Quantification of Lung Abnormalities in Cystic Fibrosis using Deep Networks

Cystic fibrosis is a genetic disease which may appear in early life with structural abnormalities in lung tissues. We propose to detect these abnormalities using a texture classification approach. Our method is a cascade of two convolutional neural networks. The first network detects the presence of abnormal tissues. The second network identifies the type of the structural abnormalities: bronchiectasis, atelectasis or mucus plugging.We also propose a network computing pixel-wise heatmaps of abnormality presence learning only from the patch-wise annotations. Our database consists of CT scans of 194 subjects. We use 154 subjects to train our algorithms and the 40 remaining ones as a test set. We compare our method with random forest and a single neural network approach. The first network reaches an accuracy of 0,94 for disease detection, 0,18 higher than the random forest classifier and 0,37 higher than the single neural network. Our cascade approach yields a final class-averaged F1-score of 0,33, outperforming the baseline method and the single network by 0,10 and 0,12.Comment: SPIE - Medical Imaging 2018: Image Processin

The effect of CFTR modulators on structural lung disease in cystic fibrosis

Background: Newly developed quantitative chest computed tomography (CT) outcomes designed specifically to assess structural abnormalities related to cystic fibrosis (CF) lung disease are now available. CFTR modulators potentially can reduce some structural lung abnormalities. We aimed to investigate the effect of CFTR modulators on structural lung disease progression using different quantitative CT analysis methods specific for people with CF (PwCF). Methods: PwCF with a gating mutation (Ivacaftor) or two Phe508del alleles (lumacaftor-ivacaftor) provided clinical data and underwent chest CT scans. Chest CTs were performed before and after initiation of CFTR modulator treatment. Structural lung abnormalities on CT were assessed using the Perth Rotterdam Annotated Grid Morphometric Analysis for CF (PRAGMA-CF), airway-artery dimensions (AA), and CF-CT methods. Lung disease progression (0–3 years) in exposed and matched unexposed subjects was compared using analysis of covariance. To investigate the effect of treatment in early lung disease, subgroup analyses were performed on data of children and adolescents aged &lt;18 years. Results: We included 16 modulator exposed PwCF and 25 unexposed PwCF. Median (range) age at the baseline visit was 12.55 (4.25–36.49) years and 8.34 (3.47–38.29) years, respectively. The change in PRAGMA-CF %Airway disease (-2.88 (−4.46, −1.30), p = 0.001) and %Bronchiectasis extent (-2.07 (−3.13, −1.02), p &lt; 0.001) improved in exposed PwCF compared to unexposed. Subgroup analysis of paediatric data showed that only PRAGMA-CF %Bronchiectasis (-0.88 (−1.70, −0.07), p = 0.035) improved in exposed PwCF compared to unexposed. Conclusion: In this preliminary real-life retrospective study CFTR modulators improve several quantitative CT outcomes. A follow-up study with a large cohort and standardization of CT scanning is needed to confirm our findings.</p

Development of characteristic airway bifurcations in 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

Association between early respiratory viral infections and structural lung disease in infants with cystic fibrosis

Background: Infants with cystic fibrosis (CF) develop structural lung disease early in life, and viral infections are associated with progressive lung disease. We hypothesized that the presence of respiratory viruses would be associated with structural lung disease on computed tomography (CT) of the chest in infants with CF. Methods: Infants with CF were enrolled before 4 months of age. Multiplex PCR assays were performed on nasal swabs to detect respiratory viruses during routine visits and when symptomatic. Participants underwent CT imaging at approximately 12 months of age. Associations between Perth–Rotterdam Annotated Grid Morphometric Analysis for CF (PRAGMA-CF) CT scores and respiratory viruses and symptoms were assessed with Spearman correlation coefficients. Results: Sixty infants were included for analysis. Human rhinovirus was the most common virus detected, on 28% of tested nasal swabs and in 85% of participants. The median (IQR) extent of lung fields that was healthy based on PRAGMA-CF was 98.7 (0.8)%. There were no associations between PRAGMA-CF and age at first virus, or detection of any virus, including rhinovirus, respiratory syncytial virus, or parainfluenza. The extent of airway wall thickening was associated with ever having wheezed (ρ = 0.31, p = 0.02) and number of encounters with cough (ρ = 0.25, p = 0.0495). Conclusions: Infants with CF had minimal structural lung disease. We did not find an association between respiratory viruses and CT abnormalities. Wheezing and frequency of cough were associated with early structural changes

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.</p

Morphometric Analysis of Explant Lungs in Cystic Fibrosis

RATIONALE: After repeated cycles of lung infection and inflammation, patients with cystic fibrosis (CF) evolve to respiratory insufficiency. Although histology and imaging have provided descriptive information, a thorough morphometric analysis of end-stage CF lung disease is lacking. OBJECTIVES: To quantify the involvement of small and large airways in end-stage CF. METHODS: Multidetector computed tomography (MDCT) and micro-CT were applied to 11 air-inflated CF explanted lungs and 7 control lungs to measure, count, and describe the airway and parenchymal abnormalities in end-stage CF lungs. Selected abnormalities were further investigated with thin section histology. MEASUREMENTS AND MAIN RESULTS: On MDCT, CF explanted lungs showed an increased median (interquartile range) number (631 [511-710] vs. 344 [277-349]; P = 0.003) and size of visible airways (cumulative airway diameter 217 cm [209-250] vs. 91 cm [80-105]; P < 0.001) compared with controls. Airway obstruction was seen, starting from generation 6 and increasing to 40 to 50% of airways from generation 9 onward. Micro-CT showed that the total number of terminal bronchioles was decreased (2.9/ml [2.6-4.4] vs. 5.3/ml [4.8-5.7]; P < 0.001); 49% were obstructed, and the cross-sectional area of the open terminal bronchioles was reduced (0.093 mm(2) [0.084-0.123] vs. 0.179 mm(2) [0.140-0.196]; P < 0.001). On micro-CT, 41% of the obstructed airways reopened more distally. This remodeling was confirmed on histological analysis. Parenchymal changes were also seen, mostly in a patchy and peribronchiolar distribution. CONCLUSIONS: Extensive changes of dilatation and obstruction in nearly all airway generations were observed in end-stage CF lung disease.status: publishe

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

Introduction: 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). Methods: 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 outcomes at follow-up and variables measured during the ACFBAL study. Results: Ninety-nine of 157 ACFBAL children (mean age 13-years, standard deviation 1.5) 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

Multicentre chest computed tomography standardisation in children and adolescents with cystic fibrosis : The way forward

Progressive cystic fibrosis (CF) lung disease is the main cause of mortality in CF patients. CF lung disease starts in early childhood. With current standards of care, respiratory function remains largely normal in children and more sensitive outcome measures are needed to monitor early CF lung disease. Chest CT is currently the most sensitive imaging modality to monitor pulmonary structural changes in children and adolescents with CF. To quantify structural lung disease reliably among multiple centres, standardisation of chest CT protocols is needed. SCIFI CF (Standardised Chest Imaging Framework for Interventions and Personalised Medicine in CF) was founded to characterise chest CT image quality and radiation doses among 16 participating European CF centres in 10 different countries. We aimed to optimise CT protocols in children and adolescents among several CF centres. A large variety was found in CT protocols, image quality and radiation dose usage among the centres. However, the performance of all CT scanners was found to be very similar, when taking spatial resolution and radiation dose into account. We conclude that multicentre standardisation of chest CT in children and adolescents with CF can be achieved for future clinical trials

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