Mild Cystic Fibrosis Lung Disease Research Articles

Lung T1 MRI assessments in children with mild cystic fibrosis lung disease.

Lung T1 MRI is a potential method to assess cystic fibrosis (CF)lung disease that is safe, quick, and widely available, but there are no data in children with mild CF lung disease. Assess the ability of lung T1 MRI to detect abnormalities in children with mild CF lung disease. We performed T1 MRI, multiple breath washout (MBW),chest computed tomography (CT),and spirometry in a cohort of 45 children with mild CF lung disease (6-11 years of age). Despite mean normal ppFEV1 values, the majority of children with CF in this study exhibited mild lung disease evident in lung clearance index (LCI)measured by MBW, chest CT Brody scores, and percent normal lung perfusion (%NLP)measured by T1 MRI. The %NLP correlated with chest CT Brody scores, as did LCI, but %NLP and LCI did not correlate with each other. Analysis of the Brody subscores showed that %NLP and LCI largely correlated with different Brody subscores. T1 MRI can detect mild CF lung disease in children and correlates with chest CT findings. The %NLPfrom T1 MRI and LCI correlate with different chest CT Brody subscores, suggesting they provide complementary information about CF lung disease.

119 Interim results of test reliability of 19F MRI in mild cystic fibrosis lung disease

119 Interim results of test reliability of 19F MRI in mild cystic fibrosis lung disease

MDCT-based longitudinal automated airway and air trapping analysis in school-age children with mild cystic fibrosis lung disease.

Quantitative computed tomography (QCT) offers some promising markers to quantify cystic fibrosis (CF)-lung disease. Air trapping may precede irreversible bronchiectasis; therefore, the temporal interdependencies of functional and structural lung disease need to be further investigated. We aim to quantify airway dimensions and air trapping on chest CT of school-age children with mild CF-lung disease over two years. Fully-automatic software analyzed 144 serial spirometer-controlled chest CT scans of 36 children (median 12.1 (10.2-13.8) years) with mild CF-lung disease (median ppFEV1 98.5 (90.8-103.3) %) at baseline, 3, 12 and 24 months. The airway wall percentage (WP5-10), bronchiectasis index (BEI), as well as severe air trapping (A3) were calculated for the total lung and separately for all lobes. Mixed linear models were calculated, considering the lobar distribution of WP5-10, BEI and A3 cross-sectionally and longitudinally. WP5-10 remained stable (P = 0.248), and BEI changed from 0.41 (0.28-0.7) to 0.54 (0.36-0.88) (P = 0.156) and A3 from 2.26% to 4.35% (P = 0.086) showing variability over two years. ppFEV1 was also stable (P = 0.276). A robust mixed linear model showed a cross-sectional, regional association between WP5-10 and A3 at each timepoint (P < 0.001). Further, BEI showed no cross-sectional, but another mixed model showed short-term longitudinal interdependencies with air trapping (P = 0.003). Robust linear/beta mixed models can still reveal interdependencies in medical data with high variability that remain hidden with simpler statistical methods. We could demonstrate cross-sectional, regional interdependencies between wall thickening and air trapping. Further, we show short-term regional interdependencies between air trapping and an increase in bronchiectasis. The data indicate that regional air trapping may precede the development of bronchiectasis. Quantitative CT may capture subtle disease progression and identify regional and temporal interdependencies of distinct manifestations of CF-lung disease.

116 Associations between lung T1 magnetic resonance imaging, chest computed tomography, and multiple-breath washout in young children with mild cystic fibrosis lung disease

116 Associations between lung T1 magnetic resonance imaging, chest computed tomography, and multiple-breath washout in young children with mild cystic fibrosis lung disease

Mild Cystic Fibrosis Lung Disease Is Associated with Bacterial Community Stability.

ABSTRACTMicrobial communities in the airways of persons with CF (pwCF) are variable, may include genera that are not typically associated with CF, and their composition can be difficult to correlate with long-term disease outcomes. Leveraging two large data sets characterizing sputum communities of 167 pwCF and associated metadata, we identified five bacterial community types. These communities explain 24% of the variability in lung function in this cohort, far more than single factors like Simpson diversity, which explains only 4%. Subjects with Pseudomonas-dominated communities tended to be older and have reduced percent predicted FEV1 (ppFEV1) compared to subjects with Streptococcus-dominated communities, consistent with previous findings. To assess the predictive power of these five communities in a longitudinal setting, we used random forests to classify 346 additional samples from 24 subjects observed 8 years on average in a range of clinical states. Subjects with mild disease were more likely to be observed at baseline, that is, not in the context of a pulmonary exacerbation, and community structure in these subjects was more self-similar over time, as measured by Bray-Curtis distance. Interestingly, we found that subjects with mild disease were more likely to remain in a mixed Pseudomonas community, providing some support for the climax-attack model of the CF airway. In contrast, patients with worse outcomes were more likely to show shifts among community types. Our results suggest that bacterial community instability may be a risk factor for lung function decline and indicates the need to understand factors that drive shifts in community composition.IMPORTANCE While much research supports a polymicrobial view of the CF airway, one in which the community is seen as the pathogenic unit, only controlled experiments using model bacterial communities can unravel the mechanistic role played by different communities. This report uses a large data set to identify a small number of communities as a starting point in the development of tractable model systems. We describe a set of five communities that explain 24% of the variability in lung function in our data set, far more than single factors like Simpson diversity, which explained only 4%. In addition, we report that patients with severe disease experienced more shifts among community types, suggesting that bacterial community instability may be a risk factor for lung function decline. Together, these findings provide a proof of principle for selecting bacterial community model systems.

Improved detection of air trapping on expiratory computed tomography using deep learning.

BackgroundRadiologic evidence of air trapping (AT) on expiratory computed tomography (CT) scans is associated with early pulmonary dysfunction in patients with cystic fibrosis (CF). However, standard techniques for quantitative assessment of AT are highly variable, resulting in limited efficacy for monitoring disease progression.ObjectiveTo investigate the effectiveness of a convolutional neural network (CNN) model for quantifying and monitoring AT, and to compare it with other quantitative AT measures obtained from threshold-based techniques.Materials and methodsPaired volumetric whole lung inspiratory and expiratory CT scans were obtained at four time points (0, 3, 12 and 24 months) on 36 subjects with mild CF lung disease. A densely connected CNN (DN) was trained using AT segmentation maps generated from a personalized threshold-based method (PTM). Quantitative AT (QAT) values, presented as the relative volume of AT over the lungs, from the DN approach were compared to QAT values from the PTM method. Radiographic assessment, spirometric measures, and clinical scores were correlated to the DN QAT values using a linear mixed effects model.ResultsQAT values from the DN were found to increase from 8.65% ± 1.38% to 21.38% ± 1.82%, respectively, over a two-year period. Comparison of CNN model results to intensity-based measures demonstrated a systematic drop in the Dice coefficient over time (decreased from 0.86 ± 0.03 to 0.45 ± 0.04). The trends observed in DN QAT values were consistent with clinical scores for AT, bronchiectasis, and mucus plugging. In addition, the DN approach was found to be less susceptible to variations in expiratory deflation levels than the threshold-based approach.ConclusionThe CNN model effectively delineated AT on expiratory CT scans, which provides an automated and objective approach for assessing and monitoring AT in CF patients.

Novel imaging techniques for cystic fibrosis lung disease.

With an increasing number of patients with cystic fibrosis (CF) receiving highly effective CFTR (cystic fibrosis transmembrane regulator protein) modulator therapy, particularly at a young age, there is an increasing need to identify imaging tools that can detect and regionally visualize mild CF lung disease and subtle changes in disease state. In this review, we discuss the latest developments in imaging modalities for both structural and functional imaging of the lung available to CF clinicians and researchers, from the widely available, clinically utilized imaging methods for assessing CF lung disease-chest radiography and computed tomography-to newer techniques poised to become the next phase of clinical tools-structural/functional proton and hyperpolarized gas magnetic resonance imaging (MRI). Finally, we provide a brief discussion of several newer lung imaging techniques that are currently available only in selected research settings, including chest tomosynthesis, and fluorinated gas MRI. We provide an update on the clinical and/or research status of each technique, with a focus on sensitivity, early disease detection, and possibilities for monitoring treatment efficacy.

CFTR-function and ventilation inhomogeneity in individuals with cystic fibrosis

BackgroundIncreased (abnormal) ventilation inhomogeneity in individuals with mild Cystic Fibrosis (CF) lung disease may become a treatable trait for small-molecule therapeutics improving Cystic Fibrosis Transmembrane Regulator (CFTR) function. The relationship between CFTR function and ventilation inhomogeneity is unknown. We aimed to identify and quantify increased ventilation inhomogeneity in relation to CFTR function. MethodsThis was an international, multi-center, cross-sectional study. We collated data from individuals aged 3–25 years with minimal (CFTR-MF) or residual (CFTR-RF) function of a variety of CFTR genotypes and FEV1 ≥ 70% predicted. We measured lung function using nitrogen multiple-breath washout and spirometry. We compared lung clearance index (LCI) and FEV1 between individuals with CFTR-MF vs CFTR-RF using a mixed effects multi-variable linear regression model to account for study differences and a logistic model based on propensity-score matching to adjust for possible confounding. ResultsWe included 141 with CFTR-MF and 35 with CFTR-RF. LCI (> 1.96 z-score) was elevated in 71.6% individuals with CFTR-MF and in 40.0% with CFTR-RF. FEV1 (< -1.96 z-score) was reduced in 11.3% individuals with CFTR-MF and in 5.7% with CFTR-RF. The mean difference (95% CI) of LCI and FEV1 between CFTR-MF and CFTR-RF was 3.71 (1.63 to 5.79) and -0.40 (-0.83 to 0.02) z-score. The LCI differences were similar after adjustment for confounders and in individuals with normal FEV1. ConclusionIncreased ventilation inhomogeneity is associated with less CFTR function. In individuals with mild CF lung disease, LCI can identify and quantify increased ventilation inhomogeneity, a candidate treatable trait.

Sensitive structural and functional measurements and 1-year pulmonary outcomes in pediatric cystic fibrosis

BackgroundTwo functional measurements (multiple breath washout [MBW] and hyperpolarized 129Xe ventilation magnetic resonance imaging [129Xe MRI]) have been shown to be more sensitive to cystic fibrosis (CF) lung obstruction than traditional spirometry. However, functional techniques may be sensitive to different underlying structural abnormalities. The purpose of this study was to determine relationships between these functional markers, their pathophysiology, and 1-year clinical outcomes. MethodsSpirometry, MBW, 129Xe MRI, and ultrashort echo-time (UTE) MRI were obtained in a same-day assessment of 27 pediatric CF patients (ages 11.5±5.0) who had not begun CFTR modulator therapies. UTE MRI was scored for structural abnormalities and functional metrics obtained via spirometry, MBW and 129Xe MRI. 1-year outcomes (ΔFEV1 and pulmonary exacerbations), during which ≈50% initiated modulator therapy, were obtained from the electronic medical record. ResultsMBW, 129Xe MRI, and UTE MRI detected clinically significant disease in more subjects (>78%) compared to spirometry (<30%). UTE MRI suggests increased odds of bronchial changes when mucus plugging is present in the same lobe. MBW and 129Xe MRI correlated best with mucus plugging, while spirometry correlated best with consolidations. Bronchial abnormalities were associated with future pulmonary exacerbations. ConclusionsMBW, 129Xe MRI, and UTE MRI are more sensitive for detection of pediatric CF lung disease when compared to spirometry. MBW and 129Xe MRI correlated with structural abnormalities which occur in early CF disease, suggesting MBW and 129Xe MRI are valuable tools in mild CF lung disease that can guide clinical decision making.

A four week trial of hypertonic saline in children with mild cystic fibrosis lung disease: Effect on mucociliary clearance and clinical outcomes

BackgroundHypertonic saline (HS) is commonly prescribed for children with cystic fibrosis (CF) despite the absence of strong data indicating clinical efficacy in a population with mild lung disease. We hypothesized that HS treatment would result in a sustained improvement in mucociliary clearance (MCC) in children with CF who had minimal lung disease, thus providing evidence for a biologically relevant effect that also may be associated with clinical improvements. MethodsWe performed a randomized, placebo controlled, double blind study of 6% versus 0.12% sodium chloride, delivered three-times daily with an eFlow nebulizer for 4 weeks. MCC was measured using gamma scintigraphy at baseline, 2-hours after the first study treatment, and ~12-hours after the final dose (at day 28). Spirometry, respiratory symptoms (CFQ-R), and safety were also assessed. ResultsStudy treatments were generally well tolerated and safe. HS (6% sodium chloride) resulted in a significant, sustained improvement from baseline in whole lung clearance after 4 weeks of therapy (p = 0.014), despite absence of a prolonged single-dose effect after the initial dose. This sustained change (12 hrs after prior dose) was significantly greater when compared to placebo (0.12% sodium chloride) treatment (p = 0.016). Improvements in spirometry with HS did not reach statistical significance but correlated with MCC changes. ConclusionsThe observed sustained improvement in MCC with HS suggests that this treatment may yield health benefits, even in relatively mildly affected children with CF. Highlighting this physiologic finding is important due to the lack of meaningful, validated endpoints in this population.

Dynamic perfluorinated gas MRI reveals abnormal ventilation despite normal FEV1 in cystic fibrosis.

We hypothesized that dynamic perfluorinated gas MRI would sensitively detect mild cystic fibrosis (CF) lung disease. This cross-sectional study enrolled 20 healthy volunteers and 24 stable subjects with CF, including a subgroup of subjects with normal forced expiratory volume in the first second (FEV1; >80% predicted, n = 9). Dynamic fluorine-19-enhanced MRI (19F MRI) were acquired during sequential breath holds while breathing perfluoropropane (PFP) and during gas wash-out. Outcomes included the fraction of lung without significant ventilation (ventilation defect percent, VDP) and time constants that described PFP wash-in and wash-out kinetics. VDP values (mean ± SD) of healthy controls (3.87% ± 2.7%) were statistically different from moderate CF subjects (19.5% ± 15.5%, P = 0.001) but not from mild CF subjects (10.4% ± 9.9%, P = 0.24). In contrast, the fractional lung volume with slow gas wash-out was elevated both in subjects with mild (9.61% ± 4.87%; P = 0.0066) and moderate CF (16.01% ± 5.01%; P = 0.0002) when compared with healthy controls (3.84% ± 2.16%) and distinguished mild from moderate CF (P = 0.006). 19F MRI detected significant ventilation abnormalities in subjects with CF. The ability of gas wash-out kinetics to distinguish between healthy and mild CF lung disease subjects makes 19F MRI a potentially valuable method for the characterization of early lung disease in CF. This study has been registered at ClinicalTrials.gov (NCT03489590).

Mucus plugging, air trapping, and bronchiectasis are important outcome measures in assessing progressive childhood cystic fibrosis lung disease.

To determine which outcome measures could detect early progression of disease in school-age children with mild cystic fibrosis (CF) lung disease over a two-year time interval utilizing chest computed tomography (CT) scores, quantitative CT air trapping (QAT), and spirometric measurements. Thirty-six school-age children with mild CF lung disease (median [interquartile range] age 12 [3.7] years; percent predicted forced expiratory volume in 1 second (ppFEV1 ) 99 [12.5]) were evaluated by serial spirometer-controlled chest CT scans and spirometry at baseline, 3-month, 1- and 2-years. No significant changes were noted at 3-month for any variable except for decreased ppFEV1 . Mucus plugging score (MPS) and QATA1andA2 increased at 1- and 2-years. The bronchiectasis score (BS), and total score (TS) were increased at 2-year. All variables tested with the exception of bronchial wall thickness score, parenchymal score (PS), and ppFEV1 , were consistent with longitudinal worsening of lung disease. Multivariate analysis revealed baseline PS, baseline TS, and 1-year changes in BS and air trapping score were predictive of 2-year changes in BS. MPS and QATA1-A2 were the most sensitive indicators of progressive childhood CF lung disease. The 1-year change in the bronchiectasis score had the most positive predictive power for 2-year change in bronchiectasis.

A four week trial of hypertonic saline in children with mild cystic fibrosis lung disease: Effect on mucociliary clearance and clinical outcomes

A four week trial of hypertonic saline in children with mild cystic fibrosis lung disease: Effect on mucociliary clearance and clinical outcomes

Cardiac Involvement in Mild Cystic Fibrosis Lung Involvement Assessed by Tissue‐Doppler Echocardiography

Background:Cystic Fibrosis (CF) is a systemic disease affecting extra pulmonary dysfunction as a result of CF-related lung disease. Because of lack of enough studies in this field and utilization of TDE in this field, we aimed to evaluate the cardiac involvement in children with CF and compare it with healthy children. Materials and Methods: In this cross sectional study, children diagnosed with cystic fibrosis aged less than 15 years who referred to Emam Hossein Children’s Hospital, affiliated to Isfahan University of Medical Sciences, Iran, during 2018, were enrolled. Participants were 2 groups: case and control. In this study 27 children with mild cystic fibrosis lung disease and 27 healthy children were evaluated. Case groups were consisted of children with CF, and control group were healthy children. FEV1, FVC, and FEV1 / FVC of all participants were recorded based on their spirometry findings. Cardiac function tests including electrocardiogram and Doppler echocardiography were evaluated by an expert pediatric cardiologist. Spirometry and Doppler echocardiography findings in two studied groups were compared. Results: Lateral wall tissue Doppler echocardiographic evaluation, annular peak velocity during systole and E’/A’ ratio was significantly higher in children with CF than healthy children (P<0.05). In the right ventricle (septal wall) tissue Doppler echocardiographic evaluation peak velocity during early diastole, peak velocity during late diastole and annular peak velocity during systole was significantly higher in healthy children than those with CF (P<0.01). E’/A’ ratio in the right ventricle (septal wall) tissue Doppler echocardiographic evaluation was significantly higher in children with CF than healthy children (P<0.01). Conclusion Based on the results, it is recommended to consider tissue Doppler echocardiography in the earlier period of CF patients’ follow- up program.

Side lying during nebulisation can significantly improve apical deposition in healthy adults and adults with mild cystic fibrosis lung disease: a randomised crossover trial

BackgroundIn people with and without Cystic Fibrosis (CF), does side lying during nebulisation change: the proportion of the dose loaded in the nebuliser that is deposited in the lungs; the uniformity of deposition throughout the lungs; or the apical drug density as a percentage of the drug density in the remaining lung? Do these effects differ depending on the degree of lung disease present?MethodsA randomised crossover trial with concealed allocation, intention-to-treat analysis and blinded assessors, involving 39 adults: 13 healthy, 13 with mild CF lung disease (FEV1 > 80%pred), and 13 with more advanced CF lung disease (FEV1 < 80%pred). In random order, 4 mL of nebulised radioaerosol was inhaled in upright sitting and in alternate right and left side lying at 2-min intervals, for 20 min.ResultsCompared to sitting upright, lung deposition and the uniformity of deposition were not significantly altered by side lying in any of the three groups. In sitting, the density of the deposition was significantly less in the apical regions than in the rest of the lung in all participants. Side lying significantly improved apical deposition in healthy adults (MD, 13%; 95% CI, 7 to 19), and in minimal CF lung disease (MD, 4%; 95% CI, 1 to 7) but not in advanced disease (MD, 4%; 95% CI, − 2 to 9).ConclusionAlternating between right and left side lying during nebulisation significantly improves apical deposition in healthy adults and in adults with mild CF lung disease, without substantial detriment to overall deposition.Trial registrationACTRN12611000674932 (Healthy), ACTRN12611000672954 (CF)Retrospectively registered 4/7/2011.

EPS4.1 Longitudinal automated airway and air-trapping analysis on CT from school age children with mild cystic fibrosis lung disease

EPS4.1 Longitudinal automated airway and air-trapping analysis on CT from school age children with mild cystic fibrosis lung disease

Hyperpolarized 129Xe for investigation of mild cystic fibrosis lung disease in pediatric patients

BackgroundCystic fibrosis (CF) is a genetic disease which carries high morbidity and mortality from lung-function decline. Monitoring disease progression and treatment response in young patients is desirable, but serial imaging via CT is often considered prohibitive, and detailed functional information cannot be obtained using conventional imaging techniques. Hyperpolarized 129Xe magnetic resonance imaging (MRI) can depict and quantify regional ventilation, but has not been investigated in pediatrics. We hypothesized that 129Xe MRI is feasible and would demonstrate ventilation defects in mild CF lung disease with greater sensitivity than FEV1. Methods11 healthy controls (age 6–16years) and 11 patients with mild CF (age 8–16years, Forced Expiratory Volume (FEV1) percent predicted >70%) were recruited for this study. Nine CF patients had an FEV1>85%. Each subject was imaged via hyperpolarized 129Xe MRI, and the ventilation defect percentage (VDP) was measured. FEV1 and VDP were compared between the groups. ResultsFEV1 for controls was 100.3%±8.5% (mean±sd) and for CF patients was 97.9%±16.0% (p=0.67). VDP was 6.4%±2.8% for controls and 18.3%±8.6% for CF (p<0.001). When considering the 9 CF patients with normal FEV1 (>85%), the mean FEV1 was 103.1%±12.3% (p=0.57 compared to controls) and VDP was 15.4%±6.3% (p=0.002). ConclusionsHyperpolarized 129Xe MRI demonstrated ventilation defects in CF patients with normal FEV1 and more effectively discriminated CF from controls than FEV1. Thus 129Xe may be a useful outcome measure to detect mild CF lung disease, to investigate regional lung function in pediatric lung diseases, and to follow disease progression.

Assessment and Detection of Early Lung Disease in Cystic Fibrosis.

It is now widely accepted that cystic fibrosis (CF) lung disease begins in infancy and early childhood, with evidence of structural, functional, and inflammatory changes present even in asymptomatic children. This realization, coupled with broad adoption of CF newborn screening in the United States, Canada, Europe, and Australia, has raised the possibility for primary prevention of CF lung disease. To intervene before respiratory symptoms develop in infants and preschool children with CF, sensitive testing modalities are necessary to define and follow mild CF lung disease, both for research and for clinical purposes. Ideal testing would be sensitive to early heterogeneous disease located in the peripheral airways, able to detect small changes in disease (either progression or therapeutic response), easy to perform without sedation, and safe for repeated measures. This article will review existing and novel modalities for identification of CF lung disease in infancy and early childhood, focusing on pulmonary function testing, structural imaging, identification of infectious pathogens, and detection of inflammation.

Peak Aerobic Capacity in Adults With Cystic Fibrosis Stratified by Lung Disease Severity

Purpose: Exercise capacity in people with cystic fibrosis (CF) is an important factor in length and quality of life. Currently, there is no standard for testing, particularly for the growing population of adults with CF. This study was designed to describe maximal aerobic capacity in adults with varying degrees of CF lung disease severity as compared with similarly aged healthy controls using the Godfrey exercise test protocol. Methods: Results of maximal exercise tests were collected from 3 CF centers (total of 56 CF tests, mean age, 25 years) and compared with results of tests performed on healthy controls (n = 141, mean age 24 years). Cystic fibrosis tests were analyzed by lung disease severity (none, mild, moderate, and severe), and analyses of variance were performed to determine the relationships between lung disease severity and exercise variables. Results: Subjects with mild (forced expiratory volume in 1 second > 70% predicted) CF lung disease did not differ from healthy controls for peak exercise capacity (VO2peak 2.47 L/min CF vs. 2.67 L/min control); however, as lung disease progressed to moderate or severe disease, exercise performance was significantly worse than controls. Conclusions: Adults with mild CF lung disease had exercise capacity that did not differ from the control group, but as the disease severity progresses, lower exercise capacity can be expected. This suggests that patients with mild lung disease should be encouraged to participate in regular exercise to maintain this function as lung disease progresses. Exercise prescription may need to be adapted for those with moderate or severe lung disease to account for declines in maximal exercise capacity.

Long-term improvement of lung clearance index in patients with mild cystic fibrosis lung disease: Does hypertonic saline play a role?

To assess whether long-term inhalation with hypertonic saline is able to halt the progression of mild CF lung disease, we analysed longitudinal data of lung clearance index (LCI) and spirometry. A total of 34 patients with mild lung disease (FEV1≥70% of predicted) had at least one LCI result before and ≥2 LCI measurements after start of hypertonic saline (HS) therapy. After a mean follow-up of 39.7 (SD 7.4) months after starting HS, LCI improved significantly from 7.89 (SD 1.35) at baseline to 6.96 (SD 1.03), and 19/34 patients had a normal LCI value at the last measurement. No decrease in mean FEV1 was observed. Thus, ventilation inhomogeneity can improve in patients with mild lung disease.