Nicola Ronan

Cystic fibrosis transmembrane conductance regulator modulators: the end of the beginning.

Cystic fibrosis (CF) represents one of the success stories of modern medicine with sustained incremental increases in the survival from one of childhood death to one of adult survival into the middle decades over the past 30 years. Improving survival has focused on multidisciplinary management centered on treating the consequences of this genetic disease. It has been firmly established for more than 20 years that mutations in the CF transmembrane conductance regulator (CFTR) gene result in a defective protein that normally functions as a chloride channel on epithelial cell surfaces. Until recently, modulating CFTR dysfunction was only a research aspiration, however, greater focus placed upon addressing the primary defect of CF has developed several clinical therapeutic strategies in this area. This review highlights the evidence to date on efforts to modulate CFTR and restore robust functional protein to the cell surface. This approach has now led to the licensing of one CFTR potentiator, which has been shown to have significant clinical improvements in a subset of CF patients. This success represents the beginning for CFTR modulation and further research is ongoing which aims to broaden the applicability of these techniques.

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.

CORK study in CF Sustained improvements in ultra-low dose chest CT scores post CFTR modulation with ivacaftor

Background Ivacaftor produces significant clinical benefit in patients with cystic fibrosis (CF) with the G551D mutation. Prevalence of this mutation at the Cork CF Centre is 23%. This study assessed the impact of cystic fibrosis transmembrane conductance regulator modulation on multiple modalities of patient assessment. Methods Thirty‐three patients with the G551D mutation were assessed at baseline and prospectively every 3 months for 1 year after initiation of ivacaftor. Change in ultra‐low‐dose chest CT scans, blood inflammatory mediators, and the sputum microbiome were assessed. Results Significant improvements in FEV1, BMI, and sweat chloride levels were observed post‐ivacaftor treatment. Improvement in ultra‐low‐dose CT imaging scores were observed after treatment, with significant mean reductions in total Bhalla score (P < .01), peribronchial thickening (P = .035), and extent of mucous plugging (P < .001). Reductions in circulating inflammatory markers, including interleukin (IL)‐1&bgr;, IL‐6, and IL‐8 were demonstrated. There was a 30% reduction in the relative abundance of Pseudomonas species and an increase in the relative abundance of bacteria associated with more stable community structures. Posttreatment community richness increased significantly (P = .03). Conclusions Early and sustained improvements on ultra‐low‐dose CT scores suggest it may be a useful method of evaluating treatment response. It paralleled improvement in symptoms, circulating inflammatory markers, and changes in the lung microbiota.

Tissue and Bronchoalveolar Lavage Biomarkers in Idiopathic Pulmonary Fibrosis Patients on Pirfenidone.

BackgroundPirfenidone is a novel anti-fibrotic agent in idiopathic pulmonary fibrosis with proven clinical benefit. Better human tissue models to demonstrate the immunomodulatory and anti-fibrotic effect of pirfenidone are required.ObjectivesThe purpose of the study was to use transbronchial lung cryobiopsy (TBLC), a novel technique which provides substantial tissue samples, and a large panel of biomarkers to temporally assess disease activity and response to pirfenidone therapy.MethodsThirteen patients with confirmed idiopathic pulmonary fibrosis (IPF) underwent full physiological and radiological assessment at diagnosis and after 6-month pirfenidone therapy. They underwent assessment for a wide range of potential serum and bronchoalveolar lavage biomarkers of disease activity. Finally, they underwent TBLC before and after treatment. Tissue samples were assessed for numbers of fibroblast foci, for Ki-67, a marker of tissue proliferation and caspase-3, a marker of tissue apoptosis.ResultsAll patients completed treatment and investigations without significant incident. There was no significant fall in number of fibroblast foci per unit tissue volume after treatment (pre-treatment: 0.14/mm2 vs. post-treatment 0.08/mm2, p = 0.1). Likewise, there was no significant change in other markers of tissue proliferation, Ki-67 or Caspase-3 with pirfenidone treatment. We found an increase in three bronchoalveolar lavage angiogenesis cytokines, Placental Growth Factor, Vascular Endothelial Growth Factor-A, and basic Fibroblast Growth Factor, two anti-inflammatory cytokines Interleukin-10 and Interleukin-4 and Surfactant Protein-D.ConclusionsTBLC offers a unique opportunity to potentially assess the course of disease activity and response to novel anti-fibrotic activity in IPF.

CORK Study in Cystic Fibrosis

Background Ivacaftor produces significant clinical benefit in patients with cystic fibrosis (CF) with the G551D mutation. Prevalence of this mutation at the Cork CF Centre is 23%. This study assessed the impact of cystic fibrosis transmembrane conductance regulator modulation on multiple modalities of patient assessment. Methods Thirty‐three patients with the G551D mutation were assessed at baseline and prospectively every 3 months for 1 year after initiation of ivacaftor. Change in ultra‐low‐dose chest CT scans, blood inflammatory mediators, and the sputum microbiome were assessed. Results Significant improvements in FEV1, BMI, and sweat chloride levels were observed post‐ivacaftor treatment. Improvement in ultra‐low‐dose CT imaging scores were observed after treatment, with significant mean reductions in total Bhalla score (P < .01), peribronchial thickening (P = .035), and extent of mucous plugging (P < .001). Reductions in circulating inflammatory markers, including interleukin (IL)‐1&bgr;, IL‐6, and IL‐8 were demonstrated. There was a 30% reduction in the relative abundance of Pseudomonas species and an increase in the relative abundance of bacteria associated with more stable community structures. Posttreatment community richness increased significantly (P = .03). Conclusions Early and sustained improvements on ultra‐low‐dose CT scores suggest it may be a useful method of evaluating treatment response. It paralleled improvement in symptoms, circulating inflammatory markers, and changes in the lung microbiota.

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.