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BackgroundAllergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis (CF) patients is associated with severe lung damage and requires specific therapeutic management. Repeated imaging is recommended to both diagnose and follow-up the response to treatment of ABPA in CF.PurposeTo evaluate whether Fourier decomposition (FD) functional lung MRI can detect the response to treatment of ABPA in CF patients.Study typeRetrospective longitudinal.PopulationA total of 12 CF patients.Field strength/sequence2D balanced steady-state free precession (bSSFP) sequence with Fourier decomposition (FD) at 1.5T scanner.AssessmentVentilation weighted (V) and perfusion weighted (Q) maps were obtained after FD processing of the 2D coronal bSSFP time resolved images before and after treatment of ABPA. Defects extent was assessed on the functional maps using a visual semi quantitative score. Mean and coefficient of variation (cv) of the ventilation signal intensity (VSI) and the perfusion signal intensity (QSI) were calculated. Measurements were performed independently by two readers and averaged. The reproducibility of the measurements was also assessed. Pulmonary function tests (PFTs) were performed as markers of the airflow limitation severity.Statistical testsComparisons of medians were assessed using paired Wilcoxon test. Reproducibility was assessed using the intraclass correlation coefficient (ICC). Correlations were assessed using Spearman test. A p value ResultsDefects extent on both V and Q maps showed a significant reduction after ABPA treatment (p0.93. ICC of the quantitative measurements was almost perfect (>0.99). VSI_cv and QSI_cv variations correlated inversely with the variation of obstructive parameters of PFTs (rho = -0.68, p=0.01).Data conclusionNon-contrast enhanced FD lung MRI appears to be able to reproducibly assess response to treatment of ABPA in CF patients and correlates with PFTs’ obstructive parameters.

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)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are closely monitored in people with cystic fibrosis (pwCF), with a special emphasis on severe cases. Previous studies used hospitalization rates as proxy for severity.We evaluated data from coronavirus disease 2019 (COVID-19) cases diagnosed in French pwCF followed in one of the 47 French CF center over the first year of the pandemic.criteria were applied for defining severity (e.g., respiratory failure and/or death). Data were compared to those from all French pwCF using the French CF Registry.As of April 30, 2021, 223 pwCF were diagnosed with COVID-19, with higher risks in adults (≥18 years, odds ratio [OR] = 2.52, 95% confidence interval [CI] = 1.82-3.48) and post-transplant individuals (OR = 2.68, 95% CI = 1.98-3.63). Sixty (26.9%) patients were hospitalized, with an increased risk in post-transplant individuals (OR = 4.74, 95% CI = 2.49-9.02). In 34 (15%) cases, COVID-19 was considered severe; 28/60 (46.7%) hospitalizations occurred in patients without objective criteria of severity. Severe cases occurred mostly in adults (85.3%) and post-transplant pwCF (61.8%, OR = 6.02, 95% CI = 2.77-13.06). In non-transplanted pwCF, risk factors for severity included low lung function (median ppFEV1 54.6% vs. 75.1%, OR = 1.04, 95% CI = 1.01-1.08) and CF-associated diabetes (OR = 3.26, 95% CI = 1.02-10.4). While most cases recovered without sequelae (n = 204, 91.5%), 16 (13%) were followed for possible sequelae, and three post-transplant females died.Severe COVID-19 cases occurred infrequently during the first year of the pandemic in French pwCF. Non-transplanted adults with severe respiratory disease or diabetes and post-transplant individuals were at risk for severe COVID-19. Thus, specific preventive measures should be proposed.

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.

In recent years, several researchers have attempted to identify COPD phenotypes using different cluster analysis. This study aimed to determine the most optimal cluster analysis (supervised vs unsupervised) to robustly identify clinical phenotypes. 2,968 COPD patients have been included from January 2014 until February 2020. General information (age, BMI, smoking, comorbidities), lung function, exacerbations and symptoms were collected. After 5 years of follow-up, vital status was recorded. A hierarchical classification on the principal components (HCPC) was performed, followed by two unsupervised classification algorithms: k-means and PAM (Partition Around Medoids). Robustness was defined according to three different indices of validation (Connectivity, Dunn and silhouette). The mean age was 70 years, 63.7% of males, current smokers: 38.7%, mean FEV1: 61.3% predicted, ≥2 exacerbations: 43.6%, mMRC dyspnea grade≥2: 56.3%, chronic cough: 58%. The 5-year mortality rate was 11.3%. Based on our hypothesis, four phenotypes were described, using the PAM method. The phenotype A (24.2%) consisted of elderly patients with severe airflow limitation, low symptoms, cardiovascular comorbidities, diabetes and a higher mortality. The phenotype B (23.9%) contained more female patients, young patients with moderate airflow limitation and a high rate of current smokers. The phenotype C (25.5%) contained patients with very severe airflow limitation, more symptoms and low BMI. The Phenotype D (26.2%) was composed of patients with mild airflow limitation and low dyspnoea. These results showed the superiority of PAM classification compared with two other algorithms (k-means and HCPC) in terms of the robustness.

International audience; 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.

Survival after lung transplantation (LTx) still remains limited by chronic lung allograft dysfunction (CLAD), thought to represent a form of chronic rejection. We investigated whether the immune checkpoint HLA-G/ILT2 expressed by peripheral T-cell subpopulations could predict CLAD.We used data for 150 LTx recipients from COLT (Cohort-For-Lung-Transplantation) cohort with ≥1 available blood sample at 1-, 6-, or 12-months post-Tx. Analysis of T cells by flow cytometry focused on the ILT2 receptor of HLA-G and other markers (CD57, CD25, CD127). T-cell subset analyses compared stable patients and those with CLAD at 3 years post-LTx.With data for 78 stable and 72 CLAD patients, among 21 T-cell subsets expressing ILT2, only CD4+CD57+ILT2+ T cells were associated with outcome. At 1-month post-Tx, low proportion of CD4+CD57+ILT2+ T cells was associated with reduced 3-year incidence of CLAD (CD4+CD57+ILT2+ T cells ≤ first IQR [25%] vsfirst IQR, log-rank test, p = 0.028). Furthermore, the incidence of CLAD was higher with2.6- vs ≤2.6-fold increased proportion of CD4+CD57+ILT2+ T cells over the first year post-LTx (3-year freedom frequencies: 27% [95%CI: 8-50] vs 64% [95%CI: 48-77] (log-rank test, p = 0.014). On multivariable analysis, increased proportion of CD4+CD57+ILT2+ T cells over the first year predicted CLAD (hazard ratio 1.25; 95%CI: 1.09-1.44; p = 0.001). Focusing on CD4+CD57+ILT2+ T cells, we demonstrated ex vivo that they are cytotoxic CD4+ T cells, selectively inhibited by HLA-G.Our data suggest that an early increase of CD4+CD57+ILT2+ T cells after LTx may be associated with CLAD onset.

Background Clinical studies demonstrate that ivacaftor (IVA) improves health-related quality of life (HRQoL) in patients aged ≥6 years with cystic fibrosis (CF). The real-world impact of IVA and standard of care (SOC) in groups of patients with G551D and F508del mutations, respectively, was assessed using a survey comprising disease-specific and generic HRQoL measures. Methods Patients with CF aged ≥12 years, or aged 6–11 years with caregiver support, with either (1) a G551D mutation and receiving IVA (G551D/IVA) for ≥3 months, or (2) homozygous for F508del and receiving SOC before lumacaftor/IVA availability (F508del/SOC), were eligible to participate in a cross-sectional survey. Demographic and clinical characteristics, and HRQoL measures were compared between patient groups, and multiple regression analyses were conducted. Results After differences in patient demographic and clinical characteristics were controlled for, significantly better scores were observed in the G551D/IVA group than in the F508del/SOC group on multiple domains of the validated Cystic Fibrosis Questionnaire-Revised and the EuroQol 5-dimensions 5-level questionnaire. Conclusions G551D/IVA patients reported better HRQoL than F508del/SOC patients on generic and disease-specific measures in a real-world setting.

Background Mucus plugging (MP), central bronchiectasis (CB), and consolidation/atelectasia (CA) are conventional CT signs to diagnose allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis (CF). Hyperattenuating mucus (HAM) has recently been described and may improve diagnostic accuracy. The goal of our study was to compare HAM versus conventional CT signs to diagnose ABPA in CF. Secondary objectives were to determine the optimal threshold of HAM quantitatively and to assess the diagnostic value of HAM using chest radiograph (CXR). Methods The study was retrospective and included 137 patients with CF, aged >6-year-old. The presence of HAM, CB, MP and CA were determined by two radiologists in consensus. HAM was quantified using an absolute mean density value (AMD) and a ratio between mucus and paraspinal muscle (DRM). Sensitivity (Se), Specificity (Sp) and Youden's J-index were calculated. The Cystic Fibrosis Conference Consensus criteria were chosen as Gold Standard. Results 23 out of 137 CF patients had ABPA. Using CT, the most sensitive structural alteration was MP (Se = 91%), followed by CB (Se = 87%) and CA (Se = 70%) whereas specificities were 28%, 19% and 58%, respectively. Conversely, HAM had the highest specificity (Sp = 100%) whereas Se was 69%. HAM had the highest Youden's J-index (p 78 HU (Se/Sp = 71%/98%) and DRM > 1.3 (Se/Sp = 82%/97%). HAM was unseen using CXR (Se = 0%). Conclusion HAM is the most specific CT biomarker of ABPA in CF, with good sensitivity. Our study suggests that characterization of mucus density may improve the accuracy of imaging criteria to diagnose ABPA early.

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: Imaging has played a pivotal role in the diagnosis of idiopathic pulmonary fibrosis (IPF). Recent reports suggest that T2 -weighted MRI could be sensitive to monitor signal-intensity modifications of the lung parenchyma, which may relate to the disease activity in IPF. However, there is a lack of automated tools to reproducibly quantify the extent of the disease, especially using MRI. PURPOSE: To assess the feasibility of T2 interstitial lung disease signal-intensity volume quantification using a semiautomated method in IPF. STUDY TYPE: Single center, retrospective. POPULATION: A total of 21 adult IPF patients and four control subjects without lung interstitial abnormalities. FIELD STRENGTH/SEQUENCE: Both free-breathing ultrashort echo time (TE) lung MRI using the spiral volume interpolated breath hold examination (VIBE) sequence (3D-UTE) and T2 -BLADE at 1.5T. ASSESSMENT: Semiautomated segmentation of the lung volume was done using 3D-UTE and registered to the T2 -BLADE images. The interstitial lung disease signal-intensity volume (ISIV) was quantified using a Gaussian mixture model clustering and then normalized to the lung volume to calculate T2 -ISIV. The composite physiological index (CPI) and forced vital capacity (FVC) were measured as known biomarkers of IPF severity. Measurements were performed independently by three readers and averaged. The reproducibility between measurements was also assessed. STATISTICAL TESTS: Reproducibility was assessed using the intraclass correlation coefficient (ICC) and Bland-Altman analysis. Correlations were assessed using Spearman test. Comparison of median was assessed using the Mann-Whitney test. RESULTS: The reproducibility of T2 -ISIV was high, with ICCs = 0.99. Using Bland-Altman analysis, the mean differences were found between -0.8 to 0.1. T2 -ISIV significantly correlated with CPI and FVC (rho = 0.48 and 0.50, respectively; P

OBJECTIVES: The study aimed to validate automated quantification of high and low signal intensity volumes using ultrashort echo-time MRI, with CT and pulmonary function test (PFT) as references, to assess the severity of structural alterations in cystic fibrosis (CF). METHODS: This prospective study was performed in a single center between May 2015 and September 2017. Participants with CF completed clinical examination, CT, MRI, and PFT the same day during routine clinical follow-up (M0), and then 1 year after (M12) except for CT. Using MRI, percentage high (%MR-HSV), low (%MR-LSV), and total abnormal (%MR-TSV) signal intensity volumes were recorded, as well as their corresponding attenuation values using CT (%CT-HAV, %CT-LAV, %CT-TAV, respectively). Automated quantifications and visual Bhalla score were evaluated independently by two observers. Correlations were assessed using the Spearman test, comparisons using the Mann-Whitney test, and reproducibility using the intraclass correlation coefficient (ICC). RESULTS: A total of 30 participants were enrolled (median age 27 years, 18 men). At M0, there was a good correlation between %MR-HSV and %CT-HAV (ρ = 0.70; p \textbackslashtextless 0.001) and %MR-LSV and %CT-LAV (ρ = 0.60; p \textbackslashtextless 0.001). Automated MR metrics correlated to PFTs and Bhalla score (p \textbackslashtextless 0.05) while %MR-TSV was significantly different between CF with and without respiratory exacerbation (p = 0.01) at both M0 and M12. The variation of %MR-HSV correlated to the variation of FEV1% at PFT (ρ = - 0.49; p = 0.008). Reproducibility was almost perfect (ICCs \textbackslashtextgreater 0.95). CONCLUSIONS: Automated quantification of abnormal signal intensity volumes relates to CF severity and allows reproducible cross-sectional and longitudinal assessment. TRIAL REGISTRATION: Clinical trial identifier: NCT02449785 KEY POINTS: • Cross-sectionally, the automated quantifications of high and low signal intensity volumes at UTE correlated to the quantification of high and low attenuation using CT as reference. • Longitudinally, the variation of high signal intensity volume at UTE correlated to the variation of pulmonary function test and was significantly reduced in CF with an improvement in exacerbation status. • Automated quantification of abnormal signal intensity volumes are objective and reproducible tools to assess structural alterations in CF and follow-up longitudinally, for both research and clinical purposes.

The main factors that increase the mortality risk of COPD patients are age, comorbidities and the severity of airflow obstruction. This study aimed to validate the clinically relevant COPD phenotypes found by Burgel P-R et al [1] and analyzed their impact on 5-year mortality in the PALOMB cohort. COPD patients (post-BD FEV1/FVC 2,653 patients (66 years old, 64.27% males) were included. Application of the CART-based algorithm to Palomb cohort confirmed that it identified 5 COPD phenotypes with different clinical characteristics. In addition: The high proportion of FEV1 decline (≥100 ml/yr) belongs to phenotype 1 and 4; the majority of patients in these phenotypes were under oxygen therapy and they were associated with higher rates of exacerbation, lung cancer, anxiety and depression. These results confirmed the identification of five clinically relevant COPD phenotypes. A novel finding of this study is that FEV1 decline, frequency of exacerbations and other comorbidities were associated with the more severe phenotypes. Fundings: Bordeaux Univ Foundation, Novartis, Isis Medical, GSK, BI, Chiesi.

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.

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

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. We performed a retrospective review of the primary colonisations (PC) observed between 2010 and 2018 in five CF Centres. Treatment regimens, microbiological and clinical data were collected. 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 FEV1 and FVC at PC and consistency of treatment with in vitro antibiotic susceptibility tended to be associated with eradication. Thus, the management of PC was shown to be heterogeneous, and the statistic power of our study insufficient. Large prospective studies are needed to define who to treat, when, and how. Pending these studies, we propose, due to possible spontaneous clearance, to check the presence of Burkholderia one month after PC before starting antibiotics, at least in the milder cases, and to evaluate a combination of IV beta-lactam + oral or IV fluoroquinolone + inhaled aminoglycoside.

BACKGROUND Ultrashort echo time (UTE) has been shown to improve lung MRI quality in three dimensions. The evaluation of 3D-UTE stack-of-spirals VIBE (3D-USV) sequence for parenchymal diseases and a comparison of performance with that of a spherical mode of acquisition is needed. PURPOSE To assess MRI quality using a prototypical 3D-USV sequence and to compare performance with that of a spherical acquisition using Pointwise Encoding Time Reduction with Radial Acquisition (PETRA). STUDY TYPE Monocenter, prospective. POPULATION Twelve healthy volunteers and 32 adult patients with either cystic fibrosis (CF; n = 16) or interstitial lung disease (ILD; n = 16). FIELD STRENGTH/SEQUENCE Both free-breathing 3D-USV and PETRA were completed at 1.5T. ASSESSMENT In healthy volunteers, visual analysis of imaging quality was scored using a Likert scale. Quantitative evaluation of apparent signal ratio (Sr) and contrast ratio (Cr) was measured. Patients with CF and ILD completed both computed tomography (CT) and MRI. Depiction of structural alterations was assessed using dedicated clinical scores. All evaluations were done in consensus by two readers. STATISTICAL TESTS Comparison of means was assessed using the Wilcoxon signed rank test. Concordance and agreement between CT and MRI were assessed using the intraclass correlation coefficient (ICC) and kappa test. RESULTS In controls, 3D-USV yielded lower artifacts owing to better automatic respiratory synchronization than PETRA (P

Introduction L’identification de sous-groupes de patients atteints de BPCO et partageant des caracteristiques cliniques et/ou paracliniques communes est a l’origine du concept de phenotypes dans cette pathologie. De nombreuses etudes de cohortes observationnelles sont en cours, pour tenter d’identifier de nouveaux phenotypes de patients BPCO. L’objectif de cette etude est de determiner l’analyse en cluster la plus optimale (supervise vs non-supervise) pour identifier de facon robuste les phenotypes cliniques dans le cadre de la cohorte PALOMB. Methodes Les patients BPCO (VEMS/CVF Resultats 2968 patients (70 ans, 63,7 % d’hommes, 38,7 % de fumeurs actuels) ont ete inclus ( Tableau 1 ). Parmi eux, 43,6 % ont eu au moins deux exacerbations au cours des 12 derniers mois, 58 % avaient de la toux chronique et 56,3 % avaient une dyspnee plus severe. Selon GOLD 2007, la severite de la BPCO etait representee par le stade I (18,2 %), le stade II (51,7 %), le stade III (24,1 %) et le stade IV (6 %). Le taux de la mortalite a 5 ans est de 11,3 %. Sur la base de notre hypothese, nous avons pu determiner quatre phenotypes, a l’issu de la methode PAM (k-medoides: partition Around Medoids): le phenotype A (24,2 %), B (23,9 %), C (25,5 %), et D (26,2 %). Le phenotype (A) etait constitue de patients âges, comorbides (cardiovasculaire et de diabete), peu symptomatiques, severe sur le VEMS. Le phenotype (B) etait tres severe, plus symptomatique, avec un IMC faible, plus de comorbidite metabolique, osteo-articulaire et neuropsychiatrique. Conclusion Ces Resultats illustrent l’aspect plurifactoriel des differents phenotypes identifies chez les patients BPCO. Parmi toutes les mesures de classification, la methode PAM (Machine Learning) apparait la plus valide.

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.

Background In patients with cystic fibrosis (CF), pulmonary structures with high MRI T2 signal intensity relate to inflammatory changes in the lung and bronchi. These areas of pathologic abnormalities can serve as imaging biomarkers. The feasibility of automated quantification is unknown. Purpose To quantify the MRI T2 high-signal-intensity lung volume and T2-weighted volume-intensity product (VIP) by using a black-blood T2-weighted radial fast spin-echo sequence in participants with CF. Materials and Methods Healthy individuals and study participants with CF were prospectively enrolled between January 2017 and November 2017. All participants underwent a lung MRI protocol including T2-weighted radial fast spin-echo sequence. Participants with CF also underwent pulmonary function tests the same day. Participants with CF exacerbation underwent repeat MRI after their treatment with antibiotics. Two observers supervised automated quantification of T2-weighted high-signal-intensity volume (HSV) and T2-weighted VIP independently, and the average score was chosen as consensus. Statistical analysis used the Mann-Whitney test for comparison of medians, correlations used the Spearman test, comparison of paired medians used the Wilcoxon signed rank test, and reproducibility was evaluated by using intraclass correlation coefficient. Results In 10 healthy study participants (median age, 21 years [age range, 18-27 years]; six men) and 12 participants with CF (median age, 18 years [age range, 9-40 years]; eight men), T2-weighted HSV was equal to 0% and 4.1% (range, 0.1%-17%), respectively, and T2-weighted VIP was equal to 0 msec and 303 msec (range, 39-1012 msec), respectively (

Background The validity of three-dimensional (3D) ultrashort echo time (UTE) MRI for the assessment of emphysema in patients with chronic obstructive pulmonary disease (COPD) at high spatial resolution is, to the knowledge of the authors, unknown. Purpose To assess whether noncontrast agent-enhanced 3D UTE MRI at submillimeter spatial resolution can be used to determine the extent of emphysema by using both qualitative visual scoring and fully automated volumetric quantification. Materials and Methods Twenty-eight participants with COPD and 10 control participants (mean age, 70 years ± 7 [standard deviation] and 64 years ± 4, respectively) were prospectively enrolled between 2015 and 2017. Participants underwent pulmonary function testing, CT, and MRI. CT was used as the reference standard. Qualitative scoring of emphysema extent was performed by two readers. Fully automated quantification of percentage of low-attenuation volume by using a threshold of -950 HU (%LAV-950HU) at CT and percentage of low-signal-intensity volume by using an adaptive threshold of 0.20 (%LSV0.20) at MRI were the respective emphysema indexes. Comparison of means was performed by using Student t test, correlation was determined by using Pearson test, agreement was found by using weighted κ index, and reproducibility was determined by using intraclass correlation coefficient. Diagnostic performance was assessed by calculating the area under the receiver operating characteristics curve (AUC). Results With qualitative scoring, agreement between UTE MRI and CT was good (weighted κ, 0.79; 95% confidence interval: 0.71, 0.83). With automated volumetric quantification, %LSV0.20 was significantly correlated with %LAV-950HU in participants with COPD (r, -0.80; P 0.99, respectively). Conclusion A fully automated method with three-dimensional ultrashort echo time MRI reproducibly quantified the volumetric extent of emphysema in participants with chronic obstructive pulmonary disease. © RSNA, 2019 Online supplemental material is available for this article.

Ultrashort echo time (UTE) has been shown to improve lung MRI quality in three dimensions. The evaluation of 3D-UTE stack-of-spirals VIBE (3D-USV) sequence for parenchymal diseases and a comparison of performance with that of a spherical mode of acquisition is needed.To assess MRI quality using a prototypical 3D-USV sequence and to compare performance with that of a spherical acquisition using Pointwise Encoding Time Reduction with Radial Acquisition (PETRA).Monocenter, prospective.Twelve healthy volunteers and 32 adult patients with either cystic fibrosis (CF; n = 16) or interstitial lung disease (ILD; n = 16).Both free-breathing 3D-USV and PETRA were completed at 1.5T.In healthy volunteers, visual analysis of imaging quality was scored using a Likert scale. Quantitative evaluation of apparent signal ratio (Sr) and contrast ratio (Cr) was measured. Patients with CF and ILD completed both computed tomography (CT) and MRI. Depiction of structural alterations was assessed using dedicated clinical scores. All evaluations were done in consensus by two readers.Comparison of means was assessed using the Wilcoxon signed rank test. Concordance and agreement between CT and MRI were assessed using the intraclass correlation coefficient (ICC) and kappa test.In controls, 3D-USV yielded lower artifacts owing to better automatic respiratory synchronization than PETRA (P 0.001). However, Sr and Cr of 3D-USV were found significantly lower by 2.25- and 2.36-fold, respectively (P 0.001). In patients, 3D-USV and PETRA showed comparable performances to assess airway severity in CF (Bhalla score, ICC = 0.89 and ICC = 0.92, respectively) and presence of structural alterations in ILD such as honeycombing (kappa = 0.68 and kappa = 0.69, respectively).3D-USV enables high-resolution morphological imaging of the lung without need of an external device to compensate respiratory motions. Automation and robustness of the method may facilitate clinical application for both airway and interstitial lung investigations.2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;48:1489-1497.

Purpose To assess the diagnostic accuracy of mucus contrast characterization by using magnetic resonance (MR) imaging to discriminate allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis (CF). Materials and Methods The study was approved by the local Ethics Committee, and all patients or their parents gave written informed consent. One hundred ten consecutive patients with CF were screened between January 2014 and July 2015. All patients underwent a non-contrast material-enhanced MR protocol that included routine T1-weighted and T2-weighted sequences. The presence of mucus with both high T1 and low T2 signal intensities and the so-called inverted mucoid impaction signal (IMIS) sign was qualitatively and quantitatively assessed by two physicians who were blinded to all other data. The reference standard for a diagnosis of ABPA was the criteria of the Cystic Fibrosis Foundation Consensus Conference. ABPA status was followed up for 1 year. Reproducibility was assessed by using the κ test, correlation was assessed by using the Spearman coefficient, and diagnostic accuracy was assessed by calculating the sensitivity and specificity of IMIS. Results One hundred eight patients with CF were included (mean age, 20 years ± 11 [standard deviation]; range, 6-53 years): 18 patients with ABPA and 90 patients without ABPA. At the lobar level, inter- and intrareader reproducibility were very good (κ0.90). IMIS had 94% sensitivity (95% confidence interval [CI]: 73%, 99%) and 100% specificity (95% CI: 96%, 100%) for the diagnosis of ABPA. A complete resolution of IMIS was observed in patients with ABPA after 3 months of specific treatment that was significantly correlated with decrease in total immunoglobulin E level (ρ = 0.47; P = .04). Conclusion The IMIS sign was both specific and sensitive for the diagnosis of ABPA in CF. Allergic fungal inflammation appears to induce characteristic modifications of mucus contrasts that are assessable by using a noninvasive, contrast material-free, and radiation-free method.

We hypothesized that non-contrast-enhanced PETRA (pointwise encoding time reduction with radial acquisition) MR (magnetic resonance) sequencing could be an alternative to unenhanced computed tomography (CT) in assessing cystic fibrosis (CF) lung structural alterations, as well as compared agreements and concordances with those of conventional T1-weighted and T2-weighted sequences. Thirty consecutive CF patients completed both CT and MRI the same day. No contrast injection was used. Agreement in identifying structural alterations was evaluated at the segmental level using a kappa test. Intraclass correlation coefficients (ICC) and Bland-Altman analysis were used to assess concordances and reproducibility in Helbich-Bhalla disease severity scoring. Agreement between PETRA and CT was higher than that of T1- or T2-weighted sequences, notably in assessing the segmental presence of bronchiectasis (Kappa = 0.83; 0.51; 0.49, respectively). The concordance in Helbich-Bhalla scores was very good using PETRA (ICC = 0.97), independently from its magnitude (mean difference (MD) = -0.3 [-2.8; 2.2]), whereas scoring was underestimated using both conventional T1 and T2 sequences (MD = -3.6 [-7.4; 0.1]) and MD = -4.6 [-8.2; -1.0], respectively). Intra- and interobserver reproducibility were very good for all imaging modalities (ICC = 0.86-0.98). PETRA showed higher agreement in describing CF lung morphological changes than that of conventional sequences, whereas the Helbich-Bhalla scoring matched closely with that of CT. • Spatial resolution of lung MRI is limited using non-ultra-short TE MRI technique • Ultra-short echo time (UTE) technique enables submillimeter 3D-MRI of airways • 3D-UTE MRI shows very good concordance with CT in assessing cystic fibrosis • Radiation-free 3D-UTE MRI enables the Helbich-Bhalla scoring without a need for contrast injection

The detection of a cancer in a potential recipient is an absolute contraindication for lung transplantation. However, there is a small proportion of unexpected neoplasms in lung explants. It seems that risk factors for neoplasms in explant could be a long period between computed tomographic scan and transplantation, COPD, idiopathic pulmonary fibrosis (IPF), and tobacco exposure. The aims of our study were to review our institution9s incidence and outcomes of malignancies found in lung explants and to identify risk factors for neoplasms in explants. 132 consecutive lung transplants files were collected from Bordeaux University9s transplant center, from 2008 to 2015. Intergroup comparisons were performed using the Mann-Whitney U test for continuous variables and the Fisher exact test for categorical variables. 5 neoplasms (adenocarcinomas) were found among the 132 lung explants, representing a 3.8% incidence. 4 of 5 were detected at an early stage (stage IA) of which 2 in the setting of emphysema and 2 in the setting of fibrosis interstitial disease (1 IPF and 1 systemic sclerosis): no recurrence was found. 1 of 5 neoplasms was detected at an advanced stage (stage IV) in the setting of IPF and recurrence occurred 6 months after transplantation. Incidence of unexpected cancer was higher (p Fibrosis lung diseases, particularly IPF seem to be risk factors for undetected neoplasms in lung explants. Efforts to improve screening in these populations seem needed.

To assess lung magnetic resonance (MR) imaging with a respiratory-gated pointwise encoding time reduction with radial acquisition (PETRA) sequence at 1.5 T and compare it with imaging with a standard volumetric interpolated breath-hold examination (VIBE) sequence, with extra focus on the visibility of bronchi and the signal intensity of lung parenchyma.The study was approved by the local ethics committee, and all subjects gave written informed consent. Twelve healthy volunteers were imaged with PETRA and VIBE sequences. Image quality was evaluated by using visual scoring, numbering of visible bronchi, and quantitative measurement of the apparent contrast-to-noise ratio (CNR) and signal-to-noise ratio (SNR). For preliminary clinical assessment, three young patients with cystic fibrosis underwent both MR imaging and computed tomography (CT). Comparisons were made by using the Wilcoxon signed-rank test for means and the McNemar test for ratios. Agreement between CT and MR imaging disease scores was assessed by using the κ test.PETRA imaging was performed with a voxel size of 0.86 mm(3). Overall image quality was good, with little motion artifact. Bronchi were visible consistently up to the fourth generation and in some cases up to the sixth generation. Mean CNR and SNR with PETRA were 32.4% ± 7.6 (standard deviation) and 322.2% ± 37.9, respectively, higher than those with VIBE (P.001). Good agreement was found between CT and PETRA cystic fibrosis scores (κ = 1.0).PETRA enables silent, free-breathing, isotropic, and submillimeter imaging of the bronchi and lung parenchyma with high CNR and SNR and may be an alternative to CT for patients with cystic fibrosis.

UNLABELLED Acquisition of Pseudomonas aeruginosa is known as a negative prognostic factor in patients with cystic fibrosis. We started a pilot study to evaluate Ps. aeruginosa gene expression directly from the sputum of infected patients. Total RNA was purified from 15 sputum samples collected from 10 patients, and the expression levels of five genes from Ps. aeruginosa were measured by RT-qPCR. Expression of algD, algR, antB, lasB and pqsA genes was determined in sputa that contained Ps. aeruginosa cells. The resultant data provided an overview of the expression of these genes in CF patients. Except for the correlation between algD expression and the mucoid phenotype, the gene expression profile could not be associated with the clinical status of patients. However, beyond the heterogeneity of the Ps. aeruginosa phenotype in sputum, we observed a correlation between the expression of antB and pqsA and a low level of lasB transcripts. SIGNIFICANCE AND IMPACT OF THE STUDY Pseudomonas aeruginosa infection leads to high morbidity and mortality in cystic fibrosis patients. The identification of Ps. aeruginosa-assigned factors is important to eradicate the colonization. We started a pilot study to evaluate the gene expression of Ps. aeruginosa directly from the sputum of infected patients. Preliminary results suggest that beyond the heterogeneity of the Ps. aeruginosa phenotype in sputum, we observe a correlation between the expression of antB and pqsA and a low level of lasB transcripts. This approach could shed some light on the behaviour of Ps. aeruginosa during pulmonary infection and may reveal some important elements for optimizing therapy.

La mucoviscidose est une maladie genetique autosomique recessive aboutissant a une dysfonction de la proteine cystic fibrosis transmembrane conductance regulator (CFTR), presente a la surface des principaux epitheliums. L’absence de CFTR fonctionnel provoque des anomalies des transports ioniques epitheliaux qui se traduisent par une atteinte de multiples organes dont les voies aeriennes (poumon, sinus), les voies biliaires et le pancreas. Alors que l’esperance de vie ne depassait pas 5 ans dans les annees 1960, les progres dans le traitement symptomatique de la mucoviscidose, avec en particulier une optimisation de l’approche nutritionnelle et de l’antibiotherapie, ont conduit a une amelioration du pronostic de la maladie. En France, environ 6 000 patients sont atteints de mucoviscidose dont plus de la moitie est adulte (âge : 18 ans) et environ 400 patients ont plus de 40 ans [1]. Les patients mucoviscidosiques sont le plus souvent suivis dans des centres specialises, appeles Centres de Ressources et de Competences pour la Mucoviscidose (CRCM). Les praticiens des Services d’Accueil des Urgences peuvent etre amenes a prendre en charge des patients adultes mucoviscidosiques lors des complications aigues. L’objectif de cet article est de decrire les principales complications respiratoires et non respiratoires survenant chez les adultes mucoviscidosiques et de decrire les elements de leur prise en charge therapeutique.

Water stress is an important factor which regulates organized development of both zygotic and somatic embryos. Somatic embryos of white spruce were cultured in the presence of polyethylene glycol (PEG), a non-plasmolyzing agent which increases embryo quality and number, and mannitol, a plasmolyzing agent. The effects of these two compounds on both ascorbate and glutathione metabolism were investigated at different stages of embryo development. Compared to control and mannitol-treated embryos, embryos treated with PEG accumulated higher levels of endogenous ascorbate (ASC) in its reduced form, especially during the first half of the maturation period. This increase, also observed in immature seeds, was mainly the result of two different processes: activation of the de novo ASC machinery, and recycling of ASC from ascorbate free radicals (AFR) which was modulated by the activity of ascorbate free radical reductase (AFRR, EC. 1.6.5.4). The activity of this enzyme increased during the early phases of development in both PEG-treated somatic embryos and seeds. Compared to control somatic embryos, mannitol and PEG were shown to change the levels of reduced (GSH) and oxidized glutathione (GSSG). In particular, a constant decline in the GSH/GSSG ratio was observed in the presence of PEG. This pattern was also observed in maturing white spruce seeds. Overall, these data indicate that applications of non-plasmolyzing agents in the culture medium of spruce somatic embryos result in seed-like fluctuations of the ascorbate-glutathione metabolism, which may have a positive effect on embryo yield.

Cystic Fibrosis is the most frequent serious genetic disease in France with more of 7000 people affected in 2017, and a prognostic which depends on respiratory disorder. Life expectancy is still increasing, so it was imperative to develop a non-irradiant imaging technique to limit the impact of radiation on human health. Pulmonary Ultra Short Echo Time Magnetic Resonance imaging (UTE MRI) could allow this technique to have a place in the follow up of the Muscoviscidosis patients. 2 studies by Dournes show a good correlation with Computed Tomography (CT) and a good reproducibility inter and intra observer. The main objective of this work is to study concordance between UTE MRI pulmonary and thoracic CT for lung parenchyma semi-quantitative analysis with Helbich-Bhalla score. Between September 2015 and September 2016, we included 30 patients followed at the adult CRCM in the pneumology service of the CHU of Bordeaux in this prospective, monocentric, pilot study of diagnostic imagery. For one year, 4 visits were planned at M0, M3, M6 and M12. A thoracic CT and a pulmonary UTE MRI was realized at M0 and M12, and the semi-quantitative Helbich-Bhalla score and hyperintensities T2 were analyzed by two double blinded radiologists. At ever visit, there was a medical visit and pulmonary function test was done. 30 patients were included, 2 came out of the study, 8 were on Orkambi®. There was no significant difference between the groups at M0. Pulmonary MRI was comparable to thoracic CT at M0 for semi-quantitative analysis with Helbich-Bhalla score, with and intra-class correlation at 0.98. Forced expiratory volume in 1 second (FEV1) correlate with Helbich-Bhalla sore in CT and MRI at M0. We could see an hyperintensities T2 diminution between M0 and M12 on patients treated by Orkambi®. This study done at the CHU of Bordeaux show that pulmonary MRI is like thoracic CT to appreciate lung parenchyma of Cystic Fibrosis patients with the semi-quantitative Helbich-Bhalla score.; La mucoviscidose est la plus fréquente des maladies génétiques graves en France, avec plus de 7000 personnes atteintes en 2017 et un pronostic qui va à l’atteinte respiratoire. L’espérance de vie ne cessant d’augmenter, il est impératif de développer une technique d’imagerie non irradiante afin de limiter l’impact des rayons X sur la santé. L’IRM pulmonaire à temps d’écho ultra court permet d’envisager l’IRM pulmonaire dans le suivi des patients atteints de mucoviscidose. Deux études réalisées par Dournes montrent une bonne corrélation avec le scanner. L’objectif principal est d’étudier la concordance entre l’IRM pulmonaire en séquence UTE et le TDM thoracique sans injection pour l’analyse semi-quantitative du parenchyme pulmonaire à l’aide du score d’Helbich-Bhalla. 30 patients suivis au Centre de Ressources et de Compétences de la Mucoviscidose adulte au sein du service de pneumologie du CHU de Bordeaux ont été inclus entre septembre 2015 et septembre 2016 dans cette étude pilote d’imagerie diagnostique, prospective, monocentrique. Cette étude s’est déroulée sur un an, avec 4 visites à MO, M3, M6 et M12. Un TDM thoracique et une IRM pulmonaire étaient réalisés à MO et M12, le score semi-quantitatif d’Helbich-Bhalla était analysé ainsi que les hypersignaux T2. A chaque visite un examen clinique et des EFR étaient réalisés. 30 patients ont été inclus, 2 sont sortis d’étude, au total 8 étaient sous Orkambi®. Il n’y avait pas de différence significative entre les groupes à M0. L’IRM pulmonaire était comparable au TDM thoracique à M0 pour l’analyse du score d’Helbich-Bhalla, avec un indice de corrélation intra classe à 0.98. Le VEMS corrélait avec le score d’Helbich-Bhalla en TDM et en IRM à M0. On pouvait voir une diminution des hypersignaux T2 chez les patients traités par Orkambi®. Cette étude montre que l’IRM pulmonaire est comparable au TDM thoracique pour évaluer le parenchyme pulmonaire des patients atteints de mucoviscidose à l’aide du score d’Helbich-Bhalla.