Factors Associated with Worse Lung Function in Cystic Fibrosis Patients with Persistent Staphylococcus aureus

Background Staphylococcus aureus is an important pathogen in cystic fibrosis (CF). However, it is not clear which factors are associated with worse lung function in patients with persistent S. aureus airway cultures. Our main hypothesis was that patients with high S. aureus density in their respiratory specimens would more likely experience worsening of their lung disease than patients with low bacterial loads. Methods Therefore, we conducted an observational prospective longitudinal multi-center study and assessed the association between lung function and S. aureus bacterial density in respiratory samples, co-infection with other CF-pathogens, nasal S. aureus carriage, clinical status, antibiotic therapy, IL-6- and IgG-levels against S. aureus virulence factors. Results 195 patients from 17 centers were followed; each patient had an average of 7 visits. Data were analyzed using descriptive statistics and generalized linear mixed models. Our main hypothesis was only supported for patients providing throat specimens indicating that patients with higher density experienced a steeper lung function decline (p<0.001). Patients with exacerbations (n = 60), S. aureus small-colony variants (SCVs, n = 84) and co-infection with Stenotrophomonas maltophilia (n = 44) had worse lung function (p = 0.0068; p = 0.0011; p = 0.0103). Patients with SCVs were older (p = 0.0066) and more often treated with trimethoprim/sulfamethoxazole (p = 0.0078). IL-6 levels positively correlated with decreased lung function (p<0.001), S. aureus density in sputa (p = 0.0016), SCVs (p = 0.0209), exacerbations (p = 0.0041) and co-infections with S. maltophilia (p = 0.0195) or A. fumigatus (p = 0.0496). Conclusions In CF-patients with chronic S. aureus cultures, independent risk factors for worse lung function are high bacterial density in throat cultures, exacerbations, elevated IL-6 levels, presence of S. aureus SCVs and co-infection with S. maltophilia. Trial Registration ClinicalTrials.gov NCT0066976

Cystic fibrosis (CF) care through the patients' eyes – A nationwide survey on experience and satisfaction with services using a disease-specific questionnaire

SummaryThe patients' perspective is an important aspect of quality management. A newly developed disease-specific questionnaire was used to assess the patients' experiences with care provided in specialised cystic fibrosis (CF) care centres.Methods90 CF centres in Germany were invited to participate. Centre staff collected patient consent forms and sent the patients' addresses to the study centre. The questionnaires for adults and parents had 100 and 104 items respectively, with 3–6 response categories each. Items were dichotomised into “problem scores” (PS), indicating the presence or absence (PS 0%) of a reported problem.Results56 CF centres took part in the survey and recruited 1642 adults with CF and 1205 parents. The response rates were 74% in each group, with 1221 completed questionnaires from adults and 891 from parents. Participants reported good experiences with care. Factor analysis revealed 10 factors covering 70 items. Participants reported the best results for the factors “Physiotherapists” (PS 6%) and “Physician–Patient Relationship” (PS 9%). Factors with the highest problem scores were inpatient and outpatient “Facilities, Hygiene and Services”. CF centres received reports of their own results and mean problem scores of all participating institutions. The problem scores differed considerably between CF centres.ConclusionsThe nation-wide CF-specific patient experience survey identified specific shortcomings which were mainly related to communication, centre organisation, and facilities. Centre staff can use the results to improve the quality of care. We suggest that patients' views should become an integral component of efforts to promote patient-centred care

Ivacaftor Reduces Inflammatory Mediators in Upper Airway Lining Fluid From Cystic Fibrosis Patients With a G551D Mutation: Serial Non- Invasive Home-Based Collection of Upper Airway Lining Fluid

In cystic fibrosis (CF) therapy, the recent approval of CF-transmembrane conductance regulator (CFTR) channel modulators is considered to be the major breakthrough. However, the current first-line approach based mainly on pulmonary function to measure effects of the novel therapy, tested by forced expiratory volumes in one second (FEV1), provides restricted sensitivity to detect early structural damages. Accordingly, there is a need for new sensitive surrogate parameters. Most interestingly, these should quantify inflammation that precedes a decline of pulmonary function. We present a novel method assessing inflammatory markers in the upper airways’ epithelial lining fluid (ELF) obtained by nasal lavage (NL). In contrast to broncho-alveolar lavage, ELF sampling by NL is an attractive method due to its limited invasiveness which allows repeated analyses, even performed in a home-based setting. In a longitudinal cohort study (ClinicalTrials.gov, Identifier: NCT02311140), we assessed changes of inflammatory mediators in 259 serially obtained nasal lavages taken up to every second day before and during therapy with ivacaftor from ten CF patients carrying a G551D mutation. Patients were trained to sample NL-fluid at home, to immediately freeze and transfer chilled secretions to centers. Neutrophil Elastase, Interleukins IL-1b, IL-6 and IL-8 in NL were quantified. During 8-12 weeks of ivacaftor-treatment, median values of IL-1b and IL-6 significantly declined 2.29-fold (2.97!1.30 pg/mL), and 1.13-fold (6.48!5.72 pg/mL), respectively. In parallel, sweat tests and pulmonary function improved considerably. This is the first study assessing changes of airway inflammation on a day-to-day basis in CF patients receiving a newly administered CFTR-modulator therapy. It proves a decline of airway inflammation during ivacaftor-therapy

Insights Into Patient Variability During Ivacaftor-Lumacaftor Therapy in Cystic Fibrosis

Background: The advent of cystic fibrosis transmembrane conductance regulator protein (CFTR) modulators like ivacaftor have revolutionised the treatment of cystic fibrosis (CF). However, due to the plethora of variances in disease manifestations in CF, there are inherent challenges in unified responses under CFTR modulator treatment arising from variability in patient outcomes. The pharmacokinetic (PK) data available for ivacaftor-lumacaftor cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator drug combination is limited. Methods: Secondary objectives were to identify (1) patient characteristics and (2) the interactions between ivacaftor-lumacaftor responsible for interindividual variability (IIV). Results: Peak plasma concentrations (Cmax) of ivacaftor - lumacaftor were >10 fold lower than expected compared to label information. The one-way ANOVA indicated that the patient site had an effect on Cmax values of ivacaftor metabolites ivacaftor-M1, ivacaftor-M6, and lumacaftor (p < 0.001, p < 0.001, and p < 0.001, respectively). The Spearman’s rho test indicated that patient weight and age have an effect on the Cmax of lumacaftor (p = 0.003 and p < 0.001, respectively) and ivacaftor metabolite M1 (p = 0.020 and p < 0.001, respectively). Age (p < 0.001) was found to effect on Cmax of ivacaftor M6 and on Tmax of ivacaftor M1 (p = 0.026). A large impact of patient characteristics on the IIV of PK parameters Cmax and Tmax, was observed among the CF patients. Conclusion: Understanding the many sources of variability can help reduce this individual patient variability and ensure consistent patient outcomes

Lung clearance index to detect the efficacy of Aztreonam lysine inhalation in patients with cystic fibrosis and near normal spirometry - A single-centre feasibility study.

Comparing the efficacy of inhaled antibiotics can be difficult in small groups of patients with cystic fibrosis and mild lung disease. In a feasibility study we compared Aztreonam lysine for inhalation solution (AZLI; Cayston®) to standard inhaled antibiotic therapy in patients with cystic fibrosis and near normal spirometry. To detect treatment responses we used both lung clearance index (LCI) and forced expiratory volume in one second (FEV1). At baseline, median FEV1 was 87% pred. and median LCI was 8.6 (upper limit of normal: 7.0). After 4 weeks, LCI improved by -0.36 after AZLI and deteriorated by +0.12 after tobramycin treatment (p = 0.039). No significant differences between treatments (p = 0.195) were observed using FEV1. These results suggest that lung clearance index can be used to detect treatment induced changes in subjects with mild lung disease

Detection of cytokines in nasal lavage samples of patients with cystic fibrosis: comparison of two different cytokine detection assays

Abstract Background Cystic fibrosis (CF) is a genetic multisystem disorder. Inflammatory processes, which presumably begin early in infancy, play a crucial role in the progression of the disease. The detection of inflammatory biomarkers, especially in the airways, has therefore gained increasing attention. Due to improved treatment options, patients with CF produce less sputum. Nasal lavage samples therefore represent a promising alternative to induced sputum or bronchoalveolar lavage specimens. However, methodology of cytokine measurements is not standardised and comparisons of results are therefore often difficult. The aim of this study was to identify suitable detection methods of cytokines in nasal lavage samples by comparison of two different assays. Methods Nasal lavage samples were obtained from the same patient at the same time by trained respiratory physiotherapists using a disposable syringe and 10 ml of 0.9% sodium chloride per nostril during outpatient visits. The cytokines IL-17 A, IL-2, IL-6 and IL-10 were measured using two different assays (BD™ and Milliplex®), which have already been applied in sputum and nasal lavage samples, despite different lower detection limits. Results 22 participants were included in the study. In 95.5% of measurements, values were below the limit of detection with respect to the BD™ assay. Only IL-6 could be detected in approximately half of the patients. Individual cytokine levels were considerably higher when measured with Milliplex®, which is also reflected in a statistically significant manner (p = < 0.01). Conclusion The right choice of analysis method is crucial for measuring inflammatory markers in nasal lavage samples. Compared to the literature, Milliplex® showed higher detection rates and similar concentrations to other studies. Trial registration Ethics approval was obtained from the ethics committee at Medical University of Innsbruck (EK Nr: 1055/2022)

Tezacaftor/ivacaftor in people with cystic fibrosis heterozygous for minimal function CFTR mutations

Background: Tezacaftor/ivacaftor is a CFTR modulator approved to treat people with cystic fibrosis (pwCF) who are homozygous (F/F) or heterozygous for the F508del-CFTR mutation and a residual function mutation (F/RF). This randomized, double-blind, placebo-controlled Phase 3 study evaluated the efficacy, safety, tolerability, and pharmacokinetics (PK) of tezacaftor/ivacaftor in participants ≥12 years of age heterozygous for the F508del-CFTR mutation and a minimal function mutation (F/MF), which produces no CFTR protein or a protein unresponsive to tezacaftor/ivacaftor in vitro. Methods: Participants were randomized 1:1 to receive tezacaftor/ivacaftor or placebo for 12 weeks. The primary endpoint was the absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV) between the tezacaftor/ivacaftor and placebo groups through week 12. Key secondary endpoints included absolute change from baseline in CF Questionnaire-Revised respiratory domain scores and the number of pulmonary exacerbations through week 12 and the absolute change from baseline in body mass index at week 12. A prespecified interim analysis (IA) for futility was conducted when approximately 50% of a planned enrollment of 300 participants reached week 12 of the study. Results: At the time of the IA, 83 participants were randomized to tezacaftor/ivacaftor and 85 to placebo; 165 participants completed treatment. The study failed to demonstrate that tezacaftor/ivacaftor significantly improved ppFEV or any of the key secondary endpoints and was terminated for futility. The safety profile and PK parameters of tezacaftor/ivacaftor were similar to those reported in prior studies in participants ≥12 years of age with CF. Conclusions: Tezacaftor/ivacaftor did not show a clinically meaningful benefit in participants with F/MF genotypes but was generally safe and well tolerated, consistent with the safety profile reported in other Phase 3 studies (NCT02516410)