Cystic Fibrosis Disease Severity Research Articles

Elevated Prostaglandin E2 Synthesis Is Associated with Clinical and Radiological Disease Severity in Cystic Fibrosis.

Background: Previous studies found high but very variable levels of tetranor-PGEM and PGDM (urine metabolites of prostaglandin (PG) E2 and PGD2, respectively) in persons with cystic fibrosis (pwCF). This study aims to assess the role of cyclooxygenase COX-1 and COX-2 genetic polymorphisms in PG production and of PG metabolites as potential markers of symptoms' severity and imaging findings. Methods: A total of 30 healthy subjects and 103 pwCF were included in this study. Clinical and radiological CF severity was evaluated using clinical scoring methods and chest computed tomography (CT), respectively. Urine metabolites were measured using liquid chromatography/tandem mass spectrometry. Variants in the COX-1 gene (PTGS1 639 C>A, PTGS1 762+14delA and COX-2 gene: PTGS2-899G>C (-765G>C) and PTGS2 (8473T>C) were also analyzed. Results: PGE-M and PGD-M urine concentrations were significantly higher in pwCF than in controls. There were also statistically significant differences between clinically mild and moderate disease and severe disease. Patients with bronchiectasis and/or air trapping had higher PGE-M levels than patients without these complications. The four polymorphisms did not associate with clinical severity, air trapping, bronchiectasis, or urinary PG levels. Conclusions: These results suggest that urinary PG level testing can be used as a biomarker of CF severity. COX genetic polymorphisms are not involved in the variability of PG production.

Cystic fibrosis in Europe: improved lung function and longevity - reasons for cautious optimism, but challenges remain.

Prognosis and disease severity in cystic fibrosis (CF) are linked to declining lung function. To characterise lung function by the number of adults in countries with different levels of Gross National Income (GNI), data from the European Cystic Fibrosis Society Patient Registry were utilised. Annual data including age, forced expiratory volume in 1 s (FEV1), anthropometry, genotype, respiratory cultures and CF-related diabetes (CFRD) were retrieved between 2011 and 2021. All countries were stratified into GNI per capita to reflect differences within Europe. A consistent improvement in FEV1 % pred and survival was observed among the 47 621 people with CF (pwCF), including subjects with chronic Pseudomonas aeruginosa infection, CFRD and/or undernutrition. Mean values of FEV1 % pred changed from 85% to 94.2% for children and from 63.6% to 74.7% for adults. FEV1 % pred further increased among those carrying the F508del mutation in 2021, when elexacaftor/tezacaftor/ivacaftor was available. The number of adult pwCF increased from 13 312 in 2011 to 21 168 in 2021, showing a 60% increase. PwCF living in European lower income countries did not demonstrate a significant annual increase in FEV1 % pred or in the number of adults. This pan-European analysis demonstrates a consistent improvement in FEV1 % pred, number of adult pwCF and survival over the last decade only in European higher and middle income countries. Urgent action is needed in the lower income countries where such improvement was not observed. The notable improvement observed in pwCF carrying the F508del mutation emphasises the need to develop treatments for all CF mutations.

Laboratory Tools to Predict CFTR Modulator Therapy Effectiveness and to Monitor Disease Severity in Cystic Fibrosis.

The implementation of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator drugs into clinical practice has been attaining remarkable therapeutic outcomes for CF, a life-threatening autosomal recessive genetic disease. However, there is elevated CFTR allelic heterogeneity, and various individuals carrying (ultra)rare CF genotypes remain without any approved modulator therapy. Novel translational model systems based on individuals' own cells/tissue are now available and can be used to interrogate in vitro CFTR modulator responses and establish correlations of these assessments with clinical features, aiming to provide prediction of therapeutic effectiveness. Furthermore, because CF is a progressive disease, assessment of biomarkers in routine care is fundamental in monitoring treatment effectiveness and disease severity. In the first part of this review, we aimed to focus on the utility of individual-derived in vitro models (such as bronchial/nasal epithelial cells and airway/intestinal organoids) to identify potential responders and expand personalized CF care. Thereafter, we discussed the usage of CF inflammatory biomarkers derived from blood, bronchoalveolar lavage fluid, and sputum to routinely monitor treatment effectiveness and disease progression. Finally, we summarized the progress in investigating extracellular vesicles as a robust and reliable source of biomarkers and the identification of microRNAs related to CFTR regulation and CF inflammation as novel biomarkers, which may provide valuable information for disease prognosis.

The association between Attention-Deficit-Hyperactivity-Disorder (ADHD) symptoms and disease severity in people with Cystic Fibrosis (pwCF)

BackgroundThe hallmarks of Cystic fibrosis (CF), chronic infection and inflammation, require intensive daily treatment to maintain and improve quality of life and outcome. The incidence of Attention Deficit/Hyperactivity Disorder (ADHD) is increased in chronic inflammatory diseases. Previous studies suggested that the prevalence of ADHD in people with CF (pwCF) is higher than in the general population. The objective of this study was to evaluate the association between ADHD symptoms and parameters of CF disease severity, measured by demographic and clinical data. MethodsBased on our previous study, the results of ADHD questionnaires and the MOXOCPT (continuous performance task) from 143 pwCF (7–68 years old) were analyzed and linked to patient data such as forced expiratory volume in 1 second (FEV1)%predicted, body mass index (BMI), number of pulmonary exacerbations, days of antibiotic (Abx) treatment and serum inflammatory markers. ResultsA positive correlation between FEV1 and ADHD questionnaire's score (p = 0.046) was observed in the children's group. Furthermore, BMI, white blood cells (WBC) count, and days of Abx treatment showed a positive correlation with some of the MOXOCPT parameters. ConclusionThere is an association between ADHD symptoms and some parameters of CF disease severity. These results highlight the need for an early diagnosis of ADHD in pwCF, which have the potential to improve their ability to deal with the burden of their disease and consequently their quality of life. Additional research is needed to understand the full spectrum of ADHD pathophysiology and the relationship with chronic inflammatory diseases such as CF.

The utility of glucose area under the curve from the oral glucose tolerance test as a screening tool for cystic fibrosis-related diabetes.

Consistently abnormal glucose levels on oral glucose tolerance test (OGTT) are the most effective screening tool for cystic fibrosis-related diabetes (CFRD). However, some cystic fibrosis (CF) patients demonstrate abnormal glucose profiles not reaching levels required for CFRD diagnosis and are, therefore, left untreated. Since CFRD is associated with disease deterioration, early diagnosis and treatment are desirable. To explore the association between the area under the curve of glucose (G-AUC) obtained during a five-point2-hstandard OGTT and CF disease severity parameters. All CF patients referred for an annual routine OGTT at the Hadassah CF Center between 2002 and 2018, were included. Disease severity parameters were correlated with the G-AUC. Two hundred forty-twoOGTTs were performed in 81 patients (mean age 19.7 ± 9.0 years); 54% were normal, 14% showed impaired glucose tolerance (IGT), 5% had values in the indeterminate range (INDET), 11% had both IGT and INDET and 16% were diagnosed with CFRD. A gradual increase in mean G-AUC was observed among the groups. In multivariate regression models, G-AUC ≥ 295 mg h/dl was independently associated with an increased number of pulmonary exacerbations (PEx). Not all the patients having this value met the CFRD definition. Patients who do not fulfill the criteria for CFRD may have abnormal glucose metabolism identifiable by abnormally high G-AUC values, which may be associated with more PEx. The potential advantage of treating these patients with insulin and the subsequent reduction in PEx needs further investigation.

Association Between Cystic Fibrosis Severity Markers and CFTR Genotypes in Turkish Children.

To compare class I/II cystic fibrosis transmembrane conductance regulator (CFTR) mutations to class III-V mutations with regards to cystic fibrosis disease severity markers in children. This study was designed as a cross-sectional study in Antalya province, located on the south coast of Turkey. The study included 38 cystic fibrosis patients aged between 0.6 and 18 years. The CFTR genotype of the patients was categorized into 2 groups based on the presence or absence of class I or class II mutations in any of the alleles. Group I comprised 8 homozygous, 8 with unknown alleles, and 8 compound heterozygous patients, and group II comprised 11 homozygous and 3 compound heterozygous patients. The groups were analyzed in respect of cystic fibrosis disease severity markers, such as spirometry, ShwachmanKulczycki score, body mass index (BMI), sweat chloride concentration, chronic Pseudomonas aeruginosa infection, annual exacerbation frequency, and severe exacerbations requiring hospitalization during the previous year. In the comparison of group I and group II patients, a significant difference was observed in pancreas insufficiency (83.3% vs. 35.7%; P = .005), chronic P. aeruginosa infection (58.3% vs. 7.1%; P = .002), cough severity score (1.7 ± 1.1 vs. 0.9 ± 1.5; P = .029), number of severe exacerbations requiring hospitalization during the previous year (0.9 ± 1 vs. 0.3 ± 0.8; P = .03), and sweat chloride levels (76.7 ± 15.2 vs. 61 ± 22.3; P = .02). All these values were higher in group I patients. The mean BMI values (15.8 ± 2.2 vs. 17.6 ± 2.8; P = .03) were lower in group I patients. There seems to be a difference between class I/II CFTR mutations and class III-V mutations on the severity of the disease in cystic fibrosis patients.

Body composition in individuals with cystic fibrosis

Because nutritional status is intimately linked with pulmonary function and survival, nutrition has been at the mainstay of cystic fibrosis (CF) care. Body Mass Index (BMI) is traditionally used to define nutritional status because of the ease with which it can be calculated, but it has a number of limitations including its inability to differentiate fat mass (FM) from lean body mass (LBM), the latter thought to confer health advantage. A number of tools are available to quantify body composition including dual-energy x-ray absorptiometry (DXA), bioelectrical impedance, MRI, CT, air displacement plethysmography, and stable isotopes, and these have been used to varying degrees in studies of CF. In CF, LBM tends to be lower for a given BMI, particularly at lower BMI. In adults, lower fat-free mass (FFM) correlates with greater CF disease severity, lower pulmonary function and higher inflammatory markers. FFM is also positively associated with greater bone mineral density, while greater FM is associated with greater loss of lumbar spine bone mineral density over 2 years. In youth, LBM is positively associated with pulmonary function. The predictive value of body composition for functional and clinical outcomes and the role of improving LBM on these outcomes remain undefined. With improvements in BMI accompanying highly-effective modulator therapy, closer evaluations of body composition may inform risk for more traditional, non-CF adult outcomes in CF.

Peripheral blood mononuclear cell response to YKL-40 and Galectin-3 in cystic fibrosis

BackgroundElevated circulating levels of YKL-40 correlate with disease severity in Cystic Fibrosis (CF), but the role of YKL-40 in the inflammatory response in CF is still under investigation. Our main goal was to evaluate if YKL-40 can modulate the expression of major cytokines (IL-6, IL-10, IL-13) implicated in the inflammatory response in CF. A secondary goal was to explore the interactions between YKL-40 and other circulating proteins to determine the impacts on cytokine modulation. MethodPeripheral blood mononuclear cells (PBMCs) were isolated from the blood of 83 adult CF patients in stable clinical condition. PBMCs were treated with human YKL-40 followed by the measure of IL-6, IL-10 and IL-13 gene expression. Protein arrays were used to explore the interactions between YKL-40 and circulating proteins. Interaction with Galectin-3 (GAL3) was identified, and confirmed by binding assay. Cytokine gene expressions were again monitored by RT-qPCR after PBMC treatment with GAL3, with or without YKL-40 co-stimulation. ResultsFollowing YKL-40 stimulation, PBMC gene expression of IL-6, IL-10 and IL-13 varies across patients. IL-6 and IL-13 are coexpressed, but this response was different in male and female patients. GAL3 protein was detected in the blood of CF patients, and a molecular interaction with YKL-40 was identified. GAL3 did not interfere with the YKL-40 stimulation of IL-6, IL-10 and IL-13 but may modulate the coexpression. ConclusionWe observed that YKL-40 stimulation had a variable impact on IL-6, IL-10, and IL-13 gene expression in CF PBMCs and uncovered an interaction between GAL3 and YKL-40 in the serum of CF patients. Our findings suggest that YKL-40 is not only a biomarker of disease severity in CF, but it might play an active role in the inflammatory pathophysiology of the disease.

Achromobacter xylosoxidans airway infection is associated with lung disease severity in children with cystic fibrosis.

BackgroundDespite the increasing prevalence of Achromobacter xylosoxidans lung infection in patients with cystic fibrosis (CF), its clinical pathogenicity remains controversial. The objective of this study was to evaluate the effects of this emerging bacterium on lung disease severity in CF children.MethodsThis case–control retrospective study took place in two French paediatric CF centres. 45 cases infected by A. xylosoxidans were matched for age, sex, CFTR genotypes and pancreatic status to 45 never-infected controls. Clinical data were retrieved from clinical records over the 2 years before and after A. xylosoxidans initial infection.ResultsAt infection onset, lung function was lower in cases compared with controls (p=0.006). Over the 2 years prior to A. xylosoxidans acquisition, compared with controls, cases had more frequent pulmonary exacerbations (p=0.02), hospitalisations (p=0.05), and intravenous (p=0.03) and oral (p=0.001) antibiotic courses. In the 2 years following A. xylosoxidans infection, cases remained more severe with more frequent pulmonary exacerbations (p=0.0001), hospitalisations (p=0.0001), and intravenous (p=0.0001) and oral antibiotic courses (p=0.0001). Lung function decline tended to be faster in cases (−5.5% per year) compared with controls (−0.5% per year).ConclusionsThis case–control study demonstrates that A. xylosoxidans occurs more frequently in the patients with the worse lung disease. Further studies assessing the pathogenicity of this emerging pathogen and international treatment recommendations are warranted.

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

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.

Quantifying Disease Severity Of Cystic Fibrosis Using Quantile Regression Methods

This article presents a classification of disease severity for patients with cystic fibrosis (CF). CF is a genetic disease that dramatically decreases life expectancy and quality. The disease is characterized by polymicrobial infections which lead to lung remodeling and airway mucus plugging. In order to quantify disease severity of CF patients and compute a continuous severity index measure, quantile regression, rank scores, and corresponding normalized ranks are calculated for CF patients. Based on the rank scores calculated from the set of quantile regression models, a continuous severity index is computed for each CF patient and can be considered a robust estimate of CF disease severity.

EPS1.06 A retrospective audit of home-based spirometry quality in a large UK adult cystic fibrosis centre

Objectives: Spirometry measurement is the gold standard for assessing disease severity in cystic fibrosis (CF). Poor-quality spirometry tests can result in inaccurate measurement of FEV1 and FVC. Manchester Adult CF Centre has transformed from hospital to home-based spirometry testing during COVID-19. Unlike hospital-based spirometry, home-based spirometry relies entirely on the subject to obtain good quality spirometry. Therefore, we sought to ascertain the quality of home-based spirometry and the test errors in our patients. Methods: A convenience sample of adults with CF attending Manchester Adult CF Centre were provided with a NuvoAir home-based spirometer to perform routine lung function between March–October 2020. NuvoAir respiratory platform consists of a mobile phone application, Bluetooth spirometer and an online results portal. The spirometer also provides feedback to patients’ spirometry quality. Initial patient set-up was performed in-hospital or virtually with a member of the CF clinical team. All patient sessions were included irrespective of quality of spirometry test session. Acceptability and repeatability criteria were applied as per NuvoAir software in line with ATS/ERS guidelines, along with assigning a quality grading A–Faccording to ATS/ERS standardised pulmonary function report criteria at time of testing. Results: 66 CF patients (32 female) mean age 31.3 (18–55) performed 343 spirometry sessions totaling 1,041 individual spirometry tests with a NuvoAir device were graded as follows: Grade A = 30.3%, Grade B = 36.2%, Grade C = 3.5%, Grade D = 2.6%, Grade E = 16.6%, Grade F = 10.8%. Further analysis of all 1,041 tests for common errors indicated BX – Back extrapolation 2%, TP- Time to Peak (slow start) 14.6%, CO – Cough 1.4%, ET – Early termination 0.5%, CE – Cessation or glottic closure 12.9%. Overall, general tests A–C considered usable was 70%. Conclusion: The results show good-quality standards can be achieved through home-based spirometry.

P136 Relationship between cystic fibrosis disease severity and susceptibility to COVID-19 infection

Objective: Since cytokine storm and hyperinflammation play a key role on CF disease severity, severe CF patients should be considered to have an increased risk of developing severe symptoms of COVID-19. In this preliminary study, we evaluated whether there was a relationship between clinical severity of CF siblings and their susceptibility to COVID-19 infection. Method: In our preliminary study, we used a targeted transcriptomic approach (CF Profiler Array) obtained from nasal samples of three families who had CF siblings harbouring same mutation but showing different severity of CF phenotype. The siblings were classified as severe or mild CF according to recurrent lung infection, hepatic involvement, and FEV1. Results: In severe CF patients (n = 4) compared to mild patients (n = 3) CXCL1 (FC:-3.53), CXCL2 (FC:-2,16), CXCL8 (FC:-5.41), IL1B (FC:-2.61), SERPINA1 (FC:-2.54), TNFSF10 (FC:-1.73) were found to be downregulated. CXCL1, CXCL2, CXCL8 play critical role during infection control in neutrophiles that release other chemotactic mediators and recruit leukocytes. Additionally IL1B and TNFSF10 also affect activation of leukocytes. In the case of COVID-19 infection, the expression of these genes increases and leads to a cytokine storm. However our results show that CXCL1, CXCL2, CXCL8, IL1B genes which have a function in IL-17, NFKB, NLRP3 signaling pathways are downregulated in severe CF patients. Significant evidence supports the role of IL-1B, NLRP3-dependent inflammasome activation which is a central mediator of severe COVID-19 in the pathogenesis of acute lung injury. However, downregulation of inflammatory pathways is detected in severe forms of CF. Conclusion: The results of our preliminary study strengthens the hypothesis that severe forms of CF may constitute an advantage to mild forms of CF in susceptibility to COVID-19 and CXC inhibitors may be a promising therapeutic option for COVID-19 in the future. Further analyses should be performed with larger sample sizes.

Drug Optimization for Cystic Fibrosis Patients Based on Disease Pathways Crosstalk

Cystic fibrosis (CF) is a common autosomal recessive disease characterized by pancreatic insufficiency and progressive deterioration of lung function. It has been shown that CF is caused by the presence of mutations in both alleles at the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The severity of CF disease reflects the change of molecular mechanism, including DNA mutations on CFTR gene and polymorphic variations in disease modifier genes. Better understanding the differences among different CF severity group is helpful for improving therapeutic plans for patients. In this paper, the authors present a computational network biology approach to screen precision drugs for CF patients, which is based on the intensity of drugs impact on the pathway crosstalk mediated by differential methylation genes. The results indicate that ivacaftor, tezacaftor, and lumacaftor are applicable to all severity cohorts, gefitinib, sorafenib, sunitinib, and imatinib mesylate have the potential to treat intermediary CF patients, and tamoxifen may be useful to mild and sever CF patients.

YKL-40 as a clinical biomarker in adult patients with CF: Implications of a CHI3L1 single nucleotide polymorphism in disease severity

BackgroundYKL-40 (chitinase 3-like 1 gene; CHI3L1) is an inflammatory marker that is increased in the blood of patients with inflammatory diseases, including cystic fibrosis (CF). The objective of our study was to explore the relationship between circulating levels of YKL-40, selected CHI3L1 single nucleotide polymorphisms (SNPs) and the severity of CF disease. MethodsA prospective cohort of 188 adult patients with CF was established in 2015. Blood samples and clinical data were collected over 2 years to analyze the circulating levels of YKL-40 and to genotype selected CHI3L1 SNPs. We also looked for an association between these factors and clinical parameters. ResultsWe found that according to the serum YKL-40 concentration, the patients could be categorized into two distinct groups: low and high YKL-40. Compared to the patients in the low YKL-40 group, the patients in the high YKL-40 group had lower lung function (P < 0.001), a higher proportion of delF508 homozygote mutations (P= 0.027) and dysglycemia (P= 0.015). They were also more colonized with Pseudomonas aeruginosa (P= 0.003) and required more frequent antibiotic intravenous courses (P < 0.001). We also observed that patients expressing the C/C-rs4950928 genotype had higher levels of YKL-40 in their blood and were more frequently dysglycemic. ConclusionOur study suggests that YKL-40 could be a potential biomarker of CF disease severity. Furthermore, the CHI3L1 rs4950928 SNP could be a susceptible gene that could be used by CF health professionals to identify patients who are the most at risk of having a severe clinical profile.

Aerosolized drug-loaded nanoparticles targeting migration inhibitory factors inhibit Pseudomonas aeruginosa-induced inflammation and biofilm formation.

Aim: Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine, which has been shown to promote disease severity in cystic fibrosis. Methods: In this study, aerosolized drug-loaded nanoparticlescontaining SCD-19, an inhibitor of MIF's tautomerase enzymatic activity, were developed and characterized. Results: The aerosolized nanoparticles had an optimal droplet size distribution for deep lung deposition, with a high degree of biocompatibility and significant cellular uptake. Conclusion: For the first time, we have developed an aerosolized nano-formulation against MIF's enzymatic activity that achieved a significant reduction in the inflammatory response of macrophages, and inhibited Pseudomonas aeruginosabiofilm formation on airway epithelial cells. This represents a potential novel adjunctive therapy for the treatment of P. aeruginosa infection in cystic fibrosis.

Baseline Cystic fibrosis disease severity has an adverse impact on pregnancy and infant outcomes, but does not impact disease progression

BackgroundWith increasing longevity and quality of life in adults with Cystic fibrosis (CF), growing maternity rates are reported. Women with severe CF are becoming pregnant, with unpredictable maternal and fetal outcomes. AimTo determine how baseline disease severity, pancreatic insufficiency (PI) and Pseudomonas aeruginosa (PA) infection affect fertility, the pregnancy course, delivery, neonatal outcome, and subsequent disease progression. MethodsA multicenter-retrospective cohort study. Data on patients that had been pregnant between 1986-2018 was collected from ten CF centers worldwide. Disease severity [mild or moderate-severe (mod-sev)] was defined according to forced expiratory volume % predicted in 1 second (FEV1) and body mass index (BMI). Three time periods were compared, 12 months prior to conception, the pregnancy itself and the 12 months thereafter. ResultsData was available on 171 pregnancies in 128 patients aged 18-45 years; 55.1% with mod-sev disease, 43.1% with PI and 40.3% with PA. Women with mod-sev disease had more CF-related complications during and after pregnancy and delivered more preterm newborns. However, FEV1 and BMI decline were no different between the mild and mod-sev groups. A more rapid decline in FEV1 was observed during pregnancy in PI and PA infected patients, though stabilizing thereafter. PI was associated with increased risk for small for gestational age infants. ConclusionBaseline disease severity, PA infection and PI have an adverse impact on infant outcomes, but do not impact significantly on disease progression during and after pregnancy. Consequently, pregnancies in severe CF patients can have a good prognosis.

The Role of Vitamin D3 Therapy in Pediatric Bronchiectasis Severity (CF versus Non-CF Patients)

Objective: To determine and compare the effect of vitamin D3 supplementation on modifying the disease severity in cystic fibrosis (CF) and non-CF bronchiectasis pediatric patients. Methods: A randomized clinical trial evaluating the role of oral vitamin D3 supplementation for six months, was performed in forty patients with CF and non-CF bronchiectasis under the age of 18 years with vitamin D deficiency or insufficiency. The primary outcome was to reach the sufficient Vitamin D level, the secondary outcome was to reevaluate bronchiectasis severity by following up the frequency, severity of pulmonary exacerbations and lung function after vitamin D3 supplementation. Results: Forty patients completed the trial. The percentage of improvement of vitamin D level after vitamin D3 supplementation for six months was significantly higher in CF (88.3%) than non-CF bronchiectasis patients (59.82%) (P = 0.03). Additionally, moderate to severe pulmonary exacerbations significantly decreased by more than 60%, 45% (P = 0.001, 0.005) and frequent exacerbations decreased by 15%, 10% (P = 0.327, 0.490), while the forced expiratory volume in 1 (FEV1) significantly increased by 17% and 15% in non CF bronchiectasis and CF patients respectively (p 0.001). Conclusions: Vitamin D3 therapy was effective in decreasing the frequency and severity of pulmonary exacerbations and preserving lung function. Thereby, improving the disease severity even more in non-CF bronchiectasis than CF patients.

Genetic variation in CFTR and modifier loci may modulate cystic fibrosis disease severity

In patients with cystic fibrosis (CF), genetic variants within and outside the CFTR locus contribute to the variability of the disease severity. CFTR transcription is tightly regulated by cis-regulatory elements (CREs) that control the three-dimensional structure of the locus, chromatin accessibility and transcription factor recruitment. Variants within these CREs may contribute to the pathophysiology and to the phenotypic heterogeneity by altering CFTR transcript abundance. In addition to the CREs, variants outside the CFTR locus, namely “modifiers genes”, may also be associated with the clinical variability. This review addresses variants at the CFTR locus itself and CFTR CREs, together with the outcomes of the latest modifier gene studies with respect to the different CF phenotypes.

P070 The effect of distance from specialist health centre on disease severity in cystic fibrosis in the UK

P070 The effect of distance from specialist health centre on disease severity in cystic fibrosis in the UK