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Research questionsPatients with severe pulmonary hypertension associated with chronic lung disease have a poor prognosis. Targeted-pulmonary arterial hypertension therapies might improve exercise capacity and outcome, but there are no guidelines of treatments which are not recommended because of an unproven benefit, with discordant results from few studies in this context.The aim of our study was to evaluate targeted pulmonary arterial hypertension therapies for severe group 3 pulmonary hypertension patients.Study Design and MethodsWe conducted an observational retrospective monocentre study on patients with severe group 3 pulmonary hypertension diagnosed on right heart catheterization treated with targeted therapies. Primary outcome was an improvement of the distance on 6-minute walk test of at least 30 meters. Secondary endpoints included changes in hemodynamic (pulmonary vascular resistance and mean pulmonary arterial pressure) and identification of potential predictive factors of therapeutic response.Results139 patients were enrolled. Most patients had monotherapy with phosphodiesterase 5 inhibitors (n=128; 92%). Mean change in 6MWD was+1.5 meters after treatment (p=0.59). Forced Expiratory Volume in one second and Forced Vital Capacity were not predictive factors for response. We found a significant improvement of pulmonary vascular resistances and mean pulmonary arterial pressure respectively of −1.0 UI Wood (pConclusionOral targeted-pulmonary arterial hypertension therapies do not improve exercise capacity in patients with severe pulmonary hypertension associated with chronic lung disease but could improve hemodynamic parameters.

Rationale and objectives: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have revolutionised the treatment of cystic fibrosis (CF). Chest computed tomography (CT) is key in the diagnosis and follow-up of anatomical damage to the lungs. Our study aimed to evaluate changes on lung CT scans of patients with CF after receiving elexacaftor-tezacaftor-ivacaftor (ETI) therapy for one year.Materials and methods: We conducted a retrospective, observational, single-centre study between 2018 and 2021 on adult patients with CF administered ETI. We reviewed chest CT scans before and at least one year after starting ETI. The Brody-II score (BSII) was measured by two experienced radiologists who were blinded to the treatment. Paranasal sinus CT scans and clinical and functional data were also compared. Wilcoxon tests were used to compare differences, and Spearman's correlation coefficient was used to evaluate changes in forced expiratory volume in one second (FEV1) and total BSII.Results: In the period, 63 patients were given ETI, and 12 met the criteria for analysis. The inter-observer reproducibility of BSII was satisfactory (intraclass correlation coefficient = 0.83, 95% confidence interval 0.57-0.91). The BSII decreased after one year of treatment (-18 ± 16, p = 0.002) due to lower mucous plugging (-7 ± 4, p < 0.001) and peribronchial thickening (-9 ± 10, p = 0.002) scores. Bronchial, parenchymal, and hyperinflation scores were unchanged. Clinical and functional parameters were significantly improved, except for total lung capacity. The correlation between ΔFEV1 and Δtotal BSII was strong (r = 0.88, p < 0.001). The paranasal sinus CT score significantly improved with ETI treatment.Conclusions: ETI decreased pulmonary and sinus morphological abnormalities after one year of treatment.

BackgroundThe European Medicines Agency has approved the cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination elexacaftor-tezacaftor-ivacaftor (ETI) for people with cystic fibrosis (pwCF) carrying at least one F508del variant. The United States Food and Drug Administration (FDA) also approved ETI for pwCF carrying one of 177 rare variants.MethodsAn observational study was conducted to evaluate the effectiveness of ETI in pwCF with advanced lung disease that were not eligible to ETI in Europe. All patients with no F508del variant and advanced lung disease (defined as having a percent predicted forced expiratory volume (ppFEV1)1.ResultsAmong the first 84 pwCF included in the program, ETI was effective in 45 (54%) and 39 (46%) were considered to be non-responders. Among the responders 22/45 (49%) carried aCFTRvariant that is not currently approved by FDA for ETI eligibility. Important clinical benefits, including suspending the indication for lung transplantation, a significant decrease in sweat chloride concentration by a median [IQR] −30 [-14;-43]mmol·l−1(n=42;p1by+10.0 [6.0; 20.5] (n=44,pConclusionClinical benefits were observed in a large subset of pwCF with advanced lung disease andCFTRvariants not currently approved for ETI.

The SARS-CoV-2 pandemic has disrupted clinical trials worldwide. The European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN) has tracked clinical trial disruption by surveying its 58 trial sites across 17 European countries and collated information on measures to mitigate the impact of the pandemic and ensure trial continuity. Here, we present recommendations on how to reduce the risk of SARS-CoV-2 exposure to patients and trial staff by implementing remote trial visits where possible, using home assessments, video and phone calls, electronic consent, and home delivery of study drugs. We discuss the practicalities of remote source data verification, protocol amendments, changing trial site location, and staff absences and home working. We outline recommendations on how to protect trial outcomes, including home assessments, safety reporting, protocol deviations, and recruitment challenges. Finally, we discuss the importance of continued access to study drugs via extension trials for some patients. This guidance was co-created from the shared knowledge and experience of sites in our network and was re-distributed directly to all ECFS-CTN sites to help mitigate the impact of further waves of the SARS-CoV-2 pandemic. We will also use this guidance to assist companies, academia, and consortia with future protocol design and risk mitigation plans. This guidance can be applied to clinical trials in other diseases and could help sites that are not supported by clinical trial networks. ispartof: TRIALS vol:22 issue:1 ispartof: location:England status: published

The SARS-CoV-2 pandemic has disrupted clinical trials worldwide. The European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN) has tracked clinical trial disruption by surveying its 58 trial sites across 17 European countries and collated information on measures to mitigate the impact of the pandemic and ensure trial continuity. Here we present recommendations on how to reduce the risk of SARS-CoV-2 exposure to patients and trial staff by implementing remote trial visits where possible, using home assessments, video and phone calls, electronic consent and home delivery of study drug. We discuss the practicalities of remote source data verification, protocol amendments, changing trial site location, and staff absences and home working. We outline how to protect trial outcomes, including home assessments, safety reporting, protocol deviations and recruitment challenges. Finally, we discuss the importance of continued access to study drug via extension trials for some patients. This guidance was co-created from the shared knowledge and experience of sites in our network and was re-distributed directly to all ECFS-CTN sites to help mitigate the impact of further waves of the SARS-CoV-2 pandemic. We will also use this guidance to assist companies, academia and consortia with future protocol design and risk mitigation plans.

International audience; 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.

Background Chronic Lung Allograft Dysfunction (CLAD) is the main cause of morbidity and mortality after the first year following lung transplantation (LTx). Risk factors of CLAD have been extensively studied, but the association between gram-negative bacteria (GNB) bronchial colonization and the development of CLAD is controversial. The purpose of our study was to investigate the association between post-transplant recolonization with the same species or de-novo colonization with a new GNB species and CLAD. The same analysis was performed on a sub-group of patients at the strain level using Matrix Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry technique. Results Forty adult cystic fibrosis (CF) patients who underwent a first bilateral LTx in the University Hospital of Marseille, between January 2010 and December 2014, were included in the study. Patients with GNB de-novo colonization had a higher risk of developing CLAD (OR = 6.72, p = 0.04) and a lower rate of CLAD-free survival (p = 0.005) compared to patients with GNB recolonization. No conclusion could be drawn from the subgroup MALDI-TOF MS analysis at the strain level. Conclusion Post-LTx GNB airway recolonization seems to be a protective factor against CLAD, whereas de-novo colonization with a new species of GNB seems to be a risk factor for CLAD. Electronic supplementary material The online version of this article (10.1186/s12866-018-1231-7) contains supplementary material, which is available to authorized users.

International audience; Purpose of the study: Vibrating-mesh nebulizers are widely used at home for cystic fibrosis (CF) treatment, with a therapeutic efficiency closely linked to the mesh performance. This national study looks at the maintenance at home by CF patients and their families of the mesh of the eFlow (R) rapid nebulizer. Ninety-two patients from 34 French CF centers, treated at home with inhaled drugs delivered with a vibrating-mesh nebulizer, answered to a phone standardized questionnaire specifying the different techniques of maintenance of the nebulizer. Principal results: Patients were aged from 2 to 68 years (58.7% of children). They inhaled a mean of 1.8 nebulizations per day. Maintenance was assumed by patients in 36% of the cases. All steps of the theoretical maintenance of a nebulizer were respected in 66% of the cases. The mesh was not cleaned in 45.6%, not disinfected or not thermically disinfected in 32.5%, and not rinsed after chemical disinfection in 45.5% of the case. Only 49% of the patients knew the role of the MeshCare (R) system in the mesh maintenance, and only 39% had already used it when the nebulization duration reached 10 min. Conclusions: Efforts about education, particularly for the maintenance of the mesh, are needed for CF patients using a vibrating-mesh nebulizer at home. (C) 2017 Elsevier Ltd. All rights reserved.

Introduction: Medium-term survival and functional outcome of patients requiring prolonged mechanical ventilation (PMV) ≥ 21 days after lung transplantation (LTx) remain unclear. Objectives and Methods: We conducted a post hoc analysis on a cohort of 82 adults patients who underwent consecutively LTx at the University Hospital of Marseille from January 2008 to May 2011 and who survived above 21 days postoperative. The main objectives were 1/to identify risk factors of VMP by univariate and multivariate analysis; 2/ to evaluate the impact of VMP on survival and functional outcome at 3 years after LTx. Results: 34 recipients required a PMV and 48 recipients did not (control group). Median duration follow-up was 1428 ± 847 days. Multivariate analysis identified graft volume reduction as the main independent risk factor for PMV (OR: 14.61, 95%CI: 1.35-157, p=0.02). Significant decrease in survival at 1, 2 and 3 years was observed in PVM group compared to controls (73.5%, 61.2%, 51% vs . 85.4%, 82.5%, 77.9%). Lung function was significantly impaired in PMV recipients compared to controls at 1 yr and 3 yrs with lower values of FEV1 (1681 ± 919ml and 1759 ± 250 ml vs. 2625 ± 1132 ml and 2626 ± 186 ml, p vs. 3450 ± 1176 ml and 3425 ± 188 ml, p vs. 555 ± 114 m and 564 ± 21 m) respectively. However no significant difference in the development of chronic allograft dysfunction at 3 yrs was observed between the 2 groups. Conclusion: Graft volume reduction was the main predictive factor of PMV. PMV limited recipient9 survival and lung functional outcome at medium-term after LTx.

Introduction La detection des variations spirometriques constitue l’element essentiel de la surveillance apres une TP. Le depistage et la prise en charge precoce des complications respiratoires pourraient ameliorer la fonctionnalite ulterieure du greffon et la survie du receveur. L’emploi de la teletransmission via Internet des mesures realisees par un spirometre electronique portable (Spirotel ® ) a domicile pourrait y participer. Objectifs Evaluer (1) impact des anomalies teletransmises ; (2) concordance avec le controle spirometrique a l’hopital ; (3) observance du patient au Spirotel ® . Methode et resultats Etude prospective observationnelle monocentrique portant sur 59 adultes ayant eu une TP au CHU de Marseille suivis par Spirotel ® quotidien a domicile entre 09/2013 et 06/2014. Un total de 285 visites ont ete realisees dont 34 etaient non programmees, liees a des anomalies cliniques seules (7) et du Spirotel ® (27). La correlation avec les valeurs controles etait satisfaisante avec un biais moyen du VEMS de +117 ml ( p ® avait une sensibilite de 65 % et une specificite de 84 % dans le depistage de complications averees. L’observance a la spirometrie et a la teletransmission etait respectivement de 48 % et 54 % pour la 1 re annee, et 36 % et 46 % a partir de la 2 e annee apres TP. Conclusion Notre etude rend compte de la faisabilite de la telesurveillance en ambulatoire et de son interet dans le depistage precoce des complications de l’allogreffe. Des etudes complementaires pourront permettre d’affiner les modalites de suivi apres TP apres optimisation de l’observance du patient a la tele-medecine.