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BACKGROUND: Treatment with Ivacaftor provides a significant clinical benefit in people with cystic fibrosis (PWCF) with the class III G551D-CFTR mutation. This study determined the effect of CFTR modulation with ivacaftor on the lung microbiota in PWCF.METHODS: Using both extended-culture and culture-independent molecular methods, we analysed the lower airway microbiota of 14 PWCF, prior to commencing ivacaftor treatment and at the last available visit within the following year. We determined total bacterial and Pseudomonas aeruginosa densities by both culture and qPCR, assessed ecological parameters and community structure and compared these with biomarkers of inflammation and clinical outcomes.RESULTS: Significant improvement in FEV1, BMI, sweat chloride and levels of circulating inflammatory biomarkers were observed POST-ivacaftor treatment. Extended-culture demonstrated a higher density of strict anaerobic bacteria (p = 0.024), richness (p = 1.59*10-4) and diversity (p = 0.003) POST-treatment. No significant difference in fold change was observed by qPCR for either total bacterial 16S rRNA copy number or P. aeruginosa density for oprL copy number with treatment. Culture-independent (MiSeq) analysis revealed a significant increase in richness (p = 0.03) and a trend towards increased diversity (p = 0.07). Moreover, improvement in lung function, richness and diversity displayed an inverse correlation with the main markers of inflammation (p < 0.05).CONCLUSIONS: Following treatment with ivacaftor, significant improvements in clinical parameters were seen. Despite modest changes in overall microbial community composition, there was a shift towards a bacterial ecology associated with less severe CF lung disease. Furthermore, a significant correlation was observed between richness and diversity and levels of circulating inflammatory markers.

Thoracic computed tomography (CT) is the imaging reference method in the diagnosis, assessment and management of lung disease. In the setting of cystic fibrosis (CF), CT demonstrates increased sensitivity compared with pulmonary function tests and chest radiography, and findings correlate with clinical outcomes. Better understanding of the aetiology of CF lung disease indicates that even asymptomatic infants with CF can have irreversible pulmonary pathology. Surveillance and early diagnosis of lung disease in CF are important to preserve lung parenchyma and to optimise long-term outcomes. CF is associated with increased cumulative radiation exposure due to the requirement for repeated imaging from a young age. Radiation dose optimisation, important for the safe use of CT in children with CF, is best achieved in a team environment where paediatric radiologists work closely with paediatric respiratory physicians, physicists and radiography technicians to achieve the best patient outcomes. Despite the radiation doses incurred, CT remains a vital imaging tool in children with CF. Radiologists with special interests in CT dose optimisation and respiratory disease are key to the appropriate use of CT in paediatric imaging. Paediatric radiologists strive to minimise radiation dose to children whilst providing the best possible assessment of lung disease.

The introduction of NBS in Ireland in July 2011, provided a unique opportunity to investigate clinical outcomes using a comparative historical cohort study. Clinical cohort: children clinically diagnosed with CF born 1 July 2008 to 30 June 2011, and NBS cohort: children diagnosed with CF through NBS born 1 July 2011 to 30 June 2016. Clinical data were collected from the CF Registry of Ireland, medical charts, and data on weight/height before diagnosis from public health nurses and family doctors. SPSS was used for analysis. A total of 232 patients were recruited (response 93%) (93 clinically diagnosed, 139 NBS-detected). Following exclusions of meconium ileus (MI) (40), diagnosis outside Ireland (4), and being designated as CFSPID (2), a total of 77 clinically diagnosed patients and 109 NBS detected children were included in analysis. Over half were homozygous for F508del mutation. Being clinically diagnosed was independently associated with hospitalization for infective exacerbation of CF

Patient registries have the potential to collect and analyze high-quality postauthorization data on new medicines.We used cystic fibrosis (CF) registry data to assess outcomes after the initiation of ivacaftor, a CF transmembrane conductance regulator (CFTR) potentiator approved for the treatment of CF with a defective gating CFTR mutation.Longitudinal trends were examined using mixed-effects regression analysis in 80 ivacaftor-treated patients with CF aged 6 to 56 years registered with the CF Registry of Ireland with at least 36 months of before and after commencement data. The effects of ivacaftor treatment on forced expiratory volume in 1 second (FEVIn the 36 months after ivacaftor initiation, FEVIn this study of real-world CF registry data, clinical outcomes improved and healthcare resource utilization decreased after commencing 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 FEV 1 , 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 P = . 035), and extent of mucous plugging ( P 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.

Thoracic computed tomography (CT) is the imaging reference method in the diagnosis, assessment and management of lung disease. In the setting of cystic fibrosis (CF), CT demonstrates increased sensitivity compared with pulmonary function tests and chest radiography, and findings correlate with clinical outcomes. Better understanding of the aetiology of CF lung disease indicates that even asymptomatic infants with CF can have irreversible pulmonary pathology. Surveillance and early diagnosis of lung disease in CF are important to preserve lung parenchyma and to optimise long-term outcomes. CF is associated with increased cumulative radiation exposure due to the requirement for repeated imaging from a young age. Radiation dose optimisation, important for the safe use of CT in children with CF, is best achieved in a team environment where paediatric radiologists work closely with paediatric respiratory physicians, physicists and radiography technicians to achieve the best patient outcomes. Despite the radiation doses incurred, CT remains a vital imaging tool in children with CF. Radiologists with special interests in CT dose optimisation and respiratory disease are key to the appropriate use of CT in paediatric imaging. Paediatric radiologists strive to minimise radiation dose to children whilst providing the best possible assessment of lung disease.

Objectives To examine the effects of Ivacaftor on growth and pancreatic function in patients attending the Paediatric Cystic fibrosis (CF) Centre at Cork University Hospital. Methods A retrospective, convenience sampled cohort analysis was conducted in patients aged 2 to 17 with genetically confirmed CF (N=28, 15 male, 13 female). Subjects who received Ivacaftor over a 1 year period had an oral dose of either 75 or 150 mg twice daily depending on weight. Patients were excluded if concurrently taking Lumacaftor. The primary end points were estimated mean change from baseline through one year in pancrealipase (Creon) consumption per day and body mass index (BMI). Secondary end points included the changes in mean percent of predicted forced expiratory volume in 1 second (FEV1) as well as exocrine pancreatic marker faecal elastase-1 (FE-1) and random blood glucose within the Ivacaftor group. Results The change in pancrealipase use was significantly decreased in the Ivacaftor group in comparison to controls (1202± 587 IU/kg, p=0.039). In addition, Ivacaftor users had a significant increase in gross BMI (0.98± 0.51 kg/m2, p=0.010) and a non-significant increase in FEV1% predicted (10.9± 5.06%, p=0.123) in comparison to controls. On subgroup analysis, there was significant improvement in FE-1 after one year of Ivacaftor use (107± 80.8μg/g, p= 0.013, N=7). As well, there was mild decrease seen in random blood glucose, however this result was not significant (-0.43± 0.87 mmol/L, p=0.153, N=10). Conclusions Ivacaftor improves paediatric CF patients’ BMI, blood glucose, and FE-1 values while reducing their reliance on pancrealipase. This data supports previous research showing increasing lung function in Ivacaftor users. Subgroup analysis of those with serial FE-1 results revealed that 43% of those taking Ivacaftor reached pancreatic exocrine sufficiency (FE-1> 200μg/g). This implies that further study of Ivacaftor’s pancreatic implications is warranted. Similarly, prospective studies of new and emerging drugs of this class in a similar manner could yield positive results for patients.

Introduction Orkambi (Lumacaftor/Ivacaftor) was first introduced for use in the Cystic Fibrosis population in Ireland in 2017. It is only licensed for those patients who are homozygous for the F508del gene mutation.Orkambi was originally approved for children aged 12 years and older in 2017 and then this was extended for those aged 6–11 years old in 2018. Recently, the EMA(European Medicines Agency) has approved use for children 2–5 years. CUH(Cork University Hospital) looks after 98 paediatric patients with CF of whom 37 have been commenced on Orkambi since July 2017. Objectives The primary objective was to assess the outcomes of Orkambi at 6 and 12 months on FEV1, BMI and BMI Centile and to compare the days on Intravenous antibiotics and weeks of oral antibiotics for pulmonary exacerbations in the year before and after commencing Orkambi. Results Thirty seven patients were included in the study population with a split of 21 females and 16 males. The average profile of our patient cohort before commencing Orkambi was 11.0 years, BMI 16.8 kg/m2, BMI Centile 43.2 and Average FEV1 96.7%. To date, 11 patients have completed over a year of treatment and the remainder will have completed 12 months by June 2019. Six month followup has shown that 30/37(81%) of patients have had an increase in their BMI with an average BMI at 6 months of 17.5 and BMI difference of +0.7 kg/m2. BMI centile was increased in 24/37(65%) with centile difference of +5.7 to an average of 48.9. Lung function did not show any improvement from Pre-Orkambi values with average FEV1 of 95.9% at 6 months. This was also shown in followup of patients who completed 12 months of treatment with average FEV1 difference of -2%. For those who had completed 12 months on Orkambi, the no of weeks on oral antibiotics and IV antibiotics both showed a reduction in the year following commencement. There was a 26% decrease in oral antibiotics prescribed with average reduction of 1.5 weeks. Three patients had required IV antibiotics in the year prior. Two of these had no IVs over the following year and one patient with severe CF disease had a 55% reduction in days on IVs from 121 to 66 days. Conclusion Orkambi has improved BMI/BMI centiles but has not shown any improvement in FEV1. Preliminary data has shown a reduction in pulmonary exacerbations although further analysis of the remaining patients will allow more accurate conclusions.

Background A previous national audit looking at sweat testing in all age groups in 2011 found Cork University Hospital (CUH) had a high number of tests with quantity not sufficient (QNS) result. Since then there has been new equipment and staff training. International laboratory audit criteria examine failure rates for under 6 months which has recently been Aims Sweat tests performed in CUH from 2011–2018 as part of newborn screening in relation to number of patients with positive (>60), negative ( Methods Ethical approval obtained Newborn screening records for all patients from July 2011 to December 2018 reviewed. Sweat testing data obtained from laboratory. Data analysed using SPSS and Chi-Square test. Results 102 infants referred to Cork for sweat testing as part of newborn screening. Patients diagnosed by meconium ileus (n=7), had sweat testing elsewhere (n=1) or had antenatal diagnosis (n=2) were not included (N= 10). On initial testing 30 patients had a QNS result (32.6%). 7 had same day repeat testing which was sufficient, the remaining having sweat testing at a later date. Ultimately there were 23 with positive tests, 67 with negative tests, 2 equivocal tests. Gestational age and birth weight of the 30 patients with initial QNS result were compared to the 62 with successful testing. Infants were divided into two groups based on gestation, 38 weeks and below and 39 weeks and above. Results were dichotomised into sufficient and insufficient (QNS) results. The Chi square test indicated that there is a statistically significant association between gestational age and sufficient or insufficient result. (p=0.004) Discussion It would be helpful to compare our data to the same cohort in other centres and national rate to see if this is an acceptable QNS rate and obtain further data regarding gestational age. Collection techniques and laboratory analysis have already been optimised with current equipment and staff. Consideration could be given to delay offering sweat test by one to two weeks to those born at 37 and 38 weeks gestation in infants who only have 1 mutation. This may reduce need for time consuming and stressful repeat testing.

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.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.Significant improvements in FEVEarly 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.

Chronic respiratory infections are a leading global cause of morbidity and mortality. However, the molecular triggers that cause respiratory pathogens to adopt persistent and often untreatable lifestyles during infection remain largely uncharacterised. Recently, bile aspiration caused by gastro-oesophageal reflux (GOR) has emerged as a significant complication associated with respiratory disease, and cystic fibrosis (CF) in particular. Based on our previous finding that the physiological concentrations of bile influence respiratory pathogens towards a chronic lifestyle in vitro, we investigated the impact of bile aspiration on the lung microbiome of respiratory patients. Sputum samples (n = 25) obtained from a cohort of paediatric CF patients were profiled for the presence of bile acids using high-resolution liquid chromatography–mass spectrometry (LC-MS). Pyrosequencing was performed on a set of ten DNA samples that were isolated from bile aspirating (n = 5) and non-bile aspirating (n = 5) patients. Both denaturing gradient gel electrophoresis (DGGE) and pyrosequencing revealed significantly reduced biodiversity and richness in the sputum samples from bile aspirating patients when compared with non-aspirating patients. Families and genera associated with the pervasive CF microbiome dominated aspirating patients, while bacteria associated with the healthy lung were most abundant in non-aspirating patients. Bile aspiration linked to GOR is emerging as a major host trigger of chronic bacterial infections. The markedly reduced biodiversity and increased colonisation by dominant proteobacterial CF-associated pathogens observed in the sputum of bile aspirating patients suggest that bile may play a major role in disease progression in CF and other respiratory diseases. Electronic supplementary material The online version of this article (doi:10.1007/s10096-014-2133-8) contains supplementary material, which is available to authorized users.

Introduction: COPD is believed to have origins in childhood, however it has not yet been traced back to infancy. Lung function tracks from infancy into adulthood and reduced FEV1/FVC is a cornerstone of COPD diagnosis. Aim: Our aim was to assess whether physiological, genetic and environmental factors in infancy affect the FEV1/FVC ratio in young adults and thus the risk for COPD in later adult life. Methods: We analysed data from the Perth Infant Asthma follow up study, a longitudinal birth cohort of 253 subjects recruited antenatally, who have had regular and comprehensive respiratory assessments from infancy up to 24 years, including genotyping of several genes known to be associated with respiratory function. Results: Neither in utero tobacco smoke exposure nor early bronchiolitis correlated with FEV1/FVC at 24 years (r=0.06, p=0.5; r=-0.12, p=0.2 respectively). There were small but significant correlations between infant lung function (VmaxFRC) at 1, 6 and 12 months and FEV1/FVC at 24 years (r=0.19 p=0.048; r=0.223 p= 0.024, r=0.22 p=0.042 respectively), with 4% of the variability at 24 years explained by lung function at 1 month. Only 12% of subjects who were exclusively breastfed for the first 3 months had an FEV1/FVC in the lowest quartile at 24 years, compared to 34% who were not (OR 0.26, p=0.014). The B2-adrenoceptor polymorphism (arg16gly) was not associated with FEV1/FVC ratio (r=-0.014 p=0.83). Conclusions: Lung function from soon after birth was predictive of FEV1/FVC ratio in young adults, suggesting that COPD may have origins in the antenatal developing lung. Breastfeeding was protective against reduced FEV1/FVC and should continue to be promoted for long term healthy lungs.

Despite aggressive antimicrobial therapy, many respiratory pathogens persist in the lung, underpinning the chronic inflammation and eventual lung decline that are characteristic of respiratory disease. Recently, bile acid aspiration has emerged as a major comorbidity associated with a range of lung diseases, shaping the lung microbiome and promoting colonisation by Pseudomonas aeruginosa in Cystic Fibrosis (CF) patients. In order to uncover the molecular mechanism through which bile modulates the respiratory microbiome, a combination of global transcriptomic and phenotypic analyses of the P. aeruginosa response to bile was undertaken. Bile responsive pathways responsible for virulence, adaptive metabolism, and redox control were identified, with macrolide and polymyxin antibiotic tolerance increased significantly in the presence of bile. Bile acids, and chenodeoxycholic acid (CDCA) in particular, elicited chronic biofilm behaviour in P. aeruginosa, while induction of the pro-inflammatory cytokine Interleukin-6 (IL-6) in lung epithelial cells by CDCA was Farnesoid X Receptor (FXR) dependent. Microbiome analysis of paediatric CF sputum samples demonstrated increased colonisation by P. aeruginosa and other Proteobacterial pathogens in bile aspirating compared to non-aspirating patients. Together, these data suggest that bile acid signalling is a leading trigger for the development of chronic phenotypes underlying the pathophysiology of chronic respiratory disease.

Objective With the increasing life expectancy for patients with cystic fibrosis (CF), and a known predisposition to certain cancers, cumulative radiation exposure from radiologic imaging is of increasing significance. This study explores the estimated cumulative effective radiation dose over a 17-year period from radiologic procedures and changing trends of imaging modalities over this period. Methods Estimated cumulative effective dose (CED) from all thoracic and extrathoracic imaging modalities and interventional radiology procedures for both adult and pediatric patients with CF, exclusively attending a nationally designated CF center between 1992-2009 for > 1 year, was determined. The study period was divided into three equal tertiles, and estimated CED attributable to all radiologic procedures was estimated for each tertile. Results Two hundred thirty patients met inclusion criteria (2,240 person-years of follow-up; 5,596 radiologic procedures). CED was > 75 mSv for one patient (0.43%), 36 patients (15.6%) had a CED between 20 and 75 mSv, 56 patients (24.3%) had a CED between 5 and 20 mSv, and in 138 patients (60%) the CED was estimated to be between 0 and 5 mSv over the study period. The mean annual CED per patient increased consecutively from 0.39 mSv/y to 0.47 mSv/y to 1.67 mSv/y over the tertiles one to three of the study period, respectively (P Conclusions This study highlights the increasing exposure to ionizing radiation to patients with CF as a result of diagnostic imaging, primarily attributable to CT scanning. Increased awareness of CED and strategies to reduce this exposure are needed.

Background: Asthma is often associated with atopy. Cluster analysis shows the prevalence of atopy varies in different phenotypic groups of asthma from 50-90% but no longitudinal studies have assessed how this changes throughout childhood [1]. Our aim was to assess whether atopy precedes an asthma diagnosis, what proportion of asthmatics is atopic at different ages and how these change during childhood, to help decipher the link between the two. Methods: We collected data from a longitudinal birth cohort of 253 subjects, the Perth Infant Asthma Follow up study. A detailed respiratory questionnaire, lung function and skin prick testing were performed at 1, 6 and 12 months, 6, 11, 18 and 24 years. Asthma was physician diagnosed only and atopy was defined by a positive skin prick test. Results: The percentage of asthmatics with atopy rose from 50% at 6 years to 100% at 24 years. Of those with atopic asthma and full sequential data, an atopy diagnosis preceded that of asthma in 45% of cases (n=21) and both were diagnosed in the same time period in 55% (n=26). This was not significantly different. Of those with a history of asthma at 24 years, 90% (n=60) had been diagnosed by 11 years. All subjects with onset of asthma after 11 years of age were atopic. Atopy was less frequent in those with early transient asthma than persistant asthma after 6 years of age (65% vs 80%, p=0.045). Conclusion: The prevalence of atopy is higher in young adult asthmatics than as young children. Both diseases were diagnosed at a similar age in more than 50% of cases, suggesting a common predecessor, rather than a causal relationship. Haldar, P., et al., Cluster analysis and clinical asthma phenotypes. AMJRCCM 2008. 178 (3):218-24.

BACKGROUND: Ivacaftor is a safe, effective treatment for cystic fibrosis (CF) in patients aged ≥6 years with a CFTR gating mutation. This open-label, multicenter, phase 3 study assessed ivacaftor in children aged 2–5 years. METHODS: Children aged 2–5 years with a CFTR gating mutation received ivacaftor (8× ULN (study drug interrupted, n=4; study discontinuation, n=1). At week 24, sweat chloride improved on average by −46·9 mmol (SD 26·2, p

With the increasing life expectancy for patients with cystic fibrosis (CF), and a known predisposition to certain cancers, cumulative radiation exposure from radiologic imaging is of increasing significance. This study explores the estimated cumulative effective radiation dose over a 17-year period from radiologic procedures and changing trends of imaging modalities over this period.Estimated cumulative effective dose (CED) from all thoracic and extrathoracic imaging modalities and interventional radiology procedures for both adult and pediatric patients with CF, exclusively attending a nationally designated CF center between 1992-2009 for1 year, was determined. The study period was divided into three equal tertiles, and estimated CED attributable to all radiologic procedures was estimated for each tertile.Two hundred thirty patients met inclusion criteria (2,240 person-years of follow-up; 5,596 radiologic procedures). CED was75 mSv for one patient (0.43%), 36 patients (15.6%) had a CED between 20 and 75 mSv, 56 patients (24.3%) had a CED between 5 and 20 mSv, and in 138 patients (60%) the CED was estimated to be between 0 and 5 mSv over the study period. The mean annual CED per patient increased consecutively from 0.39 mSv/y to 0.47 mSv/y to 1.67 mSv/y over the tertiles one to three of the study period, respectively (P.001). Thoracic imaging accounted for 46.9% of the total CED and abdominopelvic imaging accounted for 42.9% of the CED, respectively. There was an associated 5.9-fold increase in the use of all CT scanning per patient (P.001).This study highlights the increasing exposure to ionizing radiation to patients with CF as a result of diagnostic imaging, primarily attributable to CT scanning. Increased awareness of CED and strategies to reduce this exposure are needed.

There is controversy regarding whether cystic fibrosis (CF) airway epithelial cells (AECs) are intrinsically proinflammatory. The objective of the current study was to characterize the inflammatory profiles of AECs from children with CF compared with cells from healthy control subjects. We obtained AECs from healthy children (12) and children with CF (27). Biochemical and functional characteristics were assessed by stimulating cells with IFNγ, LPS, a cocktail referred to as cytomix, which consists of IFNγ, IL-1β, TNF-α, and LPS, or with human rhinovirus (HRV). Cytokine production was assessed using ELISA. Apoptotic responses to HRV infection were measured via production of single-stranded DNA. Our results indicated that CF and healthy cells exhibited similar morphology in monolayer culture. CF cells constitutively produced greater amounts of IL-6, IL-1β, and prostaglandin E(2), but similar levels of IL-8 and soluble intracellular adhesion molecule-1 compared with healthy cells, and this profile was maintained through repeated passage. Stimulation with LPS or cytomix elicited similar levels of IL-8 in CF and non-CF cells. In contrast, exposure to HRV1b resulted in a marked increase in IL-8 production from CF compared with non-CF cells. CF cells also exhibited reduced apoptosis and increased viral replication compared with non-CF cells after exposure to HRV1b. We conclude that CF and healthy AECs have similar basal and stimulated expression of IL-8 in response to proinflammatory stimuli, but elevated IL-8 release in response to HRV infection. The elevated IL-8, together with dampened apoptotic responses by CF cells to HRV, could contribute to augmented airway inflammation in the setting of recurrent viral infections early in life.

Background Ralstonia mannitolilytica is a rarely reported pathogen in cystic fibrosis. It is frequently resistant to antimicrobials and can be misidentified as Burkholderia cepacia complex using biochemical techniques. Methods We identified 7 CF patients from 4 centres in Ireland, all with advanced lung disease that were colonized or infected with this organism. Each isolate was confirmed by gyrB sequence analysis and genetic relatedness was determined using PFGE. MIC testing was performed as well as combination testing using the multiple combination bactericidal test (MCBT). Whole genome sequencing was also performed. Results Four patients from the same institution had strains that were indistinguishable by PFGE. One patient died aged 14 years awaiting lung transplantation 18 months after acquisition; another patient underwent successful lung transplantation and remains culture negative. The remaining two patients are siblings who are at present requiring frequent courses of IV antibiotics and have significant decline in FEV1 since acquisition. Three other patient strains were unique by PFGE; one patient died age 38 y. Tigecycline and minocyline were the most active single agents showing inhibition by MIC to six and five strains, respectively. Minocycline/piperacillin–tazobactam was the most active combination but was not bactericidal against any strain. Tobramycin/piperacillin–tazobactam demonstrated bactericidal activity against three strains. Conclusion Ralstonia mannitolilytica is emerging as a significant pathogen in advanced CF. Early recognition and targeted treatment may reduce cross infection and improve clinical outcome in patients undergoing transplantation.

Objectives CF causes recurrent lung infections and inflammation which causes lung damage and pulmonary decline. The cyclooxgenase signalling pathway and its major metabolite PGE 2 have been shown to increase lung inflammation. PGE 2 signals through four different receptor subtypes, EP1–EP4. Exact mechanisms underpinning mode of action of new therapies such as ivacaftor may be multifactorial with potential downstream signaling consequences. Methods PGE 2 plasma levels were detected in clinically stable CF patients (n = 25) with a G551D mutation pre and post ivacaftor treatment. CF bronchial epithelial cells (DF508 homozygote, CFBE41o-) and human bronchial epithelial cells (16HBEo-) were seeded at2×10 5 cells/ml. EP1 receptor expression was determined by qRT-PCR. Cells were stimulated with PGE 2 or EP1 receptor antagonist and cell supernatant harvested. Cell proliferation was determined and changes in cytokine levels of IL-6, IL-8 and TNFa following PGE 2 stimulation and IL-6 following EP1 receptor antagonism were detected by ELISA. Results Treatment of CF patients with ivacaftor significantly reduced PGE 2 plasma levels (p 2 stimulation significantly increased expression of IL-6, IL-8 and TNFα in CFBE41o-cells compared to 16HBEo- in vitro. EP1 receptor antagonism significantly reduced IL-6 secretion in CFBE41o- cells. No significant change in cell proliferation was detected. Conclusion The findings underscore the value of unravelling the mechanisms regulating PGE 2 signalling, potentially advancing our understanding of the mechanisms of action of existing novel therapies in CF.

Objectives Ivacaftor produces significant benefit in patients with cystic fibrosis (CF) with the G551D mutation. Prevalence of this mutation at Cork University Hospital (CUH) is 23% making it uniquely placed to provide single centre insight into CFTR modulation. Methods 33 Ivacaftor-naive Patients with CF (age ≥6) consented to routine quarterly clinical follow up (median 1 year follow up) where clinical changes pre and post ivacaftor were recorded. 3 monthly sputum, blood and low dose CT Thoraces were performed at baseline and post-ivacaftor. Sputum bacteria were detected by plating on selective agars, quantified by total viable count and identified by PCR and sequencing of 16S rRNA genes. Circulating cytokines were measured in blood samples using an MSD platform. CT Thoraces were Bhalla scored. Results Significant mean improvements in FEV1 (10.26%), BMI (1.2 kg/m2), Sweat test (–57.65 mmol/l), Respiratory Domain of CFQ-R (17.51 point), exacerbation rate requiring IV antibiotics were observed, with a significant increase in Sputum diversity (P Conclusion In a large single centre cohort CFTR modulation is associated with a sustained improvement in clinical phenotype, decrease in inflammatory markers, change in lung microbiome and reduction in intraluminal bronchiectatic radiological complications.

Importance This is the first study to link reduced lung function in early life, before the development of symptoms, to wheeze in 18-year-olds. Additionally, the study gives insight into factors other than reduced lung function that are also associated with persistent wheeze in young adults. Objective To test the hypothesis that reduced lung function in early life is associated with increased risk for persistent wheeze at age 18 years. Design Birth cohort study. Setting Perth, Western Australia. Participants Individuals followed up from age 1 month to 18 years. Main Outcome Measures Maximal flow at functional residual capacity (V′maxFRC) was measured in 1-month-old infants who were followed up at ages 6, 12, and 18 years. Based on reported symptoms, individuals were categorized as having remittent wheeze, later-onset wheeze, persistent wheeze, and no wheeze. Smoking status was noted at age 18 years. Results Of the 253 individuals originally recruited, 150 were followed up at age 18 years; 37 of the 150 had recent wheeze. Compared with the no-wheeze group (n = 96), persistent wheeze (n = 13) was independently associated with reduced percentage of predicted V′maxFRC (mean reduction, 43%; 95% CI, 13-74). Compared with the no-wheeze group, persistent wheeze was also associated with atopy in infancy (odds ratio = 7.1; 95% CI, 1.5-34.5), maternal asthma (odds ratio = 6.8; 95% CI, 1.4-32.3), and active smoking (odds ratio = 4.8; 95% CI, 1.0-21.3). When only wheeze at age 18 years was considered, reduced percentage of predicted V′maxFRC was associated with wheeze at age 18 years only among current smokers (P = .04). Conclusions and Relevance Wheeze persisting from ages 6 to 18 years is associated with multiple factors, including reduced infant lung function, infant-onset atopy, maternal asthma, and active smoking. Wheeze at age 18 years (regardless of previous wheeze status) is associated with active smoking, but only among those with reduced lung function in infancy. These findings give unique insight into the cause of obstructive airways disease in 18-year-olds, and follow-up of this cohort might be expected to further extend our understanding.

Background The Mycobacterium abscessus complex are the rapidly growing mycobacteria (RGM) most commonly causing lung disease, especially in cystic fibrosis (CF) patients. Ireland has the world's highest CF incidence. The molecular epidemiology of M. abscessus complex in Ireland is unreported. Methods We performed rpoB gene sequencing and multi-locus sequence typing (MLST) on M. abscessus complex strains isolated from thirty-six patients in 2006–2012 (eighteen known CF patients). Results Twenty-eight strains (78%) were M. abscessus subsp. abscessus , eight M. abscessus subsp. massiliense , none were M. abscessus subsp. bolletii . Sequence type 1 (ST1) and ST26 ( M. abscessus subsp. abscessus ) were commonest. Seven M. abscessus subsp. abscessus STs (25%) were novel (two with novel alleles). Seven M. abscessus subsp. massiliense STs were previously reported (88%), including two ST23, the globally successful clone. In 2012, of 552 CF patients screened, eleven were infected with M. abscessus complex strains (2%). Conclusions The most prevalent M. abscessus subsp. abscessus and M. abscessus subsp. massiliense strains in Ireland belong to widely-distributed STs, but there is evidence of high M. abscessus subsp. abscessus diversity.