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Abstract: More than 1900 different mutations in the CFTR gene have been reported. These are grouped into classes according to their effect on the synthesis and/or function of the CFTR protein. CFTR repair therapies that are mutation or mutation class specific are under development. To progress efficiently in the clinical phase of drug development, knowledge of the relative frequency of CFTR mutation classes in different populations is useful. Therefore, we describe the mutation class spectrum in 25,394 subjects with CF from 23 European countries. In 18/23 countries, 80% or more of the patients had at least one class II mutation, explained by F508del being by far the most frequent mutation. Overall 16.4% of European patients had at least one class I mutation but this varied from 3 countries with more than 30% to 4 countries with less than 10% of subjects. Overall only respectively 3.9, 3.3 and 3.0% of European subjects had at least one mutation of classes III, IV and V with again great variability: 14% of Irish patients had at least one class III mutation, 7% of Portuguese patients had at least one class IV mutation, and in 6 countries more than 5% of patients had at least one class V mutation. [Copyright &y& Elsevier]

There is great heterogeneity in the clinical manifestations of cystic fibrosis (CF). Some patients may have all the classical manifestations of CF from infancy and have a relatively poor prognosis, while others have much milder or even atypical disease manifestations and still carry mutations on each of the CFTR genes. It is important to distinguish between these categories of patients. The European Diagnostic Working Group proposes the following terminology. Patients are diagnosed with classic or typical CF if they have one or more phenotypic characteristics and a sweat chloride concentration of >60 mmol/l. The vast majority of CF patients fall into this category. Usually one established mutation causing CF can be identified on each CFTR gene. Patients with classic CF can have exocrine pancreatic insufficiency or pancreatic sufficiency. The disease can have a severe course with rapid progression of symptoms or a milder course with very little deterioration over time. Patients with non-classic or atypical CF have a CF phenotype in at least one organ system and a normal (<30 mmol/l) or borderline (30-60 mmol/l) sweat chloride level. In these patients confirmation of the diagnosis of CF requires detection of one disease causing mutation on each CFTR gene or direct quantification of CFTR dysfunction by nasal potential difference measurement. Non-classic CF includes patients with multiorgan or single organ involvement. Most of these patients have exocrine pancreatic sufficiency and milder lung disease. Algorithms for a structured diagnostic process are proposed. [ABSTRACT FROM AUTHOR]

Objective To explore the value of assessing the FEF 25–75 , a measure of “small airway disease” in addition to the FEV 1 , FVC and FEV1/FVC in patients with cystic fibrosis (CF) Methods The spirometry of the patients followed between 1998 and 2013 at the CF Centre of Leuven, Belgium, were retrospectively reviewed. For each patient, the last measurement of each age year was included, resulting in 1793 measurements in 268 patients aged between 6 and 76 years. Z-scores were calculated with the equations from the Global Lung Initiative, with −1.645 as the lower limit of normal. Medians and interquartile ranges are reported. Results Discordance between FEF 25–75 and FEV 1 /FVC was uncommon. In the 811 tests with normal FEV 1 and FVC, the 95 tests with a low FEF 25–75 but normal FEV 1 /FVC were from younger patients [12.3 years (10.0; 21.9) vs 16.6 years (13.0; 27.9), p = 0.006] and had a lower FVC Z-score [–0.53 (–0.80; −0.21) vs +0.54 (–0.04; 1.17), p<0.001] than the 126 tests with both low FEF 25–75 and low FEV 1 /FVC. In the 971 tests with a low FEV 1 , FEF 25–75 was also abnormal in 95.7% and FEV 1 /FVC in 83.3%. The 122 tests with a low FEF 25–75 but normal FEV 1 /FVC were from younger patients [15.5 years (IQR 10.9; 24.9) vs 24.9 years (17.0; 31.5), p<0.001] and had a lower FVC Z-score [–1.90 (–2.76; −1.41) vs −1.66 (–2.74; −0.71), p = 0.015] than the 807 tests with both low FEF 25–75 and low FEV1/FVC. Conclusion A spirometry with only a low FEF 25–75 was rare in patients with CF, and was seen more often at younger age and with FVC Z-scores at the lower end of the normal range. In this group of patients with CF assessment of FEF 25–75 in addition to FEV 1 , FVC and FEV 1 /FVC added little information. [ABSTRACT FROM AUTHOR]

Introduction The efficacy of inhaled antibiotics to treat chronic Pseudomonas aeruginosa pulmonary infection in patients with cystic fibrosis (CF) has been well established. Few data are available on the value of continuous alternating inhaled antibiotic therapy (CAIT), a strategy increasingly used in the management of CF. Objective To investigate the effect of CAIT on clinical outcome in adult CF patients treated at the University Hospital Leuven. Methods Patients with a documented CF diagnosis who received inhaled antibiotics between March 2010 and January 2015 were retrospectively evaluated. In patients receiving CAIT patient characteristics, recorded spirometry data and number of IV antibiotic days were collected retrospectively at fixed time intervals, from 6 months before to one year after the start of the 2nd inhaled antibiotic. For patients on inhaled antibiotic monotherapy (IAMT), the same data were obtained at similar intervals during the study period. Results A total of 49 of 89 patients using chronic inhaled antibiotic therapy received CAIT. Patients receiving CAIT had a lower baseline FEV 1 and were more likely to be homozygous for F508del compared to patients receiving IAMT. FEV 1 deteriorated on average by a factor of 0.904 per year (95% CI: 0.851–0.960) prior to the start of CAIT. The initiation of CAIT was associated with an average improvement in FEV 1 by a factor of 1.148 per year (95% CI: 1.068–1.236, p = 0.0002). The analysis of specific types of antibiotics revealed evidence of positive effects of adding COLI to TOBI and COLI to AZLI. We found no effect of the initiation of CAIT on the number of IV antibiotic days ( p = 0.80). Conclusion CF patients with more advanced lung disease are more likely to receive CAIT. In this patient group, CAIT was associated with a significant improvement in FEV 1 . Further data are warranted to identify the value of CAIT. [ABSTRACT FROM AUTHOR]

Lung clearance index (LCI), a marker of gas mixing efficiency, is a promising parameter to assess lung function in patients with CF. In cross-sectional data, LCI is often abnormal, even in subjects with normal FEV 1 . Few data are available on long-term evolution of LCI. Objectives LCI was measured prospectively in children with CF during routine follow-up. Changes in LCI were evaluated after 2 years, to explore the magnitude of changes and the relation with changes in FEV 1 . Methods LCI was measured with the Ecomedics Exhalyzer D, using a N 2 washout. Spirometry was performed at the same visit. An LCI higher than 8.3 and a FEV 1 Z-score lower than 1.97 were considered abnormal. Results In 42 patients with a median age of 12.2 years (range 5.8 to 17.2), two measurements were compared with median interval of 21 months (range 18 to 27). At first timepoint (T1), median LCI was 9.4 (range 6.0 to 14.5) and median FEV1 Z-score –0.6 (range –4.1 to 2.0). Over the observation period, individual changes in both parameters occurred, but on the whole major changes were unusual: FEV1 Z-score was normal but LCI was abnormal at T 1 in 23 patients, and this remained so at T2 in 21; both FEV 1 and LCI were normal at T1 in 12 patients, this remained so at T2 in 11; both FEV 1 Z-score and LCI were abnormal at T1 in 7 patients, and this remained so at T 2 in 6. Abnormal FEV 1 and normal LCI was never seen. Conclusion In 23/42 children with CF, FEV1 z-score was normal but LCI z score was abnormal and this remained so 2 years later in all but two subject. These data further support the notion that measuring LCI brings additional information especially in the group of children with normal FEV 1 . [ABSTRACT FROM AUTHOR]

Abstract: There are no European Guidelines on issues specifically related to travel for people with cystic fibrosis (CF). The contributors to these recommendations included 30 members of the ECORN-CF project. The document is endorsed by the European Cystic Fibrosis Society and sponsored by the Executive Agency of Health and Consumers of the European Union and the Christiane Herzog Foundation. The main goal of this paper is to provide patient-oriented advice that complements medical aspects by offering practical suggestions for all aspects involved in planning and taking a trip. The report consists of three main sections, preparation for travel, important considerations during travel and at the destination, and issues specific to immunocompromised travellers. People with CF should be encouraged to consult with their CF centre prior to travel to another country. The CF centre can advise on the necessary preparation for travel, the need for vaccinations, essential medications that should be brought on the trip and also provide information relating to CF care in the region and plan of action in case of an emergency. [ABSTRACT FROM AUTHOR]

Objectives The R117H mutation is common among CF-patients in Europe and a CFTR modulating therapy has been investigated. Methods To describe clinical characteristics of the CF patients with at least one R117H mutation, we analysed the 2010 data of the ECFS Patient Registry and requested the PolyT status from national registries and individual centres. Results There were 592 patients with a R117H mutation. The prevalence varied between countries, from 0% to 4.7% of genotyped patients (Europe 1.9%). A third was diagnosed through newborn screening. The sweat chloride result was available for only 245 patients: it was ≥60 mmol/l in 35.1% and <30 mmol/l in 18.0%. Pancreatic insufficiency was present in 16.3% (<18 years) and 41.4% (≥18 years). Infection with P. aeruginosa was present in 0.8% (<18 years) and 19.7% (≥18 years). The median FEV1% was 100.9% of predicted in 5–9 years and 81.2% in 25–29 years. Overall, 13.5% of patients were treated with rhDNase and 11.1% with inhaled antibiotics. The median BMI-z-score was 0.11 (<18 years); 4.3% of adults had a BMI ≤18.5 kg/m 2 . PolyT tract results were available for 20.2% only. The prevalence of R117H/5T in patients with known PolyT status varied between countries, from 0% to 85% (25 with 5T; 93 with7T). Adult patients with 5T were more often pancreatic insufficient (90% versus 28%), suffered more often from diabetes (18% versus 9%) and pseudomonas infection (22% versus 0%) and had a higher treatment burden (esp. inhaled antibiotics, pancreatic enzymes) than 7T patients. Conclusions The prevalence of the R117H mutation and 5T status varied across Europe. PolyT status is a relevant, but underreported cofactor. [ABSTRACT FROM AUTHOR]

Introduction Sweat chloride concentration, a biomarker of CFTR function, is an appropriate outcome parameter in clinical trials aimed at correcting the basic CF defect. Although we agree on a cut-of value to diagnose CF, we have only limited information on the natural variability of sweat chloride over time. Still, this information is useful for power calculations in clinical trials. Therefore, we analyzed sweat test results obtained in patients with G551D mutation(s) assigned to placebo in an ivacaftor interventional trial. Methods In subjects with G551D at least 12 years of age, a pilocarpine sweat test using Macroduct collector was taken on both arms at 8 time points over 48 weeks. We explored 1062 pilocarpine sweat test values obtained in 78 patients. Results Mean overall sweat chloride value (all patients, all tests) was 100.1 mmol/L (95% CI 96.4–103.7). Using a random coefficient model, the within-subject standard deviation(SD) for sweat chloride was 8.5 mmol/L (95% CI 8.1–8.9) and between-subject SD was 9.8 mmol/L (95% CI 8.1–11.9). Standard deviations were similar with results from the left and from the right arm. Taking the mean measure of both arms rather than the result of one arm decreased within-subject SD by only 0.3 mmol/L. Conclusion Although the sweat test is considered a robust measure, sweat chloride measurements in patients with CF had an inherent biological variability that is higher than commonly considered. Further analyses of placebo arm data are crucial to learn more about the natural variability of outcome parameters. [ABSTRACT FROM AUTHOR]