Phenotyping of COPD with MRI in comparison to same-day CT in a multi-centre trial.

OBJECTIVES: A prospective, multi-centre study to evaluate concordance of morphologic lung MRI and CT in chronic obstructive pulmonary disease (COPD) phenotyping for airway disease and emphysema. METHODS: A total of 601 participants with COPD from 15 sites underwent same-day morpho-functional chest MRI and paired inspiratory-expiratory CT. Two readers systematically scored bronchial wall thickening, bronchiectasis, centrilobular nodules, air trapping and lung parenchyma defects in each lung lobe and determined COPD phenotype. A third reader acted as adjudicator to establish consensus. Inter-modality and inter-reader agreement were assessed using Cohen's kappa (im-κ and ir-κ). RESULTS: The mean combined MRI score for bronchiectasis/bronchial wall thickening was 4.5/12 (CT scores, 2.2/12 for bronchiectasis and 6/12 for bronchial wall thickening; im-κ, 0.04-0.3). Expiratory right/left bronchial collapse was observed in 51 and 47/583 on MRI (62 and 57/599 on CT; im-κ, 0.49-0.52). Markers of small airways disease on MRI were 0.15/12 for centrilobular nodules (CT, 0.34/12), 0.94/12 for air trapping (CT, 0.9/12) and 7.6/12 for perfusion deficits (CT, 0.37/12 for mosaic attenuation; im-κ, 0.1-0.41). The mean lung defect score on MRI was 1.3/12 (CT emphysema score, 5.8/24; im-κ, 0.18-0.26). Airway-/emphysema/mixed COPD phenotypes were assigned in 370, 218 and 10 of 583 cases on MRI (347, 218 and 34 of 599 cases on CT; im-κ, 0.63). For all examined features, inter-reader agreement on MRI was lower than on CT. CONCLUSION: Concordance of MRI and CT for phenotyping of COPD in a multi-centre setting was substantial with variable inter-modality and inter-reader concordance for single diagnostic key features. CLINICAL RELEVANCE STATEMENT: MRI of lung morphology may well serve as a radiation-free imaging modality for COPD in scientific and clinical settings, given that its potential and limitations as shown here are carefully considered. KEY POINTS: • In a multi-centre setting, MRI and CT showed substantial concordance for phenotyping of COPD (airway-/emphysema-/mixed-type). • Individual features of COPD demonstrated variable inter-modality concordance with features of pulmonary hypertension showing the highest and bronchiectasis showing the lowest concordance. • For all single features of COPD, inter-reader agreement was lower on MRI than on CT.

Elexacaftor/tezacaftor/ivacaftor improves chronic rhinosinusitis detected by magnetic resonance imaging in children with cystic fibrosis on long-term therapy with lumacaftor/ivacaftor.

INTRODUCTION: Previous studies using magnetic resonance imaging (MRI) demonstrated early onset and progression of chronic rhinosinusitis (CRS) from infancy to school age, and response to lumacaftor/ivacaftor (LUM/IVA) therapy in children with cystic fibrosis (CF). However, the effect of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) on CRS detected by MRI in children with CF and at least one F508del mutation, and potential incremental effects of ELX/TEZ/IVA compared to LUM/IVA in F508del homozygous children have not been studied. METHODS: 30 children with CF with at least one F508del mutation underwent three longitudinal paranasal sinus MRI before (MRI1), without (n = 16) or with LUM/IVA therapy (n = 14, MRI2), and with ELX/TEZ/IVA therapy (MRI3, mean age at therapy initiation 11.1 ± 3.4y, range 6-16y). MRI were evaluated using the CRS-MRI score. RESULTS: After therapy initiation with ELX/TEZ/IVA, the prevalence and in maxillary and sphenoid sinuses the dominance of mucopyoceles decreased (35% vs. 0 %, p<0.001 and 26% vs. 8 %, p < 0.05, respectively). This leads to a reduction in mucopyocele subscore (-3.4 ± 1.9, p < 0.001), and sinus subscores in MRI3 (maxillary sinus: -5.3 ± 3.1, p < 0.001, frontal sinus: -1.0 ± 1.9, p < 0.01, sphenoid subscore: -2.8 ± 3.5, p < 0.001, ethmoid sinus: -1.7 ± 1.9, p < 0.001). The CRS-MRI sum score decreased after therapy initiation with ELX/TEZ/IVA by -9.6 ± 5.5 score points (p < 0.001). The strength in reduction of mucopyoceles subscore and CRS-MRI sum score was independent of a pretreatment with LUM/IVA from MRI1-MRI2 (p = 0.275-0.999). CONCLUSIONS: ELX/TEZ/IVA therapy leads to improvement of CRS in eligible children with CF. Our data support the role of MRI for comprehensive monitoring of CRS disease severity and response to therapy in children with CF.

Magnetic Resonance Imaging of Pulmonary and Paranasal Sinus Abnormalities in Children with Primary Ciliary Dyskinesia Compared to Children with Cystic Fibrosis.

Rationale: Primary ciliary dyskinesia (PCD) and cystic fibrosis (CF) are characterized by inherited impaired mucociliary clearance leading to chronic progressive lung disease as well as chronic rhinosinusitis (CRS). The diseases share morphological and functional commonalities on magnetic resonance imaging (MRI) of the lungs and paranasal sinuses, but comparative MRI studies are lacking. Objectives: To determine whether PCD shows different associations of pulmonary and paranasal sinus abnormalities on MRI and lung function test results in children (infants to adolescents) compared with children with CF. Methods: Eighteen children with PCD (median age, 9.5 [IQR, 3.4-12.7] yr; range, 0-18 yr) and 36 age-matched CF transmembrane conductance regulator modulator-naive children with CF (median age, 9.4 [3.4-13.2] yr; range, 0-18 yr) underwent same-session chest and paranasal sinus MRI as well as spirometry (to determine forced expiratory volume in 1 s percent predicted) and multiple-breath washout (to determine lung clearance index z-score). Pulmonary and paranasal sinus abnormalities were assessed using previously validated chest MRI and CRS-MRI scoring systems. Results: Mean chest MRI global score was similar in children with PCD and CF (15.0 [13.5-20.8] vs. 15.0 [9.0-15.0]; P = 0.601). Consolidations were more prevalent and severe in children with PCD (56% vs. 25% and 1.0 [0.0-2.8] vs. 0.0 [0.0-0.3], respectively; P < 0.05). The chest MRI global score correlated moderately with forced expiratory volume in 1 second percent predicted in children with PCD and children with CF (r = -0.523 and -0.687; P < 0.01) and with lung clearance index in children with CF (r = 0.650; P < 0.001) but not in PCD (r = 0.353; P = 0.196). CRS-MRI sum score and mucopyocele subscore were lower in children with PCD than in children with CF (27.5 [26.3-32.0] vs. 37.0 [37.8-40.0] and 2.0 [0.0-2.0] vs. 7.5 [4.8-9.0], respectively; P < 0.01). CRS-MRI sum score did not correlate with chest MRI score in PCD (r = 0.075-0.157; P = 0.557-0.788) but correlated moderately with MRI morphology score in CF (r = 0.437; P < 0.01). Conclusions: MRI detects differences in lung and paranasal sinus abnormalities between children with PCD and those with CF. Lung disease does not correlate with CRS in PCD but correlates in CF.

Characterization of transient and progressive pulmonary fibrosis by spatially correlated phase contrast microCT, classical histopathology and atomic force microscopy.

Pulmonary fibrosis (PF) is a severe and progressive condition in which the lung becomes scarred over time resulting in pulmonary function impairment. Classical histopathology remains an important tool for micro-structural tissue assessment in the diagnosis of PF. A novel workflow based on spatial correlated propagation-based phase-contrast micro computed tomography (PBI-microCT), atomic force microscopy (AFM) and histopathology was developed and applied to two different preclinical mouse models of PF - the commonly used and well characterized Bleomycin-induced PF and a novel mouse model for progressive PF caused by conditional Nedd4-2 KO. The aim was to integrate structural and mechanical features from hallmarks of fibrotic lung tissue remodeling. PBI-microCT was used to assess structural alteration in whole fixed and paraffin embedded lungs, allowing for identification of fibrotic foci within the 3D context of the entire organ and facilitating targeted microtome sectioning of planes of interest for subsequent histopathology. Subsequently, these sections of interest were subjected to AFM to assess changes in the local tissue stiffness of previously identified structures of interest. 3D whole organ analysis showed clear morphological differences in 3D tissue porosity between transient and progressive PF and control lungs. By integrating the results obtained from targeted AFM analysis, it was possible to discriminate between the Bleomycin model and the novel conditional Nedd4-2 KO model using agglomerative cluster analysis. As our workflow for 3D spatial correlation of PBI, targeted histopathology and subsequent AFM is tailored around the standard procedure of formalin-fixed paraffin-embedded (FFPE) tissue specimens, it may be a powerful tool for the comprehensive tissue assessment beyond the scope of PF and preclinical research.

Magnetic Resonance Imaging of Lung Perfusion.

"Lung perfusion" in the context of imaging conventionally refers to the delivery of blood to the pulmonary capillary bed through the pulmonary arteries originating from the right ventricle required for oxygenation. The most important physiological mechanism in the context of imaging is the so-called hypoxic pulmonary vasoconstriction (HPV, also known as "Euler-Liljestrand-Reflex"), which couples lung perfusion to lung ventilation. In obstructive airway diseases such as asthma, chronic-obstructive pulmonary disease (COPD), cystic fibrosis (CF), and asthma, HPV downregulates pulmonary perfusion in order to redistribute blood flow to functional lung areas in order to conserve optimal oxygenation. Imaging of lung perfusion can be seen as a reflection of lung ventilation in obstructive airway diseases. Other conditions that primarily affect lung perfusion are pulmonary vascular diseases, pulmonary hypertension, or (chronic) pulmonary embolism, which also lead to inhomogeneity in pulmonary capillary blood distribution. Several magnetic resonance imaging (MRI) techniques either dependent on exogenous contrast materials, exploiting periodical lung signal variations with cardiac action, or relying on intrinsic lung voxel attributes have been demonstrated to visualize lung perfusion. Additional post-processing may add temporal information and provide quantitative information related to blood flow. The most widely used and robust technique, dynamic-contrast enhanced MRI, is available in clinical routine assessment of COPD, CF, and pulmonary vascular disease. Non-contrast techniques are important research tools currently requiring clinical validation and cross-correlation in the absence of a viable standard of reference. First data on many of these techniques in the context of observational studies assessing therapy effects have just become available. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 5.

Simultaneous T1, T2 and T2⁎ mapping of the liver with multi-shot MI-SAGE.

PURPOSE: To apply multi-shot high-resolution multi inversion spin and gradient echo (MI-SAGE) acquisition for simultaneous liver T1, T2 and T2* mapping. METHODS: Inversion prepared spin- and gradient-echo EPI was developed with ascending slice order across measurements for efficient acquisition with T1, T2, and T2⁎ weighting. Multi-shot EPI was also implemented to minimize distortion and blurring while enabling high in-plane resolution. A dictionary-matching approach was used to fit the images to quantitative parameter maps, which were compared to T1 measured by modified Look-Locker (MOLLI), T1 measured by variable flip angle (VFA), T2 measured by multiple echo time-based Half Fourier Single-shot Turbo spin-Echo (HASTE), T2 measured by radial turbo-spin-echo (rTSE) and T2⁎ measured by multiple gradient echo (MGRE) sequences. RESULTS: The multi-shot variant of the sequence achieved higher in-plane resolution of 1.7 × 1.7 mm2 with good image quality in 28 s. Derived quantitative maps showed comparable values to conventional mapping methods. As measured in phantom and in vivo, MOLLI, MESE and MGRE give closest values to MISAGE. VFA, HASTE and rTSE show obvious overestimation. CONCLUSIONS: The proposed multi-shot inversion prepared spin- and gradient-echo EPI sequence allows for high-resolution quantitative T1, T2 and T2 liver tissue characterization in a single breath-hold scan.

Influence of CT dose reduction on AI-driven malignancy estimation of incidental pulmonary nodules.

OBJECTIVES: The purpose of this study was to determine the influence of dose reduction on a commercially available lung cancer prediction convolutional neuronal network (LCP-CNN). METHODS: CT scans from a cohort provided by the local lung cancer center (n = 218) with confirmed pulmonary malignancies and their corresponding reduced dose simulations (25% and 5% dose) were subjected to the LCP-CNN. The resulting LCP scores (scale 1-10, increasing malignancy risk) and the proportion of correctly classified nodules were compared. The cohort was divided into a low-, medium-, and high-risk group based on the respective LCP scores; shifts between the groups were studied to evaluate the potential impact on nodule management. Two different malignancy risk score thresholds were analyzed: a higher threshold of ≥ 9 ("rule-in" approach) and a lower threshold of > 4 ("rule-out" approach). RESULTS: In total, 169 patients with 196 nodules could be included (mean age ± SD, 64.5 ± 9.2 year; 49% females). Mean LCP scores for original, 25% and 5% dose levels were 8.5 ± 1.7, 8.4 ± 1.7 (p > 0.05 vs. original dose) and 8.2 ± 1.9 (p < 0.05 vs. original dose), respectively. The proportion of correctly classified nodules with the "rule-in" approach decreased with simulated dose reduction from 58.2 to 56.1% (p = 0.34) and to 52.0% for the respective dose levels (p = 0.01). For the "rule-out" approach the respective values were 95.9%, 96.4%, and 94.4% (p = 0.12). When reducing the original dose to 25%/5%, eight/twenty-two nodules shifted to a lower, five/seven nodules to a higher malignancy risk group. CONCLUSION: CT dose reduction may affect the analyzed LCP-CNN regarding the classification of pulmonary malignancies and potentially alter pulmonary nodule management. CLINICAL RELEVANCE STATEMENT: Utilization of a "rule-out" approach with a lower malignancy risk threshold prevents underestimation of the nodule malignancy risk for the analyzed software, especially in high-risk cohorts. KEY POINTS: • LCP-CNN may be affected by CT image parameters such as noise resulting from low-dose CT acquisitions. • CT dose reduction can alter pulmonary nodule management recommendations by affecting the outcome of the LCP-CNN. • Utilization of a lower malignancy risk threshold prevents underestimation of pulmonary malignancies in high-risk cohorts.

[Magnetic resonance imaging of the lung : State of the art]. / Magnetresonanztomographie der Lunge : Stand der Dinge.

Due to the low proton density of the lung parenchyma and the rapid signal decay at the air-tissue interfaces, for a long time the lungs were difficult to access using magnetic resonance imaging (MRI); however, technical advances could address most of these obstacles. Pulmonary alterations associated with tissue proliferation ("plus pathologies"), can now be detected with high diagnostic accuracy because of the locally increased proton density. Compared to computed tomography (CT), MRI provides a comprehensive range of functional imaging procedures (respiratory mechanics, perfusion and ventilation). In addition, as a radiation-free noninvasive examination modality, it enables repeated examinations for assessment of the course or monitoring of the effects of treatment, even in children. This article discusses the technical aspects, gives suggestions for protocols and explains the role of MRI of the lungs in the routine assessment of various diseases.

Qualitative and quantitative evaluation of computed tomography changes in adults with cystic fibrosis treated with elexacaftor-tezacaftor-ivacaftor: a retrospective observational study.

Introduction: The availability of highly effective triple cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination therapy with elexacaftor-tezacaftor-ivacaftor (ETI) has improved pulmonary outcomes and quality of life of people with cystic fibrosis (pwCF). The aim of this study was to assess computed tomography (CT) changes under ETI visually with the Brody score and quantitatively with dedicated software, and to correlate CT measures with parameters of clinical response. Methods: Twenty two adult pwCF with two consecutive CT scans before and after ETI treatment initiation were retrospectively included. CT was assessed visually employing the Brody score and quantitatively by YACTA, a well-evaluated scientific software computing airway dimensions and lung parenchyma with wall percentage (WP), wall thickness (WT), lumen area (LA), bronchiectasis index (BI), lung volume and mean lung density (MLD) as parameters. Changes in CT metrics were evaluated and the visual and quantitative parameters were correlated with each other and with clinical changes in sweat chloride concentration, spirometry [percent predicted of forced expiratory volume in one second (ppFEV1)] and body mass index (BMI). Results: The mean (SD) Brody score improved with ETI [55 (12) vs. 38 (15); p < 0.001], incl. sub-scores for mucus plugging, peribronchial thickening, and parenchymal changes (all p < 0.001), but not for bronchiectasis (p = 0.281). Quantitatve WP (p < 0.001) and WT (p = 0.004) were reduced, conversely LA increased (p = 0.003), and BI improved (p = 0.012). Lung volume increased (p < 0.001), and MLD decreased (p < 0.001) through a reduction of ground glass opacity areas (p < 0.001). Changes of the Brody score correlated with those of quantitative parameters, exemplarily WT with the sub-score for mucus plugging (r = 0.730, p < 0.001) and peribronchial thickening (r = 0.552, p = 0.008). Changes of CT parameters correlated with those of clinical response parameters, in particular ppFEV1 with the Brody score (r = -0.606, p = 0.003) and with WT (r = -0.538, p = 0.010). Discussion: Morphological treatment response to ETI can be assessed using the Brody score as well as quantitative CT parameters. Changes in CT correlated with clinical improvements. The quantitative analysis with YACTA proved to be an objective, reproducible and simple method for monitoring lung disease, particularly with regard to future interventional clinical trials.

Elexacaftor/Tezacaftor/Ivacaftor Improves Bronchial Artery Dilatation Detected by Magnetic Resonance Imaging in Patients with Cystic Fibrosis.

Rationale: Magnetic resonance imaging (MRI) detects improvements in mucus plugging and bronchial wall thickening, but not in lung perfusion in patients with cystic fibrosis (CF) treated with elexacaftor/tezacaftor/ivacaftor (ETI). Objectives: To determine whether bronchial artery dilatation (BAD), a key feature of advanced lung disease, indicates irreversibility of perfusion abnormalities and whether BAD could be reversed in CF patients treated with ETI. Methods: A total of 59 adults with CF underwent longitudinal chest MRI, including magnetic resonance angiography twice, comprising 35 patients with CF (mean age, 31 ± 7 yr) before (MRI1) and after (MRI2) at least 1 month (mean duration, 8 ± 4 mo) on ETI therapy and 24 control patients with CF (mean age, 31 ± 7 yr) without ETI. MRI was assessed using the validated chest MRI score, and the presence and total lumen area of BAD were assessed with commercial software. Results: The MRI global score was stable in the control group from MRI1 to MRI2 (mean difference, 1.1 [-0.3, 2.4]; P = 0.054), but it was reduced in the ETI group (-10.1 [-0.3, 2.4]; P < 0.001). In the control and ETI groups, BAD was present in almost all patients at baseline (95% and 94%, respectively), which did not change at MRI2. The BAD total lumen area did not change in the control group from MRI1 to MRI2 (1.0 mm2 [-0.2, 2.2]; P = 0.099) but decreased in the ETI group (-7.0 mm2 [-8.9, -5.0]; P < 0.001). This decrease correlated with improvements in the MRI global score (r = 0.540; P < 0.001). Conclusions: Our data show that BAD may be partially reversible under ETI therapy in adult patients with CF who have established disease.

[Patient-centered, value-based management of incidental findings in radiology]. / Patientenzentriertes, wertbasiertes Management von radiologischen Zufallsbefunden.

As a byproduct of the increased use of high-resolution radiological imaging, the prevalence of incidental findings (IFs) has been increasing for years. The discovery of an incidental finding can allow early treatment of a potentially health-threatening disease and thus decisively change the course of the disease. However, many incidental findings are of low risk with little or no health impact, and yet their discovery often leads to a cascade of additional investigations. It is undisputed that incidental findings can have a direct impact on the life of the person and that not only psychosocial aspects such as worries and anxiety due to false-positive findings play a role, but that insurance, legal or professional problems can also occur under certain circumstances, which is why the correct handling of incidental findings and the accompanying ethical challenges that apply to them regularly give rise to discussions. General principles to consider when managing incidental findings are responsibility for the well-being of the patient/study participant and of society. In order to avoid overdiagnosis and overtreatment and to achieve high patient benefit, radiologists and clinicians must know how to properly deal with IFs. In recent years, various national and international societies have published important guidelines ("white papers") on how to deal with the management of IFs. It is important that radiologists are fully aware of and follow these guidelines and are also available to referring physicians for further discussions and advice. The most important fact is that the well-being of the patient must always be at the center of all decisions.

Reanalysis of N2-lung clearance index and the comparison to SF6-lung clearance index and magnetic resonance imaging.

Since the finding and correction of an error in previous spiroware software versions commonly used with the Exhalyzer D for multiple-breath washout (MBW) analysis, there has been an ongoing discussion about its impact on MBW results. In this study, we reanalyzed previously published findings with the corrected spiroware version 3.3.1. In total, 31 infants and preschool children with cystic fibrosis (CF) (mean age 2.3 ±â€¯0.8 years) and 20 healthy controls (mean age 2.3 ±â€¯1.1 years) underwent consecutive sulfure hexafluoride (SF6)- and nitrogen (N2)-MBW. In addition, children with CF underwent chest magnetic resonance imaging (MRI) on the same day. After reanalysis of MBW data, the corrected N2-lung clearance index (LCI) decreased by 10-15% in both groups (P = 0.001) but remained significantly higher than the SF6-LCI (P<0.01). Diagnostic agreement between the MBW results remained moderate with a persistent correlation between SF6- and N2-MBW. The corrected upper limit of normal of the N2-LCI changed classification of nine children with CF, eight of which were within the normal range after correction. The correlation between the different LCI values and the chest MRI scores remained significant with strongest correlation with the MRI perfusion score. Consequently, the corrected N2-LCI is significantly lower than the previous N2-LCI, but key results published before are not affected by the reanalysis.

MRI Compared with Low-Dose CT for Incidental Lung Nodule Detection in COPD: A Multicenter Trial.

Purpose: To investigate morphofunctional chest MRI for the detection and management of incidental pulmonary nodules in participants with chronic obstructive pulmonary disease (COPD). Materials and Methods: In this prospective study, 567 participants (mean age, 66 years ± 9 [SD]; 340 men) underwent same-day contrast-enhanced MRI and nonenhanced low-dose CT (LDCT) in a nationwide multicenter trial (clinicaltrials.gov: NCT01245933). Nodule dimensions, morphologic features, and Lung Imaging Reporting and Data System (Lung-RADS) category were assessed at MRI by two blinded radiologists, and consensual LDCT results served as the reference standard. Comparisons were performed using the Student t test, and agreements were assessed using the Cohen weighted κ. Results: A total of 525 nodules larger than 3 mm in diameter were detected at LDCT in 178 participants, with a mean diameter of 7.2 mm ± 6.1 (range, 3.1-63.1 mm). Nodules were not detected in the remaining 389 participants. Sensitivity and positive predictive values with MRI for readers 1 and 2, respectively, were 63.0% and 84.8% and 60.2% and 83.9% for solid nodules (n = 495), 17.6% and 75.0% and 17.6% and 60.0% for part-solid nodules (n = 17), and 7.7% and 100% and 7.7% and 50.0% for ground-glass nodules (n = 13). For nodules 6 mm or greater in diameter, sensitivity and positive predictive values were 73.3% and 92.2% for reader 1 and 71.4% and 93.2% for reader 2, respectively. Readers underestimated the long-axis diameter at MRI by 0.5 mm ± 1.7 (reader 1) and 0.5 mm ± 1.5 (reader 2) compared with LDCT (P < .001). For Lung-RADS categorization per nodule using MRI, there was substantial to perfect interreader agreement (κ = 0.75-1.00) and intermethod agreement compared with LDCT (κ = 0.70-1.00 and 0.69-1.00). Conclusion: In a multicenter setting, morphofunctional MRI showed moderate sensitivity for detection of incidental pulmonary nodules in participants with COPD but high agreement with LDCT for Lung-RADS classification of nodules.Clinical trial registration no. NCT01245933 and NCT02629432Keywords: MRI, CT, Thorax, Lung, Chronic Obstructive Pulmonary Disease, Screening© RSNA, 2023 Supplemental material is available for this article.

Long-term effects of lumacaftor/ivacaftor on paranasal sinus abnormalities in children with cystic fibrosis detected with magnetic resonance imaging.

Introduction: Chronic rhinosinusitis (CRS) usually presents with nasal congestion, rhinorrhea and anosmia impacts quality of life in cystic fibrosis (CF). Especially mucopyoceles pathognomonic for CRS in CF may cause complications such as spread of infection. Previous studies using magnetic resonance imaging (MRI) demonstrated early onset and progression of CRS from infancy to school age in patients with CF, and mid-term improvements of CRS in preschool and school-age children with CF treated with lumacaftor/ivacaftor for at least 2 months. However, long-term data on treatment effects on paranasal sinus abnomalities in preschool and school-age children with CF are lacking. Methods: 39 children with CF homozygous for F508del (mean age at baseline MRI 5.9 ± 3.0 years, range 1-12 years) underwent MRI before (MRI1) and about 7 months after starting lumacaftor/ivacaftor and then annually (median 3 follow-up MRI, range 1-4) (MRI2-4). MRI were evaluated using the previously evaluated CRS-MRI score with excellent inter-reader agreement. For intraindividual analysis ANOVA mixed-effects analysis including Geisser-Greenhouse correction and Fisher's exact test, and for interindividual group analysis Mann-Whitney test were used. Results: The CRS-MRI sum score at baseline was similar in children starting lumacaftor/ivacaftor in school age and children starting therapy at preschool age (34.6 ± 5.2 vs.32.9 ± 7.8, p = 0.847). Mucopyoceles were the dominant abnormality in both, especially in maxillary sinus (65% and 55%, respectively). In children starting therapy in school age the CRS-MRI sum score decreased longitudinally from MRI1 to MRI2 (-2.1 ± 3.5, p < 0.05), MRI3 (-3.0 ± 3.7, p < 0.01) and MRI4 (-3.6 ± 4.7, p < 0.01), mainly due to a decrease in the mucopyoceles subscore (-1.0 ± 1.5, p = 0.059; -1.2 ± 2.0, p < 0.05; -1.6 ± 1.8, p < 0.01; and -2.6 ± 2.8, p = 0.417, respectively). In children starting lumacaftor/ivacaftor in preschool age, the CRS-MRI sum score remained stable under therapy over all three follow-up MRI (0.6 ± 3.3, p = 0.520; 2.4 ± 7.6, p = 0.994; 2.1 ± 10.5, p > 0.999 and -0.5 ± 0.5, p = 0.740; respectively). Conclusion: Longitudinal paranasal sinus MRI shows improvements in paranasal sinus abnormalities in children with CF starting lumacaftor/ivacaftor therapy at school age. Further, MRI detects a prevention of an increase in paranasal sinus abnormalities in children with CF starting lumacaftor/ivacaftor therapy at preschool age. Our data support the role of MRI for comprehensive non-invasive therapy and disease monitoring of paranasal sinus abnormalities in children with CF.

Magnetic resonance imaging detects onset and association with lung disease severity of bronchial artery dilatation in cystic fibrosis.

Background: Bronchial artery dilatation (BAD) is associated with haemoptysis in advanced cystic fibrosis (CF) lung disease. Our aim was to evaluate BAD onset and its association with disease severity by magnetic resonance imaging (MRI). Methods: 188 CF patients (mean±sd age 13.8±10.6 years, range 1.1-55.2 years) underwent annual chest MRI (median three exams, range one to six exams), contributing a total of 485 MRI exams including perfusion MRI. Presence of BAD was evaluated by two radiologists in consensus. Disease severity was assessed using the validated MRI scoring system and spirometry (forced expiratory volume in 1 s (FEV1) % pred). Results: MRI demonstrated BAD in 71 (37.8%) CF patients consistently from the first available exam and a further 10 (5.3%) patients first developed BAD during surveillance. Mean MRI global score in patients with BAD was 24.5±8.3 compared with 11.8±7.0 in patients without BAD (p<0.001) and FEV1 % pred was lower in patients with BAD compared with patients without BAD (60.8% versus 82.0%; p<0.001). BAD was more prevalent in patients with chronic Pseudomonas aeruginosa infection versus in patients without infection (63.6% versus 28.0%; p<0.001). In the 10 patients who newly developed BAD, the MRI global score increased from 15.1±7.8 before to 22.0±5.4 at first detection of BAD (p<0.05). Youden indices for the presence of BAD were 0.57 for age (cut-off 11.2 years), 0.65 for FEV1 % pred (cut-off 74.2%) and 0.62 for MRI global score (cut-off 15.5) (p<0.001). Conclusions: MRI detects BAD in patients with CF without radiation exposure. Onset of BAD is associated with increased MRI scores, worse lung function and chronic P. aeruginosa infection, and may serve as a marker of disease severity.

Effects of Lumacaftor/Ivacaftor on Cystic Fibrosis Disease Progression in Children 2 through 5 Years of Age Homozygous for F508del-CFTR: A Phase 2 Placebo-controlled Clinical Trial.

Rationale: Lumacaftor/ivacaftor (LUM/IVA) was shown to be safe and well tolerated in children 2 through 5 years of age with cystic fibrosis (CF) homozygous for F508del-CFTR in a Phase 3 open-label study. Improvements in sweat chloride concentration, markers of pancreatic function, and lung clearance index2.5 (LCI2.5), along with increases in growth parameters, suggested the potential for early disease modification with LUM/IVA treatment. Objective: To further assess the effects of LUM/IVA on CF disease progression in children 2 through 5 years of age using chest magnetic resonance imaging (MRI). Methods: This Phase 2 study had two parts: a 48-week, randomized, double-blind, placebo-controlled treatment period in which children 2 through 5 years of age with CF homozygous for F508del-CFTR received either LUM/IVA or placebo (Part 1) followed by an open-label period in which all children received LUM/IVA for an additional 48 weeks (Part 2). The results from Part 1 are reported. The primary endpoint was absolute change from baseline in chest MRI global score at Week 48. Secondary endpoints included absolute change in LCI2.5 through Week 48 and absolute changes in weight-for-age, stature-for-age, and body mass index-for-age z-scores at Week 48. Additional endpoints included absolute changes in sweat chloride concentration, fecal elastase-1 levels, serum immunoreactive trypsinogen, and fecal calprotectin through Week 48. The primary endpoint was analyzed using Bayesian methods, where the actual Bayesian posterior probability of LUM/IVA being superior to placebo in the chest MRI global score at Week 48 was calculated using a vague normal prior distribution; secondary and additional endpoints were analyzed using descriptive summary statistics. Results: Fifty-one children were enrolled and received LUM/IVA (n = 35) or placebo (n = 16). For the change in chest MRI global score at Week 48, the Bayesian posterior probability of LUM/IVA being better than placebo (treatment difference, <0; higher score indicates greater abnormality) was 76%; the mean treatment difference was -1.5 (95% credible interval, -5.5 to 2.6). Treatment with LUM/IVA also led to within-group numerical improvements in LCI2.5, growth parameters, and biomarkers of pancreatic function as well as greater decreases in sweat chloride concentration compared with placebo from baseline through Week 48. Safety data were consistent with the established safety profile of LUM/IVA. Conclusions: This placebo-controlled study suggests the potential for early disease modification with LUM/IVA treatment, including that assessed by chest MRI, in children as young as 2 years of age. Clinical trial registered with www.clinicaltrials.gov (NCT03625466).