UK Cystic Fibrosis Research Articles

Evaluating CRMS/CFSPID phenotypes and outcomes: A retrospective study from a large UK cystic fibrosis centre

BackgroundCystic fibrosis transmembrane conductance regulator metabolic syndrome/cystic fibrosis screen-positive, inconclusive diagnosis (CRMS/CFSPID) is a designation given following a positive newborn screen for cystic fibrosis (CF) when CF is not excluded but cannot be confirmed. We describe the long-term clinical outcomes of a CRMS/CFSPID cohort. MethodsA retrospective, single centre study of children with a current or previous diagnosis of CRMS/CFSPID. Study period extended from February 1, 2007 to August 1, 2022. Baseline and longitudinal data were assessed. Results30 children were designated as CRMS/CFSPID between 2007 and 2021. At baseline, 13 CFTR variants were identified, of which F508del and R117H 7T/9T were most common (occurring in 25 and 20 children respectively). Initial mean immunoreactive trypsinogen and sweat chloride were 82.8 mmol/L and 34.3 mmol/L respectively. During longitudinal assessment (n = 27), occurring over a mean duration of 8.5 years, five children progressed to CF at a mean age of 9.5 years. All children were pancreatic sufficient except one who reclassified to CF. Four isolated Pseudomonas aeruginosa and 12 isolated Staphylococcus aureus, of which one and two progressed to CF respectively. All recent Z-scores for weight and spirometry were above −2. Initial mean sweat chloride was higher in those who progressed to CF versus those who did not, although this did not reach statistical significance (38.4 mmol/L versus 32.0 mmol/L respectively, p = 0.105). ConclusionsMost children with CRMS/CFSPID remained well with a low progression rate to CF. This supports a less intensive medical surveillance approach. Our results highlight the importance of assessment in a dedicated CRMS/CFSPID clinic during adolescence to detect progression to CF after 6 years of age.

Long-Term Outcomes of Allergic Bronchopulmonary Aspergillosis and Aspergillus Colonization in Children and Adolescents with Cystic Fibrosis.

Observational studies indicate that Aspergillus colonization and allergic bronchopulmonary aspergillosis (ABPA) in people with cystic fibrosis (CF) are associated with poorer lung health and increased disease severity. We performed a longitudinal observational cohort study to analyse long-term outcomes of Aspergillus colonization and ABPA in children with CF. Anonymised UK CF Registry data from 2009 to 2019 for patients aged 8-17 years in 2009-2010 were collected. For the baseline cohort analysis, patients were classified based on the presence of Aspergillus colonization and ABPA in 2009 and/or 2010. For the longitudinal analysis, patients were categorised according to annual Aspergillus colonization and ABPA status. Comparisons made were (1) Aspergillus positive vs. negative; (2) excluding those with ABPA: Aspergillus positive vs. negative; and (3) ABPA positive vs. negative. Primary outcome was percentage predicted FEV1 decline and secondary outcomes included BMI decline, mortality, lung transplant, and IV antibiotic use. Of the 1675 children, 263 had Aspergillus colonization in the baseline cohort, 260 were diagnosed with ABPA, and 80 had both. Baseline cohort analysis showed significantly lower lung function (p < 0.0001) and increased antibiotic treatment (p < 0.001) in those with Aspergillus colonization and in those with ABPA. Longitudinal analysis showed ABPA was associated with increased decline in lung function (p < 0.00001) and BMI (p < 0.00001). Aspergillus colonization was associated with increased decline in BMI (p = 0.005) but not lung function (p = 0.30). ABPA was associated with increased decline in long-term lung function and BMI in children and young people with CF. Aspergillus colonization was associated with lower lung function at baseline, but no increased rate of decline was observed long-term.

Demographic factors associated with within-individual variability of lung function for adults with cystic fibrosis: A UK registry study

Background: Lung function is a key outcome used in the evaluation of disease progression in cystic fibrosis. The variability of individual lung function measurements over time (within-individual variability) has been shown to predict subsequent lung function changes. Nevertheless, the association between within-individual lung function variability and demographic and genetic covariates has not been quantified.Methods: We performed a longitudinal analysis of data from a cohort of 7099 adults with cystic fibrosis (between 18 and 49 years old) from the UK cystic fibrosis registry, containing annual review data between 1996 and 2020. A mixed-effects location-scale model is used to quantify mean FEV1 (forced expiratory volume in 1 s) trajectories and FEV1 within-individual variability as a function of sex, age at annual review, diagnosis after first year of life, homozygous F508 genotype and birth cohort.Results: Mean FEV1 decreased with age and lung function variability showed a near-quadratic trend by age. Males showed higher FEV1 mean and variability than females across the whole age range. Earlier diagnosis and homozygous F508 genotype were also associated with higher FEV1 mean and variability. Individuals who died during follow-up showed on average higher lung function variability than those who survived.Conclusions: Key variables known to be linked with mean lung function in cystic fibrosis are also associated with an individual’s lung function variability. This work opens new avenues to understand the role played by lung function variability in disease progression and its utility in predicting key outcomes such as mortality.

P121 Updating the UK Cystic Fibrosis Registry’s genotype cleaning processes and minimising free-text to improve data quality

P121 Updating the UK Cystic Fibrosis Registry’s genotype cleaning processes and minimising free-text to improve data quality

UK Cystic Fibrosis Registry Website Enhancements: A User-Centred Approach to the Data Access Transparency

BackgroundAs a member of the HDR UK Alliance, Cystic Fibrosis Trust is committed to adopting and maintaining the transparency standards within the UK CF Registry (UKCFR). Our website is the primary source for providing information on UKCFR and data access processes. We aimed to review use and accessibility across all user groups to shape website enhancements. This project aimed to improve transparency by conducting user experience (UX) research, and based on user feedback, enhance our website. For this project, we reviewed all of the HDR UK Transparency Standards. For this poster, we will focus on Standards 3 (Clear Website Navigation and 4 (Consider Target Audience). IntroductionThe primary objective was to enhance Transparency Standards by understanding audience needs and customise website improvements based on their needs. We envisaged that the outcome would be an improved and streamlined data access process to support transparency and trust among both data applicants and the public. MethodsWe employed a multi-method approach which incorporates public involvement throughout the whole process. We conducted on-site polls to intercept website visitors and gather quick feedback during their visit. Additionally, we created and distributed targeted surveys to various groups, including public and CF professionals, to delve deeper into their website experiences. Results The website’s overall rating is high at 7.4/10. UX research respondents: public 57% public and 43% CF Professionals. The top reasons for visiting the website are accessing reports and statistics and finding out more about UK CF Registry. Ease of finding information has fairly even spread, indicating room for improvement.

Levelling the playing field through the London Network of the UK clinical trials accelerator platform

Cystic fibrosis (CF) is a multisystem, genetic disease with a significantly reduced life expectancy. Despite substantial progress in therapies in the last 10–15 years, there is still no cure. There are dozens of drugs in the development pipeline and multiple clinical trials are being conducted across the globe. The UK Cystic Fibrosis Trust's (CFT) Clinical Trials Accelerator Platform (CTAP) is a national initiative bringing together 25 UK based CF centres to support the CF community in accessing and participating in CF clinical trials. CTAP enables more CF centres to run a broader portfolio of trials and increases the range of CF studies available for UK patients.There are four large specialist CF centres based in London, all within a small geographical region as well as two smaller centres which deliver CF care. At the launch of CTAP, these centres formed a sub-network in a consortium-style collaboration. The purpose of the network was to ensure equity of access to trials for patients across the UK's capital, and to share experience and knowledge. Four years into the programme we have reviewed our practices through working group meetings and an online survey. We sought to identify strengths and areas for improvement. We share our findings here, as we believe they are relevant to others delivering research in regions outside of London and in other chronic diseases.

Pancreatic enzyme prescription following ivacaftor licensing: A retrospective analysis of the US and UK cystic fibrosis registries

BackgroundRelieving gastrointestinal symptoms is a research priority in cystic fibrosis. Emerging evidence highlights effects of cystic fibrosis transmembrane conductance regulator (CFTR) modulators on gastrointestinal function, including pancreatic sufficiency. This study explores ivacaftor licensing and treatment on recorded pancreatic enzyme replacement therapy (PERT) prescription in the US and UK CF registries. MethodsRetrospective longitudinal registry study of recorded pancreatic PERT use between 2008 and 2017. Interrupted time series analysis in propensity-matched cohorts estimated annual change and step change according to ivacaftor eligibility before and after licensing year, 2012. Generalised estimating equations assessed adjusted risk of PERT use in individuals treated with ivacaftor after 2012 compared to untreated individuals. ResultsIn the US CF registry, the difference in annual change in prevalence of PERT use post-2012 between eligible cases and ineligible controls was -5.0 per 1000 people/year (95 %CI -7.6; -2.3, p = 0.001). The step change and annual change in prevalence of PERT use in eligible cases was not significantly different to controls in the UK CF registry. Relative to the relationship in 2013, ivacaftor treatment in the US CF registry was associated with a lower adjusted risk ratio of PERT use compared to untreated individuals by 2016 (0.97, 95 %CI 0.96; 0.99), which was not observed in the UK CF registry. ConclusionsLicensing of ivacaftor was followed by a lower prevalence of PERT use in the eligible US population compared to pre-licensing period, as well as lower risk of PERT use in those who received treatment. Inconsistencies in US and UK CF registries were observed.

Emulated trial investigating effects of multiple treatments: estimating combined effects of mucoactive nebulisers in cystic fibrosis using registry data

IntroductionPeople with cystic fibrosis (CF) are often on multiple long-term treatments, including mucoactive nebulisers. In the UK, the most common mucoactive nebuliser is dornase alfa (DNase). A common therapeutic approach...

Identifying the need for a UK colorectal cancer screening programme for patients with cystic fibrosis (CF): 10-year retrospective review of colonoscopy and colorectal cancer outcomes at a single CF centre

ObjectivePatients with cystic fibrosis (pwCF) have a high incidence of early colorectal cancer (CRC). In the absence of a UK CRC screening programme for pwCF, we evaluated the utility and...

Investigating Pseudomonas aeruginosa population structure and frequency of cross-infection in UK cystic fibrosis clinics - a reference laboratory perspective

BackgroundWe aimed to describe the UK Pseudomonas aeruginosa population structure amongst people with cystic fibrosis (PWCF), and to examine evidence for cross-infection. MethodsVariable Number Tandem Repeat (VNTR) typing was performed on 4640 isolates from 2619 PWCF received from 55 hospital laboratories between 2017 and 2019. A combination of whole genome sequence (WGS)-based analysis of four clusters from one hospital, and epidemiological analysis of shared strains in twelve hospitals evaluated cross-infection. ResultsOf 2619 PWCF, 1324 (51%) harboured common clusters or known transmissible strains, while 1295 carried unique strains/those shared among small numbers of patients. Of the former, 9.5% (250 patients) harboured the Liverpool epidemic strain (LES), followed in prevalence by clone C (7.8%; 205 patients), cluster A (5%;130 patients), and cluster D (3.6%; 94 patients). WGS analysis of 10 LES isolates, 9 of cluster D and 6 isolates each of cluster A and clone C from one hospital revealed LES formed the tightest cluster (between 7 and 205 SNPs), and cluster D the loosest (between 53 and 1531 SNPs). Hospital-specific shared strains were found in some centres, although cross-infection was largely historical, with few new acquisitions. Fifty-nine PWCF (2.3%) harboured “high-risk” clones; one ST235 isolate carried a blaIMP-1 allele. ConclusionOf 2619 PWCF who had P. aeruginosa isolates submitted for VNTR, 51% harboured either common clusters or known transmissible strains, of which LES was the most common. Limited evidence of recent patient-to-patient strain transmission was found, suggesting cross-infection prevention measures and surveillance effectively reduce transmission.

P415 A service evaluation to quantify real-world spirometry grading and frequency data following the introduction of the NuvoAir Air Next lung function device in one UK cystic fibrosis (CF) centre

Prior to the introduction of remote spirometry devices, people with cystic fibrosis (CF) would typically attend clinic appointments every three months or acutely where a lung function test may be performed. Evaluation of the frequency and grading of spirometry results was undertaken following the introduction of the NuvoAir Air Next lung function device.

P277 A survey of UK cystic fibrosis centres regarding stopping anti-Pseudomonas aeruginosa (PA) nebulised therapy in children who become free from Pa infection

Chronic Pseudomonas aeruginosa (PA) infection in children with cystic fibrosis (CF) has a detrimental effect on morbidity and mortality. There is clear and well referenced guidance on the diagnostic criteria for chronic PA infection and how to treat it. However, the nebulised treatment is burdensome and the guidelines do not advise how to manage children who stop isolating PA and specifically, if the treatment should be discontinued. This is particularly important in the era of highly effective CFTR modulator therapy as monitoring lower airways is more difficult in children not productive of sputum.

P309 UK cystic fibrosis physiotherapists’ knowledge and understanding of cystic fibrosis-related diabetes in relation to physical activity and exercise-national survey

Cystic Fibrosis Diabetes (CFRD) is the most common complication affecting approx. 40–50% of adults with cystic fibrosis (CF). Physical activity (PA) and exercise are recommended for the management of CF and can also benefit the management of blood glucose levels (BGL). Physiotherapists (PT) routinely counsel patients with CFRD about taking regular PA and supervise exercise sessions.

EPS7.04 Evaluating CFSPID phenotypes and outcomes a retrospective study from a large UK cystic fibrosis centre

Objectives: Cystic fibrosis screen positive inconclusive diagnosis (CFSPID) is a designation given following a positive newborn screen for cystic fibrosis (CF) when CF is not excluded but cannot be confirmed. We describe the phenotype and outcomes of a CFSPID cohort.

P429 The first UK cystic fibrosis trust exercise practitioner fellowship - an insight for the future provision of exercise services among individuals with cystic fibrosis and healthcare professionals

P429 The first UK cystic fibrosis trust exercise practitioner fellowship - an insight for the future provision of exercise services among individuals with cystic fibrosis and healthcare professionals

Therapeutic interventions alter ecological interactions among cystic fibrosis airway microbiota.

The airways of people with cystic fibrosis (CF) often harbor a diverse microbiota and in recent years, much effort has been invested in cataloguing these. In spite of providing a wealth of insight, this cataloguing tells us little about how the organisms interact with one another in the CF airways. However, such relationships can be inferred using the theoretical framework of the Lotka-Volterra (LV) model. In the current work, we use a generalized Lotka-Volterra model to interrogate the nationwide data collected and curated by the UK CF Registry. This longitudinal dataset (covering the period 2008-2020) contains annual depositions that record the presence/absence of microbial taxa in each patient, their medication, and their CF genotype. Specifically, we wanted to identify trends in ecological relationships between the CF microbiota at a nationwide level, and whether these are potentially affected by medication. Our results show that some medications have a distinct influence on the microbial interactome, especially those that potentially influence the "gut-lung axis" or mucus viscosity. In particular, we found that patients treated with a combination of antimicrobial agents (targeting the airway microbiota), digestive enzymes (assisting in the assimilation of dietary fats and carbohydrates), and DNase (to reduce mucus viscosity) displayed a distinctly different airway interactome compared with patients treated separately with these medications.

Causal inference in survival analysis using longitudinal observational data: Sequential trials and marginal structural models.

Longitudinal observational data on patients can be used to investigate causal effects of time-varying treatments on time-to-event outcomes. Several methods have been developed for estimating such effects by controlling for the time-dependent confounding that typically occurs. The most commonly used is marginal structural models (MSM) estimated using inverse probability of treatment weights (IPTW) (MSM-IPTW). An alternative, the sequential trials approach, is increasingly popular, and involves creating a sequence of "trials" from new time origins and comparing treatment initiators and non-initiators. Individuals are censored when they deviate from their treatment assignment at the start of each "trial" (initiator or noninitiator), which is accounted for using inverse probability of censoring weights. The analysis uses data combined across trials. We show that the sequential trials approach can estimate the parameters of a particular MSM. The causal estimand that we focus on is the marginal risk difference between the sustained treatment strategies of "always treat" vs "never treat." We compare how the sequential trials approach and MSM-IPTW estimate this estimand, and discuss their assumptions and how data are used differently. The performance of the two approaches is compared in a simulation study. The sequential trials approach, which tends to involve less extreme weights than MSM-IPTW, results in greater efficiency for estimating the marginal risk difference at most follow-up times, but this can, in certain scenarios, be reversed at later time points and relies on modelling assumptions. We apply the methods to longitudinal observational data from the UK Cystic Fibrosis Registry to estimate the effect of dornase alfa on survival.

External validity of machine learning-based prognostic scores for cystic fibrosis: A retrospective study using the UK and Canadian registries.

Precise and timely referral for lung transplantation is critical for the survival of cystic fibrosis patients with terminal illness. While machine learning (ML) models have been shown to achieve significant improvement in prognostic accuracy over current referral guidelines, the external validity of these models and their resulting referral policies has not been fully investigated. Here, we studied the external validity of machine learning-based prognostic models using annual follow-up data from the UK and Canadian Cystic Fibrosis Registries. Using a state-of-the-art automated ML framework, we derived a model for predicting poor clinical outcomes in patients enrolled in the UK registry, and conducted external validation of the derived model using the Canadian Cystic Fibrosis Registry. In particular, we studied the effect of (1) natural variations in patient characteristics across populations and (2) differences in clinical practice on the external validity of ML-based prognostic scores. Overall, decrease in prognostic accuracy on the external validation set (AUCROC: 0.88, 95% CI 0.88-0.88) was observed compared to the internal validation accuracy (AUCROC: 0.91, 95% CI 0.90-0.92). Based on our ML model, analysis on feature contributions and risk strata revealed that, while external validation of ML models exhibited high precision on average, both factors (1) and (2) can undermine the external validity of ML models in patient subgroups with moderate risk for poor outcomes. A significant boost in prognostic power (F1 score) from 0.33 (95% CI 0.31-0.35) to 0.45 (95% CI 0.45-0.45) was observed in external validation when variations in these subgroups were accounted in our model. Our study highlighted the significance of external validation of ML models for cystic fibrosis prognostication. The uncovered insights on key risk factors and patient subgroups can be used to guide the cross-population adaptation of ML-based models and inspire new research on applying transfer learning methods for fine-tuning ML models to cope with regional variations in clinical care.

Assessing the health risk of living near composting facilities on lung health, fungal and bacterial disease in cystic fibrosis: a UK CF Registry study

AimTo explore the health risk of living near permitted composting sites (PCSs) on disease severity in children and adults with cystic fibrosis (CF) across the UK. MethodsA semi-individual cross-sectional study was used to examine the risk of disease severity in people with CF (pwCF) within and beyond 4 km of PCSs in the UK in 2016. All pwCF registered in the UK CF Registry were eligible for this study. Linear and Poisson regressions, adjusted for age, gender, genotype, BMI, Pseudomonas aeruginosa and deprivation, were used to quantify associations between distance to a PCS and percent predicted forced expiratory volume in one second (ppFEV1), pulmonary exacerbations (#IVdays), and fungal and bacterial infections.ResultsThe mean age of the 9,361 pwCF (3,931 children and 5,430 adults) studied was 20.1 (SD = 14.1) years; 53.3% were male; and 49.2% were homozygous F508del. Over 10% of pwCF (n = 1,015) lived within 4 km of a PCS. We found no statistically significant difference in ppFEV1 and #IVdays/year in children. However, in adults, ppFEV1 was -1.07% lower (95% confidence interval (CI): -2.29%, 0.16%) and #IVdays/year were 1.02 day higher (95%CI: 1.01, 1.04) within 4 km of a PCS. Furthermore, there were statistically significant differences in mean ppFEV1 in CF adults with Aspergillus fumigatus (58.2.% vs 62.0%, p = 0.005) and Candida spp. (56.9% vs 59.9%, p = 0.029) residing within 4 km of a PCS. No associations were identified for allergic bronchopulmonary aspergillosis, P. aeruginosa or Staphylococcus aureus.ConclusionsThis novel national study provides evidence that adults with CF living near a PCS may experience small reductions in lung function, an increased risk of pulmonary exacerbations, and more frequent fungal infections. If confirmed by studies using refined exposure assessment methods accounting for bioaerosol dispersion, these results could have important implications for the living environment of pwCF.

The risk of colorectal cancer in individuals with mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene: An English population-based study

BackgroundStudies have demonstrated a higher risk of developing colorectal cancer (CRC) in individuals with Cystic Fibrosis (CF), and also a potentially increased risk in carriers of cystic fibrosis transmembrane conductance regulator (CFTR) mutations. Life expectancy for those with CF is rising, increasing the number at risk of developing CRC. MethodsThe incidence of CRC amongst individuals with CF was calculated using data from CORECT-R and linked UK CF Registry and Secondary User Services (SUS) data. Crude, age-specific and age-standardised rates were compared to those without CF. The presence of CFTR mutations in individuals with CRC was assessed using 100,000 Genomes Project data. FindingsThe crude incidence rate of CRC in the CF population was 0.29 per 1,000 person-years (28 cases). The CF population were significantly younger than those without (median age at CRC diagnosis 52 years versus 73 years; p<0·01). When age-adjusted, there was a 5-fold increased CRC incidence amongst individuals with CF compared to those without (SIR 5.0 95%CI 3.2–6.9). When compared to other population studies the overall prevalence of CFTR mutations in the CRC population was significantly higher than expected (p<0·01). InterpretationCF is linked to an increased risk of CRC. The incidence of CFTR mutations in the CRC population is higher than would be expected, suggesting an association between CFTR function and CRC risk. Further research is needed to develop effective screening strategies for these populations. FundingCancer Research UK (grants C23434/A23706 & C10674/A27140)