Tim Rosenow

PRAGMA-CF. A Quantitative Structural Lung Disease Computed Tomography Outcome in Young Children with Cystic Fibrosis

RATIONALE Chest computed tomography (CT) is the gold standard for demonstrating cystic fibrosis (CF) airway disease. However, there are no standardized outcome measures appropriate for children younger than 6 years. OBJECTIVES We developed the Perth-Rotterdam Annotated Grid Morphometric Analysis for CF (PRAGMA-CF), a quantitative measure of airway disease, and compared it with the commonly used CF-CT scoring method. METHODS CT scans from the Australian Respiratory Early Surveillance Team for CF (AREST CF) cohort in Western Australia were included. PRAGMA-CF was performed by annotating a grid overlaid on 10 axial slices for the presence of bronchiectasis, mucous plugging, or other airway abnormalities (inspiratory scans) and trapped air (expiratory scans). The separate proportions of total disease (%Dis), bronchiectasis (%Bx), and trapped air (%TA) were determined. Thirty scans were used for observer reliability, and 30 paired scans obtained at 1 and 3 years old were used for comparison with a validated standard and biologic plausibility. MEASUREMENTS AND MAIN RESULTS Intraobserver, intraclass correlation coefficients (95% confidence interval) for %Dis, %Bx, and %TA were 0.93 (0.86-0.97), 0.93 (0.85-0.96), and 0.96 (0.91-0.98), respectively. The change in %Dis (P = 0.004) and %Bx (P = 0.001) with PRAGMA-CF was related to neutrophil elastase presence at age 3, whereas only the change in bronchiectasis score was related to neutrophil elastase (P < 0.001) with CF-CT. Sample-size calculations for various effect sizes are presented. CONCLUSIONS PRAGMA-CF is a sensitive and reproducible outcome measure for assessing the extent of lung disease in very young children with CF.

Lung Clearance Index and Structural Lung Disease on Computed Tomography in Early Cystic Fibrosis

RATIONALE The lung clearance index is a measure of ventilation distribution derived from the multiple-breath washout technique. It has been suggested as a surrogate for chest computed tomography to detect structural lung abnormalities in individuals with cystic fibrosis (CF); however, the associations between lung clearance index and early structural lung disease are unclear. OBJECTIVES We assessed the ability of the lung clearance index to reflect structural lung disease on the basis of chest computed tomography across the entire pediatric age range. METHODS Lung clearance index was assessed in 42 infants (ages 0-2 yr), 39 preschool children (ages 3-6 yr), and 38 school-age children (7-16 yr) with CF before chest computed tomography and in 72 healthy control subjects. Scans were evaluated for CF-related structural lung disease using the Perth-Rotterdam Annotated Grid Morphometric Analysis for Cystic Fibrosis quantitative outcome measure. MEASUREMENTS AND MAIN RESULTS In infants with CF, lung clearance index is insensitive to structural disease (κ = -0.03 [95% confidence interval, -0.05 to 0.16]). In preschool children with CF, lung clearance index correlates with total disease extent. In school-age children, lung clearance index correlates with extent of total disease, bronchiectasis, and air trapping. In preschool and school-age children, lung clearance index has a good positive predictive value (83-86%) but a poor negative predictive value (50-55%) to detect the presence of bronchiectasis. CONCLUSIONS These data suggest that lung clearance index may be a useful surveillance tool to monitor structural lung disease in preschool and school-age children with CF. However, lung clearance index cannot replace chest computed tomography to screen for bronchiectasis in this population.

Progressive ventilation inhomogeneity in infants with cystic fibrosis after pulmonary infection

Measures of ventilation distribution are promising for monitoring early lung disease in cystic fibrosis (CF). This study describes the cross-sectional and longitudinal impacts of pulmonary inflammation and infection on ventilation homogeneity in infants with CF. Infants diagnosed with CF underwent multiple breath washout (MBW) testing and bronchoalveolar lavage at three time points during the first 2 years of life. Measures were obtained for 108 infants on 156 occasions. Infants with a significant pulmonary infection at the time of MBW showed increases in lung clearance index (LCI) of 0.400 units (95% CI 0.150–0.648; p=0.002). The impact was long lasting, with previous pulmonary infection leading to increased ventilation inhomogeneity over time compared to those who remained free of infection (p<0.05). Infection with Haemophilus influenzae was particularly detrimental to the longitudinal lung function in young children with CF where LCI was increased by 1.069 units for each year of life (95% CI 0.484–1.612; p<0.001). Pulmonary infection during the first year of life is detrimental to later lung function. Therefore, strategies aimed at prevention, surveillance and eradication of pulmonary pathogens are paramount to preserve lung function in infants with CF. Early life respiratory infections are detrimental to long-term lung function in children with cystic fibrosis http://ow.ly/PKaHn

What did we learn from two decades of chest computed tomography in cystic fibrosis

Despite our current treatment, many cystic fibrosis (CF) patients still show progressive bronchiectasis and small airways disease. Adequate detection and monitoring of progression of these structural abnormalities is needed to personalize treatment to the severity of CF lung disease of the patient. Chest computed tomography (CT) is the gold standard to diagnose and monitor bronchiectasis. Many studies have been done to validate the role of chest CT in CF and to improve the protocols. From these studies it became clear that for correct interpretation of the severity of bronchiectasis and small airways disease standardization of lung volume for the inspiratory and expiratory CT scan acquisition is needed. The risk related to the radiation exposure of a chest CT scan every second year is considered low. Automated and quantitative image analysis systems are developed to improve the reliability and sensitivity of assessments of structural lung changes in CF, particularly in early life. In this paper an overview is given of the lessons learned from two decades of monitoring CF lung disease using chest CT.

Metabolomic biomarkers predictive of early structural lung disease in cystic fibrosis

Neutrophilic airway inflammation plays a role in early structural lung disease in cystic fibrosis, but the mechanisms underlying this pathway are incompletely understood. Metabolites associated with neutrophilic inflammation were identified by discovery metabolomics on bronchoalveolar lavage fluid supernatant from 20 preschool children (2.9±1.3 years) with cystic fibrosis. Targeted mass-spectrometric detection of relevant metabolites was then applied to 34 children (3.5±1.5 years) enrolled in the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) who underwent chest computed tomography and bronchoalveolar lavage from two separate lobes during 42 visits. Relationships between metabolites and localised structural lung disease were assessed using multivariate analyses. Discovery metabolomics identified 93 metabolites associated with neutrophilic inflammation, including pathways involved in metabolism of adenyl purines, amino acids and small peptides, cellular energy and lipids. In targeted mass spectrometry, products of adenosine metabolism, protein catabolism and oxidative stress were associated with structural lung disease and predicted future bronchiectasis, and activities of enzymes associated with adenosine metabolism were elevated in the samples with early disease. Metabolomics analyses revealed metabolites and pathways altered with neutrophilic inflammation and destructive lung disease. These pathways can serve as biomarkers and potential therapeutic targets for early cystic fibrosis lung disease. Metabolomics in preschool children with CF reveals biomarkers that correlate with and predict early disease http://ow.ly/c7rb303Lc9y

Reversibility of trapped air on chest computed tomography in cystic fibrosis patients

PURPOSE To investigate changes in trapped air volume and distribution over time and compare computed tomography (CT) with pulmonary function tests for determining trapped air. METHODS Thirty children contributed two CTs and pulmonary function tests over 2 years. Localized changes in trapped air on CT were assessed using image analysis software, by deforming the CT at timepoint 2 to match timepoint 1, and measuring the volume of stable (TAstable), disappeared (TAdisappeared) and new (TAnew) trapped air as a proportion of total lung volume. We used the difference between total lung capacity measured by plethysmography and helium dilution, residual volume to total lung capacity ratio, forced expiratory flow at 75% of vital capacity, and maximum mid-expiratory flow as pulmonary function test markers of trapped air. Statistical analysis included Wilcoxons signed rank test and Spearman correlation coefficients. RESULTS Median (range) age at baseline was 11.9 (5-17) years. Median (range) of trapped air was 9.5 (2-33)% at timepoint 1 and 9.0 (0-25)% at timepoint 2 (p=0.49). Median (range) TAstable, TAdisappeared and TAnew were respectively 3.0 (0-12)%, 5.0 (1-22)% and 7.0 (0-20)%. Trapped air on CT correlated statistically significantly with all pulmonary function measures (p<0.01), other than residual volume to total lung capacity ratio (p=0.37). CONCLUSION Trapped air on CT did not significantly progress over 2 years, may have a substantial stable component, and is significantly correlated with pulmonary function markers.

Air trapping in early cystic fibrosis lung disease—Does CT tell the full story?

Mosaic attenuation on expiratory chest computed tomography (CT) is common in early life cystic fibrosis (CF) and often referred to as “air trapping”. It is presumed to be localized hyperinflation due to small airway obstruction. In order to test this assumption, we compared air trapping extent to lung volumes measured on CT in young children with CF.

Quantitative assessment of airway dimensions in young children with cystic fibrosis lung disease using chest computed tomography

To evaluate lung disease progression using airway and artery (AA) dimensions on chest CT over 2‐year interval in young CF patients longitudinally and compare to disease controls cross‐sectionally.

Ultra low dose CT screen-detected non-malignant incidental findings in the Western Australian Asbestos Review Programme.

Computed tomography (CT)‐based studies of asbestos‐exposed individuals report a high prevalence of lung cancer, but the utility of low dose CT (LDCT) to screen asbestos‐exposed populations is not established. We aimed to describe the prevalence of indeterminate pulmonary nodules and incidental findings on chest LDCT of asbestos‐exposed subjects in Western Australia.

Quantification of CT bronchiectasis and its relationship to ventilation in cystic fibrosis

Structural lung abnormalities and impaired pulmonary function are key facets of respiratory disease in cystic fibrosis (CF). Over the last decade, CT and the multiple breath washout (MBW) technique have been extensively investigated and validated as clinical and research tools to measure their severity. However, little is known about the relationship between the structural and functional aspects of CF lung disease. This may in part be due to limitations inherent to visual CT scoring: in particular, …