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A phase 3 randomized double blind controlled, trial in 238 people with cystic fibrosis (CF) and at least one nonsense mutation (nmCF) investigated the effect of ataluren on FEV1. The study was of 48 weeks duration and failed to meet its primary endpoint. Unexpectedly, while FEV1 declined, chest computed tomography (CT) scores using the Brody-II score as secondary outcome measures did not show progression in the placebo group. Based on this observation it was concluded that the role of CT scans in CF randomized clinical trials was limited. However, more sensitive scoring systems were developed over the last decade warranting a reanalysis of this unique dataset. The aim of our study was to reanalyse all chest CT scans, obtained in the ataluren phase 3 study, using 2 independent scoring systems to characterize structural lung disease in this cohort and to compare progression of structural lung disease over the 48 weeks between treatment arms. 391 study CT scans from 210 patients were reanalysed in random order by 2 independent observers using the CF-CT and Perth-Rotterdam Annotated Grid Morphometric Analysis for CF (PRAGMA-CF) scoring systems. CF-CT and PRAGMA-CF subscores were expressed as %maximal score and %total lung volume, respectively. PRAGMA-CF subscores %Disease (p = 0.008) and %Mucus Plugging (p = 0.029) progressed over 48 weeks. CF-CT subscores did not show progression. There was no difference in progression of structural lung disease between treatment arm and placebo independent of tobramycin use. PRAGMA-CF Chest CT scores can be used as an outcome measure to study the effect of potential disease modifying drugs in CF on lung structure. [ABSTRACT FROM AUTHOR]

Objectives: Follow-up of congenital lung abnormalities (CLA) is currently done with chest computer tomography (CT). Major disadvantages of CT are exposure to ionizing radiation and need for contrast enhancement to visualise vascularisation. Chest magnetic resonance imaging (MRI) could be a safe alternative to image CLA without using contrast agents. The objective of this cohort study was to develop a non-contrast MRI protocol for the follow-up of paediatric CLA patients, and to compare findings on MRI to postnatal CT in school age CLA patients. Methods: Twenty-one CLA patients, 4 after surgical resection and 17 unoperated (mean age 12.8 (range 9.4–15.9) years), underwent spirometry and chest MRI. MRI was compared to postnatal CT on appearance and size of the lesion, and lesion associated abnormalities, such as hyperinflation and atelectasis. Results: By comparing school-age chest MRI to postnatal CT, radiological appearance and diagnostic interpretation of the type of lesion changed in 7 (41%) of the 17 unoperated patients. In unoperated patients, the relative size of the lesion in relation to the total lung volume remained stable (0.9% (range − 6.2 to + 6.7%), p = 0.3) and the relative size of lesion-associated parenchymal abnormalities decreased (− 2.2% (range − 0.8 to + 2.8%), p = 0.005). Conclusion: Non-contrast-enhanced chest MRI was able to identify all CLA-related lung abnormalities. Changes in radiological appearance between MRI and CT were related to CLA changes, patients' growth, and differences between imaging modalities. Further validation is needed for MRI to be introduced as a safe imaging method for the follow-up of paediatric CLA patients. Key Points: • Non-contrast-enhanced chest MRI is able to identify anatomical lung changes related to congenital lung abnormalities, including vascularisation. • At long-term follow-up, the average size of congenital lung abnormalities in relation to normal lung volume remains stable. • At long-term follow-up, the average size of congenital lung abnormalities associated parenchymal abnormalities such as atelectasis in relation to normal lung volume decreases. [ABSTRACT FROM AUTHOR]

Imaging plays a pivotal role in the noninvasive assessment of cystic fibrosis (CF)-related lung damage, which remains the main cause of morbidity and mortality in children with CF. The development of new imaging techniques has significantly changed clinical practice, and advances in therapies have posed diagnostic and monitoring challenges. The authors summarise these challenges and offer new perspectives in the use of imaging for children with CF for both clinicians and radiologists. This article focuses on chest radiography and CT, which are the two main radiologic techniques used in most cystic fibrosis centres. Advantages and disadvantages of radiography and CT for imaging in CF are described, with attention to new developments in these techniques, such as the use of artificial intelligence (AI) image analysis strategies to improve the sensitivity of radiography and CT and the introduction of the photon-counting detector CT scanner to increase spatial resolution at no dose expense. [ABSTRACT FROM AUTHOR]

Background: The assessment of bronchus–artery (BA) metrics on chest CT is important for detecting airway abnormalities. It is less clear how BA metrics are dependent on lung volume.CTs were obtained from a COPDGene substudy investigating the impact of radiation dose on lung density. Patients with chronic obstructive pulmonary disease underwent a full-dose and a reduced-dose CT in the same imaging session. CTs were automatically analyzed by measuring diameters of the bronchial outer edge (Bout), bronchial inner wall (Bin), artery (A), and bronchial wall thickness (Bwt) from segmental (G0) and distal generations. BA ratios were computed: Bout/A, Bin/A, Bwt/A, and bronchial wall area/bronchial outer area (Bwa/Boa). The total lung volume of the CT (TLC-CT) was computed. Differences between the volumes between the two CTs were expressed as % of the highest TLC-CT (ΔTLC-CT%). For the BA metrics of each CT, we computed the median of measurements in G1–6. Mixed-effect models were used to investigate the influence of TLC-CT on BA metrics adjusted for dose protocol.One thousand three hundred nineteen patients with a mean (SD) age of 64.4 (8.7) years were included. Three hundred twenty-nine (124) BA pairs were analyzed per CT. No significant difference was found for TLC-CT in relation to dose (p = 0.17). A ΔTLC-CT% of >10% (found in 121, 9%) led to 0.03 and 0.05 decreases in Bout/A and Bin/A and 0.008 and 0.11 decrease in log (Bwt/A) and log (Bwa/Boa), and a 0.03 increase in Bin and 0.06, 0.12, and 0.04 decrease in Bout, log (Bwt), and log (A) (all p < 0.001).Variations in TLC over 10% between time points significantly influence bronchial dimensions, affecting BA metrics. Standardizing volumes is recommended for sensitive tracking of airway disease changes over time.QuestionAre BA metrics dependent on total lung capacity (TLC), and if so, how?FindingsTLC variations over 10% between time points significantly influence bronchial dimensions, affecting BA metrics. Variations below 10% between CT scans have little effect on BA metrics.Clinical relevanceSmall lung volume differences between chest CTs have little impact on bronchus and artery metrics; it is imperative to standardize chest CT lung volumes to ensure precise diagnosis and monitoring of airway disease.Methods: The assessment of bronchus–artery (BA) metrics on chest CT is important for detecting airway abnormalities. It is less clear how BA metrics are dependent on lung volume.CTs were obtained from a COPDGene substudy investigating the impact of radiation dose on lung density. Patients with chronic obstructive pulmonary disease underwent a full-dose and a reduced-dose CT in the same imaging session. CTs were automatically analyzed by measuring diameters of the bronchial outer edge (Bout), bronchial inner wall (Bin), artery (A), and bronchial wall thickness (Bwt) from segmental (G0) and distal generations. BA ratios were computed: Bout/A, Bin/A, Bwt/A, and bronchial wall area/bronchial outer area (Bwa/Boa). The total lung volume of the CT (TLC-CT) was computed. Differences between the volumes between the two CTs were expressed as % of the highest TLC-CT (ΔTLC-CT%). For the BA metrics of each CT, we computed the median of measurements in G1–6. Mixed-effect models were used to investigate the influence of TLC-CT on BA metrics adjusted for dose protocol.One thousand three hundred nineteen patients with a mean (SD) age of 64.4 (8.7) years were included. Three hundred twenty-nine (124) BA pairs were analyzed per CT. No significant difference was found for TLC-CT in relation to dose (p = 0.17). A ΔTLC-CT% of >10% (found in 121, 9%) led to 0.03 and 0.05 decreases in Bout/A and Bin/A and 0.008 and 0.11 decrease in log (Bwt/A) and log (Bwa/Boa), and a 0.03 increase in Bin and 0.06, 0.12, and 0.04 decrease in Bout, log (Bwt), and log (A) (all p < 0.001).Variations in TLC over 10% between time points significantly influence bronchial dimensions, affecting BA metrics. Standardizing volumes is recommended for sensitive tracking of airway disease changes over time.QuestionAre BA metrics dependent on total lung capacity (TLC), and if so, how?FindingsTLC variations over 10% between time points significantly influence bronchial dimensions, affecting BA metrics. Variations below 10% between CT scans have little effect on BA metrics.Clinical relevanceSmall lung volume differences between chest CTs have little impact on bronchus and artery metrics; it is imperative to standardize chest CT lung volumes to ensure precise diagnosis and monitoring of airway disease.Results: The assessment of bronchus–artery (BA) metrics on chest CT is important for detecting airway abnormalities. It is less clear how BA metrics are dependent on lung volume.CTs were obtained from a COPDGene substudy investigating the impact of radiation dose on lung density. Patients with chronic obstructive pulmonary disease underwent a full-dose and a reduced-dose CT in the same imaging session. CTs were automatically analyzed by measuring diameters of the bronchial outer edge (Bout), bronchial inner wall (Bin), artery (A), and bronchial wall thickness (Bwt) from segmental (G0) and distal generations. BA ratios were computed: Bout/A, Bin/A, Bwt/A, and bronchial wall area/bronchial outer area (Bwa/Boa). The total lung volume of the CT (TLC-CT) was computed. Differences between the volumes between the two CTs were expressed as % of the highest TLC-CT (ΔTLC-CT%). For the BA metrics of each CT, we computed the median of measurements in G1–6. Mixed-effect models were used to investigate the influence of TLC-CT on BA metrics adjusted for dose protocol.One thousand three hundred nineteen patients with a mean (SD) age of 64.4 (8.7) years were included. Three hundred twenty-nine (124) BA pairs were analyzed per CT. No significant difference was found for TLC-CT in relation to dose (p = 0.17). A ΔTLC-CT% of >10% (found in 121, 9%) led to 0.03 and 0.05 decreases in Bout/A and Bin/A and 0.008 and 0.11 decrease in log (Bwt/A) and log (Bwa/Boa), and a 0.03 increase in Bin and 0.06, 0.12, and 0.04 decrease in Bout, log (Bwt), and log (A) (all p < 0.001).Variations in TLC over 10% between time points significantly influence bronchial dimensions, affecting BA metrics. Standardizing volumes is recommended for sensitive tracking of airway disease changes over time.QuestionAre BA metrics dependent on total lung capacity (TLC), and if so, how?FindingsTLC variations over 10% between time points significantly influence bronchial dimensions, affecting BA metrics. Variations below 10% between CT scans have little effect on BA metrics.Clinical relevanceSmall lung volume differences between chest CTs have little impact on bronchus and artery metrics; it is imperative to standardize chest CT lung volumes to ensure precise diagnosis and monitoring of airway disease.Conclusions: The assessment of bronchus–artery (BA) metrics on chest CT is important for detecting airway abnormalities. It is less clear how BA metrics are dependent on lung volume.CTs were obtained from a COPDGene substudy investigating the impact of radiation dose on lung density. Patients with chronic obstructive pulmonary disease underwent a full-dose and a reduced-dose CT in the same imaging session. CTs were automatically analyzed by measuring diameters of the bronchial outer edge (Bout), bronchial inner wall (Bin), artery (A), and bronchial wall thickness (Bwt) from segmental (G0) and distal generations. BA ratios were computed: Bout/A, Bin/A, Bwt/A, and bronchial wall area/bronchial outer area (Bwa/Boa). The total lung volume of the CT (TLC-CT) was computed. Differences between the volumes between the two CTs were expressed as % of the highest TLC-CT (ΔTLC-CT%). For the BA metrics of each CT, we computed the median of measurements in G1–6. Mixed-effect models were used to investigate the influence of TLC-CT on BA metrics adjusted for dose protocol.One thousand three hundred nineteen patients with a mean (SD) age of 64.4 (8.7) years were included. Three hundred twenty-nine (124) BA pairs were analyzed per CT. No significant difference was found for TLC-CT in relation to dose (p = 0.17). A ΔTLC-CT% of >10% (found in 121, 9%) led to 0.03 and 0.05 decreases in Bout/A and Bin/A and 0.008 and 0.11 decrease in log (Bwt/A) and log (Bwa/Boa), and a 0.03 increase in Bin and 0.06, 0.12, and 0.04 decrease in Bout, log (Bwt), and log (A) (all p < 0.001).Variations in TLC over 10% between time points significantly influence bronchial dimensions, affecting BA metrics. Standardizing volumes is recommended for sensitive tracking of airway disease changes over time.QuestionAre BA metrics dependent on total lung capacity (TLC), and if so, how?FindingsTLC variations over 10% between time points significantly influence bronchial dimensions, affecting BA metrics. Variations below 10% between CT scans have little effect on BA metrics.Clinical relevanceSmall lung volume differences between chest CTs have little impact on bronchus and artery metrics; it is imperative to standardize chest CT lung volumes to ensure precise diagnosis and monitoring of airway disease.Key Points: The assessment of bronchus–artery (BA) metrics on chest CT is important for detecting airway abnormalities. It is less clear how BA metrics are dependent on lung volume.CTs were obtained from a COPDGene substudy investigating the impact of radiation dose on lung density. Patients with chronic obstructive pulmonary disease underwent a full-dose and a reduced-dose CT in the same imaging session. CTs were automatically analyzed by measuring diameters of the bronchial outer edge (Bout), bronchial inner wall (Bin), artery (A), and bronchial wall thickness (Bwt) from segmental (G0) and distal generations. BA ratios were computed: Bout/A, Bin/A, Bwt/A, and bronchial wall area/bronchial outer area (Bwa/Boa). The total lung volume of the CT (TLC-CT) was computed. Differences between the volumes between the two CTs were expressed as % of the highest TLC-CT (ΔTLC-CT%). For the BA metrics of each CT, we computed the median of measurements in G1–6. Mixed-effect models were used to investigate the influence of TLC-CT on BA metrics adjusted for dose protocol.One thousand three hundred nineteen patients with a mean (SD) age of 64.4 (8.7) years were included. Three hundred twenty-nine (124) BA pairs were analyzed per CT. No significant difference was found for TLC-CT in relation to dose (p = 0.17). A ΔTLC-CT% of >10% (found in 121, 9%) led to 0.03 and 0.05 decreases in Bout/A and Bin/A and 0.008 and 0.11 decrease in log (Bwt/A) and log (Bwa/Boa), and a 0.03 increase in Bin and 0.06, 0.12, and 0.04 decrease in Bout, log (Bwt), and log (A) (all p < 0.001).Variations in TLC over 10% between time points significantly influence bronchial dimensions, affecting BA metrics. Standardizing volumes is recommended for sensitive tracking of airway disease changes over time.QuestionAre BA metrics dependent on total lung capacity (TLC), and if so, how?FindingsTLC variations over 10% between time points significantly influence bronchial dimensions, affecting BA metrics. Variations below 10% between CT scans have little effect on BA metrics.Clinical relevanceSmall lung volume differences between chest CTs have little impact on bronchus and artery metrics; it is imperative to standardize chest CT lung volumes to ensure precise diagnosis and monitoring of airway disease. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate changes in diaphragmatic function in Pompe disease using MRI over time, both during natural disease course and during treatment with enzyme replacement therapy (ERT).Methods: In this prospective study, 30 adult Pompe patients and 10 healthy controls underwent pulmonary function tests and spirometry-controlled MRI twice, with an interval of 1 year. In the sagittal view of 3D gradient echo breath-hold acquisitions, diaphragmatic motion (cranial-caudal ratio between end-inspiration and end-expiration) and curvature (diaphragm height and area ratio) were calculated using a machine learning algorithm based on convolutional neural networks. Changes in outcomes after 1 year were compared between Pompe patients and healthy controls using the Mann-Whitney test.Results: Pulmonary function outcomes and cranial-caudal ratio in Pompe patients did not change significantly over time compared to healthy controls. Diaphragm height ratio increased by 0.04 (-0.38 to 1.79) in Pompe patients compared to -0.02 (-0.18 to 0.25) in healthy controls (p = 0.02). An increased diaphragmatic curvature over time was observed in particular in untreated Pompe patients (p = 0.03), in those receiving ERT already for over 3 years (p = 0.03), and when severe diaphragmatic weakness was found on the initial MRI (p = 0.01); no progression was observed in Pompe patients who started ERT less than 3 years ago and in Pompe patients with mild diaphragmatic weakness on their initial MRI.Conclusions: MRI enables to detect small changes in diaphragmatic curvature over 1-year time in Pompe patients. It also showed that once severe diaphragmatic weakness has occurred, improvement of diaphragmatic muscle function seems unlikely.Key Points: • Changes in diaphragmatic curvature in Pompe patients over time assessed with 3D MRI may serve as an outcome measure to evaluate the effect of treatment on diaphragmatic function. • Diaphragmatic curvature showed a significant deterioration after 1 year in Pompe patients compared to healthy controls, but the curvature seems to remain stable over this period in patients who were treated with enzyme replacement therapy for less than 3 years, possibly indicating a positive effect of ERT. • Improvement of diaphragmatic curvature over time is rarely seen in Pompe patients once diaphragmatic motion shows severe impairment (cranial-caudal inspiratory/expiratory ratio < 1.4). [ABSTRACT FROM AUTHOR]

Conventional inhaler devices have a low efficacy in targeting small airways. Smart nebulizers can be used to increase deposition to small airways by adjusting the flow and depth of each inhalation based on patients 'individual inspiratory capacity. We investigated whether targeting of high dose inhaled corticosteroids (ICS) to small airways with a smart nebulizer could reduce exacerbation rate in children with severe asthma (SA). We conducted a retrospective study in children with SA using a smart nebulizer (Akita® Jet nebulizer) for the administration of high dose ICS in our outpatient clinic at the Erasmus MC — Sophia Children's Hospital. Clinical data before and after start of treatment were collected. The primary outcome was exacerbation rate, defined as: number of asthma exacerbations for which oral corticosteroid courses (OCS) were prescribed. The exacerbation rate 1 year before treatment was compared with the exacerbation rate 1 year after start of treatment. Secondary outcomes were changes in spirometry parameters, hospital admissions and medication use. Data on OCS use was available for 28/31 patients. Median number of asthma exacerbations requiring OCS courses 1 year before decreased from 2 (interquartile range(IQR) 2) to 0.5 (IQR 3) 1 year after treatment (p = 0.021). Hospital admission decreased from 1 (IQR 3) to 0 (IQR 1)(p = 0.028). FEV1, FEF25-75 and FEF75 were not significantly improved after one year of treatment with the smart nebulizer (p = 0.191; p = 0.248; p = 0.572). Targeting small airways with high dose ICS using a smart nebulizer resulted in a significant reduction in exacerbations requiring OCS after one year of treatment. [ABSTRACT FROM AUTHOR]

For sensitive diagnosis and monitoring of pulmonary disease, ionizing radiationfree imaging methods are of great importance. A noncontrast and free‐breathing proton magnetic resonance imaging (MRI) technique for assessment of pulmonary perfusion is phase‐resolved functional lung (PREFUL) MRI. Since there is no validation of PREFUL MRI across different centers and scanners, the purpose of this study was to compare perfusion‐weighted PREFUL MRI with the well‐established dynamic contrast‐enhanced (DCE) MRI across two centers on scanners from two different vendors. Sixteen patients with cystic fibrosis (CF) (Center 1: 10 patients; Center 2: 6 patients) underwent PREFUL and DCE MRI at 1.5T in the same imaging session. Normalized perfusion‐weighted values and perfusion defect percentage (QDP) values were calculated for the whole lung and three central slices (dorsal, central, ventral of the carina). Obtained parameters were compared using Pearson correlation, Spearman correlation, Bland–Altman analysis, Wilcoxon signed‐rank test, and Wilcoxon rank‐sum test. Moderate‐tostrong correlations between normalized perfusion‐weighted PREFUL and DCE values were found (posterior slice: r = 0.69, p < 0.01). Spatial overlap of PREFUL and DCE QDP maps showed an agreement of 79.4% for the whole lung. Further, spatial overlap values of Center 1 were not significantly different to those of Center 2 for the three central slices (p > 0.07). The feasibility of PREFUL MRI across two different centers and two different vendors was shown in patients with CF and obtained results were in agreement with DCE MRI. [ABSTRACT FROM AUTHOR]

The article evaluates lung disease in adults and children with primary ciliary dyskinesia (PCD) using a modified Brody composite high-resolution computed tomography (HRCT) scan score for the assessment of the prevalence of structural abnormalities. Research findings show that lower pulmonary HRCT scan scores are exhibited by patients with PCD compared to patients with cystic fibrosis.

The objective of this study was to develop mathematically described characteristic tracheobronchial bifurcations that are representative of aerosol transport and deposition in the intermediate airways of children with cystic fibrosis (CF), where bronchiectasis is a major contributor to changes in lung anatomy. Realistic airway models in the region of bifurcations B4-B7 were extracted from CT scans of children that were scored as having either low (CT-Low) or moderate (CT-Mod) CF lung disease and served as a basis for comparison with characteristic models. Aerosol deposition characteristics in these CT-extracted models were compared with a previously developed baseline stochastic individual path model (Baseline SIP), based on mathematically defined physiologically realistic bifurcations (PRBs), and new characteristic PRB geometries with modifications made to account for the CF disease state. The Baseline SIP models provided a poor approximation of aerosol deposition in the scan-extracted geometries, as expected. In contrast, the new characteristic (modified) PRB geometries adequately captured deposition consistent with the scan-extracted geometries across the two disease states considered for multiple particle sizes and inhalation flow rates. This was surprising considering that the modified PRB geometries, which can be mathematically specified, only captured an expanded bifurcation region and extended carinal curvature, both representative of bronchiectasis, and neglected asymmetry, surface roughness and non-circular branch cross-sections. In conclusion, the new characteristic PRB geometries adequately captured the deposition characteristics of scan-extracted airway models and can be implemented to represent airway structures in the intermediate and likely deeper lung regions of children with CF for future complete-airway modeling studies. Copyright © 2021 American Association for Aerosol Research [ABSTRACT FROM AUTHOR]

This paper presents a fully automatic and end-to-end optimised airway segmentation method for thoracic computed tomography, based on the U-Net architecture. We use a simple and low-memory 3D U-Net as backbone, which allows the method to process large 3D image patches, often comprising full lungs, in a single pass through the network. This makes the method simple, robust and efficient. We validated the proposed method on three datasets with very different characteristics and various airway abnormalities: (1) a dataset of pediatric patients including subjects with cystic fibrosis, (2) a subset of the Danish Lung Cancer Screening Trial, including subjects with chronic obstructive pulmonary disease, and (3) the EXACT'09 public dataset. We compared our method with other state-of-the-art airway segmentation methods, including relevant learning-based methods in the literature evaluated on the EXACT'09 data. We show that our method can extract highly complete airway trees with few false positive errors, on scans from both healthy and diseased subjects, and also that the method generalizes well across different datasets. On the EXACT'09 test set, our method achieved the second highest sensitivity score among all methods that reported good specificity. [ABSTRACT FROM AUTHOR]

Measuring airways in chest computed tomography (CT) scans is important for characterizing diseases such as cystic fibrosis, yet very time-consuming to perform manually. Machine learning algorithms offer an alternative, but need large sets of annotated scans for good performance. We investigate whether crowdsourcing can be used to gather airway annotations. We generate image slices at known locations of airways in 24 subjects and request the crowd workers to outline the airway lumen and airway wall. After combining multiple crowd workers, we compare the measurements to those made by the experts in the original scans. Similar to our preliminary study, a large portion of the annotations were excluded, possibly due to workers misunderstanding the instructions. After excluding such annotations, moderate to strong correlations with the expert can be observed, although these correlations are slightly lower than inter-expert correlations. Furthermore, the results across subjects in this study are quite variable. Although the crowd has potential in annotating airways, further development is needed for it to be robust enough for gathering annotations in practice. For reproducibility, data and code are available online: http://github.com/adriapr/crowdairway.git. [ABSTRACT FROM AUTHOR]

Background: In Pompe disease, an inherited metabolic muscle disorder, severe diaphragmatic weakness often occurs. Enzyme replacement treatment is relatively ineffective for respiratory function, possibly because of irreversible damage to the diaphragm early in the disease course. Mildly impaired diaphragmatic function may not be recognized by spirometry, which is commonly used to study respiratory function. In this cross-sectional study, we aimed to identify early signs of diaphragmatic weakness in Pompe patients using chest MRI.Methods: Pompe patients covering the spectrum of disease severity, and sex and age matched healthy controls were prospectively included and studied using spirometry-controlled sagittal MR images of both mid-hemidiaphragms during forced inspiration. The motions of the diaphragm and thoracic wall were evaluated by measuring thoracic cranial-caudal and anterior-posterior distance ratios between inspiration and expiration. The diaphragm shape was evaluated by measuring the height of the diaphragm curvature. We used multiple linear regression analysis to compare different groups.Results: We included 22 Pompe patients with decreased spirometry results (forced vital capacity in supine position < 80% predicted); 13 Pompe patients with normal spirometry results (forced vital capacity in supine position ≥ 80% predicted) and 18 healthy controls. The mean cranial-caudal ratio was only 1.32 in patients with decreased spirometry results, 1.60 in patients with normal spirometry results and 1.72 in healthy controls (p < 0.001). Anterior-posterior ratios showed no significant differences. The mean height ratios of the diaphragm curvature were 1.41 in patients with decreased spirometry results, 1.08 in patients with normal spirometry results and 0.82 in healthy controls (p = 0.001), indicating an increased curvature of the diaphragm during inspiration in Pompe patients.Conclusions: Even in early-stage Pompe disease, when spirometry results are still within normal range, the motion of the diaphragm is already reduced and the shape is more curved during inspiration. MRI can be used to detect early signs of diaphragmatic weakness in patients with Pompe disease, which might help to select patients for early intervention to prevent possible irreversible damage to the diaphragm. [ABSTRACT FROM AUTHOR]

Objectives: This study was conducted in order to evaluate the effect of geometric distortion (GD) on MRI lung volume quantification and evaluate available manual, semi-automated, and fully automated methods for lung segmentation.Methods: A phantom was scanned with MRI and CT. GD was quantified as the difference in phantom's volume between MRI and CT, with CT as gold standard. Dice scores were used to measure overlap in shapes. Furthermore, 11 subjects from a prospective population-based cohort study each underwent four chest MRI acquisitions. The resulting 44 MRI scans with 2D and 3D Gradwarp were used to test five segmentation methods. Intraclass correlation coefficient, Bland-Altman plots, Wilcoxon, Mann-Whitney U, and paired t tests were used for statistics.Results: Using phantoms, volume differences between CT and MRI varied according to MRI positions and 2D and 3D Gradwarp correction. With the phantom located at the isocenter, MRI overestimated the volume relative to CT by 5.56 ± 1.16 to 6.99 ± 0.22% with body and torso coils, respectively. Higher Dice scores and smaller intraobject differences were found for 3D Gradwarp MR images. In subjects, semi-automated and fully automated segmentation tools showed high agreement with manual segmentations (ICC = 0.971-0.993 for end-inspiratory scans; ICC = 0.992-0.995 for end-expiratory scans). Manual segmentation time per scan was approximately 3-4 h and 2-3 min for fully automated methods.Conclusions: Volume overestimation of MRI due to GD can be quantified. Semi-automated and fully automated segmentation methods allow accurate, reproducible, and fast lung volume quantification. Chest MRI can be a valid radiation-free imaging modality for lung segmentation and volume quantification in large cohort studies.Key Points: • Geometric distortion varies according to MRI setting and patient positioning. • Automated segmentation methods allow fast and accurate lung volume quantification. • MRI is a valid radiation-free alternative to CT for quantitative data analysis. [ABSTRACT FROM AUTHOR]

Background: Inhaled tobramycin is important in the treatment of Pseudomonas aeruginosa (Pa) infections in cystic fibrosis (CF). However, despite its use it fails to attenuate the clinical progression of CF lung disease. The bactericidal efficacy of tobramycin is known to be concentration-dependent and hence changing the dosing regimen from a twice-daily (q12h) inhalation to a once-daily (q24h) inhaled double dose could improve treatment outcomes.Objectives: To predict local concentrations of nebulized tobramycin in the airways of patients with CF, delivered with the small airway-targeting Akita® system or standard PARI-LC® Plus system, with different inspiratory flow profiles.Methods: Computational fluid dynamic (CFD) methods were applied to patient-specific airway models reconstructed from chest CT scans. The following q12h and q24h dosing regimens were evaluated: Akita® (150 and 300 mg) and PARI-LC® Plus (300 and 600 mg). Site-specific concentrations were calculated.Results: Twelve CT scans from patients aged 12-17 years (median = 15.7) were selected. Small airway concentrations were 762-2999 mg/L for the q12h dosing regimen and 1523-5997 mg/L for the q24h dosing regimen, well above the MIC for WT Pa strains. Importantly, the q24h regimen appeared to be more suitable than the q12h regimen against more resistant Pa strains and the inhibitory effects of sputum on tobramycin activity.Conclusions: CFD modelling showed that high concentrations of inhaled tobramycin are indeed delivered to the airways, with the Akita® system being twice as efficient as the PARI-LC® system. Ultimately, the q24h dosing regimen appears more effective against subpopulations with high MICs (i.e. more resistant strains). [ABSTRACT FROM AUTHOR]

Objectives: To quantify airway and artery (AA)-dimensions in cystic fibrosis (CF) and control patients for objective CT diagnosis of bronchiectasis and airway wall thickness (AWT).Methods: Spirometer-guided inspiratory and expiratory CTs of 11 CF and 12 control patients were collected retrospectively. Airway pathways were annotated semi-automatically to reconstruct three-dimensional bronchial trees. All visible AA-pairs were measured perpendicular to the airway axis. Inner, outer and AWT (outer-inner) diameter were divided by the adjacent artery diameter to compute AinA-, AoutA- and AWTA-ratios. AA-ratios were predicted using mixed-effects models including disease status, lung volume, gender, height and age as covariates.Results: Demographics did not differ significantly between cohorts. Mean AA-pairs CF: 299 inspiratory; 82 expiratory.Controls: 131 inspiratory; 58 expiratory. All ratios were significantly larger in inspiratory compared to expiratory CTs for both groups (p<0.001). AoutA- and AWTA-ratios were larger in CF than in controls, independent of lung volume (p<0.01). Difference of AoutA- and AWTA-ratios between patients with CF and controls increased significantly for every following airway generation (p<0.001).Conclusion: Diagnosis of bronchiectasis is highly dependent on lung volume and more reliably diagnosed using outer airway diameter. Difference in bronchiectasis and AWT severity between the two cohorts increased with each airway generation.Key Points: • More peripheral airways are visible in CF patients compared to controls. • Structural lung changes in CF patients are greater with each airway generation. • Number of airways visualized on CT could quantify CF lung disease. • For objective airway disease quantification on CT, lung volume standardization is required. [ABSTRACT FROM AUTHOR]

Respiratory muscle strength is a proven predictor of long-term outcome of neuromuscular disease (NMD), including amyotrophic lateral sclerosis, Duchenne muscular dystrophy, and spinal muscular atrophy. Maximal inspiratory pressure (MIP), a sensitive measure of respiratory muscle strength, one of several useful tests of respiratory muscle strength, is gaining interest as a therapeutic clinical trial endpoint for NMD. In this comprehensive review we investigate the use of MIP as a measure of respiratory muscle strength in clinical trials of therapeutics targeting respiratory muscle, examine the correlation of MIP with survival, quality of life, and other measures of pulmonary function, and outline the role of MIP as a clinically significantly meaningful outcome measure. Our analysis supports the utility of MIP for the early evaluation of respiratory muscle strength, especially of the diaphragm, in patients with NMD and as a surrogate endpoint in clinical trials of therapies for NMD. [ABSTRACT FROM AUTHOR]

Objective: Bronchiectasis is an important component of cystic fibrosis (CF) lung disease but little is known about its development. We aimed to study the development of bronchiectasis and identify determinants for rapid progression of bronchiectasis on chest CT.Methods: Forty-three patients with CF with at least four consecutive biennial volumetric CTs were included. Areas with bronchiectasis on the most recent CT were marked as regions of interest (ROIs). These ROIs were generated on all preceding CTs using deformable image registration. Observers indicated whether: bronchiectasis, mucus plugging, airway wall thickening, atelectasis/consolidation or normal airways were present in the ROIs.Results: We identified 362 ROIs on the most recent CT. In 187 (51.7 %) ROIs bronchiectasis was present on all preceding CTs, while 175 ROIs showed development of bronchiectasis. In 139/175 (79.4 %) no pre-stages of bronchiectasis were identified. In 36/175 (20.6 %) bronchiectatic airways the following pre-stages were identified: mucus plugging (17.7 %), airway wall thickening (1.7 %) or atelectasis/consolidation (1.1 %). Pancreatic insufficiency was more prevalent in the rapid progressors compared to the slow progressors (p = 0.05).Conclusion: Most bronchiectatic airways developed within 2 years without visible pre-stages, underlining the treacherous nature of CF lung disease. Mucus plugging was the most frequent pre-stage.Key Points: • Development of bronchiectasis in cystic fibrosis lung disease on CT. • Most bronchiectatic airways developed within 2 years without pre-stages. • The most frequently identified pre-stage was mucus plugging. • This study underlines the treacherous nature of CF lung disease. [ABSTRACT FROM AUTHOR]

Objectives: To explore the feasibility of diffusion-weighted imaging (DWI) to assess inflammatory lung changes in patients with Cystic Fibrosis (CF) METHODS: CF patients referred for their annual check-up had spirometry, chest-CT and MRI on the same day. MRI was performed in a 1.5 T scanner with BLADE and EPI-DWI sequences (b = 0-600 s/mm2). End-inspiratory and end-expiratory scans were acquired in multi-row scanners. DWI was scored with an established semi-quantitative scoring system. DWI score was correlated to CT sub-scores for bronchiectasis (CF-CTBE), mucus (CF-CTmucus), total score (CF-CTtotal-score), FEV1, and BMI. T-test was used to assess differences between patients with and without DWI-hotspots.Results: Thirty-three CF patients were enrolled (mean 21 years, range 6-51, 19 female). 4 % (SD 2.6, range 1.5-12.9) of total CF-CT alterations presented DWI-hotspots. DWI-hotspots coincided with mucus plugging (60 %), consolidation (30 %) and bronchiectasis (10 %). DWItotal-score correlated (all p < 0.0001) positively to CF-CTBE (r = 0.757), CF-CTmucus (r = 0.759) and CF-CTtotal-score (r = 0.79); and negatively to FEV1 (r = 0.688). FEV1 was significantly higher (p < 0.0001) in patients without DWI-hotspots.Conclusions: DWI-hotspots strongly correlated with radiological and clinical parameters of lung disease severity. Future validation studies are needed to establish the exact nature of DWI-hotspots in CF patients.Key Points: • DWI hotspots only partly overlapped structural abnormalities on morphological imaging • DWI strongly correlated with radiological and clinical indicators of CF-disease severity • Patients with more DWI hotspots had lower lung function values • Mucus score best predicted the presence of DWI-hotspots with restricted diffusion. [ABSTRACT FROM AUTHOR]

Purpose: Bronchiectasis and airway wall thickening are commonly assessed in computed tomography (CT) by comparing the airway size with the size of the accompanying artery. Thus, in order to automate the quantification of bronchiectasis and wall thickening following a similar principle, there is a need for methods that automatically segment the airway and vascular trees, measure their size, and pair each airway branch with its accompanying artery. Methods: This paper combines and extends existing techniques to present a fully automated pipeline that, given a thoracic chest CT, segments, measures, and pairs airway branches with the accompanying artery, then quantifies airway wall thickening and bronchiectasis by measuring the wall-artery ratio (WAR) and lumen and outer wall airway-artery ratio (AAR). Measurements that do not use the artery size for normalization are also extracted, including wall area percentage (WAP), wall thickness ratio (WTR), and airway diameters. Results: The method was thoroughly evaluated using 8000 manual annotations of airway-artery pairs from 24 full-inspiration pediatric CT scans (12 diseased and 12 controls). Limits of agreement between the automatically and manually measured diameters were comparable to interobserver limits of agreement. Differences in automatically obtained WAR, AAR, WAP, and WTR between bronchiectatic subjects and controls were similar as when manual annotations were used: WAR and outer AAR were significantly higher in the bronchiectatic subjects (p < 0.05), but lumen AAR, WAP, and WTR were not. Only measurements that use artery size for normalization led to significant differences between groups, highlighting the importance of airway-artery pairing. Conclusions: The fully automatic method presented in this paper could replace time-consuming manual annotations and visual scoring methods to quantify abnormal widening and thickening of airways. [ABSTRACT FROM AUTHOR]

Background: Diaphragm weakness is the main reason for respiratory dysfunction in patients with Pompe disease, a progressive metabolic myopathy affecting respiratory and limb-girdle muscles. Since respiratory failure is the major cause of death among adult patients, early identification of respiratory muscle involvement is necessary to initiate treatment in time and possibly prevent irreversible damage. In this paper we investigate the suitability of dynamic MR imaging in combination with state-of-the-art image analysis methods to assess respiratory muscle weakness. Methods: The proposed methodology relies on image registration and lung surface extraction to quantify lung kinematics during breathing. This allows for the extraction of geometry and motion features of the lung that characterize the independent contribution of the diaphragm and the thoracic muscles to the respiratory cycle. Results: Results in 16 3D+t MRI scans (10 Pompe patients and 6 controls) of a slow expiratory maneuver show that kinematic analysis from dynamic 3D images reveals important additional information about diaphragm mechanics and respiratory muscle involvement when compared to conventional pulmonary function tests. Pompe patients with severely reduced pulmonary function showed severe diaphragm weakness presented by minimal motion of the diaphragm. In patients with moderately reduced pulmonary function, cranial displacement of posterior diaphragm parts was reduced and the diaphragm dome was oriented more horizontally at full inspiration compared to healthy controls. Conclusion: Dynamic 3D MRI provides data for analyzing the contribution of both diaphragm and thoracic muscles independently. The proposed image analysis method has the potential to detect less severe diaphragm weakness and could thus be used to determine the optimal start of treatment in adult patients with Pompe disease in prospect of increased treatment response. [ABSTRACT FROM AUTHOR]

Objectives: To date, PROPELLER MRI, a breathing-motion-insensitive technique, has not been assessed for cystic fibrosis (CF) lung disease. We compared this technique to CT for assessing CF lung disease in children and adults.Methods: Thirty-eight stable CF patients (median 21 years, range 6-51 years, 22 female) underwent MRI and CT on the same day. Study protocol included respiratory-triggered PROPELLER MRI and volumetric CT end-inspiratory and -expiratory acquisitions. Two observers scored the images using the CF-MRI and CF-CT systems. Scores were compared with intra-class correlation coefficient (ICC) and Bland-Altman plots. The sensitivity and specificity of MRI versus CT were calculated.Results: MRI sensitivity for detecting severe CF bronchiectasis was 0.33 (CI 0.09-0.57), while specificity was 100% (CI 0.88-1). ICCs for bronchiectasis and trapped air were as follows: MRI-bronchiectasis (0.79); CT-bronchiectasis (0.85); MRI-trapped air (0.51); CT-trapped air (0.87). Bland-Altman plots showed an MRI tendency to overestimate the severity of bronchiectasis in mild CF disease and underestimate bronchiectasis in severe disease.Conclusions: Motion correction in PROPELLER MRI does not improve assessment of CF lung disease compared to CT. However, the good inter- and intra-observer agreement and the high specificity suggest that MRI might play a role in the short-term follow-up of CF lung disease (i.e. pulmonary exacerbations).Key Points: PROPELLER MRI does not match CT sensitivity to assess CF lung disease. PROPELLER MRI has lower sensitivity than CT to detect severe bronchiectasis. PROPELLER MRI has good to very good intra- and inter-observer variability. PROPELLER MRI can be used for short-term follow-up studies in CF. [ABSTRACT FROM AUTHOR]

The article discusses problems with pediatric chest magnetic resonance imaging (MRI) in children, focusing on scans of the lungs and airways. Topics include a comparison between MRI and computed tomography (CT), the impact of low proton density in the lung on signal optimization and image quality, and pulse sequences used in chest MRI. The use of pulmonary magnetic resonance angiography (MR angiography) is addressed.

Background: Pseudomonas aeruginosa (Pa) infection is an important contributor to the progression of cystic fibrosis (CF) lung disease. The cornerstone treatment for Pa infection is the use of inhaled antibiotics. However, there is substantial lung disease heterogeneity within and between patients that likely impacts deposition patterns of inhaled antibiotics. Therefore, this may result in airways below the minimal inhibitory concentration of the inhaled agent. Very little is known about antibiotic concentrations in small airways, in particular the effect of structural lung abnormalities. We therefore aimed to develop a patient-specific airway model to predict concentrations of inhaled antibiotics and to study the impact of structural lung changes and breathing profile on local concentrations in airways of patients with CF. Methods: In- and expiratory CT-scans of children with CF (5–17 years) were scored (CF-CT score), segmented and reconstructed into 3D airway models. Computational fluid dynamic (CFD) simulations were performed on 40 airway models to predict local Aztreonam lysine for inhalation (AZLI) concentrations. Patient-specific lobar flow distribution and nebulization of 75 mg AZLI through a digital Pari eFlow model with mass median aerodynamic diameter range were used at the inlet of the airway model. AZLI concentrations for central and small airways were computed for different breathing patterns and airway surface liquid thicknesses. Results: In most simulated conditions, concentrations in both central and small airways were well above the minimal inhibitory concentration. However, small airways in more diseased lobes were likely to receive suboptimal AZLI. Structural lung disease and increased tidal volumes, respiratory rates and larger particle sizes greatly reduced small airway concentrations. Conclusions: CFD modeling showed that concentrations of inhaled antibiotic delivered to the small airways are highly patient specific and vary throughout the bronchial tree. These results suggest that anti-Pa treatment of especially the small airways can be improved. [ABSTRACT FROM AUTHOR]

The article discusses a study which aim to determine whether assessment of an early computed tomography (CT) scan-detected bronchiectasis in young children with cystic fibrosis (CF) depends on lung volume. Results show that expiratory scans had poor sensitivity to detect bronchiectasis. It concluded that lung volume during CT image acquisition should be standardized to evaluate airway dimensions in young children.

Objectives: To determine the diagnostic accuracy of high-resolution computed tomography (HRCT) for the detection of nontuberculous mycobacterium infection (NTM) in adult cystic fibrosis (CF) patients.Methods: Twenty-seven CF patients with sputum-culture-proven NTM (NTM+) underwent HRCT. An age, gender and spirometrically matched group of 27 CF patients without NTM (NTM-) was included as controls. Images were randomly and blindly analysed by two readers in consensus and scored using a modified Bhalla scoring system.Results: Significant differences were seen between NTM (+) and NTM (-) patients in the severity of the bronchiectasis subscore [45 % (1.8/4) vs. 35 % (1.4/4), P = 0.029], collapse/consolidation subscore [33 % (1.3/3 vs. 15 % (0.6/3)], tree-in-bud/centrilobular nodules subscore [43 % (1.7/3) vs. 25 % (1.0/3), P = 0.002] and the total CT score [56 % (18.4/33) vs. 46 % (15.2/33), P = 0.002]. Binary logistic regression revealed BMI, peribronchial thickening, collapse/consolidation and tree-in-bud/centrilobular nodules to be predictors of NTM status (R(2 )= 0.43). Receiver-operator curve analysis of the regression model showed an area under the curve of 0.89, P < 0.0001.Conclusion: In adults with CF, seven or more bronchopulmonary segments showing tree-in-bud/centrilobular nodules on HRCT is highly suggestive of NTM colonisation.Key Points: Lung function declines rapidly in cystic fibrosis patients with nontuberculous mycobacterium infection. High-resolution computed tomography can help identify nontuberculous mycobacterium in CF patients. Extensive collapse/consolidation and tree-in-bud/centrilobular nodules are predictive of NTM infection. Multiple bronchopulmonary segments showing tree-in-bud/centrilobular nodules strongly suggest nontuberculous mycobacterium infection. [ABSTRACT FROM AUTHOR]

Robroeks CMHHT, Roozeboom MH, de Jong PA, Tiddens HAWM, Jöbsis Q, Hendriks HJ, Yntema J-BL, Brackel HL, van Gent R, Robben S, Dompeling E. Structural lung changes, lung function, and non-invasive inflammatory markers in cystic fibrosis. Pediatr Allergy Immunol 2010: 21: 493–500. © 2010 The Authors Journal compilation © 2010 Blackwell Munksgaard Cystic fibrosis (CF) lung disease is characterized by chronic airway inflammation and recurrent infections, resulting in (ir)reversible structural lung changes and a progressive decline in lung function. The objective of this study was to investigate the relationship between non-invasive inflammatory markers (IM) in exhaled breath condensate (EBC), lung function indices and structural lung changes, visualized by high resolution computed tomography (HRCT) scans in CF. In 34 CF patients, lung function indices (forced expiratory volume in 1 s, forced vital capacity [FVC], residual volume, and total lung capacity [TLC]) and non-invasive IM (exhaled nitric oxide, and condensate acidity, nitrate, nitrite, 8-isoprostane, hydrogen peroxide, interferon-gamma) were assessed. HRCT scans were scored in a standardized and validated way, a composite score and component scores were calculated. In general, the correlations between non-invasive IM and structural lung changes, and between IM and lung function were low (correlation coefficients <0.40). Patients with positive sputum Pseudomonas cultures had higher EBC nitrite levels and higher parenchymal HRCT subscores than patients with Pseudomonas-negative cultures (p < 0.05). Multiple linear regression models demonstrated that FVC was significantly predicted by hydrogen peroxide in EBC, and the scores of bronchiectasis and mosaic perfusion (Pearson correlation coefficient R = 0.78, p < 0.001). TLC was significantly predicted by 8-isoprostane, nitrate, hydrogen peroxide in EBC, and the mucous plugging subscore ( R = 0.92, p < 0.01). Static and dynamic lung function indices in this CF group were predicted by the combination of non-invasive IM in EBC and structural lung changes on HRCT imaging. Future longitudinal studies should reveal whether non-invasive monitoring of airway inflammation in CF adds to better follow-up of patients. [ABSTRACT FROM AUTHOR]

Background: Reducing the dose for each CT scan is important for children with cystic fibrosis (CF).Objective: To determine whether the number of CT images and therefore the dose per CT scan could be reduced without any significant loss of information in children with CF.Materials and Methods: A cohort of children with CF was followed with biennial surveillance CT scans, obtained in inspiration after a voluntary breath-hold as 1-mm thick images at 10-mm intervals from lung apex to base. A random set of 20 baseline CT scans and 10 follow-up CT scans were blinded. Sets of every image (10-mm intervals), every second image (20-mm intervals), every third image (30-mm intervals) and a selection of three and five images were scored randomly using a published CT scoring system by one experienced observer.Results: The 20 subjects were 10 years of age with a range of 3.7-17.6 years at baseline. Fewer CT images resulted in a significantly lower (less abnormal) CT score and the number of patients positive for abnormalities decreased subsequently. At intervals greater than 20 mm no significant change in CT score over 2 years could be detected, while the CT scores at 10-mm (P=0.02) and 20-mm (P=0.02) intervals worsened significantly.Conclusions: A reduction in the number of inspiratory CT images by increasing the interval between images to greater than 10 mm is not a valid option for radiation dose reduction in children with CF. [ABSTRACT FROM AUTHOR]

This article presents a study related tracheomalacia and bronchomalacia in children. All flexible bronchoscopies performed between 1997 and 2004 in the Sophia Children's Hospital were analyzed. Clinical features of children with primary airway malacia were summarized. The incidence of primary airway malacia were estimated and the predictive value of a clinical diagnosis of airway malacia by pediatric pulmonologists were calculated. In a total of 512 bronchoscopies, airway malacia was diagnosed in 160 children at a median age of 4.0 years. The study concludes that with an estimated incidence of at least 1 in 2,100 children, primary airway malacia is not rare in the general population.

Infection with seasonal influenza A viruses induces immunity to potentially pandemic influenza A viruses of other subtypes (heterosubtypic immunity). We recently demonstrated that vaccination against seasonal influenza prevented the induction of heterosubtypic immunity against influenza A/H5N1 virus induced by infection with seasonal influenza in animal models, which correlated with the absence of virus-specific CD8+ T cell responses. Annual vaccination of all healthy children against influenza has been recommended, but the impact of vaccination on the development of the virus-specific CD8+ T cell immunity in children is currently unknown. Here we compared the virus-specific CD8+ T cell immunity in children vaccinated annually with that in Skip to main page content HOME CURRENT ISSUE ARCHIVE ALERTS ABOUT ASM CONTACT US TECH SUPPORT Journals. ASM.Org keywords GO Advanced » Institution: EP/IPSWICH User Name Password Sign In keywords User Name unvaccinated children. In the present study, we compared influenza A virus-specific cellular and humoral responses of unvaccinated healthy control children with those of children with cystic fibrosis (CF) who were vaccinated annually. Similar virus-specific CD4+ T cell and antibody responses were observed, while an age-dependent increase of the virus-specific CD8+ T cell response that was absent in vaccinated CF children was observed in unvaccinated healthy control children. Our results indicate that annual influenza vaccination is effective against seasonal influenza but hampers the development of virus-specific CD8+ T cell responses. The consequences of these findings are discussed in the light of the development of protective immunity to seasonal and future pandemic influenza viruses. [ABSTRACT FROM AUTHOR]