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Background: To examine safety and efficacy of tezacaftor-ivacaftor (TEZ/IVA) in a real-life setting in adults living with cystic fibrosis., Methods: A multicentre retrospective observational study, including adults living with cystic fibrosis (pwCF) eligible for TEZ/IVA, with assessments at baseline, 3 months (visit 3mo ) and 6 months (visit 6mo ) after start of treatment. Outcomes included change in FEV 1 , LCI, FeNO, CFQ-R, estimated number of annual acute exacerbations, BMI, dosage of pancreatic enzyme replacement therapy (PERT) and airway microbiology. We also assessed safety., Results: Forty-eight adult pwCF (mean (±SD) age 33 (±12) years; mean FEV 1 65 (±19) %P) were included. Three subgroups were identified: pwCF F/F CFTR modulator-naive (n = 28; 58%), pwCF F/F previously treated with lumacaftor-ivacaftor (n = 11; 23%) and pwCF F/RF (n = 9; 19%). Adverse events were described in 3 pwCF (6%) during the 6-month observation period (in one leading to treatment interruption). At visit 3mo, FEV 1 had improved in all subgroups. In the entire group, mean FEV 1 had increased from 66 (±2.9) %P to 72 (±2.9) %P (p < 0.0001). Similarly, LCI improved by approximately one unit at visit 3mo (p = 0.02). At visit 6mo mean annual acute exacerbation rate decreased significantly (p = 0.02). Only in the CFQ-R social functioning domain score, a significant improvement was observed at visit 6mo (p < 0.01)., Conclusions: We showed that TEZ/IVA is safe, well tolerated and effective in terms of improvement of lung function, ventilation inhomogeneity, health-related social functioning, and reduction of estimated annual acute exacerbation rate, in adult pwCF F/F and F/RF. Results in this real-life study reflect those observed in RCTs.

Objectives: Prevalence of MRSA in patients with CF has risen over the past decades, and chronic infection with MRSA is associated with worse outcome in this patient group., Methods: This retrospective observational study investigated long-term eradication rate in pediatric and adult CF patients with chronic MRSA infection, using a 6-month eradication regimen containing 2 oral antibiotics, combined with topical decolonisation measures. Respiratory tract cultures were performed at least every three months, from the first MRSA-positive culture onwards., Results: A total of 24 patients with chronic MRSA infection were identified from our CF patient registry, of which 13 patients underwent an eradication attempt. The regimen consisted of 2 oral antibiotics: a combination of rifampicin, fusidic acid, clindamycin and co-trimoxazol, based on the sensitivity pattern of the MRSA strain. At the end of the study period (median 8.2 years), 12 out of 13 patients (92%) were MRSA negative. None of the patients interrupted treatment due to side-effects., Conclusions: Eradication of chronic MRSA infection is feasible, well-tolerated and highly successful, and can offer a long-lasting MRSA-negative status, obviating the need for patient segregation.

Despite being an important patient group, adult cystic fibrosis patients with an FEV 1 below 40%predicted have been excluded from clinical trials with elexacaftor/tezacaftor/ivacaftor. We conducted a real-life 3 months follow-up study in 14 adult CF patients (median FEV 1 34%predicted) demonstrating significant treatment effects in terms of FEV 1 (an increase of 12%predicted at 4 weeks, remaining stable thereafter). Corresponding decreases in lung clearance index LCI (by 31%predicted, down from baseline 247%predicted) and ventilation heterogeneity in the acinar compartment (Sacin) (by 411%predicted, down from baseline 798%predicted) suggest a distinct peripheral lung effect. One patient had intermittent treatment interruptions because of drug-induced liver injury. Our real-life data confirm that treatment with elexacaftor/tezacaftor/ivacaftor is effective in severely obstructive patients, and this is the first study to show time evolution of ventilation distribution improvement, pointing to the peripheral lung as the main site of treatment effect., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Patients with cystic fibrosis have increased risk for gastrointestinal cancer, lymphoid leukemia and testicular carcinomas. Chronic inflammation does not seem to be the only contributing factor. Mutations and epigenetic alterations in the CFTR gene may alter susceptibility to develop cancer. Lung cancer is up to now not frequently observed in CF patients. In lung cancer patients without CF low CFTR expression is significantly associated with advanced staging, lymph node metastasis. As the management and life expectancy of patients with cystic fibrosis have improved substantially in recent years, we expect an increased number of these patients diagnosed with lung cancer. In addition, it is possible that they, as a result of CFTR-dysfunction, will present with more aggressive lung tumors. Treating cancer in CF patients is a challenge because of multi-organ involvement and chronic colonization by resistant pathogens. The effectiveness and safety of immunotherapy in this population needs to be further evaluated.

Background : While cystic fibrosis (CF) lung disease is generally considered to be an obstructive disorder, other pulmonary function patterns (PFP) may occur. Furthermore, little is known about possible associations between PFP and genotype or phenotypical characteristics. Methods : Cross-sectional study including CF patients aged 16 years or more, identifying different PFP and exploring associations between PFP and genotype or phenotypical characteristics. Results : Obstructive PFP was most prevalent in our population (n = 80), comprising obstructive lung disease (62.5%), small airway (obstructive) disease (11.2%), and mixed obstructive-restrictive disorder (1.3%). However, one in four adult CF patients did not show any obstruction at all: normal (13.7%) or restrictive (8.8%) lung disease and isolated diffusion disorder (2.5%). Obstructive PFP was associated with a greater proportion of CF-related diabetes mellitus (CFRD) ( P  = 0.04), Pseudomonas aeruginosa colonization ( P  = 0.02) and frequent exacerbators ( P  = 0.04). We observed no association between PFP and genotype. Conclusions : Obstructive PFP remains the most common pulmonary function pattern in adult CF and is associated with CFRD, Pseudomonas aeruginosa colonization and frequent exacerbators.

Pharmacological rescue of mutant cystic fibrosis transmembrane conductance regulator (CFTR) in cystic fibrosis (CF) depends on the specific defect caused by different mutation classes. We asked whether a patient with the rare p.Gly970Asp (c.2909G>A) mutation could benefit from CFTR pharmacotherapy since a similar missense mutant p.Gly970Arg (c.2908G>C) was previously found to be sensitive to potentiators in vitro but not in vivo. By complementary DNA transfection, we found that both mutations are associated with defective CFTR function amenable to pharmacological treatment. However, analysis of messenger RNA (mRNA) from patient's cells revealed that c.2908G>C impairs RNA splicing whereas c.2909G>A does not perturb splicing and leads to the expected p.Gly970Asp mutation. In agreement with these results, nasal epithelial cells from the p.Gly970Asp patient showed significant improvement of CFTR function upon pharmacological treatment. Our results underline the importance of controlling the effect of CF mutation at the mRNA level to determine if the pharmacotherapy of CFTR basic defect is appropriate., (© 2019 Wiley Periodicals, Inc.)

Background: This study aims to determine the prevalence and characteristics of Staphylococcus aureus in Belgian cystic fibrosis (CF) patients., Methods: Non-duplicate respiratory samples from 510 CF-patients (2012-2013) were examined. One isolate per patient was analysed unless different phenotypes were recovered. Isolates were investigated for mecA/mecC, toxins presence, spa-typing, MLST and SCCmec-typing. Potential livestock-associated (LA) isolates were examined for their immune-evasion-cluster (IEC) genes., Results: S. aureus (n = 380), including 41 small-colony variants (SCVs), were isolated from 66.7% patients. The prevalence of methicillin-resistant S. aureus (MRSA) colonization was 4.9%. Two MRSA isolates carried toxic shock syndrome toxin 1 (TSST-1). Most MRSA (65%) belonged to two nosocomial epidemic clones (CC5, CC8) widespread in Belgium. Methicillin susceptible S. aureus (MSSA) showed great genetic diversity. Five of 33 isolates belonging to potential LA-lineages were IEC negative, including three methicillin-resistant isolates, suggesting an animal origin., Conclusions: The MRSA-prevalence in Belgian CF-patients remained constant (2001-2013), but SCV-prevalence increased. Most MRSA belonged to health-care-associated clones. Three patients carrying LA-MRSA were found, requiring further investigation to determine the risk factors for LA-MRSA acquisition., (Copyright © 2018 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Effective microbiogical eradication of methicillin-resistant Staphylococcus aureus (MRSA) in patients with cystic fibrosis (CF) can be obtained, but its effect is not always clear-cut in terms of spirometric indices. The aim of this observational prospective cohort study was to study the potential effect of eradication of chronic MRSA infection on lung function including ventilation distribution. Six CF patients, chronically colonized with MRSA (median age: 21 years (range 14-46); median FEV1: 76 (95%CI 58-98)%pred) were successfully eradicated using oral rifampicin and fusidic acid in combination with topical decolonization measures. Lung function and multiple breath washout test were performed at the start and at the end of the eradication protocol and after an average follow-up period of 7·5±1·5(SD) months. One patient cultured MRSA again 4 months after successful eradication. All patients reported reduced sputum production and viscosity. By the end of the follow-up period, there was an increase in ventilated FRCMBW and no change in plethysmographic FRCPL. This resulted in a significant decrease of trapped air by half a litre (from 579 to 40 ml; P = 0·013). Lung clearance index (LCI) also showed a small but significant decrease (from 7·2 to 6·7; P = 0·014) after eradication of MRSA. We conclude that MRSA eradication can be successful, also in terms of recruitment of previously unventilated air spaces, potentially due to reduced sputum production and/or viscosity.

Background: Treating acute infectious exacerbations in cystic fibrosis (CF) patients with intravenous antibiotic therapy leads to variability in lung function and the ventilation distribution response. Part of the variable lung clearance index (LCI) response could be associated with the variable peripheral effects of intravenous antibiotic administration., Objectives: We explored to what extent the peripheral lung zones of CF patients could contribute to lung function improvements following treatment for infectious exacerbations., Methods: Over a 1-year period, 15 adult CF patients admitted for acute exacerbations were recruited. Lung function and multiple breath washout (MBW) tests were performed on the day of admission and at discharge. From the MBW test, we obtained acinar and conductive indices of ventilation heterogeneity and LCI., Results: The mean age (±SD) was 26 ± 5 years. Upon admission, the FEV1 was 54 ± 16% predicted and the LCI was 181 ± 26% predicted. After treatment, the average FEV1 increased to 61 ± 20% predicted (p < 0.001) and the LCI decreased to 173 ± 28% predicted (p = 0.042). The change in LCI was associated with a change in acinar (ρ = +0.54; p = 0.039) but not in conductive ventilation heterogeneity (p > 0.1)., Conclusions: In CF patients in whom an improvement in LCI was obtained after treatment for an acute infectious exacerbation, this was paralleled by a decrease in acinar ventilation heterogeneity., (© 2014 S. Karger AG, Basel.)

Background: Chronic airway infection with methicillin-resistant Staphylococcus aureus (MRSA) in patients with cystic fibrosis (CF) is an increasing clinical problem, and therapeutic options are limited. Because chronic infection with MRSA can be associated with accelerated decline in lung function, eradication of MRSA is attempted in most CF centres today. The aim of this observational prospective cohort study was to determine whether it is possible to eradicate MRSA from airways of CF patients using prolonged oral antibiotic combination therapy together with topical decolonization measures., Results: Eleven CF patients, (median age: 9 years (range 1-43); median FEV1: 91%pred (95%CI 74%-100%pred)) who were chronically infected with MRSA, were treated daily for six months with rifampicin and fusidic acid orally. This study did not include a patient control group. Two patients had to switch to an alternative schedule, using rifampicin and clindamycin, due to the resistance pattern of MRSA. Topical decolonization measures were applied to all patients and included mupirocin-containing nasal ointment in both nostrils three times daily for five days and chlorhexidine hair and body wash once daily for five days. Microbiological eradication was achieved in all patients at the end of the six-month eradication protocol, even when significant time (range 18 months to 9 years) had elapsed since initial isolation. In only one patient MRSA reappeared in the six-month follow-up period after the initial study period. Side-effects, like nausea, vomiting and diarrhoea were seen in five out of eleven patients, but did not lead to therapy cessation., Conclusion: Chronic MRSA infection can be eradicated from respiratory tract samples using a six month dual antibiotic regimen and topical MRSA decolonization measures., (Copyright © 2013 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Severe convective ventilation heterogeneity occurring in CF lung disease requires a modified method to determine acinar and conductive components of ventilation heterogeneity from normalized phase III slope (Sn) curves. Modified Sacin* and Scond* (as opposed to standard Sacin and Scond) are proposed and interpreted on the basis of 2 conceptual mechanisms: (a) flow asynchrony between two convection-dependent units with a different specific ventilation, but with an identical acinus inside each unit (generating an identical diffusion-convection-dependent portion of Sn); (b) different specific ventilation (without any flow asynchrony) between two convection-dependent units with the worst ventilated unit containing an abnormal acinus generating the greatest diffusion-convection-dependent portion of Sn. In CF patients with an abnormal lung clearance index (LCI), Scond* (but not Scond) and Sacin* were significant contributors to LCI (β(Scond*)=0.70; β(Sacin*)=0.49; P<0.001 for both). Mechanism (a) can entirely account for experimental Scond* values, while mechanism (b) implies that experimental Sacin* values are likely dominated by peripheral ventilation heterogeneity in the best ventilated portions of the lung., (Copyright © 2013 Elsevier B.V. All rights reserved.)

We investigated the extent of convective ventilation heterogeneity contributing to the observed lung clearance index values in adult cystic fibrosis patients, as the result of two simulated scenarios, either 1) a fixed part of the lungs becoming increasingly less compliant, or 2) an increasingly greater part of the lung being less compliant. In 25 cystic fibrosis patients and 25 matched controls, we computed the lung clearance index and also quantified curvilinearity of the washout concentration curve, where curvilinearity is equal to 0 (linear in semilog plot) reflects homogeneous ventilation and curvilinearity equal to 1 corresponds to the presence of an infinitesimally slowly emptying lung unit. In the cystic fibrosis group (forced expiratory volume in 1 s 27-100% predicted), lung clearance index and curvilinearity average±sd values were 10.3±2.3 and 0.57±0.13, respectively, and were significantly different from control values (6.2±0.4 and 0.18±0.07; both p<0.001); lung clearance index and curvilinearity were also correlated (R = 0.67; p<0.001). The average curvilinearity value in the cystic fibrosis group was found to be compatible with a cumulative volume of underventilated lung of 40-50%, depending on the simulation scenario considered. The degree of washout curvilinearity observed here indicates that a major determinant of the abnormal lung clearance index values observed in adult cystic fibrosis patients is ventilation heterogeneity generated between convection-dependent lung units, while the remainder of lung clearance index abnormality with respect to normal controls potentially represents the small airways within these lung zones.

Background: Risk factors for methicillin-resistant Staphylococcus aureus (MRSA) in Cystic Fibrosis (CF) and the impact on CF disease progression are still under debate. The objectives of this study were to determine clinical variables associated with MRSA colonization and examine impact on FEV(1) evolution in CF patients., Methods: A retrospective case-control study using the University Hospital of Brussels CF clinic patient registry from 2002 to 2010, comparing clinical variables and decline of FEV(1) of MRSA positive patients with age and sex matched controls, chronically colonized with S. aureus., Results: Thirty of the 165 CF patients, chronically colonized with S. aureus, had cultures positive for MRSA (18.2%). Excluding patients under 4 years, the prevalence became 15.2% (23/151). Chronic colonization (i.e., three or more consecutive positive cultures) was found in 19/151 (12.6%). The MRSA positive group showed a higher proportion of patients with genotype F508del, less pancreas sufficient patients, more bronchiectasis and more frequent hospitalization. The FEV(1) recorded one year prior to, and at the moment of MRSA acquisition, was lower but not significantly different from that obtained in controls (72.9%±26.6 vs 84.3±21.8 and 68.2%±27.1 vs 81.4%±24.3 respectively, p>0.1). However, FEV(1) decline over 2- and 6-year periods, were significantly greater in the chronic MRSA group than in the controls (-5%±5.5 vs -2.5±2.3 over 2 years (p=0.043) and -1.8%±4.6 vs -1.0%±1.9 over a 6-year period (p=0.026))., Conclusion: In our center the prevalence of MRSA in CF patients, chronically colonized with S. aureus and over the age of 4 years, was 15.2% (12.6% chronic infection). MRSA colonization was shown to be associated with a genotype F508del, presence of bronchiectasis and hospitalization. Our spirometric data also show that a MRSA episode entails an FEV(1) decline that is almost double that predicted for CF patients who can remain unaffected by MRSA., (Copyright © 2011 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Abstract: Background: Risk factors for methicillin-resistant Staphylococcus aureus (MRSA) in Cystic Fibrosis (CF) and the impact on CF disease progression are still under debate. The objectives of this study were to determine clinical variables associated with MRSA colonization and examine impact on FEV1 evolution in CF patients. Methods: A retrospective case–control study using the University Hospital of Brussels CF clinic patient registry from 2002 to 2010, comparing clinical variables and decline of FEV1 of MRSA positive patients with age and sex matched controls, chronically colonized with S. aureus. Results: Thirty of the 165 CF patients, chronically colonized with S. aureus, had cultures positive for MRSA (18.2%). Excluding patients under 4years, the prevalence became 15.2% (23/151). Chronic colonization (i.e., three or more consecutive positive cultures) was found in 19/151 (12.6%). The MRSA positive group showed a higher proportion of patients with genotype F508del, less pancreas sufficient patients, more bronchiectasis and more frequent hospitalization. The FEV1 recorded one year prior to, and at the moment of MRSA acquisition, was lower but not significantly different from that obtained in controls (72.9%±26.6 vs 84.3±21.8 and 68.2%±27.1 vs 81.4%±24.3 respectively, p>0.1). However, FEV1 decline over 2- and 6-year periods, were significantly greater in the chronic MRSA group than in the controls (−5%±5.5 vs −2.5±2.3 over 2years (p=0.043) and −1.8%±4.6 vs −1.0%±1.9 over a 6-year period (p=0.026)). Conclusion: In our center the prevalence of MRSA in CF patients, chronically colonized with S. aureus and over the age of 4years, was 15.2% (12.6% chronic infection). MRSA colonization was shown to be associated with a genotype F508del, presence of bronchiectasis and hospitalization. Our spirometric data also show that a MRSA episode entails an FEV1 decline that is almost double that predicted for CF patients who can remain unaffected by MRSA. [Copyright &y& Elsevier]

Background The AKITA JET is a nebulizer with breath-controlled inhalation, using individually regulated inspiratory flow and volume. As inhalation therapy contributes to treatment burden, it is important to investigate patients’ satisfaction with the introduction of any new device. Methods Clinically stable CF patients (6–65 y) were eligible for participation in this multicentre open-label trial. After using the AKITA JET for 3 months, patients were asked to complete a questionnaire, consisting of general questions about the device and satisfaction scoring of 8 parameters and their importance to the patient. Results In total 36 patients were included, mean age 23.7 y (SD 11.9 y). Two patients did not return the questionnaire at the final visit, 1 patient withdrew consent. Overall, 79% of the patients were satisfied to extremely satisfied with the AKITA JET. Whilst 76% of the patients think the device could improve their treatment, only 46% find it suitable for daily use. Cleaning/hygiene, screen information and ease of use scored highest for patients’ satisfaction (80%, 77% and 74%, respectively); the first and latter being of highest importance (81% and 82%, respectively). The lowest satisfaction scores were given for weight/size, transportability and treatment duration (41%, 44% and 56%, respectively). Parameters considered to be less important were screen information and design of the device (58% and 62%, respectively). Conclusion Overall, patients were satisfied with the AKITA JET device for inhalation therapy. Although not all stable CF patients would use the device in daily routine, it is a valuable addition to existing devices, and these patients might benefit from it at other time points in their life. [ABSTRACT FROM AUTHOR]