M. McCarthy

Inhaled versus nebulised tobramycin: A real world comparison in adult cystic fibrosis (CF)

BACKGROUND There are no published data on real-life clinical experience comparing inhaled antibiotic therapy via new rapid delivery systems with nebulised antibiotic therapy in CF. This real world study compares safety, effectiveness and tolerability using tobramycin inhaled powder (TIP) versus tobramycin inhaled solution (TIS). METHODS Adult patients with CF commencing TIP (n=78) completed a questionnaire assessing safety, efficacy, tolerability, patient-satisfaction and self-reported adherence to TIS at baseline and during 12 months of TIP therapy. FEV1% predicted and exacerbation rate were recorded at each visit. RESULTS There was a significant improvement in adherence scores, with a significant decrease in the number of intravenous antibiotic courses received during 12 months of TIP compared with the preceding 12 months using TIS. 94% of patients who had previously used TIS preferred TIP therapy over TIS. CONCLUSIONS Inhaled powder tobramycin in CF is associated with improved adherence, tolerability and decreased exacerbation rates compared to nebulised treatment in real-life practice.

74 Improved tolerability, adherence and reduced intravenous (IV) antibiotic usage in CF patients receiving inhaled versus nebulised antibiotic prophylaxis. A real world comparison of tobramycin inhaled powder (TIP) and tobramycin inhaled solution (TIS)

Objectives: Phosphodiesterase 5 inhibitors (IPDE5) are able to restore chloride transport in F508del cystic fibrosis (CF) airway epithelium. CF patients with severe lung disease are at risk of pulmonary hypertension and impaired exercise tolerance. Treatment with IPDE5 is a promising strategy in CF. Methods: We conducted a study in 12 stable F508del homozygous CF adults (5 males and 7 females) with median (IQR) age of 25.9 (22.8–27.6) years without Burkholderia cepacia complex airway colonization. We administered sildenafil for 30 days and evaluated pulmonary function, respiratory symptoms and exercise tolerance before and after treatment using spirometry (forced expiratory volume in 1 sec. [FEV1]), 6-minute walking test (6-minute walking distance [6-MWD]) and CFQ-R quality of life questionaire (physical and respiratory domain [PHYS and RESP, respectively]). 8 patients completed the study (2 dropped due to pulmonary exacerbation and further 2 due to headaches). Exercise tolerance changed significantly (median and IQR; Wilcoxon test): 6-MWD 618 (612–692) vs. 577 (562–633) m, p = 0.012, and PHYS 93.8 (68.8–100.0) vs. 89.6 (60.4–97.9), p = 0.043, whereas pulmonary function and respiratory symptoms did not. Transient headaches were common adverse events during the first 1−2 weeks of sildenafil treatment in 7 of the 12 patients. Conclusion: We conclude that short-term sildenafil treatment in CF adults led to an improvement of exercise tolerance without changing pulmonary function and respiratory symptoms. Supported by the project (Ministry of Health, Czech Republic) for conceptual development of research organization 00064203 (University Hospital Motol, Prague, Czech Republic).

WS16.1 Clinical Outcomes of Real-World Kalydeco (CORK) study – Investigating the impact of CFTR potentiation on the intestinal microbiota, exocrine pancreatic function and intestinal inflammation prospectively over 12 months

Objectives Ivacaftor is effective in the treatment of patients with CF and the G551D gating mutation. We present faecal analysis results of the CORK cohort, a single-centre, adult (n = 20), prospective, longitudinal study of G551D clinical responders (median follow-up 12 months), examining the gut microbiota, exocrine pancreatic function and intestinal inflammation on a 3 monthly basis after commencing treatment. Methods Stool samples pre- and 3 monthly post commencement of ivacaftor in 20 adult patients underwent metagenomic profiling of faecal microbiota. Faecal elastase-1 (FE-1), faecal calprotectin (FC) and faecal lactoferrin (FL) were measured using commercially available ELISA kits. Results Ivacaftor did not significantly alter gut microbial diversity, as measured by chao1 (p = 0.886). At phylum, family and genus levels significant increases were observed in Bacteroidetes (p = 0.044), Bacteroidaceae (p = 0.021) and Bacteroides (p = 0.021). Significant decreases were observed in Microbacteriaceae (p = 0.003) and Eubacteriaceae (p = 0.014). A significant positive correlation was seen between FEV1 and gut microbiota diversity following treatment (r = 0.4, p=0.002). No significant difference was measured in levels of FE-1 (p = 0.267), FC (p = 0.406) or FL (p = 0.779). Conclusion Ivacaftor therapy has a normalisation effect on the gut microbiota, directing the microbiota towards a non-CF profile. Despite this elevated intestinal inflammation was sustained. Lack of exocrine pancreatic recovery may reflect established exocrine pancreatic dysfunction in an adult cohort. On-going longitudinal prospective data may demonstrate further improvements in the gut health of this cohort.

217 Medical outcomes post transition of clinical care from a paediatric cystic fibrosis care model to an adult cystic fibrosis care model – an Irish perspective

As life-expectancy increases in CF it is paralleled by an increasing number of patients transitioning from a paediatric care-model to an adult care-model. In chronic illnesses’ including CF the transition process is often complicated by concerns about the potential implications. Traditionally studies have evaluated subjective aspects of transition including patient satisfaction. There are limited objective studies in this area. Our study investigated the change in clinical status in the year pre & post transition.

128 The metabolic consequences of CFTR modulation with ivacaftor in a single adult cystic fibrosis centre cohort

Objectives Ivacaftor produces significant benefit in patients with cystic fibrosis (CF) with the G551D mutation. Recent data have supported improved insulin secretion profile and reversal of CF related diabetes (CFRD) in patients treated with ivacaftor. Significant weight gain has been demonstrated with ivacaftor, thus raising the potential for development of dyslipidaemia in a cohort traditionally treated with a high fat diet. Methods 24 Adult patients with the G551D mutation had Oral Glucose Tolerance Test (OGTT), Fasting lipid profile and HbA1C measured before and after commencing ivacaftor therapy. 6 patients had pre-existing CFRD and Insulin requirements were analysed in this cohort before and after ivacaftor. Data was analysed using Wilcoxon signed-rank test. Results No significant change was observed in fasting glucose, 2 hour post prandial glucose, or HbA1C after commencement of ivacaftor. Significant median increase in total fasting cholesterol (0.2 mmol/L, P=0.025) and HDL (0.16 mmol/L, P=0.03) were observed after commencement of treatment. There was no significant change in LDL or Triglycerides. In the 6 patients with CFRD no significant change in either total insulin requirements or units of insulin per kilogram of weight were observed. Conclusion In a large single centre cohort with the G551D mutation we report no significant change in OGTT, HbA1c or insulin requirements after ivacaftor. While a significant increase in Fasting cholesterol was observed, median values were within normal limits. Changes in lipid profile may reflect the impact of adhering to a high fat diet as a consequence of therapy and will required long-term follow up.

48 Altered gut microbiota in stable patients with cystic fibrosis (CF) compared to controls and its relationship with intravenous (IV) antibiotic usage and lung function

Objective CF is associated with altered digestive function and thus nutrient availability for gut microbes in addition to altered gut microbiota, compared with healthy controls. Equally intensive antibiotic and nutritional therapy may further compound this. We present results from the largest CF gut microbiota study to date. Methods The gut microbiota of 43 stable adults with CF was compared to 69 age-matched controls. DNA was extracted from faecal samples and the V4 region of the 16S rRNA gene was sequenced using 454-pyrosequencing. Results were correlated with baseline %FEV 1 results and to total courses of IVs in the previous 12 months. Results The gut microbiota diversity of patients with CF was significantly reduced compared to controls (p Faecalibacterium, Roseburia and Bifidobacterium (p 1 and gut diversity (Simpsons diversity index: r=0.47, p=0.0015) was found in those with CF. Conclusion This study highlights that patients with CF have an altered gut microbiota which correlates with clinical outcomes. Further longitudinal studies will enable us to interrogate the causality of such microbiota alterations and determine the potential role of probiotics in CF therapy.

200 Prevalence of dyslipidaemia in an Irish adult cystic fibrosis cohort

Patients with cystic fibrosis (PWCF) are typically prescribed high calorie, high fat diets. With improved survival, there is emerging data that suggests an increased risk of cardiovascular disease. This study examines the prevalence of dyslipidaemia and its associated clinical phenotype in an Irish adult CF population. Biometric data and fasting lipid profiles were collected from patients attending annual assessment at the CF day unit between August 2012 and August 2013. Phenotypic information was collected from patient charts. 98 participants (mean age 28±10) were included in the study. Of this sample, 31% had CF-related diabetes and 83% were pancreatic insufficient. Across the population, mean and median lipid profiles were normal. However, 25% had lower HDL, 17% had elevated triglycerides, 17% elevated LDL, and 8% elevated total cholesterol. Total cholesterol and LDL were found to increase with increasing age and BMI. Increased total cholesterol was strongly correlated with increased LDL. On subgroup analysis, pancreatic sufficient subjects were more likely to have higher LDL (p< 0.001) and 63% of these had higher than optimal LDL. Diabetics were more likely to have higher triglycerides (p< 0.05) and 29% had higher than optimal levels. Men were found to have lower total cholesterol (p = 0.007) and lower HDL (p = 0.001). With increasing age, dyslipidaemia is an important emerging cardiovascular risk factor for PWCF. This is the first study to show this in a European population and is in keeping with previous studies.

254 The prognostic significance of hypoglycaemia on oral glucose tolerance tests in adults with cystic fibrosis (CF): A prospective clinical study

Objectives: In normal individuals, the shape of the OGTT curve (monophasic or biphasic) is influenced not only by the glucose load but also the patient’s metabolic response. This has not been studied in CF and may give an insight into the abnormal glucose handling even in those without CFRD. Method: We compared the area under the curve (AUC) for glucose, insulin, C-Peptide and glucagon following a 2-hour OGTT in 13 pancreatic insufficient adult CF (without known CFRD) and 10 healthy subjects, classified according to the OGTT curve shape. Results: See table. Biphasic curves were more common in CF (Chi2 = 4.97, p< 0.03), and these patients also had higher glucagon levels (p = 0.01) compared to their healthy counterparts, whilst CF patients with monophasic curves had reduced C-peptide levels (p = 0.04). Conclusions: This study shows that the shape of the OGTT curve in CF is related to pancreatic alpha and beta-cell function, as well as glucose load. The OGTT shape index may be a useful screening tool to make an early diagnosis of diabetes in CF.

202 Nebuliser strategies in cystic fibrosis in Ireland. Results of a national audit

The I-neb Adaptive aerosol device (AAD) is used widely by CF patients. The introduction of an online assessment tool facilitates patient self monitoring of nebuliser efficiency, treatment times and breathing techniques. Aim: To download and evaluate the use of the I-neb over a period of 1 year by 10 patients; comparing this information with the patients perceived use of the device to identify the potential benefit of a patient self monitoring tool on treatment concordance. Method: I-neb data from a 12 month period was downloaded from 10 patients who were issued with a short questionnaire asking them to outline how they had used their nebuliser. The results were returned to the CF Physiotherapist and feedback was compared with the downloaded data. Results: 70% of patients perceived their I-neb use to be higher than the data downloaded (11.56% and 70.88%) 3 patients underestimated their use ((0.48%-1.5%). Patients perceived that the I-neb provided a quick (80% estimated 75% dose delivery) method of drug delivery. The actual % dose which the patients received ranged from between 94–100% (average 98.4%) 80% perceived that they received >75% each treatment. With 20% perceiving their dose to be between 50 and 75%. 80% of patients expressed interest in the availability of a tool which provided feedback on frequency of I-neb use, time taken, % dose delivered and quality of the mesh of the device. Conclusion: Patient interest in an online method of self assessment tool indicates that this could be an effective method of improving concordance with treatment recommendations and reducing the gap between perceived and actual I-neb usage.