Structural Lung Disease and Clinical Phenotype in Bronchiectasis Patients: The EMBARC CT Study.

RATIONALE: Chest computed tomography -scans (CTs) are essential to diagnose and monitor bronchiectasis (BE). To date, little quantitative data is available about the nature and extent of structural lung abnormalities (SLA) on CTs of BE patients. OBJECTIVES: to investigate SLA on CTs of patients with bronchiectasis and the relationship of SLAs to clinical features using the European Bronchiectasis Registry (EMBARC) Methods: CTs from BE patients included in the EMBARC registry were analyzed using the validated Bronchiectasis Scoring Technique for CT (BEST-CT). BEST-CT subscores are expressed as % of total lung volume. Scored items are: atelectasis/consolidation (%ATCON), bronchiectasis with and without mucus plugging (%BEMP, %BEwMP), airway wall thickening (%AWT), mucus plugging (%MP), ground-glass opacities (%GGO), bullae (%BUL), airways and parenchyma (%A,%P). Four composite scores were calculated: Total BE (%TBE=%BEMP+%BEwMP), total MP (%TMP=%BEMP+%MP), total inflammatory changes (%TinF=%ATCON+%BEMP+%MP+%GGO) and total disease (%DIS= all but %A & %P).¬ Measurments and Main Results: CTs of 524 BE patients were analyzed. Mean (range) of subscores were: %TBE 4.6 (2.3-7.7), %TMP 4.2 (1.2-8.1), %TinF 8.3 (3.5-16.7) and %DIS 14.9 (9.1-25.9). BE associated with primary ciliary dyskinesia was associated with more SLA, while COPD was associated with less SLA. Lower FEV1, longer disease duration, Pseudomonas aeruginosa and NTM infection, and severe exacerbations were all independently associated with worse SLA. CONCLUSION: Patients with bronchiectasis have highly heterogeneous type and extent of structural lung abnormalities. Strong relationships between radiological disease and clinical features suggest CT analysis may be a useful tool for clinical phenotyping.

Improvement in Lung Clearance Index and Chest Computed Tomography Scores with Elexacaftor/Tezacaftor/Ivacaftor Treatment in People with Cystic Fibrosis Aged 12 Years and Older - The RECOVER Trial.

Rationale: Clinical trials have shown that use of elexacaftor/tezacaftor/ivacaftor (ETI) is associated with improvements in sweat chloride, pulmonary function, nutrition, and quality of life in people with cystic fibrosis (CF). Little is known about the impact of ETI on ventilation inhomogeneity and lung structure. Objectives: RECOVER is a real-world study designed to measure the impact of ETI in people with CF. The primary endpoints were lung clearance (lung clearance index; LCI2.5) and FEV1. Secondary endpoints included spirometry-controlled chest computed tomography (CT) scores. Methods: The study was conducted in seven sites in Ireland and the United Kingdom. Participants ages 12 years and older who were homozygous for the F508del mutation (F508del/F508del) or heterozygous for F508del and a minimum-function mutation (F508del/MF) were recruited before starting ETI and were followed up over 12 months. LCI2.5 was measured using nitrogen multiple breath washout (MBW) at baseline and at 6 and 12 months. Spirometry was performed as per the criteria of the American Thoracic Society and the European Respiratory Society. Spirometry-controlled chest CT scans were performed at baseline and at 12 months. CT scans were scored using the Perth Rotterdam Annotated Grid Morphometric Analysis (PRAGMA) system. Other outcome measures include weight, height, Cystic Fibrosis Quality of Life Questionnaire-Revised (CFQ-R), and sweat chloride. Measurements and Main Results: One hundred seventeen people with CF ages 12 and older were recruited to the study. Significant improvements were seen in LCI scores (-2.5; 95% confidence interval [CI], -3.0, -2.0) and in the percents predicted for FEV1 (8.9; 95% CI, 7.0, 10.9), FVC (6.6; 95% CI, 4.9, 8.3), and forced expiratory flow between 25% and 75% of expired volume (12.4; 95% CI, 7.8, 17.0). Overall PRAGMA-CF scores reflecting airway disease improved significantly (-3.46; 95% CI, -5.23, -1.69). Scores for trapped air, mucus plugging, and bronchial wall thickening improved significantly, but bronchiectasis scores did not. Sweat chloride levels decreased in both F508del/F508del (-43.1; 95% CI, -47.4, -38.9) and F508del/MF (-42.8; 95% CI, -48.5, -37.2) groups. Scores on the Respiratory Domain of the CFQ-R improved by 14.2 points (95% CI, 11.3, 17.2). At 1 year, sweat chloride levels were significantly lower for the F508del/F508del group compared with scores for the F508del/MF group (33.93 vs. 53.36, P < 0.001). Conclusions: ETI is associated with substantial improvements in LCI2.5, spirometry, and PRAGMA-CF CT scores in people with CF ages 12 years and older. ETI led to improved nutrition and quality of life. People in the F508del/F508del group had significantly lower sweat chloride on ETI treatment compared with the F508del/MF group. Clinical trial registered with www.clinicaltrials.gov (NCT04602468).

The efficacy and safety of systemic corticosteroids as first line treatment for granulomatous lymphocytic interstitial lung disease.

BACKGROUND: Granulomatous and lymphocytic interstitial lung disease (gl-ILD) is a major cause of morbidity and mortality among patients with common variable immunodeficiency. Corticosteroids are recommended as first-line treatment for gl-ILD, but evidence for their efficacy is lacking. OBJECTIVES: This study analyzed the effect of high-dose corticosteroids (≥0.3 mg/kg prednisone equivalent) on gl-ILD, measured by high-resolution computed tomography (HRCT) scans, and pulmonary function test (PFT) results. METHODS: Patients who had received high-dose corticosteroids but no other immunosuppressive therapy at the time (n = 56) and who underwent repeated HRCT scanning or PFT (n = 39) during the retrospective and/or prospective phase of the Study of Interstitial Lung Disease in Primary Antibody Deficiency (STILPAD) were included in the analysis. Patients without any immunosuppressive treatment were selected as controls (n = 23). HRCT scans were blinded, randomized, and scored using the Hartman score. Differences between the baseline and follow-up HRCT scans and PFT were analyzed. RESULTS: Treatment with high-dose corticosteroids significantly improved HRCT scores and forced vital capacity. Carbon monoxide diffusion capacity significantly improved in both groups. Of 18 patients, for whom extended follow-up data was available, 13 achieved a long-term, maintenance therapy independent remission. All patients with relapse were retreated with corticosteroids, but only one-fifth of them responded. Two opportunistic infections were found in the corticosteroid treatment group, while overall infection rate was similar between cohorts. CONCLUSIONS: Induction therapy with high-dose corticosteroids improved HRCT scans and PFT results of patients with gl-ILD and achieved long-term remission in 42% of patients. It was not associated with major side effects. Low-dose maintenance therapy provided no benefit and efficacy was poor in relapsing disease.

Automatic analysis of bronchus-artery dimensions to diagnose and monitor airways disease in cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) lung disease is characterised by progressive airway wall thickening and widening. We aimed to validate an artificial intelligence-based algorithm to assess dimensions of all visible bronchus-artery (BA) pairs on chest CT scans from patients with CF. METHODS: The algorithm fully automatically segments the bronchial tree; identifies bronchial generations; matches bronchi with the adjacent arteries; measures for each BA-pair bronchial outer diameter (Bout), bronchial lumen diameter (Bin), bronchial wall thickness (Bwt) and adjacent artery diameter (A); and computes Bout/A, Bin/A and Bwt/A for each BA pair from the segmental bronchi to the last visible generation. Three datasets were used to validate the automatic BA analysis. First BA analysis was executed on 23 manually annotated CT scans (11 CF, 12 control subjects) to compare automatic with manual BA-analysis outcomes. Furthermore, the BA analysis was executed on two longitudinal datasets (Copenhagen 111 CTs, ataluren 347 CTs) to assess longitudinal BA changes and compare them with manual scoring results. RESULTS: The automatic and manual BA analysis showed no significant differences in quantifying bronchi. For the longitudinal datasets the automatic BA analysis detected 247 and 347 BA pairs/CT in the Copenhagen and ataluren dataset, respectively. A significant increase of 0.02 of Bout/A and Bin/A was detected for Copenhagen dataset over an interval of 2 years, and 0.03 of Bout/A and 0.02 of Bin/A for ataluren dataset over an interval of 48 weeks (all p<0.001). The progression of 0.01 of Bwt/A was detected only in the ataluren dataset (p<0.001). BA-analysis outcomes showed weak to strong correlations (correlation coefficient from 0.29 to 0.84) with manual scoring results for airway disease. CONCLUSION: The BA analysis can fully automatically analyse a large number of BA pairs on chest CTs to detect and monitor progression of bronchial wall thickening and bronchial widening in patients with CF.

The clinical impact of Lumacaftor-Ivacaftor on structural lung disease and lung function in children aged 6-11 with cystic fibrosis in a real-world setting.

BACKGROUND: Data from clinical trials of lumacaftor-ivacaftor (LUM-IVA) demonstrate improvements in lung clearance index (LCI) but not in FEV1 in children with Cystic Fibrosis (CF) aged 6-11 years and homozygous for the Phe508del mutation. It is not known whether LUM/IVA use in children can impact the progression of structural lung disease. We sought to determine the real-world impact of LUM/IVA on lung structure and function in children aged 6-11 years. METHODS: This real-world observational cohort study was conducted across four paediatric sites in Ireland over 24-months using spirometry-controlled CT scores and LCI as primary outcome measures. Children commencing LUM-/IVA as part of routine care were included. CT scans were manually scored with the PRAGMA CF scoring system and analysed using the automated bronchus-artery (BA) method. Secondary outcome measures included rate of change of ppFEV1, nutritional indices and exacerbations requiring hospitalisation. RESULTS: Seventy-one participants were recruited to the study, 31 of whom had spirometry-controlled CT performed at baseline, and after one year and two years of LUM/IVA treatment. At two years there was a reduction from baseline in trapped air scores (0.13 to 0.07, p = 0.016), but an increase from baseline in the % bronchiectasis score (0.84 to 1.23, p = 0.007). There was no change in overall % disease score (2.78 to 2.25, p = 0.138). Airway lumen to pulmonary artery ratios (AlumenA ratio) were abnormal at baseline and worsened over the course of the study. In 28 participants, the mean annual change from baseline LCI2.5 (-0.055 (-0.61 to 0.50), p = 0.85) measurements over two years were not significant. Improvements from baseline in weight (0.10 (0.06 to 0.15, p < 0.0001), height (0.05 (0.02 to 0.09), p = 0.002) and BMI (0.09 (0.03 to 0.15) p = 0.005) z-scores were seen with LUM/IVA treatment. The mean annual change from baseline ppFEV1 (-2.45 (-4.44 to 2.54), p = 0.66) measurements over two years were not significant. CONCLUSION: In a real-world setting, the use of LUM/IVA over two years in children with CF aged 6-11 resulted in improvements in air trapping on CT but worsening in bronchiectasis scores. Our results suggest that LUM/IVA use in this age group improves air trapping but does not prevent progression of bronchiectasis over two years of treatment.

129 Xe and Free-Breathing 1 H Ventilation MRI in Patients With Cystic Fibrosis: A Dual-Center Study.

BACKGROUND: Free-breathing 1 H ventilation MRI shows promise but only single-center validation has yet been performed against methods which directly image lung ventilation in patients with cystic fibrosis (CF). PURPOSE: To investigate the relationship between 129 Xe and 1 H ventilation images using data acquired at two centers. STUDY TYPE: Sequence comparison. POPULATION: Center 1; 24 patients with CF (12 female) aged 9-47 years. Center 2; 7 patients with CF (6 female) aged 13-18 years, and 6 healthy controls (6 female) aged 21-31 years. Data were acquired in different patients at each center. FIELD STRENGTH/SEQUENCE: 1.5 T, 3D steady-state free precession and 2D spoiled gradient echo. ASSESSMENT: Subjects were scanned with 129 Xe ventilation and 1 H free-breathing MRI and performed pulmonary function tests. Ventilation defect percent (VDP) was calculated using linear binning and images were visually assessed by H.M., L.J.S., and G.J.C. (10, 5, and 8 years' experience). STATISTICAL TESTS: Correlations and linear regression analyses were performed between 129 Xe VDP, 1 H VDP, FEV1 , and LCI. Bland-Altman analysis of 129 Xe VDP and 1 H VDP was carried out. Differences in metrics were assessed using one-way ANOVA or Kruskal-Wallis tests. RESULTS: 129 Xe VDP and 1 H VDP correlated strongly with; each other (r = 0.84), FEV1 z-score (129 Xe VDP r = -0.83, 1 H VDP r = -0.80), and LCI (129 Xe VDP r = 0.91, 1 H VDP r = 0.82). Bland-Altman analysis of 129 Xe VDP and 1 H VDP from both centers had a bias of 0.07% and limits of agreement of -16.1% and 16.2%. Linear regression relationships of VDP with FEV1 were not significantly different between 129 Xe and 1 H VDP (P = 0.08), while 129 Xe VDP had a stronger relationship with LCI than 1 H VDP. DATA CONCLUSION: 1 H ventilation MRI shows large-scale agreement with 129 Xe ventilation MRI in CF patients with established lung disease but may be less sensitive to subtle ventilation changes in patients with early-stage lung disease. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Congenital lung abnormalities on magnetic resonance imaging: the CLAM study.

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.

Chest radiography and computed tomography imaging in cystic fibrosis: current challenges and new perspectives.

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.

MRI changes in diaphragmatic motion and curvature in Pompe disease over time.

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).

Small airways targeted treatment with smart nebulizer technology could improve severe asthma in children: a retrospective analysis.

OBJECTIVE: 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). METHODS: 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. RESULTS: 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). CONCLUSION: 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.

MRI of the upper airways in children and young adults: the MUSIC study.

RATIONALE: Paediatric laryngotracheal stenosis (LTS) is often successfully corrected with open airway surgery. However, respiratory and vocal sequelae frequently remain. Clinical care and surgical interventions could be improved with better understanding of these sequelae. OBJECTIVE: The objective of this cross-sectional study was to develop an upper airway MRI protocol to obtain information on anatomical and functional sequelae post-LTS repair. METHODS: Forty-eight patients (age 14.4 (range 7.5-30.7) years) and 11 healthy volunteers (15.9 (8.2-28.8) years) were included. Spirometry and static and dynamic upper airway MRI (3.0 T, 30 min protocol) were conducted. Analysis included assessment of postoperative anatomy and airway lumen measurements during static and dynamic (inspiration and phonation) acquisitions. MAIN RESULTS: Good image quality without artefacts was achieved for static and dynamic images in the majority of MRIs. MRI showed vocal cord thickening in 80.9% of patients and compared with volunteers, a significant decrease in vocal cord lumen area (22.0 (IQR 17.7-30.3) mm2 vs 35.1 (21.2-54.7) mm2, p=0.03) but not cricoid lumen area (62.3±27.0 mm2 vs 66.2±34.8 mm2, p=0.70). Furthermore, 53.2% of patients had an A-frame deformation at site of previous tracheal cannula, showing lumen collapse during inspiration. Dynamic imaging showed incomplete vocal cord abduction during inspiration in 42.6% and incomplete adduction during phonation in 61.7% of patients. CONCLUSIONS: Static and dynamic MRI is an excellent modality to non-invasively image anatomy, tissue characteristics and vocal cord dynamics of the upper airways. MRI-derived knowledge on postsurgical LTS sequelae might be used to improve surgery.

Efficacy and safety of TOBI Podhaler in Pseudomonas aeruginosa-infected bronchiectasis patients: iBEST study.

The study aimed to determine the efficacy of a safe and well-tolerated dose and regimen of tobramycin inhalation powder (TIP) on Pseudomonas aeruginosa sputum density in patients with bronchiectasis.This is a phase II, double-blind, randomised study in bronchiectasis patients aged ≥18 years with chronic P. aeruginosa infection. Patients were randomised 1:1:1 to either cohort A: three capsules of TIP once daily (84 mg); cohort B: five capsules once daily (140 mg) or cohort C: four capsules twice daily (224 mg). Within each cohort, patients were further randomised 2:2:1 either to TIP continuously, TIP cyclically (alternating 28 days of TIP and placebo) or placebo for 16 weeks, respectively and were followed up for 8 weeks.Overall, 107 patients were randomised to cohorts A (n=34), B (n=36) and C (n=37). All three TIP doses significantly reduced the P. aeruginosa sputum density from baseline to day 29 versus placebo in a dose-dependent manner (p≤0.0001, each). A smaller proportion of patients in the continuous-TIP (34.1%) and cyclical-TIP (35.7%) groups experienced pulmonary exacerbations versus placebo (47.6%) and also required fewer anti-pseudomonal antibiotics (38.6% on continuous TIP and 42.9% on cyclical TIP) versus placebo (57.1%) although not statistically significant. Pulmonary exacerbation of bronchiectasis was the most frequent (37.4%) adverse event. Overall, TIP was well tolerated, however, 23.4% of the patients discontinued the study drug due to adverse events.Continuous- and cyclical-TIP regimens with all three doses were safe and effective in reducing the P. aeruginosa sputum density in patients with bronchiectasis and chronic P. aeruginosa infection.

The evolving role of radiological imaging in cystic fibrosis.

PURPOSE OF REVIEW: Radiological imaging has a crucial role in pulmonary evaluation in cystic fibrosis (CF), having been shown to be more sensitive than pulmonary function testing at detecting structural lung changes. The present review summarizes the latest published information on established and evolving pulmonary imaging techniques for assessing people with this potentially life-limiting disorder. RECENT FINDINGS: Chest computed tomography (CT) has taken over the predominant role of chest radiography in many centres for the initial assessment and surveillance of CF lung disease. However, several emerging techniques offer a promising means of pulmonary imaging using less ionizing radiation. This is of particular importance given these patients tend to require repeated imaging throughout their lives from a young age. Such techniques include ultra-low-dose CT, tomosynthesis, dynamic radiography and magnetic resonance imaging. In addition, deep-learning algorithms are anticipated to improve diagnostic accuracy. SUMMARY: The recent introduction of triple-combination CF transmembrane regulator therapy has put further emphasis on the need for sensitive methods of monitoring treatment response to allow for early adaptation of treatment regimens in order to limit irreversible lung damage. Further research is needed to establish how emerging imaging techniques can contribute to this safely and effectively.

A clinical guideline for structured assessment of CT-imaging in congenital lung abnormalities.

OBJECTIVES: To develop a clinical guideline for structured assessment and uniform reporting of congenital lung abnormalities (CLA) on Computed Tomography (CT)-scans. MATERIALS AND METHODS: A systematic literature search was conducted for articles describing CT-scan abnormalities of congenital pulmonary airway malformation (CPAM), bronchopulmonary sequestration (BPS), congenital lobar emphysema (CLE) and bronchogenic cyst (BC). A structured report using objective features of CLA was developed after consensus between a pediatric pulmonologist, radiologist and surgeon. RESULTS: Of 1581 articles identified, 158 remained after title-abstract screening by two independent reviewers. After assessing full-texts, we included 28 retrospective cohort-studies. Air-containing cysts and soft tissue masses are described in both CPAM and BPS while anomalous arterial blood supply is only found in BPS. Perilesional low-attenuation areas, atelectasis and mediastinal shift may be found in all aforementioned abnormalities and can also be seen in CLE as a cause of a hyperinflated lobe. We have developed a structured report, subdivided into five sections: Location & Extent, Airway, Lesion, Vascularization and Surrounding tissue. CONCLUSIONS: CT-imaging findings in CLA are broad and nomenclature is variable. Overlap is seen between and within abnormalities, possibly due to definitions often being based on pathological findings, which is an unsuitable approach for CT imaging. We propose a structured assessment of CLA using objective radiological features and uniform nomenclature to improve reporting.

Structural determinants of long-term functional outcomes in young children with cystic fibrosis.

BACKGROUND: Accelerated lung function decline in individuals with cystic fibrosis (CF) starts in adolescence with respiratory complications being the most common cause of death in later life. Factors contributing to lung function decline are not well understood, in particular its relationship with structural lung disease in early childhood. Detection and management of structural lung disease could be an important step in improving outcomes in CF patients. METHODS: Annual chest computed tomography (CT) scans were available from 2005 to 2016 as a part of the AREST CF cohort for children aged 3 months to 6 years. Annual spirometry measurements were available for 89.77% of the cohort (167 children aged 5-6 years) from age 5 to 15 years through outpatient clinics at Perth Children's Hospital (Perth, Australia) and The Royal Children's Hospital in Melbourne (Melbourne, Australia) (697 measurements, mean±sd age 9.3±2.1 years). RESULTS: Children with a total CT score above the median at age 5-6 years were more likely to have abnormal forced expiratory volume in 1 s (FEV1) (adjusted hazard ratio 2.67 (1.06-6.72), p=0.037) during the next 10 years compared to those below the median chest CT score. The extent of all structural abnormalities except bronchial wall thickening were associated with lower FEV1 Z-scores. Mucus plugging and trapped air were the most predictive sub-score (adjusted mean change -0.17 (-0.26 - -0.07) p<0.001 and -0.09 (-0.14 - -0.04) p<0.001, respectively). DISCUSSION: Chest CT identifies children at an early age who have adverse long-term outcomes. The prevention of structural lung damage should be a goal of early intervention and can be usefully assessed with chest CT. In an era of therapeutics that might alter disease trajectories, chest CT could provide an early readout of likely long-term success.

Early markers of cystic fibrosis structural lung disease: follow-up of the ACFBAL cohort.

Little is known about early predictors of later cystic fibrosis (CF) structural lung disease. This study examined early predictors of progressive structural lung abnormalities in children who completed the Australasian CF Bronchoalveolar Lavage (ACFBAL) clinical trial at age 5-years and participated in an observational follow-up study (CF-FAB).Eight Australian and New Zealand CF centres participated in CF-FAB and provided follow-up chest computed-tomography (CT) scans for children who had completed the ACFBAL study with baseline scans at age 5-years. CT scans were annotated using PRAGMA-CF scoring. Ordinal regression analysis and linear regression were used to investigate associations between PRAGMA-CF (Perth-Rotterdam Annotated Grid Morphometric Analysis for CF) outcomes at follow-up and variables measured during the ACFBAL study.99 out of 157 ACFBAL children (mean±sd age 13±1.5 years) participated in the CF-FAB study. The probability of bronchiectasis at follow-up increased with airway disease severity on the baseline CT scan. In multiple regression (retaining factors at p<0.05) the extent of bronchiectasis at follow-up was associated with baseline atelectasis (OR 7.2, 95% CI 2.4-22; p≤ 0.001), bronchoalveolar lavage (BAL) log2 interleukin (IL)-8 (OR 1.2, 95% CI 1.05-1.5; p=0.010) and body mass index z-score (OR 0.49, 95% CI 0.24-1.00; p=0.05) at age 5 years. Percentage trapped air at follow-up was associated with BAL log2 IL-8 (coefficient 1.3, 95% CI 0.57-2.1; p<0.001) at age 5 years.The extent of airway disease, atelectasis, airway inflammation and poor nutritional status in early childhood are risk factors for progressive structural lung disease in adolescence.

Airway tapering: an objective image biomarker for bronchiectasis.

PURPOSE: To estimate airway tapering in control subjects and to assess the usability of tapering as a bronchiectasis biomarker in paediatric populations. METHODS: Airway tapering values were semi-automatically quantified in 156 children with control CTs collected in the Normal Chest CT Study Group. Airway tapering as a biomarker for bronchiectasis was assessed on spirometer-guided inspiratory CTs from 12 patients with bronchiectasis and 12 age- and sex-matched controls. Semi-automatic image analysis software was used to quantify intra-branch tapering (reduction in airway diameter along the branch), inter-branch tapering (reduction in airway diameter before and after bifurcation) and airway-artery ratios on chest CTs. Biomarkers were further stratified in small, medium and large airways based on three equal groups of the accompanying vessel size. RESULTS: Control subjects showed intra-branch tapering of 1% and inter-branch tapering of 24-39%. Subjects with bronchiectasis showed significantly reduced intra-branch of 0.8% and inter-branch tapering of 19-32% and increased airway-artery ratios compared with controls (p < 0.01). Tapering measurements were significantly different between diseased and controls across all airway sizes. Difference in airway-artery ratio was only significant in small airways. CONCLUSION: Paediatric normal values for airway tapering were established in control subjects. Tapering showed to be a promising biomarker for bronchiectasis as subjects with bronchiectasis show significantly less airway tapering across all airway sizes compared with controls. Detecting less tapering in larger airways could potentially lead to earlier diagnosis of bronchiectasis. Additionally, compared with the conventional airway-artery ratio, this novel biomarker has the advantage that it does not require pairing with pulmonary arteries. KEY POINTS: • Tapering is a promising objective image biomarker for bronchiectasis that can be extracted semi-automatically and has good correlation with validated visual scoring methods. • Less airway tapering was observed in patients with bronchiectasis and can be observed sensitively throughout the bronchial tree, even in the more central airways. • Tapering values seemed to be less influenced by variety in scanning protocols and lung volume making it a more robust biomarker for bronchiectasis detection.

The cumulative effect of inflammation and infection on structural lung disease in early cystic fibrosis.

INTRODUCTION: Pulmonary inflammation and infection are important clinical and prognostic markers of lung disease in cystic fibrosis (CF). However, whether in young children they are transient findings or have cumulative, long-term impacts on respiratory health is largely unknown. We aimed to determine whether their repeated detection has a deleterious effect on structural lung disease. METHODS: All patients aged <6 years with annual computed tomography (CT) and bronchoalveolar lavage (BAL) were included. Structural lung disease on CT (%Disease) was determined using the PRAGMA-CF (Perth-Rotterdam Annotated Grid Morphometric Analysis for CF) method. The number of times free neutrophil elastase (NE) and infection were detected in BAL were counted, to determine cumulative BAL history. Linear mixed model analysis, accounting for repeat visits and adjusted for age, was used to determine associations. RESULTS: 265 children (683 scans) were included for analysis, with BAL history comprising 1161 visits. %Disease was significantly associated with the number of prior NE (0.31, 95% CI 0.09-0.54; p=0.007) but not infection (0.23, 95% CI -0.01-0.47; p=0.060) detections. Reference equations were determined. CONCLUSIONS: Pulmonary inflammation in surveillance BAL has a cumulative effect on structural lung disease extent, more so than infection. This provides a strong rationale for therapies aimed at reducing inflammation in young children.

Technical challenges of quantitative chest MRI data analysis in a large cohort pediatric study.

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.