ERN LUNG

Cystic fibrosis (CF) is a rare genetic multisystemic disease, the manifestations of which are due to mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein and can lead to respiratory insufficiency and premature death. CFTR modulators, which were developed in the past decade, partially restore CFTR protein function. Their clinical efficacy has been demonstrated in phase 3 clinical trials, particularly in terms of lung function and pulmonary exacerbations, nutritional status, and quality of life in people with gating mutations (ivacaftor), homozygous for the F508del mutation (lumacaftor/ivacaftor and tezacaftor/ivacaftor), and in those with at least one F508del mutation (elexacaftor/tezacaftor/ivacaftor). However, many questions remain regarding their long-term safety and effectiveness, particularly in patients with advanced lung disease, liver disease, renal insufficiency, or problematic bacterial colonization. The impact of CFTR modulators on other important outcomes such as concurrent treatments, lung transplantation, chest imaging, or pregnancies also warrants further investigation. The French CF Reference Network includes 47 CF centers that contribute patient data to the comprehensive French CF Registry and have conducted nationwide real-world studies on CFTR modulators. This review seeks to summarize the results of these real-world studies and examine their findings against those of randomized control trials.

Abstract Rationale COPD and bronchiectasis are commonly reported together. Studies report varying impacts of co-diagnosis on outcomes, which may be related to different definitions of disease used across studies. Objectives To investigate the prevalence of chronic obstructive pulmonary disease (COPD) associated with bronchiectasis and its relationship with clinical outcomes. We further investigated the impact of implementing the standardized ROSE criteria (radiological bronchiectasis [R], obstruction [FEV1/FVC ratio <0.7; O], symptoms [S], and exposure [⩾10 pack-years of smoking; E]), an objective definition of the association of bronchiectasis with COPD. Methods Analysis of the EMBARC (European Bronchiectasis Registry), a prospective observational study of patients with computed tomography–confirmed bronchiectasis from 28 countries. The ROSE criteria were used to objectively define the association of bronchiectasis with COPD. Key outcomes during a maximum of 5 years of follow-up were exacerbations, hospitalization, and mortality. Measurements and Main Results A total of 16,730 patients with bronchiectasis were included; 4,336 had a clinician-assigned codiagnosis of COPD, and these patients had more exacerbations, worse quality of life, and higher severity scores. We observed marked overdiagnosis of COPD: 22.2% of patients with a diagnosis of COPD did not have airflow obstruction and 31.9% did not have a history of ⩾10 pack-years of smoking. Therefore, 2,157 patients (55.4%) met the ROSE criteria for COPD. Compared with patients without COPD, patients who met the ROSE criteria had increased risks of exacerbations and exacerbations resulting in hospitalization during follow-up (incidence rate ratio, 1.25; 95% confidence interval, 1.15–1.35; vs. incidence rate ratio, 1.69; 95% confidence interval, 1.51–1.90, respectively). Conclusions The label of COPD is often applied to patients with bronchiectasis who do not have objective evidence of airflow obstruction or a smoking history. Patients with a clinical label of COPD have worse clinical outcomes.

Congenital portosystemic shunts are often associated with systemic complications, the most challenging of which are liver nodules, pulmonary hypertension, endocrine abnormalities, and neurocognitive dysfunction. In the present paper, we offer expert clinical guidance on the management of liver nodules, pulmonary hypertension, and endocrine abnormalities, and we make recommendations regarding shunt closure and follow-up.

In the past decade, the medical management of people with cystic fibrosis (pwCF) has changed with the development of small molecules that partially restore the function of the defective CF transmembrane conductance regulator (CFTR) protein and are called CFTR modulators. Ivacaftor (IVA), a CFTR potentiator with a large effect on epithelial ion transport, was the first modulator approved in pwCF carrying gating mutations. Because IVA was unable to restore sufficient CFTR function in pwCF with other mutations, two CFTR correctors (lumacaftor and tezacaftor) were developed and used in combination with IVA in pwCF homozygous for F508del, the most common CFTR variant. However, LUM/IVA and TEZ/IVA were only moderately effective in F508del homozygous pwCF and had no efficacy in those with F508del and minimal function mutations. Elexacaftor, a second-generation corrector, was thus developed and combined to tezacaftor and ivacaftor (ELX/TEZ/IVA) to target pwCF with at least one F508del variant, corresponding to approximately 85% of pwCF. Both IVA and ELX/TEZ/IVA are considered highly effective modulator therapies (HEMTs) in eligible pwCF and are now approved for nearly 90% of the CF population over 6 years of age. HEMTs are responsible for rapid improvement in respiratory manifestations, including improvement in symptoms and lung function, and reduction in the rate of pulmonary exacerbations. The impact of HEMT on extrapulmonary manifestations of CF is less well established, although significant weight gain and improvement in quality of life have been demonstrated. Recent clinical trials and real-world studies suggest that benefits of HEMT could even prove greater when used earlier in life (i.e., in younger children and infants). This article shortly reviews the past 10 years of development and use of CFTR modulators. Effects of HEMT on extrapulmonary manifestations and on CF demographics are also discussed.

BACKGROUND: Life expectancy for people with cystic fibrosis (CF) varies considerably both within and between countries. The objective of this study was to compare survival among countries with single-payer healthcare systems while accounting for markers of disease severity. METHODS: This cohort study used data from established national CF registries in Australia, Canada, France and New Zealand from 2015 to 2019. Median age of survival for each of the four countries was estimated using the Kaplan-Meier method. A Cox proportional hazards model was used to compare risk of death between Canada, France and Australia after adjusting for prognostic factors. Due to low number of deaths, New Zealand was not included in final adjusted models. RESULTS: Between 2015 and 2019, a total of 14 842 people (3537 Australia, 4434 Canada, 6411 France and 460 New Zealand) were included. The median age of survival was highest in France 65.9 years (95% CI: 59.8 to 76.0) versus 53.3 years (95% CI: 48.9 to 59.8) for Australia, 55.4 years (95% CI: 51.3 to 59.2) for Canada and 54.8 years (95% CI: 40.7 to not available) for New Zealand. After adjusting for individual-level factors, the risk of death was significantly higher in Canada (HR 1.85, 95% CI: 1.48 to 2.32; p<0.001) and Australia (HR 2.08, 95% CI: 1.64 to 2.64; p<0.001) versus France. INTERPRETATION: We observed significantly higher survival in France compared with countries with single-payer healthcare systems. The median age of survival in France exceeded 60 years of age despite having the highest proportion of underweight patients which may be due to differences in availability of transplant.

Seismic profiles and numerous sediment cores of a planned offshore wind farm area northeast of Rügen Island provide a unique insight into the distribution and thickness of glacial deposits in the southern Baltic Sea. Fine gravel analysis enabled recognition of five tills that correspond to different ice advances. On the basis of a 3D structural model, the main Pleistocene events could be reconstructed and correlated with stratigraphical records in the circum‐Baltic area comprising Marine Isotope Stages ( MIS ) 6 to 2. The oldest till was deposited during the Late Saalian Warthe advance (qs2; c . 150–130 ka). It is only preserved in ENE – WSW trending subglacial channels incised into Upper Cretaceous soft chalk. Isolated rafts and remnants of two Middle Weichselian tills occur locally, whereas Eemian interglacial sediments are missing. The older till (qw*) has an unusual fine gravel composition and might have formed during ice advances known only from northern Denmark and northern Poland ( c . 65–60 ka). The younger till represents the Warnow advance (qw0) in NE Germany that can be correlated with the Danish Ristinge advance ( c . 55–50 ka). Furthermore, two tills deposited during the Late Weichselian Last Glacial Maximum ( c . 24–16 ka) occur. One can be correlated with the Pomeranian advance (qw2), while the other has characteristics typical for the Mecklenburg advance (qw3). These advances eroded older Pleistocene deposits, thus probably also removing the till of the Brandenburg/Frankfurt advance (qw1) – in contrast to the onshore areas. The Pomeranian till is limited to the southeast, close to the shallow Adlergrund, but the Mecklenburg till covers the whole study area. This first detailed lithostratigraphical classification of till units from the Arkona Basin allows for the identification and correlation of Pleistocene successions in other parts of the southern Baltic Sea.

Abstract Rationale Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterized by progressive lung disease. Pseudomonas aeruginosa is a major pathogen in this disease and is known to impact lung function. Previous genotype–phenotype studies have been limited by cross-sectional designs, isolated adult or pediatric populations, small numbers, or short follow-up durations. Objectives We aimed to explore long-term lung function in PCD grouped by genotypes and ultrastructural defects, considering the influence of P. aeruginosa. Methods In this retrospective observational study, we analyzed 43 years of spirometry and 20 years of microbiology data. Using linear mixed-effects models, we estimated forced expiratory volume in 1 second z-score trends and compared them at ages 10, 25, and 50 years, whereas generalized estimating equations were used to assess P. aeruginosa prevalence between groups. In a secondary analysis, we matched spirometry and microbiology samples to evaluate the influence of P. aeruginosa on lung function. Results We included 127 genotyped patients, 6,691 spirometry measurements, and 10,082 microbiology samples. CCDC39 and CCDC40 variants showed early-onset and sustained decline in lung function, whereas DNAH11 and HYDIN variants demonstrated relative stability. Lung function in the proximity of positive P. aeruginosa cultures was on average 0.06 z-score lower. Despite this, differences between groups remained largely unaffected by P. aeruginosa. Conclusions Long-term lung function in PCD follows discrete genotype-specific profiles and appears independent of P. aeruginosa infection. We confirm and extend previous findings of CCDC39 and CCDC40 as variants associated with early-onset severe lung function impairment persisting in the long term.

Background: A high proportion of patients with Cystic Fibrosis (CF) also present the rare skin disease aquagenic palmoplantar keratoderma. A possible link between this condition and absence of a functional CF Transmembrane conductance Regulator protein in the sweat acinus and collecting duct remains unknown. Methods: In-depth characterization of sweat proteome profiles was performed in 25 CF patients compared to 12 healthy controls. A 20 μL sweat sample was collected after pilocarpine iontophoresis and liquid chromatography tandem mass spectrometry (LC-MS/MS) proteomic analysis was performed. Results: Sweat proteome profile of CF patients was significantly different from that of healthy subjects with 57 differentially expressed proteins. Cystic Fibrosis sweat proteome was characterized by an increase in 25 proteins including proteases (Kallikrein 7 and 13, Phospholipase B domain containing 1, Cathepsin A L2 and B, Lysosomal Pro-X carboxypeptidase); proinflammatory proteins (Annexin A2, Chitinase-3-like protein 1); cytochrome c and transglutaminases. Thirty-two proteins were downregulated in CF sweat including proteases (Elastase 2), antioxidative protein FAM129 B; membrane-bound transporter SLC6A14 and regulator protein Sodium-hydrogen antiporter 3 regulator 1. Conclusion: This study is the first to report in-depth characterization of endogenous peptides in CF sweat and could help understand the complex physiology of the sweat gland. The proteome profile highlights the unbalanced proteolytic and proinflammatory activity of sweat in CF. These results also suggest a defect in pathways involved in skin barrier integrity in CF patients. Sweat proteome profile could prove to be a useful tool in the context of personalized medicine in CF.

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 . [1] 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. Burgel et al . [2] subsequently used the French registry to validate short-term predictions; however, the accuracy of longer term projections has not been assessed. Based on the results of this study, a model that takes into consideration changing rates over time is needed to accurately estimate future populations <http://bit.ly/35IDhQ0> We thank Cystic Fibrosis Canada for providing access to Canadian CF Registry data for this study, and we thank individuals living with CF and their families for allowing their data to be collected in the CF Registry to be used for clinical research. This work was presented as a poster presented at the North American Cystic Fibrosis Conference, Denver, Colorado, 18–21 October 2018.

It has come to our attention that we did not include the full surname of one of the authors in our publication. ‘Nitash Zwaveling’ should read ‘Nitash Zwaveling-Soonawala’. We apologise for any inconvenience caused. Expert management of congenital portosystemic shunts and their complicationsJHEP ReportsVol. 6Issue 1PreviewCongenital portosystemic shunts are often associated with systemic complications, the most challenging of which are liver nodules, pulmonary hypertension, endocrine abnormalities, and neurocognitive dysfunction. In the present paper, we offer expert clinical guidance on the management of liver nodules, pulmonary hypertension, and endocrine abnormalities, and we make recommendations regarding shunt closure and follow-up. Full-Text PDF Open Access

Einleitung und Ziel Der schwere Alpha1-Antitrypsin-Mangel wird meistens durch eine angeborene, homozygote Pi*Z Mutation im SERPINA1-Gen verursacht (Pi*ZZ Genotyp). Pi*ZZ Probanden sind stark zur Entwicklung eines Lungenemphysems sowie einer Leberfibrose prädisponiert, das Ausmaß der Leberbeteiligung ist aber sehr heterogen. Daher untersuchten wir, inwiefern metabolische Faktoren mit dem Leberphänotyp assoziieren.