Seasonal fluctuation of lung function in cystic fibrosis:A national register-based study in two northern European populations

Background Many risk factors for lung disease in cystic fibrosis (CF) display a seasonal pattern yet it is unclear whether this is reflected in seasonal fluctuations in lung function. Methods We conducted a longitudinal study using CF registries in Denmark and the UK. 485 individuals with a median of 103 FEV1 measurements per person and 7622 individuals with a median of nine FEV1 measures per person were included from Denmark and the UK respectively. We estimated the effect of seasonality on percent predicted FEV1 trajectories using mixed effects models whilst adjusting for clinically important covariates. Results We found no significant cyclical seasonal variation in lung function in either country. The maximum variation in percent predicted FEV1 around the yearly average was estimated to be 0.1 percentage points (95%CI 0 to 0.21) and 0.14 percentage points (95%CI 0 to 0.29) in Denmark and the UK, respectively. When considering possible step-like changes between the four seasons, we found that lung function was higher in spring compared to winter in the UK (0.34 percentage points, 95%CI 0.1 to 0.59) though the difference was not of clinical significance. Conclusion In both the UK and Denmark there may be small seasonal changes in lung function but this effect is not of clinical importance

Clinical features and management of children with primary ciliary dyskinesia in England

Objective In England, the National Health Service commissioned a National Management Service for children with primary ciliary dyskinesia (PCD). The aims of this study were to describe the health of children seen in this Service and compare lung function to children with cystic fibrosis (CF). Design Multi-centre service evaluation of the English National Management PCD Service. Setting Four nationally commissioned PCD centres in England. Patients 333 children with PCD reviewed in the Service in 2015; lung function data were also compared to 2970 children with CF. Results Median age at diagnosis for PCD was 2.6 years, significantly lower in children with situs inversus (1.0 vs 6.0 years, p<0.0001). Compared with national data from the CF Registry, mean (SD) %predicted FEV1 76.8% in PCD (n=240) and 85.0% in CF, and FEV1 was lower in children with PCD up to the age of 15 years. Approximately half of children had some hearing impairment, with 26% requiring hearing aids. Children with a lower BMI had lower FEV1 (p<0.001). One third of children had positive respiratory cultures at review, 54% of these grew Haemophilus influenzae. Conclusions We provide evidence that children with PCD in England have worse lung function than those with CF. Nutritional status should be considered in PCD management, as those with a lower BMI have significantly lower FEV1. Hearing impairment is common but seems to improve with age. Well designed and powered randomised controlled trials on management of PCD are needed to inform best clinical practice

Exploring the nature of perceived treatment burden: a study to compare treatment burden measures in adults with cystic fibrosis [version 1; peer review: 2 approved]

Background: Despite the importance of reducing treatment burden for people with cystic fibrosis (CF), it has not been fully understood as a concept. This study aims to quantify the treatment burden perceived by CF adults and explore the association between different validated treatment burden measures. Methods: This is a cross-sectional observational study of CF adults attending a single large UK adult center. Participants completed an online survey that contained three different treatment burden scales; CF Questionnaire-Revised (CFQ-R) subscale, CF Quality of Life (CFQoL) subscale, and the generic multimorbidity treatment burden questionnaire (MTBQ). Results: Among 101 participants, the median reported treatment burden by the CFQ-R subscale was 55.5 (IQR 33.3 – 66.6), the CFQoL subscale was 66.6 (IQR 46.6 – 86.6), and the MTBQ reversed global score was 84.6 (IQR 73.1 – 92.3). No correlation was found between respondents’ demographic or clinical variables and treatment burden measured via any of the three measures. All treatment burden measures showed correlations against each other. More treatments were associated with high treatment burden as measured by the CFQ-R, CFQoL subscales, and the MTBQ. However, longer treatment time and more complex treatment plans were correlated with high treatment burden as measured by the CFQ-R and CFQoL subscales, but not with the MTBQ. Conclusions: Treatment burden is a substantial issue in CF. Currently, the only available way to evaluate it is with the CF-specific quality of life measure treatment burden subscales (CFQ-R and CFQoL); both indicated that treatment burden increases with more treatments, longer treatment time, and more complex treatments

Barriers and facilitators in the delivery of a proportionate universal parenting program model (E-SEE Steps) in community family services

Background A proportionate universal (PU) approach to early years’ service provision has been advocated to improve children’s health and development and to reduce health inequality, by ensuring that services provide timely and high-quality parenting support commensurate with need. Process-oriented research is critical to examine the factors that contribute to, or hinder, the effective delivery/implementation of such a model in community-based family services. This study aimed to assess the delivery, acceptability and feasibility of a new PU parenting intervention model (called E-SEE Steps), using the Incredible Years® (IY) parent program, when delivered by trained health/family service staff in three “steps”—one universal step (the IY Babies Book), and two targeted steps (group-based IY Infant and Toddler programs). Methods An embedded mixed-methods process evaluation within a pragmatic parallel two-arm, assessor blinded, randomized controlled trial was conducted in community services in four local authorities in England. The process evaluation used qualitative data gathered via interviews and focus groups with intervention arm parents who were offered the targeted steps (n = 29), practitioners (n = 50), service managers (n = 7) and IY program mentors (n = 3). This was supplemented by quantitative data collected using group leader pre-training (n = 50) and post-delivery (n = 39) questionnaires, and research notes of service design decisions. Results The E-SEE Steps model was acceptable to most parents, particularly when it was accompanied by engagement strategies that supported attendance, such as providing childcare. Practitioners also highlighted the positive development opportunities provided by the IY training and supervision. However, participant views did not support the provision of the IY Babies book as a standalone universal component, and there were barriers to eligible parents—particularly those with low mood—taking up the targeted programs. Service providers struggled to align the PU model with their commissioned service contracts and with their staff capacity to engage appropriate parents, including tackling common barriers to attendance. Conclusions Despite general enthusiasm and support for delivering high-quality parenting programs in community services in the England, several barriers exist to successfully delivering IY in a proportionate universal model within current services/systems

Survival estimates in European cystic fibrosis patients and the impact of socioeconomic factors: a retrospective registry cohort study

Background Median survival for cystic fibrosis (CF) patients in Europe is unknown and is likely to be influenced by socioeconomic factors. Using the European CF Society Patient Registry (ECFSPR), median survival estimates were obtained for CF patients across Europe and the impact of socioeconomic status on survival was examined. Methods CF subjects known to be alive and in the ECFSPR between 2010 and 2014 were included. Survival curves were estimated using the Kaplan–Meier method. Differences in the survival curves were assessed using the log-rank test. Cox regression was used to estimate the association between socioeconomic factors and the age-specific hazard of death, with adjustment for sex, age at diagnosis, CF transmembrane conductance regulator (CFTR) genotype and transplant status. Results The final analysis included 13 countries with 31 987 subjects (135 833 person-years of follow-up) and 1435 deaths. Median survival age for these patients in the ECFSPR was 51.7 (95% CI 50.0–53.4) years. After adjusting for potential confounders age at diagnosis, sex, CFTR genotype and transplant status, there remained strong evidence of an association between socioeconomic factors and mortality (p<0.001). Countries in the highest third of healthcare spending had a 46% lower hazard of mortality (HR 0.54, 95% CI 0.45–0.64) than countries in the lowest third of healthcare spending. Conclusions Median survival for patients with CF in Europe is comparable to that reported in other jurisdictions and differs by socioeconomic factors

Lung function in children with cystic fibrosis in the USA and UK: a comparative longitudinal analysis of national registry data

RATIONALE: A previous analysis found significantly higher lung function in the US paediatric cystic fibrosis (CF) population compared with the UK with this difference apparently decreasing in adolescence and adulthood. However, the cross-sectional nature of the study makes it hard to interpret these results. OBJECTIVES: To compare longitudinal trajectories of lung function in children with CF between the USA and UK and to explore reasons for any differences. METHODS: We used mixed effects regression analysis to model lung function trajectories in the study populations. Using descriptive statistics, we compared early growth and nutrition (height, weight, body mass index), infections (Pseudomonas aeruginosa, Staphylococcus aureus) and treatments (rhDnase, hypertonic saline, inhaled antibiotics). RESULTS: We included 9463 children from the USA and 3055 children from the UK with homozygous F508del genotype. Lung function was higher in the USA than in the UK when first measured at age six and remained higher throughout childhood. We did not find important differences in early growth and nutrition, or P.aeruginosa infection. Prescription of rhDNase and hypertonic saline was more common in the USA. Inhaled antibiotics were prescribed at similar levels in both countries, but Tobramycin was prescribed more in the USA and colistin in the UK. S. aureus infection was more common in the USA than the UK. CONCLUSIONS: Children with CF and homozygous F508del genotype in the USA had better lung function than UK children. These differences do not appear to be explained by early growth or nutrition, but differences in the use of early treatments need further investigation

The disease-specific clinical trial network for primary ciliary dyskinesia: PCD-CTN

Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterised by impaired mucociliary clearance leading to irreversible lung damage. In contrast to other rare lung diseases like cystic fibrosis (CF), there are only few clinical trials and limited evidence-based treatments. Management is mainly based on expert opinions and treatment is challenging due to a wide range of clinical manifestations and disease severity. To improve clinical and translational research and facilitate development of new treatments, the clinical trial network for PCD (PCD-CTN) was founded in 2020 under the framework of the European Reference Network (ERN)-LUNG PCD Core. Applications from European PCD sites interested in participating in the PCD-CTN were requested. Inclusion criteria consisted of patient numbers, membership of ERN-LUNG PCD Core, use of associated standards of care, experience in PCD and/or CF clinical research, resources to run clinical trials, good clinical practice (GCP) certifications and institutional support. So far, applications from 22 trial sites in 18 European countries have been approved, including >1400 adult and >1600 paediatric individuals with PCD. The PCD-CTN is headed by a coordinating centre and consists of a steering and executive committee, a data safety monitoring board and committees for protocol review, training and standardisation. A strong association with patient organisations and industrial companies are further cornerstones. All participating trial sites agreed on a code of conduct. As CTNs from other diseases have demonstrated successfully, this newly formed PCD-CTN operates to establish evidence-based treatments for this orphan disease and to bring new personalised treatment approaches to patients

Mutations in Outer Dynein Arm Heavy Chain DNAH9 Cause Motile Cilia Defects and Situs Inversus

International audienceMotile cilia move body fluids and gametes and the beating of cilia lining the airway epithelial surfaces ensures that they are kept clear and protected from inhaled pathogens and consequent respiratory infections. Dynein motor proteins provide mechanical force for cilia beating. Dynein mutations are a common cause of primary ciliary dyskinesia (PCD), an inherited condition characterized by deficient mucociliary clearance and chronic respiratory disease coupled with laterality disturbances and subfertility. Using next-generation sequencing, we detected mutations in the ciliary outer dynein arm (ODA) heavy chain gene DNAH9 in individuals from PCD clinics with situs inversus and in one case male infertility. DNAH9 and its partner heavy chain DNAH5 localize to type 2 ODAs of the distal cilium and in DNAH9-mutated nasal respiratory epithelial cilia we found a loss of DNAH9/DNAH5-containing type 2 ODAs that was restricted to the distal cilia region. This confers a reduced beating frequency with a subtle beating pattern defect affecting the motility of the distal cilia portion. 3D electron tomography ultrastructural studies confirmed regional loss of ODAs from the distal cilium, manifesting as either loss of whole ODA or partial loss of ODA volume. Paramecium DNAH9 knockdown confirms an evolutionarily conserved function for DNAH9 in cilia motility and ODA stability. We find that DNAH9 is widely expressed in the airways, despite DNAH9 mutations appearing to confer symptoms restricted to the upper respiratory tract. In summary, DNAH9 mutations reduce cilia function but some respiratory mucociliary clearance potential may be retained, widening the PCD disease spectrum

GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5–2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility

Exploring the nature of perceived treatment burden: a study to compare treatment burden measures in adults with cystic fibrosis.

Background: Despite the importance of reducing treatment burden for people with cystic fibrosis (CF), it has not been fully understood as a concept. This study aims to quantify the treatment burden perceived by CF adults and explore the association between different validated treatment burden measures. Methods: This is a cross-sectional observational study of CF adults attending a single large UK adult center. Participants completed an online survey that contained three different treatment burden scales; CF Questionnaire-Revised (CFQ-R) subscale, CF Quality of Life (CFQoL) subscale, and the generic multimorbidity treatment burden questionnaire (MTBQ). Results: Among 101 participants, the median reported treatment burden by the CFQ-R subscale was 55.5 (IQR 33.3 – 66.6), the CFQoL subscale was 66.6 (IQR 46.6 – 86.6), and the MTBQ reversed global score was 84.6 (IQR 73.1 – 92.3). No correlation was found between respondents’ demographic or clinical variables and treatment burden measured via any of the three measures. All treatment burden measures showed correlations against each other. More treatments were associated with high treatment burden as measured by the CFQR, CFQoL subscales, and the MTBQ. However, longer treatment time and more complex treatment plans were correlated with high treatment burden as measured by the CFQ-R and CFQoL subscales, but not with the MTBQ. Conclusions: Treatment burden is a substantial issue in CF. Currently, the only available way to evaluate it is with the CF-specific quality of life measure treatment burden subscales (CFQ-R and CFQoL); both indicated that treatment burden increases with more treatments, longer treatment time, and more complex treatments