Multisystemic Effects of Elexacaftor-Tezacaftor-Ivacaftor in Adults with Cystic Fibrosis and Advanced Lung Disease.

RATIONALE: Limited data exist on safety and effectiveness of elexacaftor-tezacaftor-ivacaftor (ETI) in people with cystic fibrosis (pwCF) and advanced lung disease. OBJECTIVE: To evaluate the effects of ETI in an unselected population of pwCF and advanced lung disease. METHODS: A prospective observational study, including all adults, aged 18 years and older, with a percent predicted FEV1 (ppFEV1)≤ 40 who initiated ETI from December 2019 to June 2021 in France was conducted. PwCF were followed until August 8th, 2022. RESULTS: ETI was initiated in 434 pwCF with a median [interquartile range, IQR] ppFEV1=30 [25; 35], including 27 with severe CF liver disease and 183 with diabetes. PwCF were followed for a median [IQR] 587 [396; 728] days after ETI initiation. Discontinuation of ETI occurred in 12 (2.8%) pwCF and was mostly due to lung transplantation (n=5) or death (n=4). Absolute increase in ppFEV1 by a mean +14.2% (95% CI, 13.1-15.4) occurred at 1 month and persisted throughout the study. Increase in ppFEV1 in the younger age quartile was almost twice that of the oldest quartile (P<0.001); body mass index <18.5 kg/m2 was found in 38.6% at initiation vs. 11.3% at 12 months (P=0.0001). Increase in serum concentrations of vitamin A and E, but not 25OHD3, was observed. Significant reduction in the % of pwCF using oxygen therapy, noninvasive ventilation, nutritional support, inhaled and systemic therapies (including antibiotics) were observed; insulin was discontinued in 12% of diabetics. CONCLUSION: ETI is safe in pwCF and advanced lung disease with multisystem pulmonary and extrapulmonary benefits.

Druggable redox pathways against Mycobacterium abscessus in cystic fibrosis patient-derived airway organoids.

Mycobacterium abscessus (Mabs) drives life-shortening mortality in cystic fibrosis (CF) patients, primarily because of its resistance to chemotherapeutic agents. To date, our knowledge on the host and bacterial determinants driving Mabs pathology in CF patient lung remains rudimentary. Here, we used human airway organoids (AOs) microinjected with smooth (S) or rough (R-)Mabs to evaluate bacteria fitness, host responses to infection, and new treatment efficacy. We show that S Mabs formed biofilm, and R Mabs formed cord serpentines and displayed a higher virulence. While Mabs infection triggers enhanced oxidative stress, pharmacological activation of antioxidant pathways resulted in better control of Mabs growth and reduced virulence. Genetic and pharmacological inhibition of the CFTR is associated with better growth and higher virulence of S and R Mabs. Finally, pharmacological activation of antioxidant pathways inhibited Mabs growth, at least in part through the quinone oxidoreductase NQO1, and improved efficacy in combination with cefoxitin, a first line antibiotic. In conclusion, we have established AOs as a suitable human system to decipher mechanisms of CF-driven respiratory infection by Mabs and propose boosting of the NRF2-NQO1 axis as a potential host-directed strategy to improve Mabs infection control.

Feasibility of home initiation of an airway clearance device (SIMEOX) by telecare in people with non-cystic fibrosis bronchiectasis: a pilot study.

BACKGROUND: Mucociliary clearance is a cornerstone of the management of people with non-cystic fibrosis bronchiectasis (NCFB). SIMEOX, an innovative device, could facilitate autonomous airway clearance, but its use requires specific training. We hypothesised that telecare would be an effective means to train people with NCFB in the handling of device and to monitor and promote device adherence. OBJECTIVES: (1) To evaluate frequency of use of the SIMEOX for 10 weeks after telecare training. (2) To assess user satisfaction and clinical efficacy of the SIMEOX+telecare. METHODS: Multicentre, prospective, pilot study in adults with NCFB. A SIMEOX was provided to each participant at inclusion. Physiotherapists performed telecare sessions the first 2 weeks (3-5 sessions) for device training and every 10 days to reinforce motivation and provide technical support. RESULTS: 22 individuals were included, 21 analysed (38% male; mean±SD age 53±18 years; Bronchiectasis Severity Index 6.6±3.5). Fourteen participants (66.7%; 95% CI 43.1% to 84.5%) performed ≥3 SIMEOX sessions/week (self-reported adherence, primary outcome). Median (Q1; Q3) number of self-reported sessions/week for the whole group was 3.7 (1.8; 5.7). Adherence including web registration was 80.9%. At week 12, participant satisfaction rating was 9.0 (7.9; 10.0) on a 10-point visual analogue scale; respiratory function did not change but quality of life improved (COPD Assessment Test score -4.7, 95% CI -7.7 to -1.6, p=0.023; St Georges Respiratory Questionnaire -5.8, 95% CI -10.8 to -0.9, p=0.005). CONCLUSION: Adherence to and satisfaction with the SIMEOX airway clearance device supported by telecare were high in people with NCFB. The clinical efficacy needs to be confirmed in a randomised controlled trial. TRIAL REGISTRATION NUMBER: NCT04742270.

Cumulative Incidence and Risk Factors for Severe Coronavirus Disease 2019 in French People With Cystic Fibrosis.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are closely monitored in people with cystic fibrosis (pwCF), especially severe cases. Previous studies used hospitalization rates as proxy for severity. METHODS: We evaluated data from coronavirus disease 2019 (COVID-19) cases diagnosed in French pwCF over the first pandemic year. Objective criteria were applied for defining severity (eg, respiratory failure and/or death). Data were compared to all French pwCF using the National Registry. RESULTS: As of 30 April 2021, 223 pwCF were diagnosed with COVID-19, with higher risks in adults (odds ratio [OR], 2.52 [95% confidence interval {CI}, 1.82-3.48]) and transplant recipients (OR, 2.68 [95% CI, 1.98-3.63]). Sixty (26.9%) patients were hospitalized, with increased risk in transplant recipients (OR, 4.74 [95% CI, 2.49-9.02]). In 34 (15%) cases, COVID-19 was considered severe; 28 (46.7%) hospitalizations occurred without objective criteria of severity. Severe cases occurred mostly in adult (85.3%) and posttransplant pwCF (61.8%; OR, 6.02 [95% CI, 2.77-13.06]). In nontransplanted pwCF, risk factors for severity included low lung function (median percentage of predicted forced expiratory volume in 1 second, 54.6% vs 75.1%; OR, 1.04 [95% CI, 1.01-1.08]) and CF-related diabetes (OR, 3.26 [95% CI, 1.02-10.4]). While 204 cases fully recovered, 16 were followed for possible sequelae, and 3 posttransplant females died. CONCLUSIONS: Severe COVID-19 occurred infrequently during the first pandemic year in French pwCF. Nontransplanted adults with severe respiratory disease or diabetes and posttransplant individuals were at risk for severe COVID-19. Thus, specific preventive measures should be proposed.

Sustained effectiveness of elexacaftor-tezacaftor-ivacaftor in lung transplant candidates with cystic fibrosis.

BACKGROUND: Elexacaftor-tezacaftor-ivacaftor induces rapid clinical improvement in patients with cystic fibrosis (CF) and advanced pulmonary disease, often leading to suspend the indication for lung transplantation. Yet no long-term data is available in lung transplant candidates. METHODS: Lung transplant candidates (defined as being waitlisted for lung transplantation or considered for listing within 3 months) who have initiated elexacaftor-tezacaftor-ivacaftor were identified in the French cohort of patients with CF and advanced pulmonary disease. Patients were prospectively followed to evaluate treatment safety and effectiveness from initiation to July 20th, 2021. RESULTS: Among the 331 patients with advanced CF pulmonary disease who initiated elexacaftor-tezacaftor-ivacaftor, 65 were lung transplant candidates (17 listed for transplantation, 48 considered for listing within 3 months). Median [IQR] follow-up time was 363 [329; 377] days. At the end of the follow-up period, two patients were transplanted five and 11 days following treatment initiation, two were listed for transplantation, and 61 no longer met transplantation criteria. Improvement in percent predicted forced expiratory volume in 1 s (ppFEV1) at one month was +13.4% (95% confidence interval, 10.3%-16.5%; P < 0.0001) and remained stable thereafter. Treatment burden decreased substantially, with an 86% decrease in the need for intravenous antibiotics, 59% for oxygen therapy and 62% for non-invasive ventilation. CONCLUSION: In lung transplant candidates eligible for elexacaftor-tezacaftor-ivacaftor, the rapid improvement following initiation of treatment persisted over one year with a reduction in treatment burden and lung transplantation could be safely deferred in most patients.

Bronchiectasis and inhaled tobramycin: A literature review.

BACKGROUND: Inhaled antibiotics have been incorporated into contemporary European and British guidelines for bronchiectasis, yet no inhaled antibiotics have been approved in the United States or Europe for the treatment of bronchiectasis not related to cystic fibrosis. Pseudomonas aeruginosa infection is common in patients with bronchiectasis, contributing to a cycle of progressive inflammation, exacerbations, and airway remodelling. OBJECTIVE: The aim of the current study was to identify and evaluate published studies of inhaled tobramycin solution or powder in patients with bronchiectasis and P. aeruginosa infection not associated with cystic fibrosis. METHODS: A literature review was conducted utilising the PubMed and Cochrane databases. Studies published in the English language that reported safety and/or efficacy outcomes of inhaled tobramycin either alone or in combination with other antibiotics were included. RESULTS: Seven clinical trials published between 1999 and 2021 were identified that met inclusion criteria. Inhaled tobramycin therapy was effective in reducing P. aeruginosa microbial density in the sputum of patients with bronchiectasis. Several studies demonstrated favourable impacts on hospitalisations, number and severity of exacerbations, and symptoms. Other studies were underpowered for these clinical outcomes or were exploratory in nature. Although tobramycin was generally well tolerated, some evidence of treatment-associated wheezing was reported. CONCLUSIONS: In patients with bronchiectasis and chronic P. aeruginosa infection, inhaled tobramycin was effective in reducing the density of bacteria in sputum, which may be associated with additional clinical benefits. Definitive phase 3 trials of inhaled tobramycin in patients with bronchiectasis are indicated to determine clinical efficacy and long-term safety.

Mycobacteria-host interactions in human bronchiolar airway organoids.

Respiratory infections remain a major global health concern. Tuberculosis is one of the top 10 causes of death worldwide, while infections with Non-Tuberculous Mycobacteria are rising globally. Recent advances in human tissue modeling offer a unique opportunity to grow different human "organs" in vitro, including the human airway, that faithfully recapitulates lung architecture and function. Here, we have explored the potential of human airway organoids (AOs) as a novel system in which to assess the very early steps of mycobacterial infection. We reveal that Mycobacterium tuberculosis (Mtb) and Mycobacterium abscessus (Mabs) mainly reside as extracellular bacteria and infect epithelial cells with very low efficiency. While the AO microenvironment was able to control, but not eliminate Mtb, Mabs thrives. We demonstrate that AOs responded to infection by modulating cytokine, antimicrobial peptide, and mucin gene expression. Given the importance of myeloid cells in mycobacterial infection, we co-cultured infected AOs with human monocyte-derived macrophages and found that these cells interact with the organoid epithelium. We conclude that adult stem cell (ASC)-derived AOs can be used to decipher very early events of mycobacteria infection in human settings thus offering new avenues for fundamental and therapeutic research.

Safety and pharmacokinetics of Roscovitine (Seliciclib) in cystic fibrosis patients chronically infected with Pseudomonas aeruginosa, a randomized, placebo-controlled study.

BACKGROUND: The orally available kinase inhibitor R-roscovitine has undergone clinical trials against various cancers and is currently under clinical evaluation against Cushing disease and rheumatoid arthritis. Roscovitine displays biological properties suggesting potential benefits in CF: it partially corrects F508del-CFTR trafficking, stimulates the bactericidal properties of CF alveolar macrophages, and displays anti-inflammatory properties and analgesic effects. METHODS: A phase 2 trial study (ROSCO-CF) was launched to evaluate the safety and effects of roscovitine in Pseudomonas aeruginosa infected adult CF patients carrying two CF causing mutations (at least one F508del-CFTR mutation) and harboring a FEV1 ≥40%. ROSCO-CF was a multicenter, double-blind, placebo-controlled, dose-ranging study (200, 400, 800 mg roscovitine, orally administered daily for 4 days/week/4 weeks). RESULTS: Among the 34 volunteers enrolled, randomization assigned 11/8/8/7 to receive the 0 (placebo)/ 200/400/800 mg roscovitine doses, respectively. In these subjects with polypharmacy, roscovitine was relatively safe and well-tolerated, with no significant adverse effects (AEs) other than five serious AEs (SAEs) possibly related to roscovitine. Pharmacokinetics of roscovitine were rather variable among subjects. No significant efficacy, at the levels of inflammation, infection, spirometry, sweat chloride, pain and quality of life, was detected in roscovitine-treated groups compared to the placebo-treated group. CONCLUSION: Roscovitine was relatively safe and well-tolerated in CF patients especially at the 200 and 400 mg doses. However, there were 5 subject withdrawals due to SAEs in the roscovitine group and none in the placebo group. The lack of evidence for efficacy of roscovitine (despite encouraging cellular and animal results) may be due to high pharmacokinetics variability, short duration of treatment, and/or inappropriate dosing protocol.

Using chest CT scan and unsupervised machine learning for predicting and evaluating response to lumacaftor-ivacaftor in people with cystic fibrosis.

OBJECTIVES: Lumacaftor-ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) modulator known to improve clinical status in people with cystic fibrosis (CF). This study aimed to assess lung structural changes after one year of lumacaftor-ivacaftor treatment, and to use unsupervised machine learning to identify morphological phenotypes of lung disease that are associated with response to lumacaftor-ivacaftor. METHODS: Adolescents and adults with CF from the French multicenter real-world prospective observational study evaluating the first year of treatment with lumacaftor-ivacaftor were included if they had pretherapeutic and follow-up chest computed tomography (CT)-scans available. CT scans were visually scored using a modified Bhalla score. A k-mean clustering method was performed based on 120 radiomics features extracted from unenhanced pretherapeutic chest CT scans. RESULTS: A total of 283 patients were included. The Bhalla score significantly decreased after 1 year of lumacaftor-ivacaftor (-1.40±1.53 points compared with pretherapeutic CT; p<0.001). This finding was related to a significant decrease in mucus plugging (-0.35±0.62 points; p<0.001), bronchial wall thickening (-0.24±0.52 points; p<0.001) and parenchymal consolidations (-0.23±0.51 points; p<0.001). Cluster analysis identified 3 morphological clusters. Patients from cluster C were more likely to experience an increase in percent predicted forced expiratory volume in 1 sec (ppFEV1) ≥5 under lumacaftor-ivacaftor than those in the other clusters (54% of responders versus 32% and 33%; p=0.01). CONCLUSION: One year treatment with lumacaftor-ivacaftor was associated with a significant visual improvement of bronchial disease on chest CT. Radiomics features on pretherapeutic CT scan may help in predicting lung function response under lumacaftor-ivacaftor.

Clinical response to lumacaftor-ivacaftor in patients with cystic fibrosis according to baseline lung function.

BACKGROUND: Phase 3 trials have demonstrated the safety and efficacy of lumacaftor-ivacaftor (LUMA-IVA) in patients with cystic fibrosis (CF) homozygous for the Phe508del CFTR mutation and percent predicted forced expiratory volume in 1 s (ppFEV1) between 40 and 90. Marketing authorizations have been granted for patients at all levels of ppFEV1. METHODS: To evaluate the safety and effectiveness of LUMA-IVA over the first year of treatment in patients with ppFEV1<40 or ppFEV1≥90 in comparison with those with ppFEV1 [40-90[. Analysis of data collected during a real world study, which included all patients aged ≥12 years who started LUMA-IVA in 2016 across all 47 French CF centers. RESULTS: 827 patients were classified into 3 subgroups according to ppFEV1 at treatment initiation (ppFEV1<40, n = 121; ppFEV1 [40-90[, n = 609; ppFEV1≥90, n = 97). Treatment discontinuation rate was higher in ppFEV1<40 patients (28.9%) than in those with ppFEV1 [40-90[(16.4%) or ppFEV1≥90 (17.5%). In patients with uninterrupted treatment, significant increase in ppFEV1 occurred in the ppFEV1 [40-90[subgroup (+2.9%, P<0.001), and in those ppFEV1<40 (+0.5%, P = 0.03) but not in those with ppFEV1≥90 (P = 0.46). Compared with the year prior to initiation, the number of days of intravenous antibiotics were reduced in all subgroups, although 72% of patients with ppFEV1<40 still experienced at least one exacerbation/year under LUMA-IVA. Comparable increase in body mass index was seen in the three subgroups. CONCLUSION: Phe508del homozygous CF patients benefit from LUMA-IVA at all levels of baseline lung function, but the characteristics and magnitude of the response vary depending on ppFEV1 at baseline.

Management of initial colonisations with Burkholderia species in France, with retrospective analysis in five cystic fibrosis Centres: a pilot study.

BACKGROUND: Whereas Burkholderia infections are recognized to impair prognosis in cystic fibrosis (CF) patients, there is no recommendation to date for early eradication therapy. The aim of our study was to analyse the current management of initial colonisations with Burkholderia cepacia complex (BCC) or B. gladioli in French CF Centres and its impact on bacterial clearance and clinical outcome. METHODS: We performed a retrospective review of the primary colonisations (PC), defined as newly positive sputum cultures, observed between 2010 and 2018 in five CF Centres. Treatment regimens, microbiological and clinical data were collected. RESULTS: Seventeen patients (14 with BCC, and 3 with B. gladioli) were included. Eradication therapy, using heterogeneous combinations of intravenous, oral or nebulised antibiotics, was attempted in 11 patients. Six out of the 11 treated patients, and 4 out of the 6 untreated patients cleared the bacterium. Though not statistically significant, higher forced expiratory volume in 1 second and forced vital capacity at PC and consistency of treatment with in vitro antibiotic susceptibility tended to be associated with eradication. The management of PC was shown to be heterogeneous, thus impairing the statistical power of our study. Large prospective studies are needed to define whom to treat, when, and how. CONCLUSIONS: Pending these studies, we propose, due to possible spontaneous clearance, to check the presence of Burkholderia 1 month after PC before starting antibiotics, at least in the milder cases, and to evaluate a combination of intravenous beta-lactam + oral or intravenous fluoroquinolone + inhaled aminoglycoside.

Real-Life Safety and Effectiveness of Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis.

Rationale: Lumacaftor-ivacaftor is a CFTR (cystic fibrosis transmembrane conductance regulator) modulator combination recently approved for patients with cystic fibrosis (CF) homozygous for the Phe508del mutation.Objectives: To evaluate the safety and effectiveness of lumacaftor-ivacaftor in adolescents (≥12 yr) and adults (≥18 yr) in a real-life postapproval setting.Methods: The study was conducted in the 47 CF reference centers in France. All patients who initiated lumacaftor-ivacaftor from January 1 to December 31, 2016, were eligible. Patients were evaluated for lumacaftor-ivacaftor safety and effectiveness over the first year of treatment following the French CF Learning Society's recommendations.Measurements and Main Results: Among the 845 patients (292 adolescents and 553 adults) who initiated lumacaftor-ivacaftor, 18.2% (154 patients) discontinued treatment, often owing to respiratory (48.1%, 74 patients) or nonrespiratory (27.9%, 43 patients) adverse events. In multivariable logistic regression, factors associated with increased rates of discontinuation included adult age group, percent predicted FEV1 (ppFEV1) less than 40%, and numbers of intravenous antibiotic courses during the year before lumacaftor-ivacaftor initiation. Patients with continuous exposure to lumacaftor-ivacaftor showed an absolute increase in ppFEV1 (+3.67%), an increase in body mass index (+0.73 kg/m2), and a decrease in intravenous antibiotic courses by 35%. Patients who discontinued treatment had significant decrease in ppFEV1, without improvement in body mass index or decrease in intravenous antibiotic courses.Conclusions: Lumacaftor-ivacaftor was associated with improvement in lung disease and nutritional status in patients who tolerated treatment. Adults who discontinued lumacaftor-ivacaftor, often owing to adverse events, were found at high risk of clinical deterioration.

Numerical and experimental investigation of mucociliary clearance breakdown in cystic fibrosis.

The human tracheobronchial tree surface is covered with mucus. A healthy mucus is a heterogeneous material flowing toward the esophagus and a major defense actor against local pathogen proliferation and pollutant deposition. An alteration of mucus or its environment such as in cystic fibrosis dramatically impacts the mucociliary clearance. In the present study, we investigate the mechanical organization and the physics of such mucus in human lungs by means of a joint experimental and numerical work. In particular, we focus on the influence of the shear-thinning mucus mobilized by a ciliated epithelium for mucociliary clearance. The proposed robust numerical method is able to manage variations of more than 5 orders of magnitude in the shear rate and viscosity. It leads to a cartography that allows to discuss major issues on defective mucociliary clearance in cystic fibrosis. Furthermore, the computational rheological analysis based on measurements shows that cystic fibrosis shear-thinning mucus tends to aggregate in regions of lower clearance. Yet, a rarefaction of periciliary fluid has a greater impact than the mucus shear-thinning effects.

Case series of omalizumab for allergic bronchopulmonary aspergillosis in cystic fibrosis patients.

Allergic bronchopulmonary aspergillosis (ABPA) affects up to 15% of patients with cystic fibrosis (CF). Corticosteroids are used as first-line therapy, but relapse and adverse effects commonly occur. Case reports have suggested the efficacy of the anti-IgE recombinant humanized monoclonal antibody omalizumab. A retrospective multicenter observational French study retrieved 32 CF patients (11 children and 21 adults) who have received omalizumab for more than 3 months in the context of ABPA. Clinical characteristics, concomitant medications (inhaled and oral corticosteroids, antifungal drugs), lung function, body mass index (BMI), and serum IgE were compared at the start and during the first year of omalizumab therapy. Omalizumab-related adverse effects and costs were also evaluated. No significant difference with omalizumab could be demonstrated with regard to lung function, BMI, or the number of patients receiving oral corticosteroids. At the time of initiation of omalizumab, 56% of patients were receiving oral corticosteroids. Five patients were able to discontinue corticosteroids during follow-up and nine patients were able to reduce their daily dose. A total of 78% of the patients had received antifungal therapy at the time of the initiation of omalizumab. Treatment tolerance was good (12.5% of patients experienced side effects). The median cost of omalizumab treatment was €3,620 per patient per month. Omalizumab may represent a steroid-sparing therapy in CF patients with ABPA. A randomized-controlled trial is urgently required to provide higher level of evidence regarding the efficacy and cost-effectiveness of omalizumab in CF patients with ABPA. Pediatr Pulmonol. 2017;52:190-197. © 2016 Wiley Periodicals, Inc.

The EMBARC European Bronchiectasis Registry: protocol for an international observational study.

Bronchiectasis is one of the most neglected diseases in respiratory medicine. There are no approved therapies and few large-scale, representative epidemiological studies. The EMBARC (European Multicentre Bronchiectasis Audit and Research Collaboration) registry is a prospective, pan-European observational study of patients with bronchiectasis. The inclusion criterion is a primary clinical diagnosis of bronchiectasis consisting of: 1) a clinical history consistent with bronchiectasis; and 2) computed tomography demonstrating bronchiectasis. Core exclusion criteria are: 1) bronchiectasis due to known cystic fibrosis; 2) age <18 years; and 3) patients who are unable or unwilling to provide informed consent. The study aims to enrol 1000 patients by April 2016 across at least 20 European countries, and 10 000 patients by March 2020. Patients will undergo a comprehensive baseline assessment and will be followed up annually for up to 5 years with the goal of providing high-quality longitudinal data on outcomes, treatment patterns and quality of life. Data from the registry will be available in the form of annual reports. and will be disseminated in conference presentations and peer-reviewed publications. The European Bronchiectasis Registry aims to make a major contribution to understanding the natural history of the disease, as well as guiding evidence-based decision making and facilitating large randomised controlled trials.

Sleep quality and nocturnal hypoxaemia and hypercapnia in children and young adults with cystic fibrosis.

OBJECTIVES: The aim of the study was to evaluate sleep quality and nocturnal gas exchange in patients with cystic fibrosis (CF) and to assess if sleep quality and daytime lung function could predict nocturnal hypoxaemia or hypercapnia. STUDY DESIGN: Daytime sleepiness and objective sleep quality were evaluated by the Pittsburgh Sleep Quality Index (PSQI) and actigraphy in 25 children and 55 young adults (mean age 24±10 years, forced expiratory volume in 1 s (FEV(1)) 41±11% predicted). Nocturnal gas exchange was assessed by pulse oximetry (SpO(2)) and transcutaneous carbon dioxide (PtcCO(2)) recordings. Eleven patients underwent simultaneous polysomnography (PSG). RESULTS: PSQI was 6.3±3.4 with 51% of the patients having a score >5 corresponding to significant sleep complaints. On actigraphy, sleep efficiency was impaired at 79±11% with a fragmentation index at 41±18. Mean nocturnal SpO(2) was 93±3% with 18% of the patients exhibiting >10% of night time spent with a value below 90%. Mean PtcCO(2) was 44±6 mm Hg with 47% of the patients exhibiting >10% of night time with a value >45 mm Hg. Daytime arterial blood gases correlated with nocturnal gas exchange. FEV(1) was the only lung function parameter that correlated with nocturnal SpO(2) (p<0.01). Compared with PSG, SpO(2) and PtcCO(2) accurately identified rapid eye movement sleep hypoventilation. CONCLUSIONS: Patients with CF exhibit poor sleep quality that does not predict nocturnal gas exchange. Nocturnal hypoxaemia and hypercapnia can be identified by simple tools.

Pulmonary acceleration time to optimize the timing of lung transplant in cystic fibrosis.

Pulmonary hypertension (PH) may affect survival in cystic fibrosis (CF) and can be assessed on echocardiographic measurement of the pulmonary acceleration time (PAT). The study aimed at evaluating PAT as a tool to optimize timing of lung transplant in CF patients. Prospective multicenter longitudinal study of patients with forced expiratory volume in 1 second (FEV1) ≤60% predicted. Echocardiography, spirometry and nocturnal oximetry were obtained as part of the routine evaluation. We included 67 patients (mean FEV1 42±12% predicted), among whom 8 underwent lung transplantation during the mean follow-up of 19±6 months. No patients died. PAT was determined in all patients and correlated negatively with systolic pulmonary artery pressure (sPAP, r=-0.36, P=0.01). Patients in the lowest PAT tertile (<101 ms) had lower FEV1 and worse nocturnal oxygen saturation, and they were more often on the lung transplant waiting list compared to patients in the other tertiles. Kaplan-Meier curves showed a shorter time to lung transplantation in the lowest PAT tertile (P<0.001) but not in patients with sPAP>35 mmHg. By multivariate analysis, FEV(1)and nocturnal desaturation were the main determinants of reduced PAT. A PAT<101 ms reduction is a promising tool for timing of lung transplantation in CF.

Pharmacokinetics and safety of tobramycin administered by the PARI eFlow rapid nebulizer in cystic fibrosis.

BACKGROUND: Nebulization times have been identified as an issue in patient compliance with tobramycin solution for inhalation (TSI) therapy in cystic fibrosis (CF). METHODS: In this randomized, open-label, multicentre, two-period, crossover study, patients (n=25) with CF and chronic pulmonary pseudomonal infection received TSI for 15 days via eFlow rapid or LC PLUS nebulizer. Nebulization times and sputum/serum tobramycin concentrations were determined, and safety evaluated. RESULTS: Nebulization times were significantly shorter for eFlow rapid versus LC PLUS on Day 1 (least squares mean estimate of the difference -10.5 min, 95% confidence intervals [CI] -12.6, -8.3, p<0.0001) and Day 15 (difference -7.7 min, 95% CI -9.0, -6.5, p<0.0001). Broadly comparable sputum/systemic exposure to tobramycin was observed and the incidence of adverse events was similar for both nebulizers. CONCLUSION: Use of the eFlow rapid nebulizer reduced TSI nebulization time. The systemic exposure to tobramycin appeared to be broadly similar in this exploratory study.

Practice of noninvasive ventilation for cystic fibrosis: a nationwide survey in France.

BACKGROUND: No guidelines are available for noninvasive ventilation (NIV) for cystic fibrosis (CF). OBJECTIVE: To survey and evaluate the use of NIV for CF in France. METHODS: We surveyed the coordinator physicians of every accredited CF center in France. RESULTS: The respondents represented 36 centers (15 pediatric centers, 13 adult centers, and 8 centers that see both pediatric and adult patients), which had a total of 4,416 patients with CF at the time of the study, 168 (3.8%) of whom were using NIV. NIV was being used more often in the adults centers (7.6% of these patients) than in the pediatric centers (1.2% of these patients) or adult-and-pediatric centers (4.1% of these patients) (P= .01). All the respondent centers use NIV as first-line treatment for severe hypercapnic respiratory exacerbation and for stable diurnal hypercapnia, especially when associated with sleep disturbance. Bi-level pressure-targeted ventilation is the preferred ventilation mode. Settings are adjusted based on arterial blood gas values, noninvasive evaluation of patient-ventilator synchrony, patient comfort, and sometimes a sleep study. The surveyed centers reported a number of expected benefits from NIV, but few of those benefits have been proven. Problems with NIV are common and limit its use. CONCLUSIONS: We found a relative homogeneity in these French centers' stated indications for and use of NIV, which highlights their numerous expectations about the benefits of NIV, which contrasts with the few validated benefits. Studies of the benefits of NIV are needed.