scholarly journals The assessment of short- and long-term changes in lung function in cystic fibrosis using 129Xe MRI

2020 ◽  
Vol 56 (6) ◽  
pp. 2000441 ◽  
Author(s):  
Laurie J. Smith ◽  
Alex Horsley ◽  
Jody Bray ◽  
Paul J.C. Hughes ◽  
Alberto Biancardi ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Clinical Trials ◽  
Lung Function ◽  
Lung Disease ◽  
Forced Expiratory Volume ◽  
Longitudinal Change ◽  
Response To Treatment ◽  
Short Term Change ◽  
Term Change ◽  
Magnetic Resonance Imaging Mri

IntroductionXenon-129 (129Xe) ventilation magnetic resonance imaging (MRI) is sensitive to detect early cystic fibrosis (CF) lung disease and response to treatment. 129Xe-MRI could play a significant role in clinical trials and patient management. Here we present data on the repeatability of imaging measurements and their sensitivity to longitudinal change.Methods29 children and adults with CF and a range of disease severity were assessed twice, a median (interquartile range (IQR)) of 16.0 (14.4–19.5) months apart. Patients underwent 129Xe-MRI, lung clearance index (LCI), body plethysmography and spirometry at both visits. 11 patients repeated 129Xe-MRI in the same session to assess the within-visit repeatability. The ventilation defect percentage (VDP) was the primary metric calculated from 129Xe-MRI.ResultsAt baseline, mean±sd age was 23.0±11.1 years and forced expiratory volume in 1 s (FEV1) z-score was −2.2±2.0. Median (IQR) VDP was 9.5 (3.4–31.6)% and LCI was 9.0 (7.7–13.7). Within- and inter-visit repeatability of VDP was high. At 16 months there was no single trend of 129Xe-MRI disease progression. Visible 129Xe-MRI ventilation changes were common, which reflected changes in VDP. Based on the within-visit repeatability, a significant short-term change in VDP is >±1.6%. For longer-term follow-up, changes in VDP of up to ±7.7% can be expected, or ±4.1% for patients with normal FEV1. No patient had a significant change in FEV1; however, 59% had change in VDP >±1.6%. In patients with normal FEV1, there were significant changes in ventilation and in VDP.Conclusions129Xe-MRI is a highly effective method for assessing longitudinal lung disease in patients with CF. VDP has great potential as a sensitive clinical outcome measure of lung function and end-point for clinical trials.

scholarly journals Ivacaftor Therapy in CF Patients: Single Center Experience

2014 ◽  
Vol 2014 ◽  
pp. 1-5
Author(s):  
Pritish Mondal ◽  
Amber Loyson ◽  
Jorge Lascano ◽  
Satyanarayan Hegde
Keyword(s):  
Cystic Fibrosis ◽  
Lung Function ◽  
Lung Disease ◽  
Case Series ◽  
Forced Expiratory Volume ◽  
Third Party ◽  
Normal Lung ◽  
Single Center ◽  
Single Center Experience ◽  
Pediatric Age Group

Ivacaftor is the first novel cystic fibrosis pharmaceutical that acts at the molecular level to potentiate cystic fibrosis transmembrane conductance regulator (CFTR) function and was first approved for clinical use in 2012. We are sharing our single center experience of five patients: four from pediatric age group and one adult patient. All patients had both subjective and objective improvements in their health. Despite established lung disease, our patients had significant improvement in both their FEV1 (forced expiratory volume in 1 second) and FEF25–75and BMI (body mass index). Larger studies demonstrated only 6.7% improvement in mean FEV1 after starting Ivacaftor therapy but their patient population had normal lung function to begin with. In contrast our case series demonstrates that, in patients with established lung disease and diminished lung function, Ivacaftor can be expected to result in much higher recovery in lung function. Mean FEV1 improved by 35% in our case series. Ivacaftor is extremely expensive, costing $300,000 per patient per year requiring lifelong therapy, hence requiring prior authorizations from most third-party payers in the USA. The knowledge shared from our experience will be useful for other clinicians to petition healthcare policymakers on behalf of their patients.

scholarly journals DNA Methylation at ATP11A cg11702988 Is a Biomarker of Lung Disease Severity in Cystic Fibrosis: A Longitudinal Study

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 441
Author(s):  
Fanny Pineau ◽  
Davide Caimmi ◽  
Sylvie Taviaux ◽  
Maurane Reveil ◽  
Laura Brosseau ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Dna Methylation ◽  
Clinical Trials ◽  
Lung Disease ◽  
Disease Severity ◽  
Genome Wide ◽  
A Genome ◽  
Lung Disease Severity ◽  
Epigenetic Biomarker

Cystic fibrosis (CF) is a chronic genetic disease that mainly affects the respiratory and gastrointestinal systems. No curative treatments are available, but the follow-up in specialized centers has greatly improved the patient life expectancy. Robust biomarkers are required to monitor the disease, guide treatments, stratify patients, and provide outcome measures in clinical trials. In the present study, we outline a strategy to select putative DNA methylation biomarkers of lung disease severity in cystic fibrosis patients. In the discovery step, we selected seven potential biomarkers using a genome-wide DNA methylation dataset that we generated in nasal epithelial samples from the MethylCF cohort. In the replication step, we assessed the same biomarkers using sputum cell samples from the MethylBiomark cohort. Of interest, DNA methylation at the cg11702988 site (ATP11A gene) positively correlated with lung function and BMI, and negatively correlated with lung disease severity, P. aeruginosa chronic infection, and the number of exacerbations. These results were replicated in prospective sputum samples collected at four time points within an 18-month period and longitudinally. To conclude, (i) we identified a DNA methylation biomarker that correlates with CF severity, (ii) we provided a method to easily assess this biomarker, and (iii) we carried out the first longitudinal analysis of DNA methylation in CF patients. This new epigenetic biomarker could be used to stratify CF patients in clinical trials.

scholarly journals Early Detection of Lung Disease in Children with Cystic Fibrosis Using Lung Function

2008 ◽  
Vol 9 (3) ◽  
pp. 160-167 ◽  
Author(s):  
Sarath Ranganathan ◽  
Barry Linnane ◽  
Gary Nolan ◽  
Catherine Gangell ◽  
Graham Hall
Keyword(s):  
Cystic Fibrosis ◽  
Lung Function ◽  
Early Detection ◽  
Lung Disease

scholarly journals Effects of exercise and airway clearance (positive expiratory pressure) on mucus clearance in cystic fibrosis: a randomised crossover trial

2019 ◽  
Vol 53 (4) ◽  
pp. 1801793 ◽  
Author(s):  
Tiffany J. Dwyer ◽  
Evangelia Daviskas ◽  
Rahizan Zainuldin ◽  
Jordan Verschuer ◽  
Stefan Eberl ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Crossover Trial ◽  
Treadmill Exercise ◽  
Forced Expiratory Volume ◽  
Mean Difference ◽  
Peak Oxygen Consumption ◽  
Mucus Clearance ◽  
Airway Clearance ◽  
Positive Expiratory Pressure

Exercise improves mucus clearance in people without lung disease and those with chronic bronchitis. No study has investigated exercise alone for mucus clearance in cystic fibrosis (CF). The aim of this study was to compare the effects of treadmill exercise to resting breathing and airway clearance with positive expiratory pressure (PEP) therapy on mucus clearance in adults with CF.This 3-day randomised, controlled, crossover trial included 14 adults with mild to severe CF lung disease (forced expiratory volume in 1 s % predicted 31–113%). Interventions were 20 min of resting breathing (control), treadmill exercise at 60% of the participant's peak oxygen consumption or PEP therapy (including huffing and coughing). Mucus clearance was measured using the radioaerosol technique and gamma camera imaging.Treadmill exercise improved whole lung mucus clearance compared to resting breathing (mean difference 3%, 95% CI 2–4); however, exercise alone was less effective than PEP therapy (mean difference −7%, 95% CI −6– −8). When comparing treadmill exercise to PEP therapy, there were no significant differences in mucus clearance from the intermediate and peripheral lung regions, but significantly less clearance from the central lung region (likely reflecting the huffing and coughing that was only in PEP therapy).It is recommended that huffing and coughing are included to maximise mucus clearance with exercise.

scholarly journals Hyperpolarised 129Xe magnetic resonance imaging to monitor treatment response in children with cystic fibrosis

2019 ◽  
Vol 53 (5) ◽  
pp. 1802188 ◽  
Author(s):  
Jonathan H. Rayment ◽  
Marcus J. Couch ◽  
Nancy McDonald ◽  
Nikhil Kanhere ◽  
David Manson ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Cystic Fibrosis ◽  
Magnetic Resonance ◽  
Lung Disease ◽  
Treatment Response ◽  
Forced Expiratory Volume ◽  
Response To Therapy ◽  
Breath Hold ◽  
Pulmonary Exacerbation ◽  
Resonance Imaging

Pulmonary magnetic resonance imaging using hyperpolarised 129Xe gas (XeMRI) can quantify ventilation inhomogeneity by measuring the percentage of unventilated lung volume (ventilation defect per cent (VDP)). While previous studies have demonstrated its sensitivity for detecting early cystic fibrosis (CF) lung disease, the utility of XeMRI to monitor response to therapy in CF is unknown. The aim of this study was to assess the ability of XeMRI to capture treatment response in paediatric CF patients undergoing inpatient antibiotic treatment for a pulmonary exacerbation.15 CF patients aged 8–18 years underwent XeMRI, spirometry, plethysmography and multiple-breath nitrogen washout at the beginning and end of inpatient treatment of a pulmonary exacerbation. VDP was calculated from XeMRI images obtained during a static breath hold using semi-automated k-means clustering and linear binning approaches.XeMRI was well tolerated. VDP, lung clearance index and the forced expiratory volume in 1 s all improved with treatment; however, response was not uniform in individual patients. Of all outcome measures, VDP showed the largest relative improvement (−42.1%, 95% CI −52.1–−31.9%, p<0.0001).These data support further investigation of XeMRI as a tool to capture treatment response in CF lung disease.

scholarly journals Integrating latent classes in the Bayesian shared parameter joint model of longitudinal and survival outcomes

2020 ◽  
Vol 29 (11) ◽  
pp. 3294-3307
Author(s):  
Eleni-Rosalina Andrinopoulou ◽  
Kazem Nasserinejad ◽  
Rhonda Szczesniak ◽  
Dimitris Rizopoulos
Keyword(s):  
Cystic Fibrosis ◽  
Lung Function ◽  
Latent Class ◽  
Joint Model ◽  
Forced Expiratory Volume ◽  
Optimal Number ◽  
Latent Classes ◽  
Joint Models ◽  
Number Of Classes ◽  
Strength Of Association

Cystic fibrosis is a chronic lung disease requiring frequent lung-function monitoring to track acute respiratory events (pulmonary exacerbations). The association between lung-function trajectory and time-to-first exacerbation can be characterized using joint longitudinal-survival modeling. Joint models specified through the shared parameter framework quantify the strength of association between such outcomes but do not incorporate latent sub-populations reflective of heterogeneous disease progression. Conversely, latent class joint models explicitly postulate the existence of sub-populations but do not directly quantify the strength of association. Furthermore, choosing the optimal number of classes using established metrics like deviance information criterion is computationally intensive in complex models. To overcome these limitations, we integrate latent classes in the shared parameter joint model through a fully Bayesian approach. To choose the optimal number of classes, we construct a mixture model assuming more latent classes than present in the data, thereby asymptotically “emptying” superfluous latent classes, provided the Dirichlet prior on class proportions is sufficiently uninformative. Model properties are evaluated in simulation studies. Application to data from the US Cystic Fibrosis Registry supports the existence of three sub-populations corresponding to lung-function trajectories with high initial forced expiratory volume in 1 s ( FEV1), rapid FEV1 decline, and low but steady FEV1 progression. The association between FEV1 and hazard of exacerbation was negative in each class, but magnitude varied.

scholarly journals 1014 Relationship Between Lung Function and Obstructive Sleep Apnea in Cystic Fibrosis

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A385-A385
Author(s):  
A Shakkottai ◽  
S Z Nasr ◽  
F Hassan ◽  
L M O’Brien ◽  
R D Chervin
Keyword(s):  
Cystic Fibrosis ◽  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Lung Function ◽  
Forced Expiratory Volume ◽  
Apnea Hypopnea Index ◽  
Lung Function Decline ◽  
Obstructive Sleep ◽  
Larger Sample ◽  
Training Grant

Abstract Introduction The frequency of obstructive sleep apnea (OSA) may be high among patients with cystic fibrosis (CF), a life-shortening, genetic respiratory disease that affects approximately 30,000 Americans. Yet, the potential relationship between OSA and lung function has not been thoroughly explored. Methods Single-center retrospective review of polysomnography (PSG) results from 2009-2017 in referred patients with CF and available pulmonary function data (PFTs) obtained at time of PSG and at 3, 6, 9, and 12-months prior. Results Mean ages were 11.1±3.9 (sd) and 37.1±14.1 years, among 18 children and 16 adults, respectively. Mean body mass index (BMI) was normal in both groups (62.5±26.6% in children; 25.1±6.4 kg/m2 in adults). Twenty-six subjects (76%) had OSA (apnea-hypopnea index &gt;1 in children, ≥5 in adults). Mean forced expiratory volume in 1 second percent predicted (FEV1 PPD) was higher among subjects with vs. without OSA at PSG and at each time-point in the year prior, independent of age and BMI at PSG (longitudinal mixed effects model, β=19.0, SE=8.1, p=0.028). While FEV1 PPD remained unchanged in the non-OSA group, FEV1 PPD at PSG was lower, in comparison to the year prior in subjects with OSA, with the greatest difference observed at 9-months prior to PSG (2-sample t-test, difference of -6.6% vs 0.6% in OSA vs. non-OSA groups respectively, p=0.078). Conclusion The PFTs, as daytime markers of CF lung disease severity, do not seem to reliably predict risk for OSA. In our sample, CF patients with vs. without OSA had better PFTs at baseline but they also showed a greater tendency for decline in PFTs over the year prior to OSA diagnosis. Larger sample size and longer duration of assessment may help, going forward, to assess any potential adverse impact of OSA on lung function decline. Support NIH Training Grant (T32NS007222, F32HL145915)

scholarly journals Airway Inflammation and Host Responses in the Era of CFTR Modulators

2020 ◽  
Vol 21 (17) ◽  
pp. 6379
Author(s):  
Karen Keown ◽  
Ryan Brown ◽  
Declan F. Doherty ◽  
Claire Houston ◽  
Michael C. McKelvey ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Function ◽  
Lung Disease ◽  
Airway Inflammation ◽  
Host Responses ◽  
Current Evidence ◽  
Future Research ◽  
Clinical Endpoints ◽  
New Class ◽  
Cftr Modulators

The arrival of cystic fibrosis transmembrane conductance regulator (CFTR) modulators as a new class of treatment for cystic fibrosis (CF) in 2012 represented a pivotal advance in disease management, as these small molecules directly target the upstream underlying protein defect. Further advancements in the development and scope of these genotype-specific therapies have been transformative for an increasing number of people with CF (PWCF). Despite clear improvements in CFTR function and clinical endpoints such as lung function, body mass index (BMI), and frequency of pulmonary exacerbations, current evidence suggests that CFTR modulators do not prevent continued decline in lung function, halt disease progression, or ameliorate pathogenic organisms in those with established lung disease. Furthermore, it remains unknown whether their restorative effects extend to dysfunctional CFTR expressed in phagocytes and other immune cells, which could modulate airway inflammation. In this review, we explore the effects of CFTR modulators on airway inflammation, infection, and their influence on the impaired pulmonary host defences associated with CF lung disease. We also consider the role of inflammation-directed therapies in light of the widespread clinical use of CFTR modulators and identify key areas for future research.

scholarly journals Lung function over the life course of paediatric and adult patients with cystic fibrosis from a large multi-centre registry

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Arul Earnest ◽  
Farhad Salimi ◽  
Claire E. Wainwright ◽  
Scott C. Bell ◽  
Rasa Ruseckaite ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Function ◽  
Mixed Model ◽  
Linear Mixed Model ◽  
Pancreatic Insufficiency ◽  
Forced Expiratory Volume ◽  
Rate Of Change ◽  
Data Registry ◽  
Mortality Outcome ◽  
The Impact

Abstract A key measure of lung function in people with Cystic Fibrosis (CF) is Forced Expiratory Volume in the first second FEV1 percent predicted (FEV1pp). This study aimed to address challenges in identifying predictors of FEV1pp, specifically dealing with non-linearity and the censoring effect of death. Data was obtained from a large multi-centre Australian Cystic Fibrosis Data Registry (ACFDR). A linear mixed model was used to study FEV1pp as the endpoint. There were 3655 patients (52.4% male) included in our study. Restricted cubic splines were used to fit the non-linear relationship between age of visit and FEV1pp. The following predictors were found to be significant in the multivariate model: age of patient at visit, BMI z-score, age interaction with lung transplantation, insulin dependent diabetes, cirrhosis/portal hypertension, pancreatic insufficiency, Pseudomonas aeruginosa infection and baseline variability in FEV1pp. Those with P. aeruginosa infection had a lower mean difference in FEV1pp of 4.7 units, p < 0.001 compared to those who did not have the infection. Joint modelling with mortality outcome did not materially affect our findings. These models will prove useful for to study the impact of CFTR modulator therapies on rate of change of lung function among patients with CF.

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