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BackgroundThe lack of standardized outcome assessments during hospitalisation and follow-up for acute COPD exacerbations has hampered scientific progress and clinical proficiency.ObjectivesTo evaluate patients’ acceptance of selected outcome and experience measurements during hospitalisations for COPD exacerbations and follow-up.MethodsAn online survey was held amongst COPD patients in France, Belgium, The Netherlands, Germany and the UK. The ELF COPD Patient Advisory Group was involved in the conceptualisation, development and dissemination of the survey. The survey was complementary to a previously obtained expert consensus. We assessed patients’ views and acceptance of selected patient reported outcomes or experiences and corresponding measurement instruments (for dyspnoea, frequent productive cough, health status and hospitalisation experience), and of selected clinical investigations (blood-draw, pulmonary function test, six-minute walk test, chest computed tomography, echocardiography).FIndings200 patients completed the survey. All selected outcomes and experiences were deemed important, and acceptance of their methods of assessment was high. The modified Medical Research Council (mMRC) scale and a numerical rating scale (NRS) to address dyspnoea, the COPD Assessment Test (CAT) for quality of life and frequent productive cough and the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) for hospital experiences were the instruments preferred by patients. Consensus on importance of blood draw and spirometry was higher compared with the other investigations.InterpretationThe survey results endorse the use of the selected outcome and experience measurements during hospitalisations for COPD exacerbations. They can be used to optimise standardized and patient-centred care and facilitate multicentric data collection.

RationaleNontuberculous mycobacterial (NTM) diseases are difficult-to-treat infections, especially in lung transplant (LTx) candidates. Currently, there is a paucity of recommendations on the management of NTM infections in LTx, focusing onMycobacterium aviumcomplex (MAC),M. abscessusandM. kansasii.MethodsPulmonologists, infectious disease specialists, LTx surgeons and Delphi experts with expertise in NTM were recruited. A patient representative was also invited. Three questionnaires comprising questions with multiple response statements were distributed to panellists. Delphi methodology with a Likert scale of 11 points (5 to −5) was applied to define the agreement between experts. Responses from the first two questionnaires were collated to develop a final questionnaire. The consensus was described as a median rating >4 or ResultsPanellists recommend performing sputum cultures and a chest computed tomography scan for NTM screening in LTx candidates. Panellists recommend against absolute contraindication to LTx even with multiple positive sputum cultures for MAC,M. abscessusorM. kansasii.Panellists recommend MAC patients on antimicrobial treatment and culture negative can be listed for LTx without further delay. Panellists recommend 6 months of culture-negative forM. kansasii, but 12 months of further treatment from the time of culture-negative forM. abscessusbefore listing for LTx.ConclusionThis NTM LTx study consensus statement provides essential recommendations for NTM management in LTx and can be utilised as an expert opinion while awaiting evidence-based contributions.

Background: Bronchiectasis is a heterogeneous, neglected disease with few multicentre studies exploring the causes, severity, microbiology, and treatment of the disease across Europe. This aim of this study was to describe the clinical characteristics of bronchiectasis and compare between different European countries. Methods: EMBARC is an international clinical research network for bronchiectasis. We report on a multicentre, prospective, observational, non-interventional, cohort study (the EMBARC registry) conducted across 27 European countries and Israel. Comprehensive clinical data were collected from adult patients (aged ≥18 years) at baseline and annual follow-up visits using electronic case report form. Data from individual countries were grouped into four regions (the UK, northern and western Europe, southern Europe, and central and eastern Europe according to modified EU EuroVoc classification). Follow-up data were used to explore differences in exacerbation frequency between regions using a negative binomial regression model. Findings: Between Jan 12, 2015, and April 12, 2022, 16 963 individuals were enrolled. Median age was 67 years (IQR 57–74), 10 335 (60·9%) participants were female and 6628 (39·1%) were male. The most common cause of bronchiectasis in all 16 963 participants was post-infective disease in 3600 (21·2%); 6466 individuals (38·1%) were classified as idiopathic. Individuals with bronchiectasis experienced a median of two exacerbations (IQR 1–4) per year and 4483 (26·4%) patients had a hospitalisation for exacerbation in the previous year. When examining the percentage of all isolated bacteria, marked differences in microbiology were seen between countries, with a higher frequency of Pseudomonas aeruginosa and lower Haemophilus influenzae frequency in southern Europe, compared with higher H influenzae in the UK and northern and western Europe. Compared with other regions, patients in central and eastern Europe had more severe bronchiectasis measured by the Bronchiectasis Severity Index (51·3% vs 35·1% in the overall cohort) and more exacerbations leading to hospitalisations (57·9% vs 26·4% in the overall cohort). Overall, patients in central and eastern Europe had an increased frequency of exacerbations (adjusted rate ratio [RR] 1·12, 95% CI 1·01–1·25) and a higher frequency of exacerbations leading to hospitalisations (adjusted RR 1·71, 1·44–2·02) compared with patients in other regions. Treatment of bronchiectasis was highly heterogeneous between regions. Interpretation: Bronchiectasis shows important geographical variation in causes, microbiology, severity, and outcomes across Europe. Funding: European Union–European Federation of Pharmaceutical Industries and Associations Innovative Medicines Initiative. Translations: For the Arabic, French, German, Greek, Hebrew, Irish, Russian and Spanish translations of the abstract see Supplementary Materials section.

RATIONALE: Studies estimating rate of lung function decline in cystic fibrosis (CF) have been inconsistent regarding methods used. How the methodology used impacts validity of the results and comparability between studies is unknown.OBJECTIVES: The Cystic Fibrosis Foundation established a workgroup whose tasks were to examine the impact of differing approaches to estimating rate of decline in lung function and to provide analysis guidelines.METHODS: We utilized a natural history cohort of 35,252 individuals with CF aged > 6 years of the Cystic Fibrosis Foundation Patient Registry (CFFPR), 2003-2016. Modeling strategies using linear and nonlinear forms of marginal and mixed-effects models, which have previously quantified rate of forced expiratory volume in 1 second (FEV1) decline (% predicted/year), were evaluated under clinically relevant scenarios of available lung function data. Scenarios varied by sample size (overall CFFPR, medium-sized cohort of 3,000 subjects, and small-sized cohort of 150), data collection/reporting frequency (encounter, quarterly, and annual), inclusion of FEV1 during pulmonary exacerbation, and follow-up length (RESULTS: Rate-of-FEV1-decline estimates (% predicted/year) differed between linear marginal and mixed-effects models; overall cohort estimates (95% confidence interval) were 1.26 (1.24-1.29) and 1.40 (1.38-1.42), respectively. Marginal models consistently estimated less rapid lung function decline than mixed-effects models across scenarios except for short-term follow-up (both were ~1.4). Rate-of-decline estimates from nonlinear models diverged by age 30. Among mixed-effects models, nonlinear and stochastic terms fit best except for short-term follow-up (< 2 years). Overall CFFPR analysis from a joint longitudinal-survival model implied that an increase in rate of decline of 1% predicted/year in FEV1 associated with a 1.52-fold (52%) increase in the hazard of death/lung transplantation, but results exhibited immortal cohort bias.CONCLUSIONS: Differences were as high as 0.5% predicted/year between rate-of-decline estimates, but we found estimates were robust to lung function data availability scenarios except short-term follow-up and older age ranges. Inconsistencies among previous study results may be attributable to inherent differences in study design, inclusion criteria, or covariate adjustment. Results-based decision points reported herein will support researchers in selecting a strategy to model lung function decline most reflective of nuanced, study-specific goals.

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.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.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 (ppFEVIn 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.

Background People with cystic fibrosis (pwCF) are central in the development of patient-led assessment tools. Qualitative analysis of a frequently used CF-specific patient-reported outcome measure (PROM) sought patient recommendations for development of a new quality of life (QoL) tool. Methods We performed an inventory of PROMs, symptom-report and QoL tools used in clinical trials within the European Cystic Fibrosis Society Clinical Trial Network (ECFS-CTN) and in routine clinical practice among Cystic Fibrosis Europe and ECFS members. A qualitative study using cognitive interviews with pwCF and their caregivers reviewed the Cystic Fibrosis Questionnaire (CFQ), the French initial form of the Cystic Fibrosis Questionnaire-Revised (CFQ-R). Results Survey results from 33 countries revealed over 70 tools used in routine clinical practice, utilized by clinical specialists (n=124), pwCF/parents/carers (n=49) and other allied health professionals (n=60). The CFQ-R was the main PROM used in clinical trials. The qualitative study enrolled 99 pwCF, 6 to 11 years (n=31); 12 to 18 years (n=38); >18 years (n=30) and 26 parents. Inductive thematic analysis based on the CFQ, revealed 19 key themes. Themes common across all cohorts included burden of treatment, impact of disease on day-to-day life, relationships/family, stress/mood, and nutrition. Themes unique to individual groups included, treatment when not symptomatic for the paediatric group; education/studies and planning for the future for adolescents, impact of anxiety and depression on day-to-day life for adults, and for parents, questions addressing anxiety and their role as carers. Conclusions Patient-centeredness is paramount in development of an up-to-date PROM in the era of novel therapies.

International audience; Rationale: Elexacaftor-tezacaftor-ivacaftor is a CFTR (cystic fibrosis [CF] transmembrane conductance regulator) modulator combination, developed for patients with CF with at least one Phe508del mutation. Objectives: To evaluate the effects of elexacaftor-tezacaftor- ivacaftor in patients with CF and advanced respiratory disease. Methods: A prospective observational study, including all patients aged ⩾12 years and with a percent-predicted FEV1 (ppFEV1)

International audience

INTRODUCTION: Fungal aspergillosis colonization and allergic bronchopulmonary aspergillosis (ABPA) can have a strong impact on the prognosis in cystic fibrosis (CF). We conducted round table discussions involving French experts from pediatric and adult centers caring for patients with CF, microbiologists, radiologists and pharmacists. The aim was to explore the current state of knowledge on: the pathophysiological mechanisms of Aspergillus and other micromycetes infections in CF (such as Scedosporium sp.), and on the clinico-biological diagnosis of ABPA. In perspective, the experts explored the role of imaging in the diagnosis of APBA, specifically CT and MRI; as well as the role of bronchoscopy in the management. We also reviewed the therapeutic management, including different corticosteroid regimens, antifungals and anti-IgE antibodies. CONCLUSION: The diagnosis of ABPA in CF should be based on more standardized biological assays and imaging to optimize treatment and follow-up.; INTRODUCTION: Les colonisations fungiques aspergillaires et l’aspergillose bronchopulmonaire allergique (ABPA) peuvent impacter fortement le pronostic dans la mucoviscidose. Nous avons réalisé des tables rondes d’experts français de centres pédiatriques et adultes prenant en charge des patients atteints de mucoviscidose, des microbiologistes, radiologues et pharmaciens. Le but était d’explorer l’état des connaissances actuelles sur les mécanismes physiopathologiques d’Aspergillus et autres micromycètes dans la mucoviscidose (tel que Scedosporium sp.), et sur le diagnostic clinicobiologique d’ABPA actualisé. En perspectives, les experts ont exploré l’intérêt de l’imagerie dans le diagnostic d’APBA et des signaux spécifiques au scanner et en IRM, ainsi que l’intérêt de la fibroscopie dans la prise en charge. Enfin, la prise en charge thérapeutique revoit les différents schémas de corticothérapie, les antifungiques et la place des anti-IgE. CONCLUSION: Le diagnostic d’ABPA dans la mucoviscidose peut s’appuyer sur des dosages biologiques plus standardisés et sur l’imagerie pour optimiser une prise en charge et le suivi.

International audience; No abstract available

Background Coronavirus disease 2019 (COVID-19) is a disease caused by severe acute respiratory syndrome-coronavirus-2. Consensus suggestions can standardise care, thereby improving outcomes and facilitating future research. Methods An International Task Force was composed and agreement regarding courses of action was measured using the Convergence of Opinion on Recommendations and Evidence (CORE) process. 70% agreement was necessary to make a consensus suggestion. Results The Task Force made consensus suggestions to treat patients with acute COVID-19 pneumonia with remdesivir and dexamethasone but suggested against hydroxychloroquine except in the context of a clinical trial; these are revisions of prior suggestions resulting from the interim publication of several randomised trials. It also suggested that COVID-19 patients with a venous thromboembolic event be treated with therapeutic anticoagulant therapy for 3 months. The Task Force was unable to reach sufficient agreement to yield consensus suggestions for the post-hospital care of COVID-19 survivors. The Task Force fell one vote shy of suggesting routine screening for depression, anxiety and post-traumatic stress disorder. Conclusions The Task Force addressed questions related to pharmacotherapy in patients with COVID-19 and the post-hospital care of survivors, yielding several consensus suggestions. Management options for which there is insufficient agreement to formulate a suggestion represent research priorities., For patients with acute COVID-19 pneumonia who require oxygen support, the International Task Force made suggestions for remdesivir and dexamethasone, but against hydroxychloroquine. Post-discharge management of COVID-19 survivors is a research priority. https://bit.ly/32B96uI

BACKGROUND To better understand the mechanisms of infection with nontuberculous mycobacteria (NTM) in patients with cystic fibrosis (CF), we explore different risk factors associated with NTM positivity in a meta-analysis. METHODS Studies published before 31 July 2019 were selected from MEDLINE. Combined odds ratios (ORs) were calculated by pooling the ORs of each study. The weighted mean difference (WMD) was used for continuous numerical measurements. Summary data were pooled using fixed- or random-effects models according to the presence of heterogeneity (P 50%). RESULTS Nineteen studies with a total of 23 418 patients, of whom 1421 (6%) were diagnosed as NTM positive, were included. Older age was significantly associated with NTM positivity (WMD = 2.12, 95% confidence interval [CI]: 1.11-3.13; P

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.

Rationale: The relative roles of mucus plugs and emphysema in mechanisms of airflow limitation and hypoxemia in smokers with chronic obstructive pulmonary disease (COPD) are uncertain. Objectives: To relate image-based measures of mucus plugs and emphysema to measures of airflow obstruction and oxygenation in patients with COPD. Methods: We analyzed computed tomographic (CT) lung images and lung function in participants in the Subpopulations and Intermediate Outcome Measures in COPD Study. Radiologists scored mucus plugs on CT lung images, and imaging software automatically quantified emphysema percentage. Unadjusted and adjusted relationships between mucus plug score, emphysema percentage, and lung function were determined using regression. Measurements and Main Results: Among 400 smokers, 229 (57%) had mucus plugs and 207 (52%) had emphysema, and subgroups could be identified with mucus-dominant and emphysema-dominant disease. Only 33% of smokers with high mucus plug scores had mucus symptoms. Mucus plug score and emphysema percentage were independently associated with lower values for FEV(1) and peripheral oxygen saturation (P

The development of resistome analysis, i.e. the comprehensive analysis of antibiotic-resistance genes (ARGs), is enabling a better understanding of the mechanisms of antibiotic-resistance emergence. The respiratory microbiome is a dynamic and interactive network of bacteria, with a set of ARGs that could influence the response to antibiotics. Viruses such as bacteriophages, potential carriers of ARGs, may also form part of this respiratory resistome. Chronic respiratory diseases (CRDs) such as cystic fibrosis, severe asthma, chronic obstructive pulmonary disease and bronchiectasis, managed with long-term antibiotic therapies, lead to multidrug resistance. Antibiotic susceptibility testing provides a partial view of the bacterial response to antibiotics in the complex lung environment. Assessing the ARG network would allow personalised, targeted therapeutic strategies and suitable antibiotic stewardship in CRDs, depending on individual resistome and microbiome signatures. This review summarises the influence of pulmonary antibiotic protocols on the respiratory microbiome, detailing the variable consequences according to antibiotic class and duration of treatment. The different resistome-profiling methods are explained to clarify their respective place in antibiotic-resistance analysis in the lungs. Finally, this review details current knowledge on the respiratory resistome related to therapeutic strategies and provides insight into the application of resistome analysis to counter the emergence of multidrug-resistant respiratory pathogens.

Purpose of review The COVID-19 global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a dramatic impact that is still ongoing around the world. Cystic fibrosis (CF) has been identified as a possible risk factor of poor outcome. Recent findings Data collected by multiple National CF registries around the world have indicated that persons with CF (PwCF) are not more likely to be affected by SARS-CoV-2 than the general population. The course of SARS-CoV-2 is usually mild in PwCF who are relatively young. Severe outcomes have been described in patients with low lung function and in those with immune suppression (i.e. solid organ transplantation). Indirect impact of the pandemic on the CF community has also been observed, including difficulties in the organization of CF care, leading to a dramatic increase in telehealth for PwCF. The pandemic has further affected clinical research by complicating ongoing clinical trials. Vaccination appears important to all PwCF, with special priority on developing adequate vaccination scheme for transplant recipients. Long-term effects of COVID-19 on the CF population remains unknown. Summary The COVID-19 pandemic has caused significant impacts on PwCF and on healthcare professionals who provide specialized CF care and clinical research.

Rationale: Sputum biomarkers hold promise as a direct measure of inflammation within the cystic fibrosis (CF) lung, but variability in study design and sampling methodology have limited their use. A full evaluation of the reliability, validity and clinical relevance of individual biomarkers is required to optimise their use within CF clinical research.Objectives: A biomarker Special Interest Working Group was established within the European Cystic Fibrosis Society-Clinical Trials Network Standardisation Committee, to perform a review of the evidence regarding sputum biomarkers in CF. Methods: From the 139 included articles, we identified 71 sputum biomarkers to undergo evaluation of their clinimetric properties, responsiveness, discriminate, concurrent and convergent validity. Results: Current evidence confirms the potential of sputum biomarkers as outcome measures in clinical trials. Inconsistency in responsiveness, concurrent and convergent validity require further research into these markers and processing standardisation before translation into wider use. Of the 71 biomarkers identified Neutrophil Elastase (NE), IL-8, TNF-α and IL-1β, demonstrated validity and responsiveness to be currently considered for use in clinical trials. Other biomarkers show future promise, including IL-6, calprotectin, HMGB-1 and YKL-40. Conclusion: A concerted international effort across the cystic fibrosis community is needed to promote high quality biomarker trial design, establish large population-based biomarker studies, and work together to create standards for collection, storage and analysis of sputum biomarkers.

Background: Viral infections can cause significant morbidity in cystic fibrosis (CF). The current Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic could therefore have a serious impact on the health of people with CF (pwCF). Methods: We used the 38-country European Cystic Fibrosis Society Patient Registry (ECFSPR) to collect case data about pwCF and SARS-CoV-2 infection. Results: Up to 30 June 2020, 16 countries reported 130 SARS-CoV-2 cases in people with CF, yielding an incidence of 2.70/10 0 0 pwCF. Incidence was higher in lung-transplanted patients (n = 23) versus non transplanted patients (n = 107) (8.43 versus 2.36 cases/10 0 0). Incidence was higher in pwCF versus the age-matched general population in the age groups < 15, 15-24, and 25-49 years (p < 0.001), with similar trends for pwCF with and without lung transplant. Compared to the general population, pwCF (regardless of transplantation status) had significantly higher rates of admission to hospital for all age groups with available data, and higher rates of intensive care, although not statistically significant. Most pwCF recovered (96.2%), however 5 died, of whom 3 were lung transplant recipients. The case fatality rate for pwCF (3.85%, 95% CI: 1.26-8.75) was non-significantly lower than that of the general population (7.46%; p = 0.133). Conclusions: SARS-CoV-2 infection can result in severe illness and death for pwCF, even for younger patients and especially for lung transplant recipients. PwCF should continue to shield from infection and should be prioritized for vaccination. (c) 2021 The Authors. Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )

Background: Patients with mild asthma represent a substantial proportion of the population with asthma, yet there are limited data on their true burden of disease. We aimed to describe the clinical and healthcare resource utilisation (HCRU) burden of physician-assessed mild asthma. Methods: Patients with mild asthma were included from the NOVEL observational longiTudinal studY (NOVELTY; NCT02760329), a global, 3-year, real-world prospective study of patients with asthma and/or chronic obstructive pulmonary disease from community practice (specialised and primary care). Diagnosis and severity were based on physician discretion. Clinical burden included physician-reported exacerbations and patient-reported measures. HCRU included inpatient and outpatient visits. Results: Overall, 2004 patients with mild asthma were included; 22.8% experienced >= 1 exacerbation in the previous 12 months, of whom 72.3% experienced >= 1 severe exacerbation. Of 625 exacerbations reported, 48.0% lasted >1 week, 27.7% were preceded by symptomatic worsening lasting >3 days, and 50.1% required oral corticosteroid treatment. Health status was moderately impacted (St George's Respiratory Questionnaire score: 23.5 [standard deviation +/- 17.9]). At baseline, 29.7% of patients had asthma symptoms that were not well controlled or very poorly controlled (Asthma Control Test score = 2 exacerbations in the previous year. In terms of HCRU, at least one unscheduled ambulatory visit for exacerbations was required by 9.5% of patients, including 9.2% requiring >= 1 emergency department visit and 1.1% requiring >= 1 hospital admission. Conclusions: In this global sample representing community practice, a significant proportion of patients with physician-assessed mild asthma had considerable clinical burden and HCRU.

ObjectivesLumacaftor-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.MethodsAdolescents 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.ResultsA 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; p1) ≥5 under lumacaftor–ivacaftor than those in the other clusters (54% of responders versus 32% and 33%; p=0.01).ConclusionOne 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.

International audience

In 2019, The Global Initiative for Chronic Obstructive Lung Disease (GOLD) modified the grading system for patients with COPD, creating 16 subgroups (1A–4D). As part of the COPD Cohorts Collaborative International Assessment (3CIA) initiative, we aim to compare the mortality prediction of the 2015 and 2019 COPD GOLD staging systems. We studied 17 139 COPD patients from the 3CIA study, selecting those with complete data. Patients were classified by the 2015 and 2019 GOLD ABCD systems, and we compared the predictive ability for 5-year mortality of both classifications. In total, 17 139 patients with COPD were enrolled in 22 cohorts from 11 countries between 2003 and 2017; 8823 of them had complete data and were analysed. Mean±sd age was 63.9±9.8 years and 62.9% were male. GOLD 2019 classified the patients in milder degrees of COPD. For both classifications, group D had higher mortality. 5-year mortality did not differ between groups B and C in GOLD 2015; in GOLD 2019, mortality was greater for group B than C. Patients classified as group A and B had better sensitivity and positive predictive value with the GOLD 2019 classification than GOLD 2015. GOLD 2015 had better sensitivity for group C and D than GOLD 2019. The area under the curve values for 5-year mortality were only 0.67 (95% CI 0.66–0.68) for GOLD 2015 and 0.65 (95% CI 0.63–0.66) for GOLD 2019. The new GOLD 2019 classification does not predict mortality better than the previous GOLD 2015 system., GOLD 2019 staging system created 16 subgroups. GOLD 2015 and GOLD 2019 are not strong predictors of mortality, and do not have sufficient discriminatory power to be used as a tool for risk classification of mortality in patients with COPD. https://bit.ly/3idBuaN

International audience

International audience; 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

International audience

National cystic fibrosis (CF) data registries track patient characteristics over time and have provided insight into both emerging trends and current clinical needs. In a recent study, Burgel et al . utilised the flow method, a demographic model that predicts future trends in populations, and forecasted a 50% increase in the Western European CF population by 2025, with the adult population experiencing the largest increase [1]. Burgel et al . subsequently used the French registry to validate short-term predictions [2]; however, the accuracy of longer term projections has not been assessed. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Martelli has nothing to disclose. Conflict of interest: Ms. Sykes has nothing to disclose. Conflict of interest: Dr. Burgel reports personal fees from Astra-Zenaca, grants and personal fees from Boehringer Ingelheim, personal fees from Chiesi, personal fees from GSK, personal fees from Novartis, personal fees from Pfizer, personal fees from Teva, personal fees from Vertex, personal fees from Zambon, outside the submitted work. Conflict of interest: Dr. Bellis has nothing to disclose. Conflict of interest: Dr. Coriati has nothing to disclose. Conflict of interest: Dr. Stanojevic has nothing to disclose. Conflict of interest: Dr. Stephenson reports grants and personal fees from Cystic Fibrosis Canada, personal fees from Vertex Pharmceuticals, outside the submitted work.

International audience; Studies of large CF populations using registry data are important to identify people at high risk for death. Nkam et al. published a prognostic score developed on French CF registry data to predict death or lung transplantation (LT) over a 3-year period in the adult CF population. The goal of our study was to validate the proposed tool using the Canadian CF registry. Using data between 2011 and 2014, a total of 2043 adult CF patients were included. We found that the French prognostic score was a good predictor of death or LT in the Canadian CF population (OR for each unit increase: 3.12, 95% CI: 2.74-3.55; p value

Survival is improving for people with cystic fibrosis in European countries albeit with persistent disparities in prognosis among countrieshttps://bit.ly/34GF3SA

BackgroundFrance implemented a high emergency lung transplantation (HELT) programme nationally in 2007. A similar programme does not exist in Canada. The objectives of our study were to compare health outcomes within France as well as between Canada and France before and after the HELT programme in a population with cystic fibrosis (CF).MethodsThis population-based cohort study utilised data from the French and Canadian CF registries. A cumulative incidence curve assessed time to transplant with death without transplant as competing risks. The Kaplan–Meier method was used to estimate post-transplant survival.ResultsBetween 2002 and 2016, there were 1075 (13.0%) people with CF in France and 555 (10.2%) people with CF in Canada who underwent lung transplantation. The proportion of lung transplants increased in France after the HELT programme was initiated (4.5% versus 10.1%), whereas deaths pre-transplant decreased from 85.3% in the pre-HELT period to 57.1% in the post-HELT period. Between 2008 and 2016, people in France were significantly more likely to receive a transplant (hazard ratio (HR) 1.56, 95% CI 1.37–1.77; pConclusionsFollowing the implementation of the HELT programme, people living with CF in France were more likely to receive a transplant than die. Post-transplant survival in the post-HELT period in France did not change compared with the pre-HELT period, despite potentially sicker patients being transplanted, and was comparable to Canada.

Objective To investigate the short-term adverse events and effectiveness of lumacaftor/ivacaftor combination treatment in adults with cystic fibrosis (CF) and severe lung disease in a real life setting. Methods A multicentre observational study investigated adverse events, treatment discontinuation, FEV 1 and body mass index (BMI) one month and three months after lumacaftor/ivacaftor initiation in adults with CF and FEV 1 below 40% predicted. Results Respiratory adverse events (AEs) were reported by 27 of 53 subjects (51%) and 16 (30%) discontinued treatment. The mean absolute change in FEV 1 was +2.06% after one month of treatment ( P =0.086) and +3.19% after 3 months ( P =0.009). BMI was unchanged. Conclusions Treatment with lumacaftor/ivacaftor in patients with CF and severe lung disease was discontinued more frequently than reported in clinical trials, due to respiratory AEs. Nevertheless, the patients who continued treatment had an increase in lung function comparable to what was observed in pivotal trials.

Introduction Aspergillus fumigatus (A.f.) est le champignon le plus frequemment isole dans les secretions bronchiques des patients mucoviscidosiques. Il peut entrainer un ensemble de manifestations respiratoires allant de la colonisation asymptomatique a l’aspergillose bronchopulmonaire allergique (ABPA). Nos objectifs ont ete de caracteriser la prevalence des atteintes aspergillaires selon les classifications internationales dans une cohorte d’adultes mucoviscidosiques et d’etudier les performances du dosage du galactomannane (GM) et de la PCR A.f. dans les expectorations. Methodes Nous avons inclus 134 adultes mucoviscidosiques suivis au CRMR de l’hopital Cochin. Pour tous les patients, nous avons dose, les IgE totales, les IgE aspergillaires, la serologie aspergillaire (ELISA, IgG) et le taux de polynucleaires eosinophiles. Une culture fongique, le dosage du GM (BioRad) et la PCR A.f. (Ademtech) ont ete realise sur les expectorations. Les patients ont ete repartis selon les classifications usuelles de la pathologie aspergillaire. Resultats La culture des expectorations etait positive pour A.f. chez 47 % (63/134) des patients. Le dosage du GM dans les expectorations etait positif (> 0,5) chez 76,1 % (102/134) des patients alors que la PCR A.f. dans les expectorations n’etait positive que chez 35,8 % (48/134) des patients. Parmi les 48 patients dont la PCR etait positive, 43 (89,6 %) avaient un dosage du GM positif. Aucun marqueur aspergillaire (culture negative, IgG negatives, IgE normales) n’etait retrouve chez 20,5 % (27/134) des patients. Chez 9,5 % (13/134) des patients, la culture fongique etait positive sans marqueur serologique associe (IgE normales, IgG negatives). Dans ce groupe, 8 patients (62,5 %) avaient une PCR negative et 2 (15,4 %) avaient un GM negatif. Une immunisation anti-aspergillaire (IgG elevees sans elevation des IgE totales ou specifiques A.f.) etait retrouvee chez 17,9 % (24/134) des patients. Dans ce groupe, 83,3 % des cultures etaient positives et le GM et la PCR etaient positifs chez respectivement 83,3 % et 70,8 % des patients. Une sensibilisation aspergillaire (IgE A.f. > 0,35 kUI/L et IgE totales Conclusion L’ABPA ou la sensibilisation aspergillaire sont presentes chez plus de 50 % des adultes mucoviscidosiques. Le dosage du GM serait plus sensible que la culture fongique et la PCR pour detecter A.f. dans les expectorations.

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.

The past six decades have seen remarkable improvements in health outcomes for people with cystic fibrosis (CF), which was once a fatal disease of infants and young children. However, although life expectancy for people with CF has increased substantially, the disease continues to limit survival and quality of life, and results in a significant burden of care for people with CF and their families. Moreover, recent epidemiological studies in the past two decades have shown that CF occurs and is more frequent than was previously thought in non-European populations and in regions of the world where it had not previously been described. The Lancet Respiratory Medicine Commission was formed to assess the global health and economic costs of CF care over the next three decades and to identify opportunities for progress in the care of people with CF. challenges that need to be addressed, and to serve as a blueprint for the future of CF care. This Commission was established at a time of immense change in CF clinical care including enhanced survival, widespread genetic testing supporting the diagnosis of CF in regions of the world where it was previously thought to be or non-existent and the advent of a growing number of CFTR-directed therapies which are likely to further alter the natural trajectory of the disease. This document is intended to bring to the attention of patients, health-care professionals, researchers, funders, service providers, policy makers the variety of challenges associated with this changing landscape and to serve as a blueprint for the future of CF care. what was previously a universally fatal disease of children. In considering the future of CF care, the Commission focused on five key areas, which are discussed in this report: the changing epidemiology of CF (section 1); future challenges of clinical care and its delivery (section 2); the building of CF care globally (section 3); novel therapeutics (section 4); and patient engagement (section 5) (summarized in panel 1). Since the discovery of the cystic fibrosis transmembrane regulator (CFTR) gene in the late 1980’s, triggered a surge of basic research which has enhanced understanding of the pathophysiology and the genotype/phenotype relationships of this clinically variable disease. Until recently, available treatments could be used to control symptoms and limit the complications of CF, but advances in CFTR modulator therapies to address the basic defect of CF have been phenomenal and the field is evolving rapidly. Advances in clinical care have been multifaceted and include earlier diagnosis through the implementation of newborn screening programmes, formalised airway clearance therapy, and reduced malnutrition through the use of effective pancreatic enzyme replacement and a high-energy, high protein diet. Centre-based care has become the norm in high-income countries, allowing patients to benefit from the skills of expert members of multi-disciplinary teams. Pharmacological interventions to address pulmonary manifestations now include agents that target airway mucus and airway surface liquid hydration, as well as antimicrobial therapy, including antibiotic eradication treatment in early infection and protocols for maintenance therapy in chronic infection. The challenges faced by all stakeholders in building and developing CF care globally are substantial, but many opportunities exist for improved care and better health outcomes for patients. Here, we discuss changes in diagnostic approaches including advances in genetic testing, advances in newborn screening and how it is changing landscape of the CF population, The occurrence and impact of CF in non-European populations and on different continents is explored as is. We highlight the current and future opportunities as well are the challenges for clinical care in both countries with established CF care programs and what care might look like for low- and middle-income countries where care programs more fragmented and less well funded. to the availability of integrated multi-disciplinary care and new disease-modifying treatments. The recent advances in CFTR modulator therapies to address the basic defect of CF have been phenomenal and current knowledge and future directions are appraised. The cost of new therapies is currently high and there are concerns about the affordability of those medications currently available and those under development especially when considered from a global perspective. As median age of CF has increased, there has been an associated rapid rise in the adult population, we evaluate opportunities for the use of new technologies to support engagement between patients and healthcare providers in novel ways to positively impact on the burden of care and support patient choice and yet to optimise healthcare outcomes. Challenges and opportunities in these key areas are being discussed to provide a conceptional framework for future CF care throughout the world. PANEL 1 KEY MESSAGES OF THE LANCET COMMISSION FOR CYSTIC FIBROSIS: SECTION 1 THE CHANGING EPIDEMIOLOGY OF CYSTIC FIBROSIS: 1. Newborn screening testing has been implemented in many parts of the world supporting an early diagnosis of CF. 2. Improved molecular genetic diagnostics have allowed the identification of CF in non-European populations and in individuals with nonclassical presentations of CF and related disorders. 3. CFTR related disease represents a spectrum ranging from single organ manifestations to a multi-system disease. Defining the threshold of CFTR function associated with disease manifestations is a priority to guide monitoring and treatment decisions. SECTION 2 CLINICAL CARE AND ITS DELIVERY: 1. Children with CF are healthier and the vast majority are living well into adulthood. 2. Diagnostics to allow earlier diagnosis of disease manifestations, deterioration of organ function and new airway infections are key priorities. 3. Models of care need to consider management approaches (including disease monitoring) to maintain health and delay lung transplantation and yet limit the burden of care. SECTION 3 CYSTIC FIBROSIS CARE IN DEVELOPING NATIONS: 1. Information about genetic and clinical features CF in non-European populations have improved understanding of the disease in low- and middle-income countries. 2. Access to CF therapies which is sustained and affordable for people with CF living in LMIC is needed which requires partnerships between lay organisations, governments and the pharmaceutical industry. 3. Clinical registries in countries where CF is now recognised are developing and there is a need to harmonise data elements including established CF registries to support understanding of health care outcomes especially in LMIC. SECTION 4 NOVEL THERAPEUTICS: 1. CFTR modulator therapy targeting the basic molecular defect have been developed for specific CFTR mutations and is associated with improved health outcomes including better pulmonary function and nutritional status and enhanced quality of life. 2. New CFTR modulator drugs are showing promise in CFTR mutation where earlier modulators were ineffective. Early commencement of CFTR-directed therapies may prevent the establishment of irreversible airways complications and slow progression disease in older patients. 3. Drug development requires substantial investment and contributes to the current high-cost of approved CFTR modulators. This has in turn contributed to delays in funding for such therapies in many countries and current drug prices make them unaffordable for many LMICs. SECTION 5 PATIENT EXPERIENCE, ENGAGEMENT AND INVOLVEMENT: 1. Complexity of care has increased for people with CF in parallel with increased life expectancy leading to significant burden of care and disease monitoring. Novel technologies have the potential to support self-monitoring and shared decision making between patient and health care team. 2. Mental health complications are more common in people with CF (including parents of children with CF) than the general community, impacting on quality of life. Adherence to complex therapeutic regimens is often sub-optimal and impacts of clinical outcomes. 3. Patients are highly engaged in the approaches to delivery of clinical care and their perspective of the important research priorities. CF patient organisations provide important roles in patient advocacy to delivery of clinical care, treatment access, and support and education for patients with CF and their families.

The CODEX index was developed and validated in patients hospitalized for COPD exacerbation to predict the risk of death and readmission within one year after discharge. Our study aimed to validate the CODEX index in a large external population of COPD patients with variable durations of follow-up. Additionally, we aimed to recalculate the thresholds of the CODEX index using the cutoffs of variables previously suggested in the 3CIA study (mCODEX). Individual data on 2,755 patients included in the COPD Cohorts Collaborative International Assessment Plus (3CIA+) were explored. A further two cohorts (ESMI AND EGARPOC-2) were added. To validate the CODEX index, the relationship between mortality and the CODEX index was assessed using cumulative/dynamic ROC curves at different follow-up periods, ranging from 3 months up to 10 years. Calibration was performed using univariate and multivariate Cox proportional hazard models and Hosmer-Lemeshow test. A total of 3,321 (87.8% males) patients were included with a mean ± SD age of 66.9 ± 10.5 years, and a median follow-up of 1,064 days (IQR 25–75% 426–1643), totaling 11,190 person-years. The CODEX index was statistically associated with mortality in the short- (≤3 months), medium- (≤1 year) and long-term (10 years), with an area under the curve of 0.72, 0.70 and 0.76, respectively. The mCODEX index performed better in the medium-term (

IntroductionA reduction in pulmonary artery relaxation is a key event in the pathogenesis of pulmonary arterial hypertension (PAH). Cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction in airway epithelial cells plays a central role in cystic fibrosis; CFTR is also expressed in pulmonary arteries and has been shown to control endothelium-independent relaxation.Aim and objectivesWe aimed to delineate the role of CFTR in PAH pathogenesis through observational and interventional experiments in human tissues and animal models.Methods and resultsReverse-transcriptase quantitative PCR, confocal imaging and electron microscopy showed that CFTR expression was reduced in pulmonary arteries from patients with idiopathic PAH (iPAH) and in rats with monocrotaline-induced pulmonary hypertension (PH). Moreover, using myography on human, pig and rat pulmonary arteries, we demonstrated that CFTR activation induces pulmonary artery relaxation. CFTR-mediated pulmonary artery relaxation was reduced in pulmonary arteries from iPAH patients and rats with monocrotaline- or chronic hypoxia-induced PH. Long-term in vivo CFTR inhibition in rats significantly increased right ventricular systolic pressure, which was related to exaggerated pulmonary vascular cell proliferation in situ and vessel neomuscularisation. Pathologic assessment of lungs from patients with severe cystic fibrosis (F508del-CFTR) revealed severe pulmonary artery remodelling with intimal fibrosis and medial hypertrophy. Lungs from homozygous F508delCftr rats exhibited pulmonary vessel neomuscularisation. The elevations in right ventricular systolic pressure and end diastolic pressure in monocrotaline-exposed rats with chronic CFTR inhibition were more prominent than those in vehicle-exposed rats.ConclusionsCFTR expression is strongly decreased in pulmonary artery smooth muscle and endothelial cells in human and animal models of PH. CFTR inhibition increases vascular cell proliferation and strongly reduces pulmonary artery relaxation.

Objectives: As the novel coronavirus (SARS-CoV-2) pandemic continues, people with cystic fibrosis (CF) have been identified as being a vulnerable group. It is essential that people with CF, their families and their clinical teams have the most up-to-date information on the impact of SARS-CoV-2 on their health. This study aims to characterise the impact of SARS-CoV-2 infection in people with CF throughout 2020, identify factors that predict clinical progression of COVID-19, and to describe medium-term follow-up of people who have been infected. Methods: The ‘Cystic Fibrosis Registry Global Harmonization Group’ is a worldwide network of CF Registries that each contributed data on people with CF diagnosed with SARS-CoV-2 infection. In this analysis, we will report on cases contributed from 22 countries diagnosed between 1st February and 13th December 2020. We will present demographic, pre-infection clinical characteristics, symptoms, infection management and outcomes. We will use multivariable logistic regression to assess predictors for hospitalisation with respiratory support and intensive care admission as the outcomes of interest representing clinical progression of COVID-19. Descriptive analysis of medium-term follow-up BMI and FEV1% predicted values will also be undertaken. Results: Results pending. Expected cohort size >1,000, including the 181 previously reported in our paper “The global impact of SARS-CoV-2 in 181 people with cystic fibrosis.” Conclusion: It is expected that the findings of this study will have important implications for shielding advice, clinical care and vaccine prioritisation for people with CF.

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.

International audience; Introduction: Primary ciliary dyskinesia (PCD) is a genetic disease characterised by abnormalities in ciliary function, responsible for chronic pulmonary and sinonasal diseases. Adult clinical features and outcome are poorly described.Objectives: To assess the clinical characteristics and disease progression in adults with PCD.Methods: Bicentric retrospective study, focusing on adults (≥18 years) with an asserted diagnosis of PCD based on the presence of bronchiectasis with typical ultrastructural defect of cilia and/or situs inversus (SI). Clinical symptoms, respiratory function, extent of bronchiectasis, microbiology and molecular analysis were assessed. Results are expressed as median (25th; 75th centile).Results: 78 patients were included with a median follow-up of 8.1 years. 91% of patients had respiratory symptoms and 95% had chronic rhinosinusitis. Half of ultrastructural defects concerned dynein arms. Respiratory function was significantly lower in women (FEV1=60% predicted (50; 76), vs 77% (62; 95), p=0.009) and in patients with chronic airway Pseudomonas aeruginosa (PA, n=21) infection (FEV1=60% (48; 71) vs 75% (55; 89), p=0.04). FEV1 was associated with gender (regression coefficient for men =13.8, p=0.009), chest CT score (r=-0.42, p