In cystic fibrosis, highly variable glucose tolerance is suspected. However, no study provided within-patient coefficients of variation. The main objective of this short report was to evaluate ...within-patient variability of oral glucose tolerance.
In total, 4,643 standardized oral glucose tolerance tests of 1,128 cystic fibrosis patients (median age at first test: 15.5 11.5; 21.5 years, 48.8% females) were studied. Patients included were clinically stable, non-pregnant, and had at least two oral glucose tolerance tests, with no prior lung transplantation or systemic steroid therapy. Transition frequency from any one test to the subsequent test was analyzed and within-patient coefficients of variation were calculated for fasting and two hour blood glucose values. All statistical analysis was implemented with SAS 9.4.
A diabetic glucose tolerance was confirmed in 41.2% by the subsequent test. A regression to normal glucose tolerance at the subsequent test was observed in 21.7% and to impaired fasting glucose, impaired glucose tolerance or both in 15.2%, 12.0% or 9.9%. The average within-patient coefficient of variation for fasting blood glucose was 11.1% and for two hour blood glucose 25.3%.
In the cystic fibrosis patients studied, a highly variable glucose tolerance was observed. Compared to the general population, variability of two hour blood glucose was 1.5 to 1.8-fold higher.
Defects in expression, maturation or function of the epithelial membrane glycoprotein CFTR are causative for the progressive disease cystic fibrosis. Recently, molecular therapeutics that improve ...CFTR maturation and functional defects have been approved. We aimed to verify whether we could detect an improvement of CFTR protein expression and maturation by triple therapy with elexacaftor-tezacaftor-ivacaftor (ELX/TEZ/IVA).
Rectal suction biopsies of 21 p.Phe508del homozygous or compound heterozygous CF patients obtained pre- and during treatment with ELX/TEZ/IVA were analyzed by CFTR Western blot that was optimized to distinguish CFTR glycoisoforms.
CFTR western immunoblot analysis revealed that-compared to baseline-the levels of CFTR protein increased by at least twofold in eight out of 12 patients upon treatment with ELX/TEZ/IVA compared to baseline (
< 0.02). However, polydispersity of the mutant CFTR protein was lower than that of the fully glycosylated wild type CFTR Golgi isoform, indicating an incompletely glycosylated p.Phe508el CFTR protein isoform C* in patients with CF which persists after ELX/TEZ/IVA treatment.
Treatment with ELX/TEZ/IVA increased protein expression by facilitating the posttranslational processing of mutant CFTR but apparently did not succeed in generating the polydisperse spectrum of N-linked oligosaccharides that is characteristic for the wild type CFTR band C glycoisoform. Our results caution that the lower amounts or immature glycosylation of the C* glycoisoform observed in patients' biomaterial might not translate to fully restored function of mutant CFTR necessary for long-term provision of clinical benefit.
Triple-combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy with elexacaftor/tezacaftor/ivacaftor (ETI) was introduced in August 2020 in Germany for people with CF ...(pwCF) ≥12 years (yrs.) of age and in June 2021 for pwCF ≥6 yrs of age. In this single-center study, we analyzed longitudinal data on the percent-predicted forced expiratory volume (ppFEV1) and body-mass-index (BMI) for 12 months (mo.) after initiation of ETI by linear mixed models and regression analyses to identify age- and severity-dependent determinants of response to ETI.
We obtained data on 42 children ≥6-11 yrs, 41 adolescents ≥12-17 yrs, and 143 adults by spirometry and anthropometry prior to ETI, and 3 and 12 mo. after ETI initiation. Data were stratified by the age group and further sub-divided into age-specific ppFEV1 impairment. To achieve this, the age strata were divided into three groups, each according to their baseline ppFEV1: lowest 25%, middle 50%, and top 25% of ppFEV1.
Adolescents and children with more severe lung disease prior to ETI (within the lowest 25% of age-specific ppFEV1) showed higher improvements in lung function than adults in this severity group (+18.5 vs. +7.5;
= 0.002 after 3 mo. and +13.8 vs. +7.2;
= 0.012 after 12 mo. of ETI therapy for ≥12-17 years and +19.8 vs. +7.5;
= 0.007 after 3 mo. for children ≥6-11 yrs). In all age groups, participants with more severe lung disease showed higher BMI gains than those with medium or good lung function (within the middle 50% or top 25% of age-specific ppFEV1). Regression analyses identified age as a predictive factor for FEV1 increase at 3 mo. after ETI initiation, and age and ppFEV1 at ETI initiation as predictive factors for FEV1 increase 12 mo. after ETI initiation.
We report initial data, which suggest that clinical response toward ETI depends on age and lung disease severity prior to ETI initiation, which argue for early initiation of ETI.
Published estimates on age-dependent frequency of diabetes in cystic fibrosis (CF) vary widely, and are based mostly on older data. However, CF treatment and prevention of comorbidities changed over ...recent years. In many studies, definition of cystic fibrosis-related diabetes (CFRD) is not in line with current guideline recommendations. Therefore, we evaluated age-dependent occurrence of glucose abnormalities and associated risk factors in CF patients who participated in a multicenter screening program using oral glucose tolerance tests (OGTT).
Between 2001 and 2010, 43 specialized CF centers from Germany and Austria serially performed 5,179 standardized OGTTs in 1,658 clinically stable, non-pregnant CF patients with no prior steroid medication or lung transplantation. Age-dependent occurrence of impaired fasting glucose (IFG), impaired glucose tolerance (IGT), IFG+IGT, one (DGT) or two consecutive (CFRD) diabetic OGTTs was analyzed, using Kaplan Meier curves. Cox proportional-hazards models were created to elucidate the influence of sex or underweight.
At baseline/last OGTT, median age was 15.9 years/18.2 years and 30.6%/31.8% of patients were underweight. 25% of patients showed IFG at age 14.3 years; IGT at age 16.3 years; IFG+IGT combined at age 17.7 years. DGT was observed in 25% of patients at age 22.6 years; CFRD at age 34.5 years. Females had a 3.54 95% CI 1.23-10.18 times higher risk for CFRD; risk for DGT was 2.21 1.22-3.98 times higher. Underweight was a risk factor for IGT (HR 95% CI: 1.38 1.11-1.71) and IFG+IGT (1.43 1.11-1.83), and in males also for DGT (1.49 1.09-2.04).
If confirmation of diabetes by a second test is required, as recommended in current guidelines, age at CFRD diagnosis was higher compared to most previous studies. However, known risk factors for glucose abnormalities in CF were confirmed. Confirmation of diabetic OGT by a repeat test is important for a consistent diagnosis of CFRD.
BackgroundNasal potential difference (NPD) and intestinal current measurements (ICM) are cystic fibrosis transmembrane conductance regulator (CFTR) biomarkers recommended to make a diagnosis in ...individuals with inconclusive sweat test and CFTR genetics and a clinical suspicion for cystic fibrosis (CF) or CFTR-related disorder (CFTR-RD).MethodsNPD and ICM were measured according to standard operating procedures of the European Cystic Fibrosis Society Diagnostic Network Working Group.ResultsWe assessed 219 individuals by NPD or ICM who had been referred to our laboratory due to clinical symptoms suggestive of CF, but inconclusive sweat test and CFTR genetics (median age: 16.3 years, range 0.4 to 76 years). CF or CFTR-related disorder was diagnosed in 22 of 29 patients (76%) with a CFTR genotype of unknown or variable clinical significance and in 51 of 190 carriers (27%) of one (35/42) or no (16/148) identified CFTR mutation. If two CFTR sequence variants had been identified, the outcome of NPD and ICM was consistent with the classification of the CFTR2 database. Moreover, a suspected false-positive diagnosis of CF was confirmed in seven and withdrawn in eight patients. Of 26 individuals assessed by both NPD and ICM, eleven individuals exhibited discordant tracings of ICM and NPD, with one measurement being in the CF range and the other in the normal range.ConclusionThe majority of patients whom we diagnosed with CF or CFTR-RD by extended electrophysiology are carriers of the wild-type CFTR coding sequence on at least one of their CF alleles. The disease-causing genetic lesions should reside in the non-coding region of CFTR or elsewhere in the genome, affecting the regulation of CFTR expression in a tissue-depending fashion which may explain the large within-group variability of CFTR activity in the respiratory and intestinal epithelium seen in this group.
The prognostic value of cardiopulmonary exercise testing (CPET) for survival in cystic fibrosis (CF) in the context of current clinical management, when controlling for other known prognostic ...factors, is unclear.
To determine the prognostic value of CPET-derived measures beyond peak oxygen uptake (
o
peak) following rigorous adjustment for other predictors.
Data from 10 CF centers in Australia, Europe, and North America were collected retrospectively. A total of 510 patients completed a cycle CPET between January 2000 and December 2007, of which 433 fulfilled the criteria for a maximal effort. Time to death/lung transplantation was analyzed using Cox proportional hazards regression. In addition, phenotyping using hierarchical Ward clustering was performed to characterize high-risk subgroups.
Cox regression showed, even after adjustment for sex, FEV
% predicted, body mass index (z-score), age at CPET, Pseudomonas aeruginosa status, and CF-related diabetes as covariates in the model, that
o
peak in % predicted (hazard ratio HR, 0.964; 95% confidence interval CI, 0.944-0.986), peak work rate (% predicted; HR, 0.969; 95% CI, 0.951-0.988), ventilatory equivalent for oxygen (HR, 1.085; 95% CI, 1.041-1.132), and carbon dioxide (HR, 1.060; 95% CI, 1.007-1.115) (all P < 0.05) were significant predictors of death or lung transplantation at 10-year follow-up. Phenotyping revealed that CPET-derived measures were important for clustering. We identified a high-risk cluster characterized by poor lung function, nutritional status, and exercise capacity.
CPET provides additional prognostic information to established predictors of death/lung transplantation in CF. High-risk patients may especially benefit from regular monitoring of exercise capacity and exercise counseling.
Lumacaftor and ivacaftor combination treatment showed efficacy in patients aged 12 years or older with cystic fibrosis homozygous for F508del-cystic fibrosis transmembrane conductance regulator ...(CFTR) in placebo-controlled studies and patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR in an open-label study. We report efficacy and safety of lumacaftor and ivacaftor in patients with cystic fibrosis aged 6-11 years homozygous for F508del-CFTR.
In this phase 3, randomised, double-blind, placebo-controlled, multicentre study, patients were enrolled at 54 hospitals and medical centres in nine countries (the USA, Australia, Belgium, Canada, Denmark, France, Germany, Sweden, and the UK). Eligible patients weighed at least 15 kg, with a confirmed diagnosis of cystic fibrosis, percent predicted forced expiratory volume in 1 s (FEV
) of 70 or more, and lung clearance index
(LCI
) of 7·5 or more at screening (values less than these thresholds were permitted at day 1). All patients were tested for CFTR genotype at screening; eligible patients had to have the F508del-CFTR mutation on both alleles. Exclusion criteria included any comorbidity or laboratory abnormality that might confound the study results or pose additional risk to the patient. Patients were stratified by weight (<25 kg vs ≥25 kg) and ppFEV
severity (<90 vs ≥90) determined at the screening visit, and randomly assigned 1:1 to treatment using an interactive web response system to receive 200 mg lumacaftor and 250 mg ivacaftor every 12 hours or placebo for 24 weeks. Patients, all site personnel including the investigator and the site monitor, and the study team were blinded, with the exception of site personnel needing this information in the event of medical emergency or pregnancy and patient safety and regulatory affairs personnel to meet serious adverse event reporting requirements. The primary endpoint was the mean absolute change in LCI
from all on-treatment study visits up to and including week 24. All randomly assigned patients who were exposed to any amount of study drug, with treatment assignment as assigned were included in primary and other efficacy analyses. All patients who were exposed to any amount of study drug, with treatment assignment as treated, were included in the safety analysis. This study was registered with ClinicalTrials.gov, number NCT02514473.
Between July 23, 2015, and Sept 20, 2016, a total of 206 patients were enrolled and randomly assigned to receive lumacaftor and ivacaftor (n=104) or placebo (n=102). Two randomly assigned patients were never dosed with study drug (one in the placebo arm due to ineligibility arising from a streptococcal throat infection and one in the lumacaftor and ivacaftor arm due to withdrawal based on refusal to provide blood tests) and were not included in the analyses. 103 patients received at least one dose of lumacaftor and ivacaftor and 101 patients received at least one dose of placebo. For the primary endpoint, the average absolute change in LCI
from baseline over all study visits up to and including the week 24 visit, least squares mean difference was -1·09 units (95% CI -1·43 to -0·75, p<0·0001) for lumacaftor and ivacaftor versus placebo. For the key secondary endpoint of sweat chloride concentration, the least squares mean difference versus placebo was -20·8 mmol/L (95% CI -23·4 to -18·2, average absolute change at day 15/week 4; p<0·0001). The least squares mean difference compared with placebo in absolute change in ppFEV
from all on-treatment study visits until week 24 was 2·4 (95% CI 0·4-4·4, p=0·0182). 196 (96%) of 204 patients reported adverse events, most of which were mild (87 43%) or moderate (98 48%). Treatment was discontinued due to adverse events in three (3%) of 103 patients in the lumacaftor and ivacaftor group and two (2%) of 101 patients in the placebo group. Serious adverse events were reported in 13 (13%) of 103 patients in the lumacaftor and ivacaftor group and 11 (11%) of 101 patients in the placebo group.
Treatment with lumacaftor and ivacaftor was associated with statistically significant improvements in lung function, as measured by LCI
and ppFEV
, versus placebo in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR. The overall safety profile was consistent with previous phase 3 studies of lumacaftor and ivacaftor.
Vertex Pharmaceuticals.
Health-related and disease-specific quality of life (HRQoL) has been increasingly valued as relevant clinical parameter in cystic fibrosis (CF) clinical care and clinical trials. HRQoL measures ...should assess - among other domains - daily functioning from a patient's perspective. However, validation studies for the most frequently used HRQoL questionnaire in CF, the Cystic Fibrosis Questionnaire (CFQ), have not included measures of physical activity or fitness. The objective of this study was, therefore, to determine the cross-sectional and longitudinal relationships between HRQoL, physical activity and fitness in patients with CF.
Baseline (n = 76) and 6-month follow-up data (n = 70) from patients with CF (age ≥12 years, FEV1 ≥35%) were analysed. Patients participated in two multi-centre exercise intervention studies with identical assessment methodology. Outcome variables included HRQoL (German revised multi-dimensional disease-specific CFQ (CFQ-R)), body composition, pulmonary function, physical activity, short-term muscle power, and aerobic fitness by peak oxygen uptake and aerobic power.
Peak oxygen uptake was positively related to 7 of 13 HRQoL scales cross-sectionally (r = 0.30-0.46). Muscle power (r = 0.25-0.32) and peak aerobic power (r = 0.24-0.35) were positively related to 4 scales each, and reported physical activity to 1 scale (r = 0.29). Changes in HRQoL-scores were directly and significantly related to changes in reported activity (r = 0.35-0.39), peak aerobic power (r = 0.31-0.34), and peak oxygen uptake (r = 0.26-0.37) in 3 scales each. Established associates of HRQoL such as FEV1 or body mass index correlated positively with fewer scales (all 0.24 < r < 0.55).
HRQoL was associated with physical fitness, especially aerobic fitness, and to a lesser extent with reported physical activity. These findings underline the importance of physical fitness for HRQoL in CF and provide an additional rationale for exercise testing in this population.
ClinicalTrials.gov, NCT00231686.
Abstract Background Long-term exercise interventions have been shown to improve vital capacity in cystic fibrosis (CF). Yet, no data are available indicating positive effects of long-term exercise ...training on FEV1. Methods 39 Swiss patients with CF were randomly divided into strength training (ST, n = 12), endurance training (AT, n = 17) and controls (CONCH , n = 10), and also compared with age-matched Swiss (n = 35) and German (n = 701) CF registry data. A partially supervised training of 3 × 30 min/week for 6 months took place with measurements at baseline and after 3, 6, 12 and 24 months. Primary outcome was FEV1 at 6 months. Results FEV1 increased significantly in both training groups compared with CONCH (AT:+5.8 ± 0.95, ST:+7.4 ± 2.5, CONCH :− 11.5 ± 2.7% predicted, p < 0.001) and both registry groups at 6 months. At 24 months, changes in favour of the training groups persisted marginally compared with CONCH , but not compared with registry data. Conclusions A partially supervised training over 6 months improved FEV1 but effects were basically gone 18 months off training. Regular long-term training should be promoted as essential part of treatment in CF.
The long-term effects of vigorous physical activity (PA) on lung function in cystic fibrosis are unclear.
To evaluate effects of a 12-month partially supervised PA intervention using motivational ...feedback.
In a parallel-arm multicenter randomized controlled trial (ACTIVATE-CF), relatively inactive patients aged at least 12 years were randomly assigned (1:1 ratio) to an intervention group or control group. The intervention group consented to add 3 hours of vigorous PA per week, whereas the control group was asked not to change their PA behavior. Primary endpoint was change in percent predicted FEV
(ΔFEV
) at 6 months. Secondary endpoints included PA, exercise capacity, exercise motives, time to first exacerbation and exacerbation rates, quality of life, anxiety, depression, stress, and blood glucose control. Data were analyzed using mixed linear models.
A total of 117 patients (40% of target sample size) were randomized to an intervention (n = 60) or control group (n = 57). After 6 months, ΔFEV
was significantly higher in the control group compared with the intervention group (2.70% predicted 95% confidence interval, 0.13-5.26;
= 0.04). The intervention group reported increased vigorous PA compared with the control group at each study visit, had higher exercise capacity at 6 and 12 months, and higher PA at 12 months. No effects were seen in other secondary outcomes.
ACTIVATE-CF increased vigorous PA and exercise capacity, with effects carried over for the subsequent 6 months, but resulted in better FEV
in the control group.
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