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In patients with cystic fibrosis, most treatments addressing the underlying basic defect are mutation or mutation class specific. These treatments are disease modifying if they lower the year to year change in lung function. We therefore calculated the current loss of lung function, measured by year to year change in forced expired volume in 1 s in 11,417 patients included in the European Cystic Fibrosis Society Patient Registry. Whereas patients with at least one mutation of class IV or V have on average a lower year to year change, we did not find a difference between patients with a stop codon mutation, homozygous for F508del or at least one class III mutation. These data are useful background information to discuss the impact of different disease modifying treatments. [ABSTRACT FROM AUTHOR]

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]

Background: In patients with symptoms suggestive of cystic fibrosis (CF) and intermediate sweat chloride values (30-60 mmol/l), extensive CFTR gene mutation analysis and nasal potential difference (NPD) measurement are used as additional diagnostic tests and a positive result in either test provides evidence of CFTR dysfunction. To define the phenotype of such patients and confirm the validity of grouping them, patients with intermediate sweat chloride values in whom either additional CF diagnostic test was abnormal were compared with subjects in whom this was not the case and patients with classic CF. Methods: The phenotypic features of four groups were compared: 59 patients with CFTR dysfunction, 46 with an intermediate sweat chloride concentration but no evidence of CFTR dysfunction (CF unlikely), 103 patients with CF and pancreatic sufficiency (CF-PS) and 62 with CF and pancreatic insufficiency (CF-PI). Results: The CFTR dysfunction group had more lower respiratory tract infections (p = 0.01), more isolation of CF pathogens (p<0.001) and clubbing (p = 0.001) than the CF unlikely group, but less frequent respiratory tract infections with CF pathogens than the CF-PS group (p = 0.05). Patients in the CF-PS group had a milder phenotype than those with PI. Many features showed stepwise changes through the patient groups. Conclusion: Patients with intermediate sweat chloride values and two CFTR mutations or an abnormal NPD measurement have a CF-like phenotype compatible with CFTR dysfunction and, as a group, differ phenotypically from patients with intermediate sweat chloride values in whom further CF diagnostic tests are normal as well as from CF-PS and CF-PI patients. [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 there is consensus on a cut-off value to diagnose CF, we have only limited information on the within subject variability of sweat chloride over time. Such information would be useful for sample size calculations in clinical trials. Therefore, we retrospectively analyzed repeated sweat chloride values 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 placebo patients of the VX08-770-102 trial. Results Mean overall sweat chloride value (all patients, all tests, n = 1062) was 100.8 mmol/L (SD 12.7 mmol/L). Using a multilevel mixed model, the between-subject standard deviation (SD) for sweat chloride was 8.9 mmol/L (95% CI 7.4–10.6) and within-subject SD was 8.1 mmol/L (95% CI 7.5–8.7). Limits of repeatability for repeat measurements were − 19.7 to + 21.6 mmol/L using values from one arm, and − 13.3 to 11.8 mmol/L using mean of values obtained at 4 test occasions. Sample size calculations showed that the minimal treatment effect on sweat chloride concentration that can be demonstrated for a group of 5 patients is around 15 mmol/L, using a cross-over design and combinations of 4 tests for each phase of the trial. Conclusion Although the sweat test is considered a robust measure, sweat chloride measurements in patients with CF and a G551D mutation had an inherent biological variability that is higher than commonly considered. Further analyses of placebo group data are crucial to learn more about the natural variability of this outcome parameter. [ABSTRACT FROM AUTHOR]

Abstract: Several diseases have been clinically or genetically related to cystic fibrosis (CF), but a consensus definition is lacking. Here, we present a proposal for consensus guidelines on cystic fibrosis transmembrane conductance regulator (CFTR)-related disorders (CFTR-RDs), reached after expert discussion and two dedicated workshops. A CFTR-RD may be defined as “a clinical entity associated with CFTR dysfunction that does not fulfil diagnostic criteria for CF”. The utility of sweat testing, mutation analysis, nasal potential difference, and/or intestinal current measurement for the differential diagnosis of CF and CFTR-RD is discussed. Algorithms which use genetic and functional diagnostic tests to distinguish CF and CFTR-RDs are presented. According to present knowledge, congenital bilateral absence of vas deferens (CBAVD), acute recurrent or chronic pancreatitis and disseminated bronchiectasis, all with CFTR dysfunction, are CFTR-RDs. [Copyright &y& Elsevier]

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]

Background and Objectives The prevalence of cystic fibrosis (CF) among Asians (A) is low. Yet A with CF may have a worse course than non-Asians (NA) [1]. The diagnosis of CF is based on (1) clinical phenotype (Ph), (2) sweat chloride (SCl) and (3) CFTR mutation analysis (M). Whether and how ethnicity impacts these criteria has been studied poorly. We aimed to analyze Ph, SCl and M of A and NA with CF. Methods A cross sectional analysis of CFTR2 and the UK CF registry allowed comparing 415 A and 39,952 NA with CF for: 1. Ph by meconium ileus (MI), pancreatic status (PS), lung function (LF) (FEV1 %predicted) and chronic Pseudomonas aeruginosa (PA) infection 2. SCl 3. M of both alleles Statistical analysis was done in SPSS. Results Compared to NA, A were younger (mean age 16 vs 19 years, p<0.01). There was no difference for MI or PA infection. More A were pancreas sufficient (χ 2 p = 0.002). The FEV1 of A with CF was reduced (68±22 vs 71±20 %pred, p<0.01). Yet healthy A are found to have a mean FEV1 of –6.5%pred compared to Caucasians [2]. SCl was lower in A (92.6, CI 89.2–95.9, vs 96.8, CI 96.5–97.0 mmol/l; p = 0.01) including in the subset of the ΔF508 homozygous. Genetic diversity was high (27.8% vs 0.8% of UK patients had 2 alleles with a rare mutation) and ΔF508 homozygosity was less common (22.6% vs 50.5%). In 64.3% of A vs 7% of NA neither mutation was included in the UK newborn screening panel. Ongoing research will validate these findings for other CF databases. Conclusion A with CF are younger and more often pancreas sufficient. Their genotype corrected SCl is lower than in NA. Genetic diversity is high which is challenging for newborn screening. [ABSTRACT FROM AUTHOR]