also showed moderate correlations with hospital length of stay (r≈0.44–0.51), indicating that greater ventilation impairment was associated with longer recovery. Multivariable analyses demonstrated that VDP, measured by either SPECT or MRI, was the strongest independent predictor of postoperative complications and hospital stay, outperforming traditional lung function measures such as FEV₁ and DLCO. Clinically, these findings suggest that ventilation imaging captures regional lung dysfunction not detected by conventional tests and may provide mechanistic insight into postoperative risk, potentially enabling improved risk stratification and personalized surgical planning. The authors propose that identifying and potentially modifying ventilation defects preoperatively could reduce complications or guide decisions about resection extent or alternative therapies. However, several limitations temper interpretation. The study was single-center and lacked an external validation cohort, reducing generalizability. The definition of abnormal VDP relied on locally derived thresholds from a small healthy cohort, and variability between imaging modalities complicates standardization. The study did not incorporate quantitative CT or detailed structural imaging correlations, limiting mechanistic attribution of defects, and its modest sample size restricts power for subgroup analyses. Despite these limitations, the study provides prospective evidence that imaging-derived ventilation metrics may outperform current guideline-recommended pulmonary function tests in predicting postoperative outcomes after lung cancer resection.
In a prospective, open-label study of adults with poorly controlled eosinophilic asthma, McIntosh et al (2022) evaluated whether hyperpolarized xenon‑129 (¹²⁹Xe) MRI could detect early airway functional changes after a single dose of benralizumab and whether baseline airway mucus influenced treatment response. The investigators enrolled 29 participants (27 with CT imaging) who received a single 30‑mg subcutaneous dose and underwent detailed assessments at baseline and 28 days, including spirometry, oscillometry, patient-reported outcomes (ACQ‑6, AQLQ, SGRQ), blood eosinophils, thoracic CT for mucus plug scoring, and ¹²⁹Xe MRI to quantify ventilation defect percentage (VDP). Results showed rapid and significant biologic and functional improvements by day 28, including near-complete depletion of blood eosinophils, reductions in MRI VDP, improved asthma control (ACQ‑6), and improved quality of life (AQLQ), along with modest improvements in peripheral airway resistance, although FEV₁ changes were not statistically significant. Importantly, treatment effects were heterogeneous and appeared to be mediated by baseline mucus burden: patients with ≥5 mucus plugs demonstrated significant improvements in both ventilation defects and symptom control, whereas those with fewer plugs did not show statistically significant changes in these endpoints. Multivariable analyses further demonstrated that baseline VDP and CT-derived mucus plug scores were independent predictors of improvement in asthma control, supporting a mechanistic link among eosinophilic inflammation, mucus occlusion, and regional ventilation abnormalities. These findings suggest that ¹²⁹Xe MRI is a sensitive biomarker of early treatment response and that patients with greater mucus plugging may derive greater functional benefit from eosinophil-depleting therapy. Key limitations include the small sample size and subgroup imbalances (particularly few patients with high mucus burden), short follow-up duration limited to 28 days, and the open-label, nonrandomized design without a control group, which increases the risk of bias and limits causal inference; additionally, the absence of repeat CT or sputum analyses prevents direct confirmation that mucus plug resolution mediated the observed ventilation improvements. The cohort was also predominantly older and female, potentially limiting generalizability, and imaging at functional residual capacity plus 1 L may differ from standard CT protocols. Despite these constraints, the study provides novel mechanistic insight by linking imaging-based ventilation heterogeneity with mucus pathology and clinical response after benralizumab.
McIntosh et al. (2023) evaluated whether early improvements in lung ventilation after initiating benralizumab persist long term and whether airway structure and mucus plugging improve over 2.5 years in patients with poorly controlled eosinophilic asthma. The study followed a cohort from a prior 28‑day trial, using longitudinal assessments including spirometry, Asthma Control Questionnaire (ACQ‑6), fraction of exhaled nitric oxide (FENO), hyperpolarized xenon‑129 MRI ventilation defect percentage (VDP), and CT imaging for mucus plug scoring and airway structure at baseline and extended follow-up. A total of 29 participants were assessed at baseline and 28 days, with 16 and 13 participants remaining for 1‑year and 2.5‑year follow-up, respectively, reflecting real-world continuation of therapy. Results demonstrated that asthma control improved substantially and durably, with mean ACQ‑6 scores decreasing from 2.0 at 28 days to approximately 0.5 at both 1 year and 2.5 years. Early improvements in ventilation heterogeneity (VDP) observed at 28 days persisted over 2.5 years, with changes exceeding clinically important thresholds, although not significantly different from the early post-treatment measurement, indicating sustained rather than progressive improvement. In parallel, there were significant structural airway improvements on CT at 2.5 years, including reduced mucus scores (from ~3–4 to ~1), increased total airway count, increased lumen area, and decreased or normalized wall thickness, suggesting improved airway patency. Mucus plug resolution was notable: most patients with baseline plugs demonstrated complete or substantial clearance, supporting a mechanistic link between eosinophil depletion and mucus disruption. Importantly, baseline VDP and mucus scores (but not FEV₁ or FENO) independently predicted long-term improvements in asthma control, reinforcing these imaging biomarkers as prognostic indicators of response. Clinically, pulmonary function (FEV₁), quality of life, and central airway resistance also improved significantly by 2.5 years, although distal airway resistance did not show significant change, suggesting differential effects across airway compartments. The observed increase in CT-visible airway count suggests that airway obstruction and apparent “pruning” may be reversible with therapy, likely reflecting reopening of previously occluded airways rather than structural regeneration. Key limitations include the small sample size and substantial attrition at follow-up, with analyses restricted largely to participants who continued therapy and responded clinically, introducing selection bias. The lack of a control group and open-label design limit causal inference, while COVID‑19 disruptions and access issues further reduced retention. CT imaging was only repeated at 2.5 years, preventing characterization of earlier mucus dynamics, and the predominance of older participants may limit generalizability. Overall, this study demonstrates that benralizumab produces sustained improvements in asthma control, ventilation heterogeneity, and airway structure over 2.5 years, with evidence suggesting that eosinophil depletion may lead to mucus plug resolution and potentially disease-modifying effects in eosinophilic asthma.
In an accompanying editorial, Fain and Comellas (2023) discuss the clinical implications of imaging biomarkers, particularly hyperpolarized xenon‑129 (¹²⁹Xe) MRI ventilation defect percentage (VDP) and CT-derived mucus plug scores, for monitoring response to biologic therapy in asthma, contextualizing findings from the McIntosh et al study. The authors highlight that despite the growing number of high-cost biologics, current tools (eg, FEV₁ and FENO) are inadequate for early and precise assessment of treatment response, creating a need for more sensitive, patient-specific biomarkers that can guide therapeutic decisions and optimize cost-effectiveness. They describe how advanced imaging modalities enable regional and mechanistic assessment of airway obstruction, with VDP reflecting ventilation heterogeneity and CT mucus scoring capturing central airway occlusion, both of which have been linked to asthma severity and airflow limitation. The editorial synthesizes longitudinal evidence from follow-up data to the McIntosh trial, showing that baseline VDP and mucus scores not only predicted short-term improvements in asthma control at 28 days but also remained predictive at 1 year and 2.5 years after initiation of benralizumab therapy, while traditional measures did not. Improvements in ventilation defects and symptoms were sustained over time, with reductions in mucus plugging and structural airway changes on CT (eg, increased lumen area and airway count) suggesting improved airway patency and possibly enhanced distal drug delivery. However, the authors note that improvements plateaued between 1 and 2.5 years, which may reflect persistent airway remodeling that is not fully reversible with anti–IL‑5 receptor therapy, particularly in an older population with more advanced disease. Importantly, the editorial emphasizes the potential clinical role of combining baseline CT with serial ¹²⁹Xe MRI to monitor biologic therapy, enabling earlier identification of responders versus nonresponders and facilitating timely switching or de-escalation of costly treatments. The authors propose that imaging could also help tailor inhaled therapy delivery and better characterize central versus peripheral airway disease, advancing precision medicine in asthma. Key limitations discussed include the small, single-center cohort with attrition over long-term follow-up, the particularly small subset with quantitative CT data, and demographic skew toward older patients, which may limit generalizability and contribute to the observed plateau in response due to fixed airway remodeling. Additionally, lack of detailed longitudinal bronchodilator responsiveness data limits interpretation of reversible versus fixed obstruction. Despite these limitations, the editorial concludes that functional imaging biomarkers show strong promise for improving early response assessment and long-term management of biologic therapy in asthma.
Eddy et al. (2024) conducted a multicenter observational study to determine whether hyperpolarized xenon‑129 MRI could identify distinct pulmonary phenotypes in patients with long COVID by integrating ventilation and gas-exchange metrics. The study enrolled 135 participants across three centers, including COVID-negative controls, fully recovered individuals, and 73 patients with long COVID assessed approximately 14 months after infection, and defined long COVID based on persistent symptoms such as dyspnea, fatigue, and cough. Participants underwent 129Xe MRI to measure ventilation defect percent (VDP) and gas-exchange parameters (Mem/Gas, RBC/Mem, RBC/Gas), alongside pulmonary function testing and clinical assessments; these imaging variables were used in k-means clustering to identify phenotypic subgroups. The results demonstrated that conventional pulmonary function tests were largely normal across groups, despite significant reductions in RBC/Mem (indicating impaired gas transfer) in long COVID patients. Cluster analysis identified four distinct long COVID phenotypes with unique imaging and clinical characteristics: Cluster 1 showed near-normal MRI with mild gas trapping; Cluster 2 demonstrated reduced RBC/Mem suggestive of microvascular dysfunction despite normal spirometry; Cluster 3 exhibited increased membrane uptake consistent with possible interstitial inflammation; and Cluster 4 showed marked abnormalities with high membrane uptake, low RBC/Mem, restrictive lung physiology, and CT evidence of parenchymal disease. These clusters represent different underlying mechanisms, including small airway disease, microvascular impairment, and interstitial pathology, which were not distinguishable using standard clinical tests alone. Clinically, the findings highlight that gas-exchange abnormalities, not ventilation defects, are the dominant drivers of long COVID pathophysiology in most patients, and that 129Xe MRI can detect subtle regional dysfunction even when spirometry and CT appear normal. The study suggests that these imaging-defined phenotypes could guide personalized management strategies, such as targeting microvascular dysfunction or interstitial inflammation, and help stratify patients for clinical trials. Key limitations include the cross-sectional design, which prevents assessment of longitudinal changes or causal relationships, and the aggregation of heterogeneous multicenter data with some variability in imaging and clinical protocols. Not all participants underwent concurrent CT or pulmonary function testing, limiting comprehensive comparisons. The absence of pre-COVID baseline data also restricts interpretation of whether abnormalities were pre-existing, and the study may be underpowered to detect differences in symptom profiles across clusters. Additionally, variability in timing post-infection and lack of detailed virologic or biologic correlates limit mechanistic conclusions. Overall, this study demonstrates that 129Xe MRI can uncover distinct, physiologically meaningful subtypes of long COVID that are not apparent with conventional diagnostic tools, supporting its potential role in advancing precision medicine approaches for post-COVID respiratory disease.
In an accompanying editorial, Comellas and Fain (2024) discussed the clinical implications of the multicenter study by Eddy et al., emphasizing the role of hyperpolarized xenon‑129 MRI (¹²⁹Xe MRI) in identifying distinct pulmonary phenotypes in long COVID and its potential to guide targeted therapies. The authors highlight that persistent respiratory symptoms are common after COVID‑19, even in patients with initially mild disease and normal conventional testing, underscoring limitations of standard imaging and pulmonary function tests in detecting subtle lung abnormalities. The editorial summarizes how advanced functional imaging with ¹²⁹Xe MRI reveals abnormalities in ventilation, inflammation (Mem/Gas), and gas transfer (RBC/Mem) that are often missed by traditional approaches, reflecting small airway dysfunction, parenchymal inflammation, and microvascular impairment. Building on this, the authors interpret the Eddy et al. findings of four imaging-defined long COVID clusters, ranging from mild gas trapping with normal MRI to severe phenotypes characterized by impaired gas exchange, inflammation, and restrictive physiology. A key insight is that the majority of patients fall into milder or intermediate clusters, while a smaller proportion exhibits severe fibroproliferative changes with worse symptoms and imaging abnormalities. Importantly, the authors emphasize the clinical implications of these phenotypes, proposing that each cluster may represent a “treatable trait” with targeted therapeutic strategies. For example, milder phenotypes associated with small airway disease might respond to inhaled bronchodilators or corticosteroids, whereas microvascular-dominant disease could be addressed with anticoagulation or vasodilators, and inflammatory or fibrotic phenotypes might benefit from anti-inflammatory or antifibrotic therapies. This framework suggests that ¹²⁹Xe MRI could enable precision medicine approaches by aligning treatment selection with underlying pathophysiology rather than symptoms alone. The editorial also notes key limitations of the underlying study, including lack of pre-COVID baseline imaging, incomplete pulmonary function and CT data, limited diversity of the study population, and absence of data on vaccination status or viral variants, all of which constrain interpretation of causality and generalizability. In addition, the need for longitudinal studies is emphasized to determine whether these imaging phenotypes are stable, progressive, or reversible over time. Overall, the authors conclude that ¹²⁹Xe MRI provides a sensitive tool for uncovering otherwise undetected lung abnormalities in long COVID and offers a promising pathway toward mechanistically driven, phenotype-specific clinical trials and therapies, though further validation and longitudinal research are required before routine clinical implementation.
Driehuys et al. (2025) described the design, execution, and operational lessons from the XeCITE trial, a prospective multi-center, multi-platform study aimed at evaluating whether hyperpolarized xenon‑129 MRI (¹²⁹Xe MRI) can serve as a sensitive biomarker for disease progression and treatment response in chronic obstructive pulmonary disease (COPD). The primary objective was not only to explore the relationship between imaging-derived metrics (particularly ventilation defect percentage, VDP) and clinical outcomes such as exacerbations, but also to establish a standardized framework for deploying ¹²⁹Xe MRI across multiple sites, vendors, and international settings. The study implemented a multicenter, randomized, open-label design across eight sites in the US, Canada, and UK, enrolling patients with COPD and applying harmonized imaging protocols developed by the 129Xe MRI Clinical Trials Consortium. Imaging included ventilation MRI, gas-exchange MRI, and spectroscopy during breath-hold maneuvers, capturing metrics of ventilation (VDP), membrane uptake, and red blood cell transfer, while a centralized core laboratory performed reconstruction, quality control, and quantitative analysis to ensure consistency across sites. Site qualification with test–retest imaging in healthy volunteers was required to ensure reproducibility before enrolling patients, and image quality was systematically scored to maintain standardization. Results demonstrated that harmonized ¹²⁹Xe MRI acquisition and analysis were feasible across different MRI vendors and institutions, with acceptable repeatability and consistent quantitative metrics across sites. Qualification studies showed strong test–retest agreement for key imaging metrics, supporting reproducibility of ventilation and gas-exchange measures . Imaging of healthy volunteers across centers showed consistent patterns with predominantly normal signal distributions, indicating cross-site standardization was successful. These findings suggest that ¹²⁹Xe MRI provides sensitive regional functional information that may detect disease progression earlier than conventional measures such as spirometry or CT. The study highlights several key operational insights for future trials, including the importance of standardized imaging protocols, centralized analysis, rigorous site qualification, and continuous quality assurance. It also identified technical challenges, such as variability in gas dosing, signal-to-noise differences, and vendor-specific imaging artifacts, which required mitigation through protocol adjustments and data harmonization strategies. Limitations include early termination of the trial for business reasons, which prevented full evaluation of clinical endpoints and reduced the ability to assess longitudinal associations between imaging biomarkers and exacerbations. The study also reflects a methodological and implementation focus rather than definitive clinical efficacy outcomes, and variability in imaging execution across vendors—even with harmonization—remains a challenge. Additionally, incomplete standardization of gas dosing and lack of some physiological validation measures during site qualification may have introduced residual variability. Overall, this study demonstrates that multi-center deployment of ¹²⁹Xe MRI is feasible and reproducible, establishing a practical framework for incorporating advanced functional lung imaging into clinical trials, and supporting its potential role as a sensitive biomarker for COPD progression and therapeutic evaluation.
Tcherner et al. (2025) summarized clinical evidence on the use of hyperpolarized xenon‑129 MRI ventilation defect percentage (VDP) to assess airway dysfunction and treatment response in asthma. The objective of this narrative review was to evaluate how inhaled bronchodilator therapies affect airway function and whether advanced imaging methods, particularly 129Xe MRI, provide mechanistic insights beyond traditional spirometry. The authors conducted a structured literature review of clinical studies over the past 15 years, identifying five relevant studies (four using single bronchodilator therapy and one evaluating triple inhaled therapy) that used 129Xe MRI to quantify changes in ventilation defects. Across these studies, imaging methodology was relatively consistent, involving inhalation of hyperpolarized 129Xe gas with MRI acquisition during breath-hold and calculation of VDP as a measure of poorly ventilated lung regions. The results demonstrate that 129Xe MRI VDP is a sensitive and reproducible biomarker of airway dysfunction that captures treatment-related improvements across a range of asthma populations, including children, adults, and patients with both controlled and uncontrolled disease. In studies of short-acting bronchodilators (eg, salbutamol), significant reductions in VDP were consistently observed, often aligning with improvements in FEV₁, though in some cases VDP improved even when spirometry did not, suggesting superior sensitivity to small airway changes. The most clinically notable findings come from a recent open-label mechanistic study of single-inhaler triple therapy (fluticasone furoate/umeclidinium/vilanterol) in patients with uncontrolled moderate–severe asthma, where VDP improved significantly within 6 weeks (from ~13% to ~9%), alongside parallel improvements in lung function, airway resistance, and quality of life. These findings suggest that combined ICS/LAMA/LABA therapy restores airway caliber and function by addressing inflammatory bronchoconstriction and small airway disease. Overall, the review concludes that 129Xe MRI enables direct visualization and quantification of airway functional changes, providing mechanistic insight into how inhaled therapies improve ventilation beyond what is captured by conventional pulmonary function tests. This approach has potential applications in early response detection, treatment personalization, and drug development, particularly given its ability to detect clinically meaningful changes as early as 6 weeks after therapy initiation. However, the authors emphasize important limitations, including the small number of available studies, small sample sizes within individual studies, lack of control groups, and heterogeneity in imaging protocols, all of which limit statistical power and generalizability. As a narrative review, the analysis is also subject to selection bias and does not provide quantitative synthesis or causal inference. Despite these limitations, the consistency of findings across studies supports the robustness of VDP as a biomarker, although further standardized, larger-scale controlled trials are needed to validate its routine clinical use.
Walkup, et al. (2025) evaluated the reliability of hyperpolarized xenon‑129 MRI (Xe MRI) as a quantitative imaging biomarker of regional ventilation in children with mild cystic fibrosis (CF), specifically assessing same-day repeatability and short-term (28‑day) reproducibility across multiple centers. This four-center prospective longitudinal study enrolled 38 children (median age 12 years) with clinically stable, mild CF (FEV₁ ≥80% predicted) and used standardized Xe MRI acquisition protocols along with spirometry and multiple-breath washout (lung clearance index, LCI₂.₅) at two visits separated by ~28 days. At the first visit, two Xe MRI scans were performed to assess same-day repeatability, while a single scan at the second visit assessed reproducibility; ventilation defects were quantified using ventilation defect percentage (VDP) and reader-defined defect volume (RDV). Results demonstrated excellent repeatability and reproducibility of Xe MRI metrics. Same-day measurements showed minimal differences (mean VDP difference 0.12%, RDV difference 0.42%) with narrow limits of agreement, indicating stable ventilation measurements within individuals and no relationship between variability and baseline lung function. At 28 days, there were no significant changes in VDP or RDV, and 84% of participants remained within same-day limits of agreement, supporting short-term stability in clinically stable patients. Importantly, deviations in a small subset of patients appeared related to true clinical changes (e.g., infection, adherence issues), suggesting Xe MRI may be sensitive to physiologic variation rather than measurement error. Inter-site analysis demonstrated no significant differences in VDP or RDV despite variability in scanner platforms, gas dosing, and signal-to-noise ratios, indicating robustness of the technique across centers. Clinically, these findings support Xe MRI as a precise and reproducible biomarker of regional ventilation heterogeneity that can detect subtle airflow abnormalities even in patients with preserved spirometry, making it highly suitable for monitoring disease and evaluating treatment response in CF clinical trials. The study also suggests a potential threshold for clinically meaningful VDP change (~2–3%), aligning with prior literature on treatment response imaging. Key limitations include modest sample size per site, which may limit statistical power for inter-site comparisons, and restriction to children with mild CF, limiting generalizability to more advanced disease or other populations. Variability in gas dosing strategies and scanner hardware across sites introduced heterogeneity, although this also demonstrates real-world robustness. Additionally, inter-reader reliability was not fully assessed, and Xe MRI remains a specialized modality requiring dedicated equipment and expertise, potentially limiting widespread implementation.
Bdaiwi et al. (2025) evaluated the ability of hyperpolarized xenon‑129 MRI to monitor lung disease progression and response to lumacaftor/ivacaftor therapy in pediatric cystic fibrosis. The objective was to determine whether ¹²⁹Xe MRI metrics, specifically ventilation defect percentage (VDP) and defect distribution index (DDI), could detect treatment effects and disease evolution more sensitively than conventional pulmonary function tests. The investigators enrolled 18 children with cystic fibrosis in a single‑center, longitudinal study: nine initiated lumacaftor/ivacaftor therapy and nine served as controls. Participants underwent spirometry, lung clearance index (LCI), and ¹²⁹Xe MRI at baseline, approximately 6 months, and 15 months, enabling assessment of both short‑term and longer‑term changes in lung function. The results showed that traditional measures (spirometry and LCI) did not significantly change over time in either group, highlighting their limited sensitivity in mild pediatric disease. In contrast, ¹²⁹Xe MRI detected meaningful differences. In the short term, treatment with lumacaftor/ivacaftor stabilized ventilation abnormalities (minimal change in VDP and DDI), whereas controls showed worsening ventilation defects and increased defect clustering. In the longer term, however, the treatment group demonstrated a delayed increase in VDP, indicating progressive regional ventilation impairment despite initial stability. Mechanistically, the findings suggest that ¹²⁹Xe MRI can detect subtle regional changes, such as expansion and clustering of ventilation defects, that are not captured by global measurements. The short‑term stability likely reflects initial therapeutic benefits (e.g., reduced infection and inflammation), whereas later worsening may reflect disease progression or microbiologic rebound. Importantly, the significant differences observed in MRI metrics between groups (VDP and DDI) were not mirrored by spirometry or LCI, reinforcing the superior sensitivity of functional imaging for early or mild disease. The study has several important limitations. The sample size was small (n=9 per group), limiting statistical power and generalizability. The control group was significantly older than the treatment group, introducing potential confounding due to age and disease stage. Follow‑up intervals varied across participants, reducing temporal consistency. Attrition in the control group at later visits further limited longitudinal comparisons. Additionally, the absence of structural imaging limited the ability to correlate functional MRI findings with anatomical changes. Overall, this study demonstrates that ¹²⁹Xe MRI is a highly sensitive tool for detecting both early treatment response and subsequent disease progression in pediatric cystic fibrosis, outperforming conventional pulmonary function tests and highlighting its potential role in longitudinal monitoring and clinical trials.
Matheson et al. (2026) conducted a retrospective cohort study to determine whether structural and functional lung MRI measures could predict future pulmonary exacerbations (PExs) in patients with cystic fibrosis (CF). The study analyzed 106 patients aged 6–45 years using ultrashort echo time (UTE) MRI to assess structural abnormalities and hyperpolarized xenon‑129 MRI to quantify ventilation defect percent (VDP), with exacerbations defined as hospitalization or IV antibiotic treatment and evaluated over a 2‑year follow-up period. The results showed that functional MRI (VDP) was strongly associated with future exacerbations: patients who experienced PExs had significantly higher VDP (median ~11% vs 4%), and those with frequent exacerbations exhibited markedly worse ventilation defects (median up to ~26%). Patients with abnormal VDP (>3%) had nearly a threefold higher incidence rate of exacerbations (IRR ~2.8) and were more likely to experience earlier events on time-to-event analysis. Structural abnormalities on UTE MRI, particularly bronchiectasis, airway wall thickening, and consolidation in the highest severity quartiles, were also associated with increased exacerbation rates in univariate analyses, although they were less consistently predictive than VDP. Predictive modeling demonstrated that imaging-based models outperformed clinical-only models, with VDP emerging as an independent predictor of exacerbations even after adjusting for prior exacerbation history, whereas traditional spirometry (FEV₁) lost significance in adjusted analyses. The study concludes that MRI-based structural and functional measures directly capture underlying lung pathology and provide meaningful prognostic information beyond conventional clinical measures, supporting their use in risk stratification and disease monitoring in CF. However, several limitations must be considered: the retrospective design limits causal inference and introduces potential selection and treatment-related confounding; imaging protocols and technology evolved over the long study period, potentially affecting measurement consistency; structural scoring systems may lack sensitivity due to coarse categorization; and the cohort experienced heterogeneous treatment regimens during a rapidly changing therapeutic era, including CFTR modulators. Additionally, the study focused primarily on severe exacerbations and group-level associations, and relatively small sample size and loss to follow-up limit generalizability. Despite these constraints, the findings support further prospective evaluation of MRI biomarkers—particularly VDP—as predictive tools for exacerbation risk in cystic fibrosis.
Alam et al. (2026) conducted a prospective longitudinal cohort study to evaluate whether multiple‑breath washout xenon MRI (MBW Xe‑MRI) provides additional sensitivity over single‑breath Xe‑MRI and standard pulmonary function tests (PFTs) for monitoring disease progression in pediatric cystic fibrosis patients receiving elexacaftor/tezacaftor/ivacaftor (ETI) therapy. The study enrolled 14 adolescents with cystic fibrosis (median age 15.5 years), with 12 contributing longitudinal data across at least two of four follow-up visits at 1, 6, 12, and 24 months after ETI initiation, and compared regional ventilation metrics from MRI (ventilation defect percent [VDP] from single‑breath imaging, and fractional ventilation [FV] and its heterogeneity [CoV FV] from MBW imaging) with spirometry (ppFEV₁) and lung clearance index (LCI). The findings showed that conventional clinical measures (ppFEV₁, LCI) and single‑breath MRI (VDP) remained stable over the 24‑month period, consistent with prior evidence that lung function stabilizes after ETI initiation. In contrast, MBW Xe‑MRI detected a small but statistically significant increase in CoV FV (reflecting worsening spatial heterogeneity of ventilation) over time, while global FV itself did not change significantly. Importantly, MBW‑derived heterogeneity metrics identified abnormalities in some patients who had normal VDP, suggesting that MBW imaging can capture subtle regional ventilation differences not detectable with threshold-based defect measures. Mechanistically, the study suggests that increased CoV FV may reflect evolving ventilation redistribution or compensatory airflow around persistent defect regions, indicating ongoing regional adaptation or pathology even when global measures remain unchanged. However, MBW Xe‑MRI metrics exhibited substantially greater within-subject variability compared with PFTs and VDP (intraclass correlation coefficients: FV 0.41, CoV FV 0.55 vs. ≥0.92 for PFTs/VDP), indicating lower measurement stability and highlighting technical and physiological variability inherent to multi-breath imaging. Additionally, while MBW metrics were generally concordant with VDP, discordance in some patients demonstrated that MBW imaging may be more sensitive to regional heterogeneity rather than gross ventilation defects alone. Several limitations affect interpretation. The sample size was small (n=12 analyzed), limiting statistical power and generalizability, and data completeness varied across visits. Methodological differences between imaging approaches (single‑breath multi-slice vs. MBW single-slice projection) limited direct regional comparison. MBW Xe‑MRI was also constrained by the use of a single xenon inhalation and limited washout duration, making it less sensitive to slow-emptying lung regions compared with standard multiple-breath washout tests. Additional sources of variability included breath-hold dependence, lack of precise gas volume control, and technical limitations such as absence of pneumotachograph monitoring. These factors, along with higher intrinsic variability of MBW metrics, led the authors to emphasize that findings are exploratory and require validation in larger cohorts. Overall, the study concludes that while conventional lung function tests and single‑breath MRI suggest stability after ETI therapy, MBW Xe‑MRI, particularly CoV FV, may reveal subtle, evolving regional ventilation heterogeneity over time, indicating its potential as a complementary, more sensitive imaging biomarker for long-term monitoring of pediatric cystic fibrosis.
Xenon Xe-129 is a novel imaging technique that may have a future role in several pulmonary disease states and may provide new or additional information concerning disease progress and effectiveness of therapy. However, this technology is still awaiting definitive clinical research to prove its benefit. There are at least 45 clinical trials that are either recruiting, enrolling, or active at this time on ClinicalTrials.gov.
XV LVAS Pulmonary Tissue Ventilation Analysis
XV LVAS pulmonary tissue ventilation analysis software is used for quantification of pulmonary tissue ventilation. However, there is insufficient evidence regarding its clinical value.
Yamashiro et al. (2019) examined the accuracy of four-dimensional (4D) dynamic-ventilation computed tomography (CT) scanning coupled with their novel image analysis software to diagnose parietal pleural invasion/adhesion of peripheral (subpleural) lung cancer. A total of 18 patients with subpleural lung cancer underwent both 4D dynamic-ventilation CT during free breathing and conventional (static) chest CT during pre-operative assessment. The absence of parietal pleural invasion/adhesion was surgically confirmed in 13 patients, while the presence of parietal pleural invasion/adhesion was confirmed in 5 patients. Two chest radiologists, who were blinded to patient status, cooperatively examined the presence of pleural invasion/adhesion using two different imaging modalities: conventional high-resolution CT images, reconstructed in the axial, coronal, and sagittal directions, as well as 4D dynamic-ventilation CT images combined with a color map created by image analysis software to visualize movement differences between the lung surface and chest wall. Parameters of diagnostic accuracy were assessed, including a receiver operating characteristic (ROC) analysis. Software-assisted 4D dynamic-ventilation CT images achieved perfect diagnostic accuracy for pleural invasion/adhesion (sensitivity, 100%; specificity, 100%; area under the curve [AUC], 1.000) compared to conventional chest CT (sensitivity, 60%; specificity, 77%; AUC, 0.846). The authors concluded that software-assisted 4D dynamic-ventilation CT could be considered a novel imaging approach for accurate pre-operative analysis of pleural invasion/adhesion of peripheral lung cancer. Moreover, these researchers stated that future studies with a larger number of enrolled patients are needed to verify the clinical utility of this imaging technique.
The authors stated that this study had several drawbacks. First, the study included a small number of patients (n = 18). Since this study was considered technical development of the methodology, these researchers prioritized promptness of the publication. More detailed studies, with an increased number of patients enrolled and including different affected lung areas, are needed to confirm the reproducibility of these findings. Second, the conventional CT scans were only viewed in 2D. Third, extra radiation exposure was needed, especially at a tube current setting of 40 mA. Therefore, these investigators used a 20-mA setting for some patients and confirmed that the 20-mA setting was more appropriate for future use (3.0 mSv for 6.5 s). However, an even greater reduction in radiation exposure, such as a 10-mA setting, may be tried in the future to increase the clinical utility of the 4D CT evaluation, especially with a combination of novel iterative reconstruction techniques. Fourth, since it has been reported that the lung surface around the lung apex or in patients with severe obstructive diseases does not reveal much movement during ventilation, their approach should be re-evaluated in a larger population including cancers in the apex and patients with obstructive diseases. Finally, this trial included only two radiologists.
In a preliminary study, Nagatani et al. (2020) examined the usefulness of software analysis using dynamic-ventilation CT for localized pleural adhesion (LPA). A total of 51 patients scheduled to undergo surgery underwent both dynamic-ventilation CT and static chest CT as pre-operative assessments. A total of 5 observers independently examined the presence and severity of LPA on a 3-point scale (none, mild, and severe LPA) for 9 pleural regions (upper, middle, and lower pleural aspects on ventral, lateral, and dorsal areas) on the chest CT by three different methods: observing images from static high-resolution CT (static image), dynamic-ventilation CT (movie image), and dynamic-ventilation CT while referring to the adhesion map (movie image with color map), which was created using research software to visualize movement differences between the lung surface and chest wall. The presence and severity of LPA were confirmed by intra-operative thoracoscopic findings. Parameters of diagnostic accuracy for LPA presence and severity were assessed among the three methods using Wilcoxon signed rank test in total and for each of the three pleural aspects. Mild and severe LPA were confirmed in 14 and 8 patients. The movie image with color map had higher sensitivity (56.9 ± 10.7%) and negative predictive value (NPV) (91.4 ± 1.7%) in LPA detection than both the movie image and static image. Furthermore, for severe LPA, detection sensitivity was the highest with the movie image with color map (82.5 ± 6.1%), followed by the movie image (58.8 ± 17.0%) and static image (38.8 ± 13.9%). For LPA severity, the movie image with color map was similar to the movie image and superior to the static image in accuracy as well as underestimation and overestimation, with a mean value of 80.2%. The authors concluded that software-assisted dynamic-ventilation CT may be a useful novel imaging approach to improve the detection performance of LPA.
The authors stated that this study had several drawbacks. First, because this study was carried out as a preliminary study to examine the usefulness of dedicated software analysis for LPA on dynamic-ventilation CT, the total number of enrolled patients was small (n = 51). The presence of lung tumors might have affected the movement of the lung periphery. Therefore, the findings of this study should be evaluated further in a larger study population without lung tumors. Second, the scanning area did not include the whole thorax on dynamic-ventilation CT. Pleural regions demonstrated at end inspiration were not always included in the scanning area with 16 cm coverage in the cranio-caudal direction in the remaining phases during respiration. Thus, it may make visual assessment of the movie image difficult and reduce LPA detectability using the 3D color map, especially for the lower pleural aspects. Furthermore, if dynamic ventilation CT data were obtained with the whole thorax contained in the scan in more cases in the future, motion vector from inside to outside lung field at specific respiratory phases from end inspiration, such as 1.05 s later, might be standardized and used for prediction of LPA presence and severity. Third, a relatively high radiation exposure for dynamic-ventilation CT may lead to concerns regarding the use of dynamic-ventilation CT in routine clinical series for LPA detection. In combination with iterative reconstruction, static-conventional CT at a considerably reduced dose (less than 0.3 mSv) has recently demonstrated similar pulmonary nodule detectability and equivalent quantification in larger sub-solid nodules to CT at reduced dose (0.92 to 1.74 mSv). Thus, the tube current was fixed at 7 mAs in this study, which was theoretically thought to correspond to less than 0.3 mSv for a single rotation during DVCT. However, a reduced tube current, such as 3.5 mAs, which is as low as achievable at this stage for this scanner, may be feasible in the future, especially in combination with full iterative reconstruction techniques or deep learning-based reconstruction techniques. Fourth, the most advanced area-detector CT with the rotation time of 0.275 s/rotation, which is theoretically less susceptible to faster lung motion, was not employed in this study. If this latest scanner is adopted in future studies, improvement in image quality at time phases in mid-inspiration or mid-expiration, as well as further dose reduction, can be realized on dynamic-ventilation CT. Fifth, pleural aspects were assigned to upper, middle, and lower lung fields at thoracoscopy based on rib locations. On the other hand, they were assigned to the three lung fields with the pre-defined two trans-axial planes at end-inspiration passing to the bronchial bifurcation and the superior edge of the diaphragm. Therefore, both of them could not correspond to each other in some cases. Sixth, subjective judgments of LPA by using CT images depend on individual observers’ experience and recognition, which may partly impair concordance in severe judgment for LPA between CT and VATS.
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The above policy is based on the following references:
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